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Roseroot herb shows promise as potential depression treatment option

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Originally posted on lyranara.me:

Rhodiola rosea (R. rosea), or roseroot, may be a beneficial treatment option for major depressive disorder (MDD), according to results of a study in the journal Phytomedicine led by Jun J. Mao, MD, MSCE, associate professor of Family Medicine, Community Health and Epidemiology and colleagues at the Perelman School of Medicine of University of Pennsylvania.

The proof of concept trial study is the first randomized, double-blind, placebo-controlled, comparison trial of oralR. rosea extract versus the conventional antidepressant therapy sertraline for mild to moderate major depressive disorder.

Depression is one of the most common and debilitating psychiatric conditions, afflicting more than 19 million Americans each year, 70 percent of whom do not fully respond to initial therapy. Costs of conventional antidepressants and their sometimes substantial side effects often result in a patient discontinuing use prematurely. Others opt to try natural products or supplements instead.

All of the study’s…

View original 293 more words


Filed under: Uncategorized

K 912, NC 6300, Epirubicin nano

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Epirubicin.png

PHASE 1 JAPAN SOLID TUMOURS

DNA/RNA Synthesis Inhibitor

WITH Nano Carrier Co.,Ltdhttp://pdf.irpocket.com/C4571/qnwX/eFou/vG1J.pdf

KOWA COMPANY LTD

CAS FREE FORM. 56420-45-2

Smiles

NC-6300, an epirubicin-incorporating micelle, extends the antitumor effect and reduces the cardiotoxicity of epirubicin.

Epirubicin is widely used to treat various human tumors. However, it is difficult to achieve a sufficient antitumor effect because of dosage limitation to prevent cardiotoxicity. We hypothesized that epirubicin-incorporating micelle would reduce cardiotoxicity and improve the antitumor effect. NC-6300 comprises epirubicin covalently bound to PEG polyaspartate block copolymer through an acid-labile hydrazone bond. The conjugate forms a micellar structure of 40-80 nm in diameter in an aqueous milieu. NC-6300 (10, 15 mg/kg) and epirubicin (10 mg/kg) were given i.v. three times to mice bearing s.c. or liver xenograft of human hepatocellular carcinoma Hep3B cells. Cardiotoxicity was evaluated by echocardiography in C57BL/6 mice that were given NC-6300 (10 mg/kg) or epirubicin (10 mg/kg) in nine doses over 12 weeks. NC-6300 showed a significantly potent antitumor effect against Hep3B s.c. tumors compared with epirubicin. Moreover, NC-6300 also produced a significantly longer survival rate than epirubicin against the liver orthotopic tumor of Hep3B. With respect to cardiotoxicity, epirubicin-treated mice showed significant deteriorations in fractional shortening and ejection fraction. In contrast, cardiac functions of NC-6300 treated mice were no less well maintained than in control mice. This study warrants a clinical evaluation of NC-6300 in patients with hepatocellular carcinoma or other cancers.

K-912(NC-6300)の概要 K-912(NC-6300)は、世界的に幅広く使用されているアントラサイクリン系の抗が ん剤の一つであるエピルビシンを内包したミセル化ナノ粒子製剤で、その特性により、 エピルビシンの有する心毒性の軽減が期待できます。さらに、pH 応答性システムを採 用することで、腫瘍細胞内でのエピルビシンの放出量を高め、既存のエピルビシンに比 べより強力な抗腫瘍効果が期待できます。

Epirubicin is an anthracycline drug used for chemotherapy. It can be used in combination with other medications to treat breast cancer in patients who have had surgery to remove the tumor. It is marketed by Pfizer under the trade name Ellence in the US andPharmorubicin or Epirubicin Ebewe elsewhere.

Similarly to other anthracyclines, epirubicin acts by intercalating DNA strands. Intercalation results in complex formation which inhibits DNA and RNA synthesis. It also triggers DNA cleavage by topoisomerase II, resulting in mechanisms that lead to cell death. Binding to cell membranes and plasma proteins may be involved in the compound’s cytotoxic effects. Epirubicin also generates free radicalsthat cause cell and DNA damage.

Epirubicin is favoured over doxorubicin, the most popular anthracycline, in some chemotherapy regimens as it appears to cause fewer side-effects. Epirubicin has a different spatial orientation of the hydroxyl group at the 4′ carbon of the sugar – it has the opposite chirality – which may account for its faster elimination and reduced toxicity. Epirubicin is primarily used against breast and ovarian cancer, gastric cancer, lung cancer and lymphomas.

Development history

The first trial of epirubicin in humans was published in 1980.[1] Upjohn applied for approval by the U.S. Food and Drug Administration(FDA) in node-positive breast cancer in 1984, but was turned down because of lack of data.[2] It appears to have been licensed for use in Europe from around this time however.[3] In 1999 Pharmacia (who had by then merged with Upjohn) received FDA approval for the use of epirubicin as a component of adjuvant therapy in node-positive patients.

Patent protection for epirubicin expired in August 2007.

References

  1.  Bonfante, V; Bonadonna, G; Villani, F; Martini, A (1980). “Preliminary clinical experience with 4-epidoxorubicin in advanced human neoplasia”. Recent results in cancer research 74: 192–9. PMID 6934564. PM6934564.
  2.  “On Target”.
  3.  According to the proprietary database iddb.com

External links

1H NMR PREDICT

Epirubicin NMR spectra analysis, Chemical CAS NO. 56420-45-2 NMR spectral analysis, Epirubicin H-NMR spectrum

 

 

13C NMR PREDICT

Epirubicin NMR spectra analysis, Chemical CAS NO. 56420-45-2 NMR spectral analysis, Epirubicin C-NMR spectrum

 

COSY

 

COSY NMR prediction EPI

 

 

1H NMR

 

1H  NMR prediction EPI

 

 

 

1H  NMR prediction EPI 2

 

 

 

Epirubicin
Epirubicin.png
Epirubicin ball-and-stick.png
Systematic (IUPAC) name
(8R,10S)-10-((2S,4S,5R,6S)-4-amino-5-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-7,8,9,10-tetrahydrotetracene-5,12-dione
Clinical data
Trade names Ellence
AHFS/Drugs.com monograph
MedlinePlus a603003
  • ℞-only (U.S.), POM (UK)
Intravenous
Pharmacokinetic data
Bioavailability NA
Protein binding 77%
Metabolism Hepatic glucuronidationand oxidation
Excretion Biliary and renal
Identifiers
56420-45-2 Yes
L01DB03
PubChem CID 41867
DrugBank DB00445 Yes
ChemSpider 38201 Yes
UNII 3Z8479ZZ5X Yes
KEGG D07901 Yes
ChEBI CHEBI:47898 Yes
ChEMBL CHEMBL417 Yes
Chemical data
Formula C27H29NO11
543.519 g/mol

 

 

KOWA COMPANY LTD

Nano Carrier Co

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.


Filed under: cancer, Japan marketing, Japan pipeline, PHASE1, Uncategorized Tagged: epirubicin, Epirubicin nano, JAPAN, K 912, K-912 NC-6300, kowa, NC 6300, PHASE 1

Flupirtine Revisited

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Flupirtine3Dan.gif

Flupirtine, D 9998

2-amino-6-(4-fluoro-benzylamino)- pyridin-3-yl)-carbamic acid ethyl ester, is unique as a non-opioid, non-NSAID, non-steroidal analgesic with a favorable tolerability. It first became available in Europe in 1984, and was sold mainly under the names Katadolon, Trancolong, Awegal, Efiret, Trancopal Dolo, and Metanor

PHASE 2

MS

  • Neuronal potassium channels (7)
  • Membrane resting potential (6)
  • NMDA receptor channels (indirectly)(14)
  • Originally developed by Asta Medica (1) (4)
  • Being developed and commercialized to treat fibromyalgia by Synthetic Biologics (1)

Flupirtine

Flupirtine.svg

75507-68-5 maleate
56995-20-1 (free base)
LAUNCHED 1986 NEUROPATHIC PAIN

Flupirtine maleate is the INN for 2-amino-3-ethylcarbamato-6- (4-fluoro-benzylamino) maleate, CAS: 75507-68-5, molar mass 420.40 g / mol, molecular formula C1 5 H17FN4O2 • C4H4O4, and corresponds to the structure of formula I.

Figure imgf000002_0001

Flupirtine maleate is used, for example, under the trade name Katadolon® as an analgesic.

56995-20-1
CAS Name: [2-Amino-6-[[(4-fluorophenyl)methyl]amino]-3-pyridinyl]carbamic acid ethyl ester
Additional Names: 2-amino-6-[(p-fluorobenzyl)amino]-3-pyridinecarbamic acid ethyl ester
Trademarks: D-9998
Molecular Formula: C15H17FN4O2
Molecular Weight: 304.32
Percent Composition: C 59.20%, H 5.63%, F 6.24%, N 18.41%, O 10.51%
Properties: Crystals from isopropanol, mp 115-116°. 5% ethanol soln is colorless, turns green on exposure to air for 20 hours. LD50 orally in mice, rats: 617, 1660 mg/kg (Jakovlev).
Melting point: mp 115-116°
Toxicity data: LD50 orally in mice, rats: 617, 1660 mg/kg (Jakovlev)
Derivative Type: Hydrochloride
Molecular Formula: C15H17FN4O2.HCl
Molecular Weight: 340.78
Percent Composition: C 52.87%, H 5.32%, F 5.57%, N 16.44%, O 9.39%, Cl 10.40%
Properties: Crystals from water, mp 214-215°. When prepd industrially contains intensely blue by-product.
Melting point: mp 214-215°
Derivative Type: Maleate
CAS Registry Number: 75507-68-5
Trademarks: Katadolon (AWD)
Molecular Formula: C15H17FN4O2.C4H4O4
Molecular Weight: 420.39
Percent Composition: C 54.28%, H 5.04%, F 4.52%, N 13.33%, O 22.84%
Properties: Colorless crystals from isopropanol, mp 175.5-176°. Formed as mixture of two crystalline forms A and B; mixtures containing 60-90% A are preferred.
Melting point: mp 175.5-176°
Therap-Cat: Analgesic.

TARGET:

Neuronal potassium channels
Membrane resting potential

NMDA receptor channels (indirectly)

STATUS FOR MS:
Phase II
COMMERCIAL:
Originally developed by Asta Medica
Being developed and commercialized to treat fibromyalgia by Synthetic Biologics
Marketed for pain indications in various European countries by Meda
TRADE NAME:
Effirma (US)

Katadolon (Brazil, Germany, Latvia, Estonia, Slovakia, Lithiania, Russian Federation)

SYNONYMS:
EINECS 260-503-8,UNII-MOH3ET196H, Effirma (US), Katadolon (Brazil, Germany, Latvia, Estonia, Slovakia, Lithiania, Russian Federation)
SYSTEMATIC NAME:
Carbamic acid, (2-amino-6-(((4-fluorophenyl)methyl)amino)-3-pyridinyl)-, ethyl ester
PROPERTIES:
Molecular weight: 304

MECHANISMS/EFFECTS

HUMAN:

Stabilizes membrane resting potential by activating neuronal Kv7 potassium channels

Indirectly antagonizes NMDA receptors

Reduces muscle spasticity in humans

Prevents apoptosis and reduced formation of reactive oxygen species by in cultured human retinal pigment epithelial cells

 Scheme 1.
Structures of flupirtine, D13223, and retigabine.

Regulatory and Commercial Status

STATUS FOR MS:

Phase II

HIGHEST STATUS ACHIEVED (FOR ANY CONDITION):
Approved in Europe
ADMINISTRATION:
Oral
COMMERCIAL:
Originally developed by Asta Medica
Being developed and commercialized to treat fibromyalgia by Synthetic Biologics

Marketed for pain indications in various European countries by Meda

Flupirtine is an aminopyridine that functions as a centrally acting non-opioid analgesic. It first became available in Europe in 1984, and is sold mainly under the names Katadolon, Trancolong, Awegal, Efiret, Trancopal Dolo, and Metanor.[5] Flupirtine is sold by Intas Pharma under the brand name Pruf in India. Like nefopam, it is unique among analgesics in that it is a non-opioid, non-NSAID, non-steroidal centrally acting analgesic. In 2010 the chemically related drug (the difference being that the pyridine group in flupirtine is replaced with a phenyl group) retigabine (INN; ezogabine [USAN]) was approved by the FDA as an anticonvulsant for the treatment of refractory partial-onset seizures in treatment-experienced patients.[6] Retigabine also works by opening the neuronal KCNQ/Kv7 potassium channel, just like flupirtine.

History

Flupirtine was originally developed by Asta Medica, with the synthesis of the compound and the development of the drug described in patents from the 1970s to the 2000s.[7][8][9][10][11][12]

It was approved for the treatment of pain in 1984 in Europe. However, it has never been introduced to the United States market for any indication. In 2008, Adeona Pharmaceuticals, Inc. (now called Synthetic Biologics, Inc.) obtained an option to license issued and patent pending applications relating to flupirtine’s use in the treatment of ophthalmic indications, particularly retinitis pigmentosa.[13]

Mechanism of Action

Flupirtine is a selective neuronal potassium channel opener that also has NMDA receptor antagonist and GABAA receptor modulatory properties.[14]

Uses

Flupirtine is used as an analgesic for acute and chronic pain, in moderate-to-severe cases.[15] Its muscle relaxant properties make it popular for back pain and other orthopedic uses, but it is also used for migraines, in oncology, postoperative care, and gynecology.

Flupirtine has been noted for its neuroprotective properties, and it is being investigated for possible use in Creutzfeldt–Jakob disease, Alzheimer’s disease, and multiple sclerosis.[16][17] It has also been proposed as a possible treatment for Batten disease.[18]

Flupirtine underwent a clinical trial as a treatment for multiple sclerosis[19] and fibromyalgia.[20] Flupirtine showed promise for fibromyalgia due to its different action than the three approved by U.S. FDA drugs: Lyrica (pregabalin), Savella (milnacipran), and Cymbalta (duloxetine).[21] Additionally, there are case reports regarding flupirtine as a treatment for fibromyalgia.[22] Adeona Pharmaceuticals (now called Synthetic Biologics) sub-licensed its patents for using flupirtine for fibromyalgia to Meda AB in May 2010.[21]

Side Effects

The most serious side effect is frequent hepatotoxicity which prompted regulatory agencies to issue several warnings and restrictions.[23][24]

Flupirtine is devoid of negative psychological or motor function effects, or effects on reproductive function.[25][26]

Abuse and Dependence

Although some studies have reported flupirtine has no addictive properties,[27][28] there was suggestion that it may possess some abuse potential and liability.[29] There were at least two registered cases of flupirtine abuse.[30] Drug tolerance does not develop in most cases; however, tolerance may develop in single cases.[30]

Flupirtine is 2-amino-3-carbethoxyamino-6-(p-fluorobenzylamino) pyridine; CAS No: 56995-20-1 , an aminopyridine that functions as a centrally acting non-opioid analgesic. It first became available in Europe in 1984, and is sold mainly under the names atadolon, Trancolong, Awegal, Efiret, Trancopal Dolo, and Metanor. It is unique as a non- opioid, non-NSAID, non-steroidal analgesic. Flupirtine is used as an analgesic for acute and chronic pain, in moderate to severe cases. Its muscle relaxant properties make it popular for back pain and other orthopaedic uses, but it is also used for migraines, in oncology, postoperative care, and gynaecology. Flupirtine has been noted for its neuro-protective properties, as well as its possible uses for Creutzfeld- Jakob disease, Alzheimer’s disease, and multiple sclerosis are being investigated. It has also been proposed as a possible treatment for Batten disease. Flupirtine also acts as an antioxidant and prevent free radical- mediated structural damage.

US3481943 (hereinafter referred as ‘943) discloses the process for the preparation of flupirtine hydrochloride of formula (T) wherein p- fluorobenzylamine (formula R) is reacted with 2-amino-3-nitro-6- chloropyridine (Q) in n-propanol using potassium carbonate to prepare 2-amino-3-nitro-6-p-fluorobenzylamino-pyridine of formula (S) which is hydrogenated in dioxane using raney nickel at 50 C under a gauge pressure of 30 atmospheres. Solution is filtered off to remove the catalyst and then reacted with chloroformic acid ethyl ester (ethyl chloroformate) while stirring. The product is filtered off and recrystallized from water to give flupirtine hydrochloride salt of formula (T). The process disclosed therein in ‘943 is depicted as given below

Drawbacks associated with the process disclosed in ‘943 are:

1) The yield of 2-amino-3-nitro-6-p-fluorobenzylamino-pyridine of formula S obtained is around 40% only. ‘943 does not disclose the preparation of maleate salt of flupirtine.

2) During the preparation hydrochloride salt of flupirtine on an industrial scale, intensely blue colored by products are formed which are either difficult to remove or can not be removed completely.

3) Use of n-propanol as reaction solvent is expensive. reaction mass thereby hindering the progress of the reaction. Another most probable reason attributed for getting poor yield of 40% in the said process could be masking of hydrochlorides of both the reactants of formulae (Q’) and (R’) (as both reactants are amino compounds and form hydrochlorides) over potassium carbonate making it unavailable for further reaction posing problem towards the completion of reaction thereby adversely affecting the yield.

DE3133519 (US4481205) discloses the preparation of flupirtine maleate of formula (IA), wherein 2-amino-3-nitro-6-chloro-pyridine of formula (S) is prepared by taking 2,6-dichloro-3-nitropyridine of formula (P) (90%, water wet) in isopropanol at 20°-30°C and purging ammonia gas (or dropping liquid ammonia) into the said reaction mixture and then resulting 2-amino-3-nitro-6-chloro-pyridine of formula (Q) is reacted with p-fluorobenzylamine (R) in isopropanol using triethyl amine as a base ; the reaction mixture is refluxed for 6 hours. Thereupon after addition of a large volume of water the compound 2-amino-3-nitro-6-(p- fluorobenzylamino)-pyridine of formula (S) precipitates.

2-amino-3-nitro-6-(4-fluorobenzylamino) pyridine of formula (S) is then hydrogenated in the presence of raney nickel at 5 bar at 60°C to give 2,3- diamino-6-(4-fluorobenzylamino) pyridine using 2-methoxy ethanol as hydrogenating solvent. This is followed by acylation with ethyl chloroformate using triethylamine as a base under inert gas atmosphere to obtain flupirtine base of formula (I). The catalyst is filtered off and filtrate containing dissolved triethyi amine hydrochloride is directly added to solution of maleic acid in isopropanol resulting into formation of crude flupirtine maleate (IA). It also discloses the importance of the exclusion of atmospheric oxygen by an intensive supply of inert gas and closed reactor system to avoid development of troublesome coloured complexes.

The purification of crude flupirtine maleate is carried out by converting crude flupirtine maleate into crude flupirtine base by contacting with ammonia or sodium hydroxide solution. Then the crude flupirtine base is recrystallized from isopropanol and, after contacting with activated carbon/kieselguh’r, it is reacted with a solution of maleic acid in isopropanol to give flupirtine maleate of formula (IA). The reaction scheme of DE3133519 is depicted herein below.

Drawbacks associated with the process disclosed in DE3133519 (US4481205) are:

1) Use of gaseous ammonia or liquid ammonia for the preparation of 2-amino-3-nitro-6-chloro-pyridine of formula (Q) starting from 2, 6- dichloro-3-nitropyridine of formula (P) contributes towards increased level of impurities of formulae X and Y as the gaseous ammonia and liquid ammonia as sources of ammonia are in concentrated forms and it is not easy to control the purging or addition in appropriate quantities and as a consequence it results in the formation of higher amounts of impurities and poor yield of the desired compound.

Another disadvantage of using ammonia gas is that it is classified as a hazardous material and is subject to strict regulations and risk management procedures for transport, storage, and handling. These requirements result in additional costs and may generate local community concerns over transporting and storing hazardous materials. While aqueous ammonia used by the inventors requires minimal special handling, social and regulatory requirements.

2) Preparation of 2-amino-3-nitro-6-(p-fluorobenzylamino)-pyridine of formula (S comprises reaction between 2-amino-3-nitro-6-chloro- pyridine of formula (Q) and p-fluorobenzylamine of formula (R) using isopropanol as solvent and triethyl amine as base. To induce separation of 2-amino-3-nitro-6-(p-fluorobenzylamino)-pyridine of formula (S from the reaction mixture in IP A a large volume of water is required which makes reaction mass highly voluminous therefore, not preferred at industrial scale. 3) Basification of crude flupirtine maleate comprising the process of liberating free flupirtine base using ammonia or sodium hydroxide produces an ammonium or sodium salt which pollutes the water.

4) Use of activated charcoal and kieselgulir during the purification of flupirtine base (that contains three amino groups known for their light and colour sensitive nature) takes prolonged time for filtration through filtering bed thereby exposing to environment producing high coloration.

5) The crude flupirtine maleate remains trapped with triethyl amine hydrochloride.

US59591 15A (hereinafter referred as Ί 15) discloses a process for the preparation of flupirtine maleate (IA) as discussed under DE3133519 (US4481205). It also discloses crystalline form “A” of flupirtine maleate by the use of water soluble alcohols (such as ethanol or isopropanol) during synthesis and/or purification. There are three proposed variants in Ί 15 as shown below: process variant:

A: ANFP (S)→hydrogenation→acylation→crude flupirtine base.

B: crude flupirtine base→maleic acid→crude flupirtine maleate

C-E (as shown in scheme-II): not applicable F: crude maleate→pure maleate.

1 s process variant comprises synthesis of oxygen sensitive crude base in situ in process step A and it was converted by a “very rapid” suction filtration process into an aqueous maleic acid solution from which coloured crude flupirtine maleate (IA) is obtained, which is to be purified by recrystallization from isopropanol-water.

2″ process variant:

A: ANFP (S)→hydrogenation→acylation→crude flupirtine base.

B: flupirtine base→maleic acid→crude flupirtine maleate.

C-F (as shown in scheme-II): Not applicable.

G: without isolation of the crude maleate→pure maleate.

As compared to the process step F in 1st variant, process step G in 2nd variant represents substantially shorter alternative process in which the precipitation of crude flupirtine maleate from the flupirtine base formed in situ in isopropanol is effected by Alteration with suction into an aqueous maleic acid solution at 50-60°C and, after that without isolation of the crude maleate, colourless pure material is obtained.

3rd process variant:

A: ANFP (S)→hydrogenation→acylation→cmde flupirtine base (isolated)

B: pure flupirtine base→maleic acid→pure flupirtine maleate.

Herein, after acylation, the flupirtine base (I) is precipitated preferably in ethanol or water and is purified by recrystallization and than treated with maleic acid to prepare pure flupirtine maleate (IA).

Ί 15 disclose hydrogenation of ANFP (S), acylation and precipitation in water-soluble alcohols, such as ethanol or isopropanol.

1) In 1st process variant “very rapid” suction filtration process is a great limitation at plant scale.

2) 2nd process variant also does not produce colorless pure maleate.

3) In 3 process variant, after acylation, the flupirtine base is precipitated preferably in ethanol or water and is purified by recrystallization and than treated with maleic acid to prepare pure flupirtine maleate salt (IA).

It also discloses that although the treatment of final product with activated carbon and recrystallization is known as a reasonably successful procedure to remove impurities. This approach is reluctantly accepted because of the losses in overall yield as it is applied in the last production step of a drug and particularly in the case of flupirtine, it is not a preferred/desirable procedure as it may result into the formation of colored impurities.

US47851 10A discloses a process for the preparation of 2-amino-3-nitro- 6-fluorobenzylamino pyridine of formula (S) comprising reaction of 2- amino-3-nitro-6-methoxypyridine of formula (T) (1 mole) with 4-fluoro- benzylamine of formula R (2-4 mole) optionally as a mineral acid salt in water at a temperature between 70°C and 150°C; preferably between 90° and 120°C. The said condensation is also performed in autoclave as the temperature is above 100°C.It also discloses the necessity of using basic material suitably as an aqueous solution in case when acid addition salts of 4-fluoro-benzylamine of formula (R) is used to liberate the free base for the reaction. It also discloses subsequent reduction of nitro group of 2-amino-3-nitro-6-methoxypyridine by various modes with preference to catalytic hydrogenation optionally in the presence of carriers selected from barium sulphate, calcium sulphate, magnesium sulphate, sodium sulphate etc.

The drawbacks associated with the process described in US47851 10A are: 1) As per the experimental section of the said process of condensation for the preparation of 2-amino-3-nitro-6-fluorobenzylamino pyridine of formula (S) discloses heating at boiling for ten hours. The temperature would be around 100°C as water is used as solvent. However, inventors of the subject invention disclose herein the same process comprising using 6-chlorpyridine instead of 6-methoxy pyridine and water as solvent’, wherein the reaction is carried out at temperature much below boiling point of water and reaction gets completed in 3 hrs compare to 10 hrs at temperature of boiling water as in’ 1 10. Furthermore, the said reaction disclosed herein in the present invention does not require autoclave. There is no teaching or anticipation on this aspect from Ί 10.

2) Excessive use of 2-4 moles of 4-fluoro-benzylamine of formula ( ) for the preparation of 2-amino-3-nitro-6-fluorobenzylamino pyridine of the formula (S) comprising the reaction of 2-amino-3-nitro-6- methoxypyridine of formula (T)with 4-fluoro-benzylamine of formula (R).Unreacted 4-fluoro-benzylamine is then removed by steam distillation which is not only time and energy consuming but also increase in an extra unit operation.

3) In case when acid addition salts of 4-fluoro-benzylamine are used that requires another additional operation of basification to liberate free base to enable 4-fluoro-benzylamine to be available to react further with 2- amino-3-nitro-6-methoxypyridine forming 2-amino-3-nitro-6- fluorobenzylamino pyridine of the formula (S)

DE 31 33 519 describes a process for the preparation of flupirtine maleate as a mixture of polymorphic forms A and B, wherein A is present in a proportion> 60%. The key reaction steps are the hydrogenation of 2-amino-6- (4-fluorobenzylamino) -3-nitropyridine (Formula II) shown in Figure 1, hereinafter also referred to as ANFP, by means of Ra-Nickel for 2,3-diamino- 6- (4-fluoro-benzylamino) -pyridine (Formula III) and subsequent regioselective acylation with chloroformate for free flupirtine base. By precipitation as maleate to blue contaminants that are incurred in the production of HCl salt, are eliminated. Purification of flupirtine maleate is obtained as maleate by releasing the base from the maleate, treatment with activated carbon and reprecipitation. Despite this lengthy and economically expensive purification strategy traces of colored impurities can be difficult to remove.

In WO 98/47872 a process for the preparation of flupirtine maleate is described, in which, in water-soluble alcohols (IPA) is carried out. There are three proposed variants. Option 1 includes an implementation of ANFP to Ra-nickel in the IPA is directly attached to the acylation and the precipitation of a product by Rohmaleat called “very fast” extraction process in an aqueous solution of maleic acid. It falls on a colored Rohmaleat which is to be purified by recrystallization from isopropanol / water. However, the enactment of this variant in the laboratory showed a colored product. In variant 2 should already be colorless an image obtained by aspiration in 50 to 60 0 C warm maleic Rohmaleat. This also could not be confirmed. According to the third variant, the Flupirtinbase formed after acylation is not converted in situ but precipitated in ethanol or water and recrystallized before further reaction with maleic acid. Even with the procedure referred to in this document is a pure white flupirtine maleate is not readily available.

………………….

PATENT

http://www.google.com.tr/patents/WO2010136113A1?cl=en&hl=tr

Example 3 Preparation of flupirtine maleate

50 g of 2-amino-6- (4-fluorobenzylamino) -3-nitropyridine, 2.5 g of palladium on activated carbon and 267 g of isopropanol were hydrogenated with hydrogen at 4.5 bar and 70 0 C. After completion of the reaction was additionally hydrogenated for 8 hours at 70 0 C. Then 20.2 g of ethyl chloroformate, 24.8 g of triethylamine and 4.96 g of ethyl chloroformate at 20 0 C was added. Thereafter, the reaction mixture was stirred for 1.5 h at 55 0 C. It was then filtered at room temperature. The filtrate was then added to a solution of 35.6 g of maleic acid in 1000 g of water at room temperature slowly. The resulting suspension was stirred for 1 h at room temperature. The precipitate was filtered off and washed with water and isopropanol. Dried filter cake (HPLC purity 91.5%) was dissolved in 828 g of isopropanol / water mixture (mass ratio 5.3: 1), and heated to 70 0 C. The resulting clear solution was cooled to room temperature and stirred at room temperature. The precipitate was filtered off and washed with isopropanol / water mixture. The filter cake was dried at 50 0 C. 43 g flupirtine maleate (HPLC purity 97.8%) was obtained as a white-gray solid. The yield was 55%.

………………

PATENT

http://www.google.com/patents/WO2013080215A1?cl=en

The invention relates to an improved process for the preparation of flupirtine of formula (I) and its pharmaceutically acceptable salts, particularly flupirtine maleate of formula (IA) preferably pure crystal modification A of flupirtine maleate.

A process for the preparation of the compound of formula (I)
and pharmaceutically acceptable acid addition salts thereof comprising the steps of:
(a) contacting 2, 6-dichloro-3-nitro pyridine of formula (P) with aqueous ammonia solution in a compatible solvent to produce 2-amino-3-nitro-6- chloro-pyridine of formula (Q);
(b) contacting said compound of formula (Q) with p-fluorobenzylamine taking water as a solvent in presence of a base to produce 2-amino-3- nitro-6-p-fluorobenzylamino-pyridine of formula (S);

(c) reducing nitro group of 2-amino-3-nitro-6-p-fluorobenzylamino- pyridine of formula (S) in a solvent base combination as solvent system in the presence of a catalyst;

(d) contacting 2,3-diamino-6-p-fluorobenzyl amino pyridine produced in step c with an ethyl chloroformate in presence of a base optionally insitu without isolation to produce flupritine base of formula (I);
(e) contacting the said flupritine base of formula (I) with acid solution to produce corresponding acid addition salt.

Scheme (I):

EXAMPLE 1 : Preparation of 2-amino-3-nitro-6-chloro-pyridine.

A solution of 100 gm. 2, 6-dichloro-3-nitro-pyridine in 800 ml isopropyl alcohol is taken in round bottom flask. 300 ml of aqueous ammonia solution (20-25%) is added at 20-25°C. The reaction mass is stirred for 20-24 hours at 20-25°C. After completion of the reaction

The solid is filtered and washed with 100 ml isopropyl alcohol then dried to obtain 70-75 gm 2-amino-3-nitro-6-chloro-pyridine.

EXAMPLE 2: Preparation of 2-amino-3-nitro-6-p-fluorobenzylamino- pyridine.

100 gm of 2-amino-3-nitro-6-chloro-pyridine is taken in 800 ml of water. 90 gm of p-fluorobenzylamine is added dropwise into the reaction mixture at 20-25°C. Then 87 gm triethylamine is also added dropwise into the reaction mixture at 20-25°C. After complete addition, the reaction mass is stirred at 40-45°C for half an hour again the reaction mass is heated to 80-85°C and stirred at this temperature for 3-4 hours. After completion of the reaction, the reaction mass is cooled to 20-25°C and stirred at this temperature for 2-3 hours and then stirred at 15-20°C for 3-4 hours. The solid mass is filtered and then washed with 200 ml of water and 100 ml isopropyl alcohol and then dried in air oven till constant weight to get 140-150 gm. of 2-amino-3-nitro-6-p- fluorobenzylamino-py ridine .

EXAMPLE 3: Preparation of flupirtine maleate.

In an autoclave, 100 gm. 2-amino-3-nitro-6-p-fluorobenzylamino- pyridine is taken in 500 ml. 1, 4-dioxane and 20 ml aqueous ammonia solution. 10 gm of raney nickel is added under nitrogen atmosphere and hydrogenated at 75-80°C for 2-3 hours under 4-5 kg pressure. After completion of the reaction, the reaction mass is cooled and filtered at 40- 45°Cthen in filtrate 45 ml of ethyl chloroformate is added slowly at 5- 10°C. The temperature is raised to 25-30°C and 80 ml triethyl amine is added under nitrogen atmosphere. The reaction mass, is heated at 55- 60°C under stirring for 3-4 hours. After completion of the reaction, the reaction mass is distilled up to 70-80% under vacuum. This concentrated reaction mass is added into aqueous solution of maleic acid (72 gm in 2000 ml DM water at 65-70°C and maintained at 65-70°C for 2 hours under nitrogen to get crude Flupirtine Maleate as a solid. The reaction mass is cooled to 25-30°C in 5-6 hours and maintained at this temperature for next 2-3 hours then filtered. The wet cake is washed with 200 ml water and dried to get 145 gm of flupirtine maleate.

EXAMPLE 4: Preparation of pure flupirtine maleate crystalline modification A.

1 15 gm crude Flupirtine maleate obtained in example 3 is taken in 1 150 ml methanol and 58 ml water. This mixture is heated to reflux and 58 ml water is added slowly to get a clear solution and refluxed for about half an hour. The reaction mixture is cooled slowly to 60°C and seeded with crystals of modification A. Then it is cooled slowly to 20-25°C and maintained at this temperature for 2 hours. The crystalline mass is filtered and washed with 100 ml chilled methanol and dried to give 92 gm. flupirtine maleate crystalline modification A.

………………….

PATENT

http://www.google.com.tr/patents/WO1998047872A1?cl=en

1. Example

Preparation of flupirtine maleate

75 g (0.286 mol) ANFP be in a suspension of 12.5 g of Raney nickel in 400 ml of isopropanol was hydrogenated at 65 ° C and 5 bar hydrogen pressure. After hydrogenation, the solution is then mixed with 26.4 ml of ethyl chloroformate and 50.6 ml of triethylamine. After adding a further 6.3 ml of ethyl chloroformate the reaction solution is stirred at 60 ° C. for 1 hour. Then sucks the hot solution with stirring in a 50 – 60 ° C heated solution of 53.3 g of maleic acid in 1, 5 IH 2 O and washed the catalyst with little isopropanol.

The flupirtine maleate is precipitated in colorless crystal suspension is cooled with further stirring at 20 ° C and maintained at this temperature for 20 minutes. It is suctioned off, washed with 500 ml of water and dried flupirtine maleate in vacuo at 35 ° C.

Yield: 107.55 g (89.6% of theory, based on ANFP.) Example 2

Preparation of flupirtine maleate

18.5 g (0.07 mol) ANFP be analogous to Example 1 in a suspension of 2.0 g of Raney nickel in 140 ml of ethanol 60 – 70 ° C and 5 bar hydrogen pressure After hydrogenation, the further reaction takes place at 40 – 50 ° C with 9.3 g of ethyl chloroformate (0.86 mol) of triethylamine and 9.2 g (0.91 mol) The separated from the catalyst reaction solution is added with stirring to 540 ml of water After 2 hours of stirring at room temperature suctioned the failed base off and washed with water and isopropanol and crystallized in the 3.7-fold amount of isopropanol to yield 18.4 g (86.0% of theory)

The precipitation and modification of pure flupirtine maleate is carried out according to the Examples 7 and 8

………………….

PATENT

CN104086481 (A)  –  Synthesis method of flupirtine maleate

http://worldwide.espacenet.com/publicationDetails/biblio?CC=CN&NR=104086481A&KC=A&FT=D

The invention provides a synthesis method of flupirtine maleate. Recrystallization by use of methanol is carried out in the refining step of the crude product of the flupirtine maleate so that the product is white in appearance and high in purity, and the crystal form of the product is pure A crystal and same as the crystal form of the commercial products. The optimal reaction solvent, reaction time and reaction temperature are explored and found out by use of a simplified process flow, and a method for preparing the flupirtine maleate in the pure A crystal form, which is high in yield, low in cost and simple to operate, uses easily available raw materials and is applicable to the industrial production is found.

………………

PATENT

http://www.google.com/patents/CN103333103A?cl=en

The preparation of a comprehensive literature about the ratio of maleic acid fluoride Jie Ting to 2_-amino-3-nitro-6-chloro-Jie ratio 唳 as a starting material, by condensation, reduction, acylation, salt and other processes for The most common route, however, due to the reduction, acylation, salt formation method of a three-step operation is different, not only the yield of the synthesis varies widely, and also on the flupirtine maleate product quality. This is mainly because of the intermediate 2,3-diamino-6-fluoro-benzyl amino pyridine and flupirtine multi-aminopyridine derivative, is easy to oxidative deterioration. So the use of continuous operation, not only simple steps, and can improve product quality and yield.

  Chinese patent CN102241626 reported to 2,6_ dichloro _3_ nitropyridine as raw material by selective ammonia solution to give 2-amino-3-nitro-6-chloro-approved Li, then with amine fluoride Festival to afford a yellow solid 2-amino-3-nitro-6-p-fluoro-benzylamino-pyridine. After vacuum drying, the use of hydrogenation, and then under nitrogen and ethyl chloroformate acylation catalyst is filtered off and then a salt with maleic acid to give a pale green crude product yield was about 37% (2-amino-3-nitro-6-chloro-pyridin-meter).

Patent No. CN102838534 reported 2-amino-3-nitro-6-chloro-pyridine as starting material, the use of sub-step processing method, in a first reactor, and a condensation-fluorobenzyl amine, and dried in vacuo to give the intermediate 2-amino-3-nitro-6-p-fluorobenzyl-aminopyridine, in a second reactor to Raney nickel as the catalyst, the catalytic hydrogenation of hydrazine hydrate, after filtration the solvent was evaporated to give the intermediate 2,3-solid – diamino-6-p-fluorobenzyl-aminopyridine, in a third reactor with ethyl chloroformate acylated intermediate distillation under reduced pressure to give solid form of flupirtine with an aqueous solution of a salt of maleic acid, after purification, the total Yield 25% ~ 30%.

Patent W02012004391 discloses a method for preparing a high yield of flupirtine maleate method. In 2_-amino-3-nitro-6-chloro-fluoro-section batch Li and amines as raw material for condensation to give 2-amino-3-nitro-6-fluoro-section based on the amino pyridine granted, then using high-pressure hydrogenation the reduction, acylation step in a high pressure hydrogenation reactor concentrated completed, after the catalyst was filtered off and then the salt, the crude yield of greater than 70%. The preparation method using high-pressure hydrogenation apparatus, there are security risks, and takes too long, is not suitable for industrial production.

  Patent No. CN102260209 discloses a 2_ amino _3_ _6_ fluorobenzyl nitro-pyridine as starting material, the reduction, acylation and salt-forming step of the continuous operation, the synthetic yield was improved to 58% so, no mention of product purity. Since the acylation step taken ethyl chloroformate, while an organic base is added, so that an increase in a side reaction, the product yield decreases; the same time, 2-amino-3-nitro-6-p-fluoro-benzylamino-pyridine as the raw material, the production cost high.

  In the present invention, we consider the key intermediate 2,3-diamino-6-p-fluorobenzyl-aminopyridine and chemical properties of flupirtine, condensation, reduction, acylation, salt formation reaction is concentrated to the same conventional the reactor is completed, each step without intermediate separation, simplifying the process route and operations, improve efficiency, reduce costs, improve the overall yield of the crude by 40 percent following the step by step operation for more than 70% crude purity of more than 99% suitable for industrial scale production.

Figure CN103333103AD00041

Example 4:

The 4Kg2_ amino-3-nitro-6-chloropyridine, 4.5Kg triethylamine, 40L of isopropanol into the reactor, stirred and heated to reflux for turn; the 4.4Kg of benzylamine was added to the fluorine reactor, the reaction under reflux conditions for 3 hours. After heating was stopped, the reaction solution was added to 40L of purified water, a lot of yellow solid was precipitated was filtered and the resulting wet product remains in the reaction vessel. To the reaction kettle was added 1.8Kg Raney nickel, 40L of isopropanol, stirred and heated to reflux for open, 7Kg80% hydrazine hydrate was added dropwise, the reaction was refluxed for 3 hours, after completion of the reaction down to room temperature in a nitrogen atmosphere, was added rapidly 3.6Kg chloro carboxylic acid ethyl ester, the reaction at room temperature for 3 hours. 3Kg of triethylamine was added, free 2 hours, filtered and the filtrate was added to 5Kg / 100L of maleic acid in isopropanol, cooling crystallization to give an off-white solid, 50 ° C blast drying, weight 7.8Kg, the yield was 80.5 %, purity 99.6%.

A sub-step treatment process research and data [0034] Comparative Example

The method according to Chinese patent CN102838534 disclosed flupirtine maleate was prepared, and a number of specific steps

………….

PATENT

FIG. 1 is flupirtine maleate 1H NMR.

[0021] FIG. 2 is flupirtine maleate A crystal X-ray diffraction pattern

Inline image 1

Inline image 2

Inline image 3

Figure CN103086963AD00061

 

Figure CN103086963AD00062

 

Figure CN103086963AD00071

Example 3

2-Amino-3-nitro-6-chloropyridine 246g, and 254g of triethylamine were added to 800ml of ethanol-necked flask and stirred under heating to reflux, fluorine was slowly added dropwise benzylamine 80g, reaction of 6 hours, the reaction was completed After the dropwise addition of purified water 500ml, cooled slowly with stirring to room temperature, filtered, dried to give 2-amino-3-nitro-6-p-fluoro-benzylamino-pyridine.

[0033] The ferric chloride hexahydrate was dissolved in purified water 41g 200ml, adding activated charcoal 20g, heated to 50 ° C, a saturated solution of sodium hydroxide was added 45g (24g of sodium hydroxide dissolved in 21ml water), 60 ° C with stirring I hours, cooled to room temperature, filtered, and dried to give ferric hydroxide / activated carbon catalyst.

[0034] A mixture of 2-amino-3-nitro-6-p-fluorobenzyl-aminopyridine 104.Sg, ferric hydroxide / activated carbon catalyst was added to 20g 2L reaction flask was added 95% ethanol 1200ml, heated with stirring to 90 ° C. Insulation 60% hydrazine hydrate was added dropwise 250g. Drops Bi insulation response to 3h. Completion of the reaction, the reaction solution is filtered hot with concentrated hydrochloric acid to 240ml and 95% ethanol IOOOml reaction flask. (TlO ° C crystallization I h, filtered, dried to give 2,3-amino-6-fluoro-benzyl-aminopyridine on

Hydrochloride.

[0035] A mixture of 2,3-diamino-6-p-fluoro-benzylamino-pyridine hydrochloride 132g, 800ml of isopropanol was added to a 2L reaction flask, the temperature control to 28 至 30 ° C, was slowly added dropwise acetic acid ester 39g. Stirred for 0.5 hours, was slowly added dropwise triethylamine 70g, after stirring for 0.5 hours, complement ethyl chloroformate 5g, stirred for 15 minutes, additional triethylamine remaining 10g. Continue stirring for I hour. The reaction solution was concentrated under reduced pressure to about 800ml of distillate was distilled out. The remaining reaction solution was poured into an aqueous solution of maleic acid with a good (39g of maleic acid was dissolved in purified water IlOOml), stirred for 30 minutes at room temperature, (T5 ° C was stirred for 5 ~ 8 hours, filtered, dried to give the maleic acid flupirtine crude.

[0036] The crude flupirtine maleate product 100g, 2000ml of ethanol into the reaction flask and heated to 70~80 ° C, was added 5g of activated carbon and dissolved, and incubated I hour, filtered hot, O~5 ° C CRYSTALLIZATION 3 hours, filtered and dried to give crude I. The crude product I 90g, 450ml of ethanol into the reaction flask and heated 20h, and then slowly cooled to room temperature, O~5 ° C for 2 hours, filtered, and dried to give crystal form A of flupirtine maleate product.

…………………..

PATENT

http://www.google.com/patents/CN102838534A?cl=en

flupirtine maleate is a non-opioid analgesic effects on the central nervous system drugs, which is a selective neuronal potassium channel opener (Selective Neuronal Potassium Channel Opener, SNEPCO), has analgesic, muscle relaxant and neuroprotective triple effect. Acute pain treatment is mainly used for various types of moderate, such as surgery, trauma-induced pain and headache / migraine and abdominal spasms.

  flupirtine maleate English name: Flupirtine Maleate, chemical name: 2_ amino-6 – [((4-fluorophenyl) methyl) amino] pyridine-3-carboxylic acid ethyl ester maleic salt; Chemical Abstracts (CAS) number = 75507-68-5; formula = C15H17FN4O2 · C4H4O4; molecular weight: 420.39; its structural formula is:

Figure CN102838534AD00041

  From a structural perspective, flupirtine maleate molecular compounds, the derivatives of benzene and pyridine derivatives synthetically produced flupirtine, flupirtine and then forming an organic salt with maleic acid. Comprehensive literature, synthetic routes flupirtine maleate there are two major, now its main synthetic steps described below.

  Route 1 (W0 98 / 47872Α1): The route to 2,6_ dichloro _3_ nitropyridine as raw material substitution, ammoniated, high-pressure hydrogenation, acylation, a process salt, refined and so on. The reaction formula is as follows:

Figure CN102838534AD00051

  Route 2 (US5959115A) to 2_ amino _3_ nitro _6_ methoxypyrido as the starting material, and on fluorobenzylamine substitution reaction to produce 2-amino-3-nitro–6 – fluorobenzyl amine of pyridine, the yield was 95.2%, and the high-pressure hydrogenation, the catalyst was filtered off, and then the occurrence of an acylation reaction with ethyl chloroformate to give the hydrochloride salt of flupirtine, three-step total yield of 53.3%. The reaction formula is as follows:

Figure CN102838534AD00061

Route 1 starting material is different, but relatively speaking, the route I easily controlled reaction conditions, and 2-amino-3-nitro-6-chloro-pyridine is a common chemical raw materials, easy to buy on the market, This can shorten the reaction route. Route 2 two-step reaction process route is short, but the starting 2-amino-3-nitro-6-methoxy-approved Li expensive, hydrogenation, acidification two steps yield only 56.0%.

Chinese Patent Application Publication No. CN102241626A are disclosed and CN102260209A flupirtine maleate preparation method, but the application of these two methods for the preparation of a laboratory scale, for the industrial mass production were not optimized.

The method for purifying of flupirtine maleate in the final product are as follows:

650C ± 5 ° C under the flupirtine maleate crude and ethanol mass ratio of 1: 30-40 mixed, crude completely dissolved, then add 680g of activated carbon and stirred for 15–30 minutes, and hot filtration, the filtrate, stirring down to room temperature, and then cooled to 0 ° C crystallization 5–10 hours, filtered and the filter cake to take the filter cake can be dried.

BELOW AS FREE BASE

Ethyl N-[2-amino-6-[(4-fluorophenyl)methylamino]pyridin-3-yl]carbamate
CAS No.: 56995-20-1
Synonyms:
  • Flupirtine;
  • Effirma;
Formula: C15H17FN4O2
Exact Mass: 304.13400

1H NMR INTERPRETATIONS/PREDICTIONS

ethyl N-[2-amino-6-[(4-fluorophenyl)methylamino]pyridin-3-yl]carbamate NMR spectra analysis, Chemical CAS NO. 56995-20-1 NMR spectral analysis, ethyl N-[2-amino-6-[(4-fluorophenyl)methylamino]pyridin-3-yl]carbamate H-NMR spectrum

13C  NMR INTERPRETATIONS/PREDICTIONS

ethyl N-[2-amino-6-[(4-fluorophenyl)methylamino]pyridin-3-yl]carbamate NMR spectra analysis, Chemical CAS NO. 56995-20-1 NMR spectral analysis, ethyl N-[2-amino-6-[(4-fluorophenyl)methylamino]pyridin-3-yl]carbamate C-NMR spectrum

…….

PAPER

Helvetica Chimica Acta, , vol. 77, # 8 p. 2175 – 2190

AND GIVES PRODUCT

ALSO AN INTHelvetica Chimica Acta, , vol. 77, # 8 p. 2175 – 2190

…………..

HPLC

Instrumentation An HPLC system (Agilent HPLC Model-1200) equipped with a C18 (Agilent BDS, 250 mm x 4.6 mm, 5µ) column, binary pump, rheodyne loop injector with 20 μL, and a photodiode array detector was used. The software used for HPLC data acquisition was EZChrome Elite. A flash chromatograph equipped with silica gel as the column material, and VWD-UV detection (using the software Analogix IF 280 V 5.10) was used for the isolation and purification of degradation products. 1 H-NMR was recorded on the Varian Unity Inova at 400 MHz (using TMS as internal standard and DMSO-d6 as solvent), 13C-NMR (Mercury Plus at (abundance 100 MHz), using DMSO-d6 as solvent), and mass spectral studies were performed on the API 3000 ABPCIES instrument.

Method Development and Optimization of the Chromatographic Conditions In preliminary experiments, the drug was subjected to the reversed-phase mode using a C18 column (Agilent, 250 x 4.6 mm, 5µ) and mobile phases consisting of water (pH 3.0 adjusted with orthophosphoric acid) and methanol by varying the % aqueous phase from 10% to 30%. The drug was retained on the column, but the peak shape was not good. It was noted that increasing the % aqueous phase in the mobile phase composition increases the retention time of flupiritine maleate. Based on the suitable retention time for SIAM, the 20% aqueous phase was optimized. To reduce the tailing effect, 0.2% triethylamine (TEA) was added and the pH was adjusted to 3.0 with orthophosphoric acid and the corresponding retention of FLU was 10.3 ± 0.3 min. Finally, the mobile phase of 0.2% v/v TEA (pH-adjusted to 3.0 with OPA) and methanol in the ratio of 20:80% v/v was optimized. The flow rate was 1.0 mLmin−1. The injection volume was 20 µL and the PDA detection wavelength was at 254 nm. The chromatogram obtained in the optimized condition is shown in Fig. 2. It was observed that eight degradation products were formed with retention times 3.9 ± 0.2 min (D1), 4.8 ± 0.2 min (D2), 6.4 ± 0.1 min (D3), 6.8 ± 0.2 min (D4), 8.2 ± 0.2 min(D5), 12.0 ± 0.2 min (D6), 14.1 ± 0.1 min (D7), and 15.0 ± 0.1 min (D8), respectively. The chromatographic resolution among all of the peaks was more than 2. The % degradation was about 5–30% depending on stress conditions.

………………..

paper

J Pharm Biomed Anal. 2014 Mar;90:27-34. doi: 10.1016/j.jpba.2013.11.015. Epub 2013 Nov 27.

Flupirtine maleate is a centrally acting, non-opioid, nonsteroidal antiinflammatory analgesic. During the manufacturing of flupirtine maleate, two unknown impurities present in the laboratory batches in the range of 0.05-1.0% along with the known impurities in HPLC analysis. These unknown impurities were obtained from the enriched mother liquor by column chromatography. Based on the complete spectral analysis (MS, (1)H, (13)C, 2D NMR and IR) and knowledge of the synthetic scheme of flupirtine maleate, these two new impurities were designated as diethyl 5-((4-fluorobenzyl)amino)-2-oxo-1H-imidazo[4,5-b]pyridine-1,3(2H)-dicarboxylate (impurity-I) and diethyl(6-((4-fluorobenzyl)amino)pyridine-2,3-diyl)dicarbamate (impurity-II). Impurity isolation, identification, structure elucidation and the formation of impurities were also discussed. Preparation and structure elucidation of impurity-III were also first reported in this paper.

…………………

journal of pharmaceutical and biomedical analysis, 90, 2014, 27-34

References: Substituted pyridine with central analgesic properties. Prepn: K. Thiele, W. von Bebenburg, ZA 6902364(1970 to Degussa); W. von Bebenburg et al., Chem. Ztg. 103, 387 (1979); eidem, ibid. 105, 217 (1981).

Prepn of maleate: W. von Bebenburg, S. Pauluhn, BE 890331; eidem, US 4481205 (1980, 1984 both to Degussa).

Comparison of pharmacology with other analgesics: V. Jakovlev et al., Arzneim.-Forsch. 35, 30 (1985).

Pharmacokinetic studies: K. Obermeier et al., ibid. 60.

Effect on driving ability: B. Biehl, ibid. 77.

Clinical trials in treatment of cancer pain: W. Scheef, D. Wolf-Gruber, ibid. 75.

Efficacy in treatment of pain after hysterectomy: R. A. Moore et al., Br. J. Anaesth. 55, 429 (1983).

Symposium on pharmacology and clinical efficacy: Postgrad. Med. J. 63, Suppl. 3, 1-113 (1987).

References

 1

Stoessel, C; Heberlein, A; Hillemacher, T; Bleich, S; Kornhuber, J (Aug 16, 2010). “Positive Reinforcing Effects of Flupirtine—Two Case Reports”. Progress in Neuro-psychopharmacology & Biological Psychiatry 34 (6): 1120–1121. doi:10.1016/j.pnpbp.2010.03.031. PMID 20362025. Retrieved 2 June 2014.

References

Fleckenstein J, Sittl R, Averbeck B, Lang PM, Irnich D, Carr RW
J Transl Med. 2013; 11:34. Epub 2013 Feb 08. PMID: 23394517. Abstract
WO2008110357A1 * 12 Mar 2008 18 Eyl 2008 Elbion Gmbh Method for preparing a flupirtine maleate of a crystal modification b
WO2010136113A1 * 5 May 2010 2 Ara 2010 Corden Pharmachem Gmbh Method for producing flupirtine
DE102009023162A1 29 May 2009 13 Oca 2011 Corden Pharmachem Gmbh Verfahren zur Herstellung von Flupirtin
DE102009023162B4 * 29 May 2009 7 Tem 2011 Corden PharmaChem GmbH, 68305 Verfahren zur Herstellung von Flupirtin
SEE
S SCHWOCH ET AL.: “2,3-Dihydrospiro[1H-4- and 5-azabenzimidazole-2,1′-cyclohexaneÜ: Reactions with nucleophiles” HELVETICA CHIMICA ACTA., Bd. 77, Nr. 8, 1994, Seiten 2175-2190, XP002073789 BASEL CH
WO1998047872A1 * 11 Nis 1998 29 Eki 1998 Asta Medica Ag Process for preparing pure flupirtin maleate and its modification a
EP0199951A2 * 15 Mar 1986 10 Ara 1986 ASTA Pharma Aktiengesellschaft Process for the preparation of 2-amino-3-nitro-6-(4-fluorobenzylamino) pyridine and of 2-amino-3-carbethoxyamino-6-(4-fluorobenzylamino) pyridine
DE3133519A1 Aug 25, 1981 Jun 9, 1982 Degussa 2-Amino-3-carbethoxyamino-6-(p-fluorobenzylamino)pyridine maleate
US3481943 May 10, 1967 Dec 2, 1969 Degussa Benzyl and pyridylmethyl substituted amido amino pyridines
US4481205 Sep 2, 1981 Nov 6, 1984 Degussa Aktiengesellschaft Antiphlogistic, analgesic
US4785110 Mar 24, 1986 Nov 15, 1988 Degussa Aktiengesellschaft 4-fluorobenzylamine with 2-amino-3-nitro-6-(4-fluorobenzylamino) pyridine
US5959115 Apr 23, 1998 Sep 28, 1999 Asta Medica Aktiengesellschaft Multistage reaction of catalytic hydrogenation, acylation and salt formation
US20060080790 * Aug 3, 2005 Apr 20, 2006 Jubilant Organosys Limited Process for producing 2,3-diamino-6-methoxypyridine

Quantitative HPLC Analysis. The quantitative analyses of flupirtine maleate and D13223 were done with an Dionex HPLC system consisting of a P580 pump, an ASI-100 automated sample injector, a UVD170S UV/visible detector, and a STH585 column oven. Analysis of the chromatograms was done with the Chromeleon software package. For the analysis of flupirtine and D13223, a 250 × 4 mm Nucleosil 100–5 C18 AB column (Macherey-Nagel GmbH & Co KG, Düren, Germany) preceded by a precolumn of the same material was used. The column was heated to 35°C. Samples were diluted 1:1 into phosphate buffer, and 100 μl of the sample was injected. Mobile phases were 30% acetonitrile-phosphate buffer (50 mM, pH 2.8) for flupirtine and 20% acetonitrile-phosphate buffer (50 mM, pH 2.8) for D13223. The flow rate was 0.7 ml/min. The retention times for flupirtine and D13223 were 6.67 ± 0.13 and 7.41 ± 0.30 min, respectively, with their respective eluents. Detection was done at λ = 345 and 344 nm for flupirtine and D13223, respectively. Peak height, which was more sensitive than peak area, was used to calculate the percentage decrease in the amount of substrate in the incubations. The molar concentrations were calculated with a calibration curve by using five external standards of either flupirtine or D13223. The relative precision of the analysis with microsomal incubations was <1% for both flupirtine and D13223. The methods were linear (r > 0.999) between 10 and 23.3 μM for flupirtine and D13223.

HPLC/HRMS Analysis. All chromatographic separations for HRMS measurements and the isolation of metabolites were done with an Agilent 1100 HPLC system consisting of a quaternary gradient pump, an autosampler, and a solvent degasser. The column was connected to the BNMI-HP unit for beam splitting (20:1) followed by the Bruker diode array UV detector (Bruker BioSpin GmbH, Rheinstetten, Germany) in parallel with the micrOTOF mass spectrometer (Bruker Daltonics, Bremen, Germany). The micrOTOF mass spectrometer was equipped with an electrospray ion source (temperature 180°C). Mass spectra were acquired with a scan range from 50 to 1500 m/z. All measurements were done in the positive mode. For all separations, a 125 × 4 mm LiChrospher 100 RP-18e (5 μm) column (Merck, Darmstadt, Germany) preceded by a precolumn of the same material was used. The flow rate was 0.5 ml/min. The chromatography was performed at 23 ± 2°C. Detection was done at λ = 204, 247, and 319 nm (maxima of absorption) and 362 nm (minimum of absorption) for analytes. Metabolite fractions for MS/MS analysis with an API 4000 mass spectrometer were collected manually. Eluents used in the gradients were acetonitrile (solvent B) and 50 mM ammonium acetate adjusted to pH 7.5 with 2.5% ammonia (solvent D). Solvent gradients for all chromatographic separations ran from 10 to 100% solvent B in 25 min, with the shapes of the gradients optimized for separations. These methods were used in the analysis of incubations of flupirtine or D13223 in the presence of microsomes with UDP-GA or in the presence of HRP and H2O2 with GSH.

HPLC/MS/MS Analysis. The MS/MS analysis of the two glucuronides of flupirtine and partly of metabolites from incubations of flupirtine with HRP were done in cooperation with Dr. Marcus Mickel from Applied Biosystems (Applera Deutschland GmbH, Darmstadt, Germany). The equipment consisted of an Agilent gradient pump 1100, a column oven, an autosampler, and a linear ion trap quadrupole mass spectrometer 3200 Q TRAP (Applied Biosystems/MDS Sciex, Foster City, CA). The source type was Turbo Spray with a source temperature of 450°C. For all measurements the positive mode was used. A Phenomenex Synergi Hydro RP column, 150 × 2 mm (4 μm), was used for the chromatography with a flow rate of 0.3 ml/min. Separations were performed using 95% A and 5% B for 30 s as a gradient, followed by a linear increase to 100% B over 15.5 min and then by 2 min of 100% B. Afterward the column was reconstituted to the starting conditions over 7 min. Solvent A used in the gradient was 5 mM ammonium acetate and solvent B was methanol containing 5 mM ammonium acetate. The column was heated to 30°C.

MS/MS Analysis. MS/MS analyses of all other metabolites of flupirtine and D13223, respectively, were done with an API 4000 mass spectrometer (AB/MDS Sciex). Purified metabolite fractions were analyzed by flow injection analysis by using a solvent flow of acetonitrile-50 mM ammonium acetate buffer (pH = 7.5) (solvent ratios resulting from the further separations) at flow rates of 10 and 20 μl/min, respectively. The mass spectrometer was equipped with an electrospray ion source (temperature 300°C). Collision-induced dissociation (CID) spectra were acquired for all metabolites with nitrogen as the collision gas. Collision energies used were in a range between 20 and 65 eV.

Flupirtine3Dan.gif
Systematic (IUPAC) name
ethyl {2-amino-6-[(4-fluorobenzyl)amino]pyridin-3-yl}carbamate
Clinical data
AHFS/Drugs.com International Drug Names
Pharmacokinetic data
Bioavailability 90% (oral), 70% (rectal)[1]
Metabolism Hepatic to 2-amino-3-acetylamino-6-(para-fluorobenzylamino) pyridine (which has 20-30% the analgesic potential of its parent compound), para-fluorohippuric acid[2] and a mercapturic acid metabolite, presumably formed from a glutathione adduct[3]
Half-life 6.5 hrs (average), 11.2-16.8 hrs (average 14 hrs) (elderly), 8.7-10.9 hrs (average 9.8 hrs) (in those with moderate-level renal impairment)[1]
Excretion 72% of flupirtine and its metabolites appear in urine and 18% appear in feces[4]
Identifiers
56995-20-1 
N02BG07
PubChem CID 53276
IUPHAR ligand 2598
ChemSpider 48119 
UNII MOH3ET196H Yes
KEGG D07978 Yes
ChEMBL CHEMBL255044 
Chemical data
Formula C15H17FN4O2
304.32 g/mol

Filed under: Phase2 drugs Tagged: D-9998, Flupirtine, Katadolon, phase 2

Firategrast, T-0047

$
0
0

Japan

Firategrast.png

Firategrast, 402567-16-2;

Firategrast, MS, Alpha4beta1 integrin

PHASE 2 GSK

Mitsubishi Tanabe Pharma INNOVATOR

Tanabe Seiyaku Co

Glaxo Group Limited, Mitsubishi Tanabe Pharma Corporation

SB 683699, SB-683699, UNII-OJY3SK9H5F
Firategrast; UNII-OJY3SK9H5F; SB-683699; Firategrast (USAN); 402567-16-2; SB683699; T-0047  
Molecular Formula: C27H27F2NO6
Molecular Weight: 499.503186 g/mol
SYSTEMATIC NAME:
1,1′-Biphenyl)-4-propanoic acid, alpha-((2,6-difluorobenzoyl)amino)-4′-(ethoxymethyl)-2′,6′-dimethoxy-, (alphaS)-
N-(2,6-Difluorobenzoyl)-4-[4-(ethoxymethyl)-2,6-dimethoxyphenyl]-L-phenylalanine
N- (2 , 6-Difluorobenzoyl) -4- (2 , 6-dimethoxy-4- ethoxymethylphenyl) -L-phenylalanine .
2S)-2-((2,6-Difluorobenzoyl)amino)-3-(4′-(ethoxymethyl)-2′,6′-dimethoxybiphenyl-4- yl)propanoic acid
(2S)-2-{[(2,6- difluorophenyl)carbonyl]amino}-3-[4′-[(ethyloxy)methyl]-2′,6′-bis(methyloxy)-4- biphenylyl]propanoic acid
(2S)-2-[[2,6-bis(fluoranyl)phenyl]carbonylamino]-3-[4-[4-(ethoxymethyl)-2,6-dimethoxy-phenyl]phenyl]propanoic acid

Pharmacological half-life is 2.5 – 4.5 hours, compared to 11 days for natalizumab, a drug in the same class

Orally bioavailable small molecule α4-integrin antagonist
see

http://www.msdiscovery.org/node/1377#node-biblio-1338

http://multiple-sclerosis-research.blogspot.com/2012/01/research-oral-tysabri-analogue.html

SB683699 is an alpha4 integrin antagonist that had been studied in phase II trials at GlaxoSmithKline under a license from Mitsubishi Tanabe Pharma for the oral treatment of multiple sclerosis (MS) in Europe. GlaxoSmithKline and Tanabe Seiyaku (now Mitsubishi Tanabe Pharma) had been studying the drug candidate for the treatment of asthma, rheumatoid arthritis (RA) and Crohn’s disease

MECHANISMS/EFFECTS

HUMAN:

Similar mechanism of action to natalizumab (α4-integrin blocker), but its faster elimination could improve safety profile

 Firategrast
Firategrast
SYNTHESIS
………………….
PATENT

Scheme 1

Figure imgf000010_0001

Scheme 2

Figure imgf000012_0001

In a further aspect the present invention provides for a process for the preparation of compound of formula (II) which comprises coupling the compound of formula (V)

Figure imgf000012_0002

Suitable coupling conditions for the compound of formula (V) and the compound of formula (VI) include those shown in Scheme 2. In a further aspect of the invention there is provided the compound of formula (V):

Figure imgf000013_0001

1H NMR characterisation data for the compound of formula (V) were generated on an isolated and purified batch. 1H-NMR spectra were recorded on a Bruker Avance 400 at 400MHz, using TMS as an internal reference.1H NMR (400 MHz, DMSO-D6) δ ppm 1.17 (t, J=7.09 Hz, 3 H) 2.96 (dd, J=13.82, 9.90 Hz, 1 H) 3.1 1 (dd, J=13.82, 5.26 Hz, 1 H) 4.12 (q, J=7.09 Hz, 2 H) 4.63 (ddd, J=9.78, 7.82, 5.38 Hz, 1 H) 7.15 (t, J=7.95 Hz, 2 H) 7.25 (d, J=8.31 Hz, 2 H) 7.47 – 7.55 (m, 3 H) 9.23 (d, J=7.83 Hz, 1 H).

The present invention provides a process for the preparation of the compound of formula

Figure imgf000003_0001

which process comprises the steps: a) hydrolysis of an ester of formula (I la):

Figure imgf000004_0001

Recrvstallisation of (2S)-2-{r(2,6-difluorophenyl)carbonyllamino)-3-r4′-r(ethyloxy)methyll- 2′,6′-bis(methyloxy)-4-biphenylyllpropanoic acid

(2S)-2-{[(2,6-difluorophenyl)carbonyl]amino}-3-[4′-[(ethyloxy)methyl]-2′,6′-bis(methyloxy)- 4-biphenylyl]propanoic acid (9.38Kg) was charged into a clean reactor, followed by ethyl acetate (46.9L). The solution was heated to 50°C and filtered into the pre-warmed (35°C) crystallizing vessel. A line-wash with ethyl acetate (9.4L) was carried out. The combined ethyl acetate solutions were heated to 50°C, stirred to ensure complete dissolution. Filtered heptane (9.4L) was added maintaining the temperature at 50°C then the solution cooled to 30°C and seeded with (2S)-2-{[(2,6-difluorophenyl)carbonyl]amino}-3-[4 – [(ethyloxy)methyl]-2′,6′-bis(methyloxy)-4-biphenylyl]propanoic acid (47g) slurried in 1 :9 ethyl acetate:heptane (0.47L). The slurry was aged for 2 hours at 30°C. Filtered heptane (75L) was added over 3 hours. The slurry was then cooled to 0°C over 1 hour. The mixture was aged at 0°C for 1 hour then the solid was filtered off, washed with isopropyl ether (29.6L and dried under vacuum at 50±3°C to give the product (8.55Kg, 91 %). Characterised by having an infrared absorption spectrum with significant absorption bands at about 754, 768, 800, 820, 849, 866, 1006, 1 100, 1 122, 1 157, 1 188, 1225, 1242, 1268, 1292, 1317, 1352, 1417, 1466, 1530, 1580, 1624, 1650, 1662, 171 1 , 1728, 2938, 3302cm

…………………………………..
PATENT

Example 10: N- (2 , 6-Difluorobenzoyl) -4- (2 , 6-dimethoxy-4- ethoxymethylphenyl) -L-phenylalanine ethyl ester.

(1) The product obtained in Example l-(4) (2.1 g) was acylated with 2 , 6-difluorobenzoyl chloride in a similar manner as described in Example 1 -(5) to give N- (2, 6-difluorobenzoyl) – 4- (2 , 6-dimethoxy-4-hydroxymethylphenyl) -L-phenylalanine ethyl ester (2.75 g) . mp . 70-72 °C; IR (Nujol) 3400, 3263, 1735, 1654, 1624 cm“1; MS (APCI) m/z 500 (M+H) . (2) To a solution of the product obtained above (1.72 g) in DMSO (20 ml) were added Et3N (4.8 ml) and S03«pyridine (5.6 g) successively at room temperature. The whole mixture was stirred at room temperature for 25 minutes. The reaction mixture was poured into ice-water, and then the mixture was extracted with EtOAc. The organic layer was sequentially washed with 5% aqueous HCl, H20 and brine, dried (Na2S04) and then evaporated. The residue was purified by column chromatography (silica gel; eluent: n-hexane/EtOAc 5:1 to 1:1) to yield N-(2,6- difluorobenzoyl) -4- (2 , 6-dimethoxy-4-formylphenyl) -L- phenylalanine ethyl ester (1.54 g) . mp. 114-116°C; IR (Nujol)

3332, 1735, 1695, 1657, 1644, 1623 cm“1; MS (APCI) m/z 498 (M+H) .

(3) The product obtained above (716 mg) was converted into the title compound (428 mg) in a similar manner as described in Example 1- (7) . mp . 87-89°C; IR (Neat+CHC13) 3300, 1739, 1668 cm 1; MS (APCI) m/z 528 (M+H) .

Example 11: N- (2 , 6-Difluorobenzoyl) -4- (2 , 6-dimethoxy-4- ethoxymethylphenyl ) -L-phenylalanine methyl ester.

(1) The product obtained in Example 2- (4) (1.00 g) was acylated with 2 , 6-difluorobenzoyl chloride to give N-(2,6- difluorobenzoyl) -4- (2 , 6-dimethoxy-4-hydroxymethylphenyl) -L- phenylalanine methyl ester (873 mg) in a similar manner as described in Example l-(5). IR (Nujol) 3257, 1743, 1655, 1624 cm 1; MS (APCI +Q1MS) m/z 503 (M+NH4) , 486 (M+H) . (2) The product obtained above (860 mg) was converted into the title compound (220 mg) in a similar manner as described in Example 2- (6) and (7).

Example 12: N- (2 , 6-Difluorobenzoyl) -4- (2 , 6-dimethoxy-4- ethoxymethylphenyl) -L-phenylalanine .

The product obtained in Example 10 (200 mg) was hydrolyzed in a similar manner as described in Example 3 to give the title compound (160 mg) . The product obtained in Example 11 (220 mg) was also hydrolyzed in a similar manner as described in Example 3 to give the title compound (167 mg) . mp. 156-158°C; IR (Nujol) 1735, 1655 cm“1; MS (ESI) m/z 498 (M-H) .

…………………….

PATENT

 https://www.google.com/patents/WO2003072536A1?cl=en

OUT LINE

phenylalanine derivative of the formula (I) :

Figure imgf000003_0001

wherein X1 is a halogen atom, X2 is a halogen atom, Q is a group of the formula -CH2- or -(CH2)2- and Y is a lower alkyl group, or a pharmaceutically acceptable salt thereof, which has excellent inhibitory activity against α4 integrin-mediated cell adhesion.

Thus, the present invention relates to a process for preparing a compound of the formula (I) :

Figure imgf000004_0001

wherein the symbols are the same as defined above, or a pharmaceutically acceptable salt thereof, comprising : (1) coupling a compound of the formula (VI) :

Figure imgf000004_0002

wherein Z is a leaving group, R1NH is a protected amino group and C02R is a protected carboxyl group with a compound of the formula (V) :

Figure imgf000004_0003

wherein the symbols are the same as defined above, removing the protecting group from the protected amino group, and if necessary, converting the resulting compound into a salt, to yield a compound of the formula (IV) :

Figure imgf000005_0001

wherein the symbols are the same as defined above, or a salt thereof,

(2) condensing the compound (IV) or a salt thereof with a compound of the formula (III) :

Figure imgf000005_0002

wherein the symbols are the same as defined above, a salt or a reactive derivative thereof to yield a compound of the formula (II) :

Figure imgf000005_0003

Ethyl (ocS) – – [ [ (1, 1-dimethylethoxy) carbonyl] amino] -4- hydroxybenzene propionate and ethyl (otS) -α- [ [ (1, 1- dimethylethoxy) carbonyl] amino] -4-

(trifluoromethanesulfonyloxy) benzene propionate are described in J. Med. Chem. , 33: 1620 (1990) and JP-A-7- 157472, respectively. 4-Bromo-3, 5-dimethoxybenzyl alcohol is described in, for example, J. Med. Chem. , 20: 299 (1977), and can also be prepared according to the following process.

Figure imgf000019_0001

Firstly, 4-bromo-3, 5-dihydroxybenzoic acid is methylated to give methyl 4-bromo-3, 5-dimethoxybenzoate, which is then reduced to yield 4-bromo-3, 5-dimethoxy benzyl alcohol. The methylation can be carried out by reacting with dimethyl sulfate in the presence of a base in a suitable solvent (e.g., ethyl acetate). The reduction can be carried out by reacting with an reducing agent (e.g., lithium alminium hydride, sodium borohydride and calcium borohydride) in a suitable solvent (e.g., tetrahydrofuran) .

EXAMPLES

The following Examples are provided to further illustrate the process of preparation according to the present invention. In the following examples, some compounds may be referred to by different compound name depending on the nomenclature, as illustrated below.

Ethyl (αS) -α-amino-4′ -ethoxymethyl-2′ , 6′ – dimethoxy (1, 1′ -biphenyl) -4-propionate

Another name: ethyl (2S) -2-amino-3- [4- (4-ethoxymethyl- 2, 6-dimethoxyphenyl) phenyl]propanoate

Ethyl (αS) – [ [1, 1-dimethylethoxy] carbonyl] amino] -4′ – ethoxymethyl-2′ , 6′ -dimethoxy (1,1′ -biphenyl) -4-propionate

Another name 1: ethyl (2S) -2- [ (t-butoxycarbonyl) – amino] -3- [4- (4-ethoxymethyl-2, 6-dimethoxyphenyl) – phenyl]propanoate

Another name 2: Ethyl N- (t-butoxycarbonyl) -4- (4- ethoxymethyl-2, 6-dimethoxyphenyl) -L-phenylalanine

Ethyl (αS) – – [ (2, 6-difluorobenzoyl) amino] -4′ – ethoxymethyl-2′ , 6′ -dimethoxy (1, 1′ -biphenyl) -4-propionate Another name 1: Ethyl (2S) -2- [ (2, 6- difluorobenzoyl) amino] -3- [4- (4-ethoxymethyl-2, 6- di ethoxyphenyl) phenyl] propanoate

Another name 2: Ethyl N- [2 , 6-difluorobenzoyl) -4- (4- ethoxymethyl-2, 6-dimethoxyphenyl) -L-phenylalanine

(ocS) – – [ (2, 6-Difluorobenzoyl) amino] -4′ -ethoxymethyl- 2′ , 6′ -dimethox (1,1′ -biphenyl) -4-propionic acid

Another name 1: (2S) -2- [ (2, 6-difluorobenzoyl) amino] -3- [4- (4-ethoxymethyl-2, 6-dimethoxyphenyl) phenyl]propanoic acid

Another name 2: N- [ 2 , 6-difluorobenzoyl) -4- (4- ethoxymethyl-2, 6-dimethoxyphenyl) -L-phenylalanine

EXAMPLE 1 (1) Under nitrogen atmosphere, pyridine (130.3 g) and trifluoromethanesulfonic anhydride (170.4 g) were added dropwise to a solution of ethyl (αS) -α- [ [ (1, 1- dimethylethoxy) carbonyl] amino] -4-hydroxybenzenepropionate

(170.0 g) in dichloromethane (1.7 L) at 10 ° C or below. After stirring for 1 hour at the same temperature, water

(850 ml) was added dropwise to the mixture and the mixture was stirred for 2 hours at the same temperature. The organic layer was washed with 10 % aqueous citric acid solution and aqueous saturated sodium hydrogen carbonate solution, and dried over magnesium sulfate. The solvent was removed in vacuo to yield ethyl (αS) -α- [ [ (1, 1- dimethylethoxy) carbonyl] amino] -4-

(trifluoromethanesulfonyloxy)benzenepropionate (242.5 g) as oil . MS (m/z) : 441 (M+) (2) Under nitrogen atmosphere, to a mixture of ethyl (αS)- – [ [ (1, 1-dimethylethoxy) carbonyl] amino] -4-

(trifluoromethanesulfonyloxy) benzenepropionate (66.2g), 4- ethoxymethyl-2, 6-dimethoxyphenylboric acid (54.0 g) , triphenylphosphine (9.83 g) and N-methylpyrrolidone (330 ml) were added palladium acetate (1.68 g) and diisopropylamine (24.9 g ), and the mixture was heated at 90 °C. After stirring for 1 hour at the same temperature, the mixture was cooled and toluene and water were added. The organic layers were washed with 10% aqueous citric acid solution and saturated aqueous NaCl solution and dried over magnesium sulfate. The solvent was removed in vacuo to yield ethyl (αS) -α- [[ (1, 1-dimethylethoxy) carbonyl] amino] – 4′ -ethoxymethyl-2′ , 6′ -dimethox (1,1′ -biphenyl) -4-propionate (90.1 g) as oil.

The product was dissolved in ethanol (330 ml) , and after addition of p-toluenesulfonic acid monohydrate (28.5 g) , the mixture was stirred for 2 hours at 75 °C. After cooling to room temperature, the mixture was filtrated over charcoal and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate with heating. After cooling, the crystalline precipitates were collected by filtration and dried to yield ethyl (αS)-α- amino-4′ -ethoxymethyl-2′ , 6′ -dimethoxy (1, 1′ -biphenyl) -4- propionate p-toluenesulfonate (63.4 g) .

MS (m/z) : 387 (M+-p-toluenesulfonic acid), M.p. 127-129°C

(3) To a mixture of ethyl (αS) -α-amino-4′ -ethoxymethyl- 2′ , 6′ -dimethox (1, 1′ -biphenyl) -4-propionate p- toluenesulfonate (29.0 g) , sodium hydrogen carbonate (15. 2 g) , water (290 ml) and ethyl acetate (290 ml) was added dropwise 2, 6-difluorobenzoyl chloride (9. 6 g) at 15 °C or below and the mixture was stirred for 30 minutes at the same temperature. The ethyl acetate layer was washed with saturated aqueous NaCl solution and dried over magnesium sulfate. The solvent was removed in vacuo. The residue was recrystallized from isopropanol-water to yield ethyl (αS) -oi- [ (2, 6-difluorobenzoyl) amino] -4′ -ethoxymethyl-2′ , 6′ – dimethox (1, 1′ -biphenyl) -4-propionate (26.4 g) . MS (m/z) : 527 (M+) , M.p. 87-89°C (4) To a solution of sodium hydroxide (2.9 g) in water- tetrahydrofuran (317 ml-159 ml) was added ethyl (oιS)-α- [ (2, 6-difluorobenzoyl) amino] -4′ -ethoxymethyl-2′ , 6′ – dimethoxy (1, 1′ -biphenyl) -4-propionate (31.7 g) at 15°C and the mixture was stirred for 4 hours at the same temperature. After neutralizing with IN HC1, the organic solvent was removed in vacuo. The aqueous layer was cooled, the crystalline precipitates were collected by filtration and recrystallized from ethanol-water to yield (αS) -a- [ (2, 6- difluorobenzoyl) amino] -4′ -ethoxymethyl-2′ , 6′ – dimethoxy (1, 1′ -biphenyl) -4-propionic acid (28.8 g) . MS (m/z): 499 (M+) , M.p. 154-155°C

EXAMPLE 2 (1) Under nitrogen atmosphere, a mixture of ethyl (oιS)-o:- [[ (1, 1-dimethylethoxy) carbonyl] amino] -4-bromobenzene propanoate (11.17 g) , 4-ethoxymethyl-2, 6- dimethoxyphenylboronic acid (10.80 g ), palladium acetate (0.34 g), triphenylphosphine (1.57 g) , anhydrous potassium carbonate (12.44 g) , iV-methylpyrrolidone (56 ml) and water (11 ml) was stirred for 50 minutes at 80 °C. After completion of the reaction, the mixture was cooled to room temperature and extracted with ethyl acetate and water. The organic layer was washed with 10% aqueous citric acid solution and saturated aqueous NaCl solution, dried over magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure to yield ethyl (αS)-α- [ [ (1, 1-dimethylethoxy) carbonyl] amino] -4′ -ethoxymethyl- 2′ , 6′ -dimethox (1, 1′ -biphenyl) -4-propionate (20.4 g) as oil. The product was dissolved in ethanol (100 ml) , and after addition of p-toluenesulfonic acid monohydrate (5.7 g) , the mixture was stirred for 1.5 hours at 75 °C. After cooling, the mixture was filtrated over charcoal and the filtrate was concentrated under reduced pressure. The residue was suspended in toluene with heating. After cooling, the crystalline precipitates were collected by filtration and dried to yield ethyl (αS) – -amino-4′ – ethoxymethyl-2′ , 6′ -dimethoxy (1,1′ -biphenyl) -4-propionate p- toluenesulfonate (13.80 g) . (2) The compound obtained in the above step (1) was treated in the same manner as described in Example 1 (2) to (4) to yield (αS) -a- [ [2 , 6-difluorobenzoyl) amino] -4′ – ethoxymethyl-2′ , 6′ -dimethoxy (1, 1′ -biphenyl) -4-propionic acid. The physicochemical data were the same as that obtained in Example 1.

EXAMPLE 3

To a solution of ethyl (αS) -α- [ (2, 6- difluorobenzoyl) amino] -4′ -ethoxymethyl-2′ , 6′ – dimethox (1, 1′ -biphenyl) -4-propionate (500 g ) in water (12.6 ml) and dioxane (50 ml) was added hydrochloric acid (12.4 g) and the mixture was stirred for 60 hours at 60 “C. The organic solvent was removed in vacuo and the aqueous layer was cooled. The crystalline precipitates were collected by filtration and recrystallized from ethanol- water to yield (αS) – – [ (2, 6-difluorobenzoyl) amino] -4′ – ethoxymethyl-2′ , 6′ -dimethoxy (1,1′ -biphenyl) -4-propionic acid (426 mg) . The physicochemical data were the same as that obtained in Example 1.

REFERENCE EXAMPLE 1

(1) To a mixture of 4-bromo-3, 5-dimethoxybenzylalcohol (44.5 g) , triethylammonium benzyl chloride (2.05 g) and 20% aqueous sodium hydroxide solution (288 g) was added diethyl sulfate (41.7 g) under ice-cooling, and the mixture was stirred overnight at 25-30 °C. After stirring for 1 hour at 70 °C, the mixture was cooled and extracted with toluene. The toluene layer was washed with water and saturated aqueous NaCl solution and dried over magnesium sulfate. The solvent was removed in vacuo to yield 4-bromo-3, 5- dimethoxybenzyl ethyl ether (49.5 g) as colorless oil. MS (m/z): 276 (M++2) , 274 (M+)

(2) Under nitrogen atmosphere, to a solution of 4-bromo- 3, 5-dimethoxybenzyl ethyl ether (440.0 g) in tetrahydrofuran (4.0 L) was added dropwise n-butyl lithium (1.6 M n-hexane solution, 1.1 L) at -60°C. After stirring for 15 minutes at the same temperature, trimethyl borate (249.3 g) was added. The temperature of the mixture was gradually elevated, followed by stirring for 1 hour under ice-cooling. To the mixture was added dropwise 10% aqueous sulfuric acid solution (835 g ) . The mixture was extracted with ethyl acetate and the organic layer was washed with water and saturated aqueous NaCl solution. After drying over magnesium sulfate, the solvent was removed in vacuo. The residue was dissolved in isopropyl ether with heating and cooled. The crystalline precipitates were collected by filtration and dried to yield 4-ethyoxymethyl-2, 6- dimetoxyphenylboronic acid (312.9 g) . M.p. 59-61°C

REFERENCE EXAMPLE 2

(1) To a suspension of 4-bromo-3, 5-dihydroxybenzoic acid (95.0 kg) in ethyl acetate (950 L) were added anhydrous potassium carbonate (270.8 kg) and dimethyl sulfate (174.7 kg) . The mixture was heated at 50-80 ‘C for about 4 hours and partitioned by adding water. The organic layer was washed with water and saturated aqueous NaCl solution and concentrated under reduced pressure. The residue was suspended into methanol, stirred under heating and cooled. The crystalline precipitates were collected by filtration and dried to yield methyl 4-bromo-3, 5-dimethoxybenzoate (98.8 kg) as pale yellow crystals. MS (m/z): 277 (M++2) , 275 (M+) , M.p. 120-122°C

(2) To a solution of calcium chloride (46.5 kg) in ethanol (336 L) were added tetrahydrofuran (672 L) and methyl 4- bromo-3, 5-dimethoxybenzoate (96.0 kg) to obtain a suspension. To the suspension was added sodium borohydride

(31.7 kg) by portions at room temperature, and the mixture was stirred for about 9 hours at temperature of room temperature to 45 °C. The reaction mixture was added dropwise to aqueous HC1 solution and stirred for about 16 hours at room temperature. Organic solvent was removed in vacuo, and water (1440 L) was added to the residue and stirred for 1 hour at 50 °C. After cooling, the crystalline precipitates were collected by filtration and dried to yield 4-bromo-3, 5-dimethoxybenzyl alcohol (83.3 kg) as colorless crystals. MS (m/z): 249 (M++2), 247 (M+) , M.p. 100-102°C.

INDUSTRIAL APPLICABILITY The process for preparation of the present invention makes it possible to afford a compound of the formula (I) or a pharmaceutically acceptable salt thereof with high- purity, in a high yield and inexpensively, and, therefore, the process of the present invention is industrially very useful.

References

GlaxoSmithKline website
US8822527 16 Out 2012 2 Set 2014 Biotheryx, Inc. Substituted biaryl alkyl amides
WO2002018320A2 27 Ago 2001 7 Mar 2002 Tanabe Seiyaku Co INHIBITORS OF α4 MEDIATED CELL ADHESION
WO2003072536A1 27 Fev 2003 4 Set 2003 Tanabe Seiyaku Co A process for preparing a phenylalanine derivative and intermediates thereof
WO2003072537A2 6 Fev 2003 4 Set 2003 Abbott Lab Selective protein tyrosine phosphatatase inhibitors

Mitsubishi Tanabe Pharma Corporation

Mitsubishi Tanabe Pharma Corporation
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Mitsubishi Tanabe Pharma Corporation
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Pharmacological research building

 

 

 

 

 

 

 

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

 

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.


Filed under: Japan marketing, Japan pipeline, Phase2 drugs Tagged: APCI, Firategrast, GlaxoSmithKline, gsk, JAPAN, Mitsubishi Tanabe Pharma, MULTIPLE SCLEROSIS, phase 2, SB 683699, T 0047, Tanabe Seiyaku Co Glaxo Group Limited

Simple and effective method for two-step synthesis of 2-(1,3-dithian-2-ylidene)-acetonitrile

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Simple and effective method for two-step synthesis of 2-(1,3-dithian-2-ylidene)-acetonitrile (75% overall yield) and molecular modeling calculation of the mechanism by B3LYP and the 6-311++G(2df,2p) basis set.

http://dx.doi.org/10.5935/0100-4042.20140308

Publicado online: dezembro 12, 2014

Método alternativo para a síntese e mecanismo de 2-(1,3-ditiano-2-ilideno)-acetonitrila

Marcelle S. Ferreira; José D. Figueroa-Villar*

Quim. Nova, Vol. 38, No. 2, 233-236, 2015

Artigo http://dx.doi.org/10.5935/0100-4042.20140308

*e-mail: jdfv2009@gmail.com

MÉTODO ALTERNATIVO PARA A SÍNTESE E MECANISMO DE 2-(1,3-DITIANO-2-ILIDENO)-ACETONITRILA

Marcelle S. Ferreira e José D. Figueroa-Villar* Departamento de Química, Instituto Militar de Engenharia, Praça General Tiburcio 80, 22290-270

Rio de Janeiro – RJ, Brasil

Recebido em 18/08/2014; aceito em 15/10/2014; publicado na web em 12/12/2014

ALTERNATIVE METHOD FOR SYNTHESIS AND MECHANISM OF 2-(1,3-DITHIAN-2-YLIDENE)-ACETONITRILE. We report an alternative method for the synthesis of 2-(1,3-dithian-2-ylidene)-acetonitrile using 3-(4-chlorophenyl)-3-oxopropanenitrile and carbon disulfide as starting materials. The methanolysis of the intermediate 3-(4-chlorophenyl)-2-(1,3-dithian-2-ylidene)-3- oxopropanenitrile occurs via three possible intermediates, leading to the formation of the product at a 75% overall yield. Molecular modeling simulation of the reaction pathway using B3LYP 6-311G++(2df,2p) justified the proposed reaction mechanism. Keywords: 2-(1,3-dithian-2-ylidene)-acetonitrile; reaction mechanism; methanolysis; molecular modeling.

3-(4-clorofenil)-2-(1,3-ditiano-2-ilideno)-3-oxopropanonitrila (3): Cristal amarelo. Rendimento: 95%, 2,80 g, pf 158-160 °C, lit.21 159-160 °C;

IV (KBr, cm-1): 2198 (CN), 1612 (C=O), 1585, 1560 (aromático), 678 cm -1 (C-S);

1H RMN (300 MHz, CDCl3) δ 2,38 (m, J 6,9, 2H, CH2); 3,01 (t, J 6,6, 2H, SCH2); 3,17 (t, J 7,2 , 2H, SCH2); 7,43 (d, J 8,5, 2H); 7,83 (d, J 8,5, 2H);

13C RMN (75 MHz, CDCl3) δ 23,9 (CH2), 30,4 (SCH2), 104,2 (CCO), 117,5 (CN), 128,9, 130,5, 135,6, 139,2 (aromático), 185,2 (C=CS), 185,4 (CO).

21…….Rudorf, W. D.; Augustin, M.; Phosphorus Sulfur Relat. Elem. 1981, 9, 329.

…………………………………….

Síntese da 2-(1,3-ditiano-2-ilideno)-acetonitrila (1) Em um balão de fundo redondo de 100 mL foram adicionados 0,400 g (1,4 mmol) de 3-(4-clorofenil)-2-(1,3-ditiano-2-ilideno)-3- -oxopropanonitrila (2) dissolvidos em 15 mL de THF seco, 0,140 g (20 mmol) de sódio e 15 mL de metanol seco sob atmosfera de nitrogênio. A mistura reacional foi mantida sob agitação à 25 °C por 48 h. Em seguida, a mistura reacional foi dissolvida em 30 mL de água destilada e extraída com acetato de etila (3 x 20 mL). A fase orgânica foi seca em sulfato de sódio anidro, filtrada e concentrada a vácuo para se obter o produto bruto, que foi purificado por cromatografia em coluna (silica gel e hexano:acetato de etila 7:3).

2-(1,3-ditiano-2-ilideno)-acetonitrila (1): Cristal branco. Rendimento: 75%, 165 mg, pf. 60-63 °C, lit1 60-62 °C;

1 H RMN (300 MHz, CDCl3) δ 2,23 (m, J 6,8, 2H, CH2); 3,01 (t, J 7,5, 2H, SCH2); 3,06 (t, J 6,9, 2H, SCH2), 5,39 (s, 1H, CH);

13C RMN (75 MHz, CDCl3) δ 22,9 (CH2), 28,7 (SCH2), 28,8 (SCH2), 90,4 (CHCN), 116,3 (CN), 163,8 (C=CS).

1………Yin, Y.; Zangh, Q.; Liu, Q.; Liu, Y.; Sun, S.; Synth. Commun. 2007, 37, 703.

 Acetonitrile, 1,3-dithian-2-ylidene-

CAS 113998-04-2

  • C6 H7 N S2
  • Acetonitrile, 2-​(1,​3-​dithian-​2-​ylidene)​-
  • 157.26
Melting Point 60-62 °C

1H  NMR  predict

2-(1,3-dithian-2-ylidene)-acetonitrile

BR 1H

BR 1H 1

ACTUAL 1H NMR VALUES

1 H RMN (300 MHz, CDCl3)

δ 2,23 (m, J 6,8, 2H, CH2);

3,01 (t, J 7,5, 2H, SCH2);

3,06 (t, J 6,9, 2H, SCH2),

5,39 (s, 1H, CH);

……………………..

13C NMR PREDICT

BR 13C

BR 13C 1

ACTUAL 13C NMR VALUE

13C RMN (75 MHz, CDCl3)

δ 22,9 (CH2),

28,7 (SCH2),

28,8 (SCH2),

90,4 (CHCN),

116,3 (CN),

163,8 (C=CS)

COSY NMR PREDICT

COSY NMR prediction (6)

SYNTHESIS

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WILL BE UPDATED WATCH OUT…………………

Departamento de Química, Instituto Militar de Engenharia, Praça General Tiburcio

Instituto Militar de Engenharia, Rio de Janeiro. BELOW

Entrada do antigo Instituto de Química da UFRGS, um prédio histórico

Equipe – Os módulos foram fabricados na Unisanta sob a supervisão do professor Luiz Renato Lia, coordenador do Curso de Engenharia Química, …

Instituto de Florestas da Universidade Federal Rural do Rio de Janeiro

Praça General Tibúrcio

Praça General Tibúrcio com o Morro da Urca ao fundo

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.


Filed under: spectroscopy, SPOTLIGHT Tagged: 2-(1, 3-dithian-2-ylidene)-acetonitrile, José D. Figueroa-Villar, Marcelle S. Ferreira, molecular modeling, organic synthesis, Rio de Janeiro

Rosa canina for osteoarthritis

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Rosiflex contains a unique natural supplement that is good for joint health. If you are looking forward to a natural way to minimize your joint pain and stiffness, then Rosiflex is the ideal choice for you. Rosiflex is for anyone who wants healthy, flexible and mobile joints for a better quality of life. The unique natural ingredient in Rosiflex has been clinically proven to soothe the inflamed joints and improve joint comfort and flexibility.
What is Rosiflex?
Rosiflex is a Unique Dietary Supplement containing 100% Rosehip powder, made from a species of wild rose, Rosa canina. Rosiflex is available in capsule form with each capsule containing 750 mg (of imported) rosehip powder. Rosehip powder has been shown to decrease joint pain, improve joint health and increase mobility and flexibility in arthritic patients, particularly osteoarthritic patients.

The speciality of Rosiflex is as given below:
  • European supplement now brought to Indian arthritic patients
  • Huge success internationally
  • Effective within 3 weeks
  • Good pain relief
  • Reduces the need for regular pain killers
  • Very Safe, being a herbal supplement
  • Dosage: 2 capsules thrice daily for the initial 3 weeks followed by maintenance dose of 2 capsules twice daily
  • Rosa canina
    Divlja ruza cvijet 270508.jpg
    Photograph showing Rosa canina flowers.
    Scientific classification
    Kingdom: Plantae
    (unranked): Angiosperms
    (unranked): Eudicots
    (unranked): Rosids
    Order: Rosales
    Family: Rosaceae
    Genus: Rosa
    Species: R. canina
    Binomial name
    Rosa canina
    L.
    Synonyms
    See text

 

History:

Click here for a larger image. ROSE HIPS
Rose Hips (also called rose haws) are the pomaceous fruit of the rose plant.  Roses are a group of herbaceous shrubs found in temperate regions throughout both hemispheres and grown in sunny areas or light shade and thrive in well-drained, slightly acid soil.  Probably cultivated first in ancient Persia and carried to Greece and Rome, there are now hundreds of species of this beautiful flower cultivated throughout the world that occupy a vital place in medicine, as well as cosmetics, perfumes, soaps and foods.  The leaves of Rosa canina were once even used as a substitute for tea.  The botanical genus, Rosa, is derived from the Greek, roden, meaning “red” and the Latin, ruber, also meaning “ruby” or “red,” as apparently, the Roses of the ancient Mediterranean region were deep crimson, giving birth to the legend that the flowers sprang from the blood of Adonis.

Roses have a long tradition of medicinal use.  The ancient Romans used Rosa canina (or Dog Rose) for the bites of rabid dogs, and in the first century A.D., the Roman, Pliny, recorded thirty-two different disorders that responded well to Rose preparations.  An oriental species (Rosa laevigata) was mentioned in Chinese medical literature about A.D. 470, and in China, Rose Hips are still used for chronic diarrhea with stomach weakness.

It is typically red to orange but may be dark purple to black in some species.  In Ayurvedic medicine, Roses have long been considered “cooling” to the body and a tonic for the mind, and Native Americans used Rose Hips to treat muscle cramps.  In 1652, the esteemed British herbalist, Nicholas Culpeper, prescribed them for “consumptive persons,” for “tickling rheums,” to “break the stone” (kidneys) and to help digestion.

Long used for medicinal purposes in Great Britain, Rose Hips remained listed in the official British Pharmacopœia well into the 1930s, and were considered an overall cooling tonic, an astringent, a great help for sore throats and a source of the essential vitamin C.  During World War II, there was a shortage of citrus fruit in England, and the British government organized the harvesting of all the Rose Hips in England as a substitute for vitamin C.  This illuminated the importance of Rose Hips as a superior source of the vitamin and began its worldwide popularity.  Rose Hips have a reported sixty times the amount of vitamin C than citrus fruit, and we now know how absolutely essential vitamin C is to the maintenance of good health and the prevention of many diseases.

Rose Hips contain one of the highest measures of vitamin C (about 1700-2000 mgs. per 100 g. in the dried product) than is known in other herbs.  Rose Hips are the fruits of the Rose, the ripe seed receptacles that remain after the petals are removed, and they contain many vitamins and other beneficial supplements, including lycopene, essential fatty acids, beta-carotene, bioflavonoids, pectin, sugar, resin, wax, malates, citrates and other salts, tannin, malic and citrus acids, magnesium, calcium, iron, manganese, sulfur, phosphorus, potassium, selenium, zinc and vitamins A, B-1, B-2, B-3, B-5, C, D, E and K.

Beneficial Uses:
Probably the greatest known use of Rose Hips is as an extraordinary and powerful source of vitamin C, which is most beneficial for the prevention and treatment of infection and a great many common diseases, including the common cold, flu and pneumonia.  It is said to prevent ailments before they happen by using a prophylactic dosage on a daily basis.  Vitamin C is necessary for every cell in our bodies and without it, we would not be able to sustain life.

Natural vitamin C and bioflavonoids are combined in nature, and for efficacy, it is vital that they be used together. Rose Hips are rich in both, and together they help to strengthen body tissues and build and maintain a healthy vascular system and are said to heal and prevent damage to fragile capillaries.  The combination is also thought to enhance the body’s ability to absorb vitamin C in those who have difficulty absorbing it.

Rose Hips, with its abundance of vitamin C, are useful in treating infections of all kinds and have been used for centuries for the relief of diarrhea and dysentery.  It is considered to be a cleansing agent and may be helpful for temporary bladder problems, gallbladder dysfunction, kidney health, general debility and exhaustion.

Current research indicates that large doses of vitamin C in Rose Hips could be helpful in enhancing our immune systems, which may be valuable in warding off infectious invaders and serious malignant disease.

Rose Hips are said to have mild laxative and diuretic properties.

Rosa canina, commonly known as the dog-rose,[1] is a variable climbing wild rose species native to Europe, northwest Africa and western Asia.

It is a deciduous shrub normally ranging in height from 1–5 m, though sometimes it can scramble higher into the crowns of taller trees. Its stems are covered with small, sharp, hooked prickles, which aid it in climbing. The leaves are pinnate, with 5-7 leaflets. The flowers are usually pale pink, but can vary between a deep pink and white. They are 4–6 cm diameter with five petals, and mature into an oval 1.5–2 cm red-orange fruit, or hip.

dried-rose-hipsIt’s that time of year again and the hedgerows are heaving with fruit. But with most people intent on collecting juicy blackberries, the vibrantly coloured and perhaps mystifying rose-hip is often overlooked. Maybe it’s because they are a suspicious red colour or maybe it’s because they’re a fruit that’s never seen in supermarkets. Whatever the reason, the conclusion is the same: there’s more to collect for yourself!

Rose-hips are the fruit of the rose bush and in the summer are found as a swollen green part of the stem just underneath the flower. Every rose left uncut will eventually produce a hip but some will appear in the summer and others later in the autumn depending on species. To my knowledge all rose hips are edible, though some varieties have better flavour than others.

Blessed with a delicate fruity taste and rich in vitamins A, B and C, Rose-hips can be used to make an assortment of products including jellies, syrups, teas, wine and even cosmetics. Both the fruit and the seeds are edible but you should not eat rose-hips whole due to irritating hairs which are found inside the berries. These hairs must be removed either by filtering during the cooking process.

The best variety for making edible products is the hip of the common wild rose, also known as the Dog Rose, Latin name Rosa Canina. It produces small, firm, deep-red hips that are rich in flavour and easy to find and harvest. They are available in the autumn but it’s said the best time to harvest them is directly after a frost. Being that birds favour other foods over these hard seed-laden hips, you can often find them hanging onto bare branches in the darkest days of winter. If you choose to use them to make edible products please know that it’s not necessary to separate the seeds from the red fruit as both have their own nutritious values. But of course beware the hairs mentioned previously and make sure they are excluded from your end product.

Dog-Rose-Hips

Synonyms

From DNA analysis using amplified fragment length polymorphisms of wild-rose samples from a transect across Europe (900 samples from section Caninae, and 200 from other sections), it has been suggested that the following named species are best considered as part of a single Rosa canina species complex, and are therefore synonyms of R. canina:[2]

  • R. balsamica Besser
  • R. caesia Sm.
  • R. corymbifera Borkh.
  • R. dumalis Bechst.
  • R. montana Chaix
  • R. stylosa Desv.
  • R. subcanina (Christ) Vuk.
  • R. subcollina (Christ) Vuk.
  • R. × irregularis Déségl. & Guillon

Cultivation and uses

A botanical illustration showing the various stages of growth by Otto Wilhelm Thomé

The plant is high in certain antioxidants. The fruit is noted for its high vitamin C level and is used to make syrup, tea and marmalade. It has been grown or encouraged in the wild for the production of vitamin C, from its fruit (often as rose-hip syrup), especially during conditions of scarcity or during wartime. The species has also been introduced to other temperate latitudes. During World War II in the United States Rosa canina was planted in victory gardens, and can still be found growing throughout the United States, including roadsides, and in wet, sandy areas up and down coastlines. In Bulgaria, where it grows in abundance, the hips are used to make a sweet wine, as well as tea. In the traditional Austrian medicine Rosa canina fruits have been used internally as tea for treatment of viral infections and disorders of the kidneys and urinary tract.[3]

Forms of this plant are sometimes used as stocks for the grafting or budding of cultivated varieties. The wild plant is planted as a nurse or cover crop, or stabilising plant in land reclamation and specialised landscaping schemes.

Numerous cultivars have been named, though few are common in cultivation. The cultivar Rosa canina ‘Assisiensis’ is the only dog rose without prickles. The hips are used as a flavouring in Cockta, a soft drink made in Slovenia.

Canina meiosis

A tall, climbing Rosa canina shrub
Rose hips
Rose bedeguar gall on a dog rose

The dog roses, the Canina section of the genus Rosa (20-30 species and subspecies, which occur mostly in Northern and Central Europe), have an unusual kind of meiosis that is sometimes called permanent odd polyploidy, although it can occur with even polyploidy (e.g. in tetraploids or hexaploids). Regardless of ploidy level, only seven bivalents are formed leaving the other chromosomes as univalents. Univalents are included in egg cells, but not in pollen.[4][5] Similar processes occur in some other organisms.[6] Dogroses are most commonly pentaploid, i.e. five times the base number of seven chromosomes for the genus Rosa, but may be tetraploid or hexaploid as well.

Names and etymology

The botanical name is derived from the common names ‘dog rose’ or similar in several European languages, including classical Latin and ancient (Hellenistic period) Greek.

It is sometimes considered that the word ‘dog’ has a disparaging meaning in this context, indicating ‘worthless’ (by comparison with cultivated garden roses) (Vedel & Lange 1960). However it also known that it was used in the eighteenth and nineteenth centuries to treat the bite of rabid dogs, hence the name “dog rose” may result from this[7] (though it seems just as plausible that the name gave rise to the treatment).

Other old folk names include dogberry and witches’ briar.[citation needed]

Invasive species

Dog rose is an invasive species in the high country of New Zealand. It was recognised as displacing native vegetation as early as 1895[8] although the Department of Conservation does not consider it to be a conservation threat.[9]

Dog rose in culture

The dog rose was the stylized rose of medieval European heraldry, and is still used today.[citation needed] It is also the county flower of Hampshire.[10] Legend states the Thousand-year Rose or Hildesheim Rose, that climbs against a wall of Hildesheim Cathedral dates back to the establishment of the diocese in 815.[11]

 

Rose hip, rose hip and seed and rose hip seed, all were negatively monographed by the German Commission E due to insufficient evidence of effects and effectiveness. Therefore a comprehensive review of the literature was conducted to summarize the pharmacological and clinical effects of Rosa canina L. to reevaluate its usefulness in traditional medicine. For various preparations of rose hip and rose hip and seed, antioxidative and antiinflammatory effects have been demonstrated. Lipophilic constituents are involved in those mechanisms of action. The proprietary rose hip and seed powder Litozin has been employed successfully in a number of exploratory studies in patients suffering from osteoarthritis, rheumatoid arthritis and low back pain. However, the sizes of the clinical effects for the different indications need to be determined to assure clinical significance. There is also a rationale behind the use of Litozin as part of a hypocaloric diet based on the rose hip probiotic, stool regulating and smooth muscle-relaxing actions, as well as the rose hip seed lipid-lowering, antiobese and antiulcerogenic effects. Further research is needed to clarify the importance of the reported promising experimental effects in clinical use and to characterize the optimum rose hip seed oil preparation for topical use in the treatment of skin diseases.

Rosiflex Discovery

Rosiflex Discovery

The Rosiflex™ story began in the early 1990s, when Erik Hansen, a farmer from Langeland, Denmark, discovered, quite by chance that rosehips from the Rosa Canina plant appeared to help soothe his aching joints.

Encouraged by this realisation, he developed the first of his rosehip powders. Made from rosehips grown on his own farm, he sold the powder to friends and neighbours after telling them of his own positive experiences.

The response from these early customers was so positive that Erik, and his son Torbjorn, decided to seek scientific verification of what they had found. They contacted scientists at the local hospital to see if they could find what it was in the rosehip that was producing the positive joint-health benefits being reported.

At first, the scientists were sceptical about the claimed benefits of the rosehip fruit – more commonly associated with teas and marmalades than with potential joint-health benefits. They did however agree to begin some scientific studies.

As the results of the testing began to emerge, the researchers became more and more convinced about the Langeland rosehip powder. Since then, several well designed scientific studies involving a couple of hundred people have been undertaken and published in recognised scientific journals.

 

Anti-inflammatory action of Rose hip

Rose hip is a typical daily food supplement traditionally used for its vitamin C content and other active principles to treat several discomforts: respiratory disorders, infectious diseases, gastrointestinal and urinary system illnesses and prophylaxis of vitamin C deficiencies. Rose hips have been eaten as jam or drunken as fruit tea for centuries. Therefore the separated Rose hip peels have always been regarded as everyday food.

In the last ten years it was scientifically documented, that the daily use of food containing rose hip fruits was positive to treat inflammatory joint diseases, in particular osteoarthritis. Several human studies with rose hip powder showed pain reducing properties and could also reduce symptoms such stiffness or even the need for additional medication.
However, the daily amount of 5 g over a period of 12 weeks showed moderate beneficial effects and low compliance demonstrating what the limits of a treatment with rose hip powder are.

Rose hip fruit skin powder contains remarkable active principles able to inhibit pro-inflammatory mediators and oxidative substances as well as enzymes responsible for the degradation of the organic matrix of joints and bones. A marked action on the inhibition of different cytokines has been observed as the interleukin 1β (IL-1β), the interleukin 6 (IL-6) and the alpha tumoral necrosis factor (TNF- α).

However herbal drug powders are usually not as stable and uniform as extracts. Using purification techniques and water as extraction solvent Finzelberg get a new extract, which compared with the rose hip drug powder is 7 fold stronger in their anti-inflammatory activity.

References

  1. ^ “BSBI List 2007″ (xls). Botanical Society of Britain and Ireland. Retrieved 2014-10-17.
  2. ^ De Riek, Jan; De Cock, Katrien; Smulders, Marinus J.M.; Nybom, Hilde (2013). “AFLP-based population structure analysis as a means to validate the complex taxonomy of dogroses (Rosa section Caninae)”. Molecular Phylogenetics and Evolution 67 (3): 547–59. doi:10.1016/j.ympev.2013.02.024. PMID 23499615.
  3. ^ Vogl, Sylvia; Picker, Paolo; Mihaly-Bison, Judit; Fakhrudin, Nanang; Atanasov, Atanas G.; Heiss, Elke H.; Wawrosch, Christoph; Reznicek, Gottfried; Dirsch, Verena M.; Saukel, Johannes; Kopp, Brigitte (2013). “Ethnopharmacological in vitro studies on Austria’s folk medicine—An unexplored lore in vitro anti-inflammatory activities of 71 Austrian traditional herbal drugs”. Journal of Ethnopharmacology 149 (3): 750–71. doi:10.1016/j.jep.2013.06.007. PMC 3791396. PMID 23770053.
  4. ^ Täckholm, Gunnar (1922) Zytologische Studien über die Gattung Rosa. Acta Horti Bergiani 7, 97-381.
  5. ^ Lim, K Y; Werlemark, G; Matyasek, R; Bringloe, J B; Sieber, V; El Mokadem, H; Meynet, J; Hemming, J; Leitch, A R; Roberts, A V (2005). “Evolutionary implications of permanent odd polyploidy in the stable sexual, pentaploid of Rosa canina L”. Heredity 94 (5): 501–6. doi:10.1038/sj.hdy.6800648. PMID 15770234.
  6. ^ Stock, M.; Ustinova, J.; Betto-Colliard, C.; Schartl, M.; Moritz, C.; Perrin, N. (2011). “Simultaneous Mendelian and clonal genome transmission in a sexually reproducing, all-triploid vertebrate”. Proceedings of the Royal Society B: Biological Sciences 279 (1732): 1293. doi:10.1098/rspb.2011.1738.
  7. ^ Howard, Michael. Traditional Folk Remedies (Century, 1987); p133
  8. ^ Kirk, T (1895). “The Displacement of Species in New Zealand”. Transactions of the New Zealand Institute 1895 (Wellington: Royal Society of New Zealand) 28. Retrieved 2009-04-17.
  9. ^ Owen, S. J. (1997). Ecological weeds on conservation land in New Zealand: a database. Wellington: Department of Conservation.
  10. ^ “County Flowers | Wild plants”. Plantlife. Retrieved 2012-02-04.
  11. ^ Lucy Gordan. “Hildesheim’s Medieval Church Treasures at the Met”. Inside the Vatican. Archived from the original on 30 April 2014. Retrieved 30 April 2014.

Further reading

  • Flora Europaea: Rosa canina
  • Blamey, M. & Grey-Wilson, C. (1989). Flora of Britain and Northern Europe. Hodder & Stoughton. ISBN 0-340-40170-2.
  • Vedel, H. & Lange, J. (1960). Trees and bushes. Metheun, London.
  • Graham G.S. & Primavesi A.L. (1993). Roses of Great Britain and Ireland. B.S.B.I. Handbook No. 7. Botanical Society of the British Isles, London.

External links

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Contraindications:
As a natural diuretic, Rose Hips Herbal Supplement may increase the efficacy of prescription diuretics and should not be used at the same time.   Make sure your doctor knows if you are taking a blood thinner, such as Coumadin®.

Disclaimer:
The information presented herein by this post is intended for educational purposes only. These statements have not been evaluated by the FDA and are not intended to diagnose, cure, treat or prevent disease. Individual results may vary, and before using any supplements, it is always advisable to consult with your own health care provider.


Filed under: AYURVEDA Tagged: AYURVEDA, finzelberg, germany, osteoarthritis, Rosa canina, Rosiflex

The 10-Hydroxy-2-Decenoic Acid (10-2-HDA) content in Royal Jelly, is said to possess strong inhibition of malignant cell growth, namely transferable AKR leukemia, TA3 breast malignancy

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 Developing queen larvae surrounded by royal jelly

Royal jelly is a honey bee secretion that is used in the nutrition of larvae, as well as adult queens.[1] It is secreted from the glands in the hypopharynx of worker bees, and fed to all larvae in the colony, regardless of sex or caste.[2]

When worker bees decide to make a new queen, because the old one is either weakening or dead, they choose several small larvae and feed them with copious amounts of royal jelly in specially constructed queen cells. This type of feeding triggers the development of queen morphology, including the fully developed ovaries needed to lay eggs.[3]

Other Common Names:  Apilak, Gelée Royale, Queen Bee Jelly

Royal Jelly has been called the “Crown Jewel” of the beehive that has become extremely popular since the 1950s as a wonderful source of energy and natural way to increase stamina; perhaps that is the reason why the Queen Bee is so strong and enduring.  It is also thought to be a great nutritional source of enzymes, proteins, sugars and amino acids, but there is no scientific proof to verify the supplement’s efficacy for its use as an overall health tonic.  You’ll have to decide.

History:
Royal Jelly is a thick, milky material that is secreted from the hypopharyngea- salivary glands in the heads of the young nurse bees between the sixth and twelfth days of life, and when honey and pollen are combined and refined within the nurse bee, Royal Jelly is naturally created.  While all larvæ in a colony are fed Royal Jelly, it is the only food that is fed to the Queen Bee throughout her life; other adult bees do not consume it at all.  All female eggs may produce a Queen Bee, but this occurs only when – during the whole development of the larvæ – she is cared for and fed by this material – in large quantities.  As a result of this special nutrition, the Queen develops reproductive organs (while the worker bee develops traits that relate only to work, i.e., stronger mandibles, brood food, wax glands and pollen baskets).  The Queen develops in about fifteen days, while the workers require twenty-one; and finally, the Queen endures for several years, while workers survive only a few months. “10-2 HDA,” thought to be the principle active substance in Royal Jelly, makes the Queen Bee fifty percent larger than the other female worker bees and gives her incredible stamina, ovulation ability and longevity, living four to five years longer than worker bees who only live forty or more days.  Perhaps this is the reason why so many positive qualities have been attributed to Royal Jelly as a truly rare gift of nature, but it should be noted that there is no clinical evidence to support the claims.  There is even great controversy as to the constituents included in the supplement.  Most researchers claim that it includes all the B-vitamins and vitamins A, C, D and E; some disagree.  It does contain proteins, sugars, lipids (essential fatty acids), many essential amino acids, collagen, lecithin, enzymes and minerals, in addition to the very valuable

10-2-HDA (10-Hydroxy-2-Decenoic Acid).  It is said that Royal Jelly may be most effective when combined with honey.  You can decide whether any improvements you derive from Royal Jelly’s use are purely coincidental, but if  (and when) you feel better when using it, just enjoy the benefits.

10-2-HDA (10-Hydroxy-2-Decenoic Acid)

Beneficial Uses:
Many fans claim that Royal Jelly is a great way to increase energy, as well as a remarkable stamina booster.  In addition, it is also considered a means to enhance the immune system and maintain overall health.

Royal Jelly is said to alleviate a variety of problems, such as exhaustion, anxiety, mild depression, insomnia and lack of energy and stamina.   Royal Jelly is also believed to have a calming effect on the nervous system.

Some people maintain that Royal Jelly has helped to improve skin disorders and has slowed down the ageing process.  Royal Jelly’s collagen, lecithin and vitamins A, C, D and E all benefit the skin, helping to moisturize dry skin and soothe dermatitis.

In 1977, scientists at the Beijing Medical University reported that when Royal Jelly was administered to male and female neurasthenia patients, all patients reported very effective (86%) or effective (14%) improvement.  Insomnia was eliminated, quality of sleeping increased and headache and dizziness were alleviated.  It was also said that physical and mental abilities, appetite and working efficiency were improved.

The 10-Hydroxy-2-Decenoic Acid (10-2-HDA) content in Royal Jelly, is said to possess strong inhibition of malignant cell growth, namely transferable AKR leukemia, TA3 breast malignancy, etc., and recent studies indicated immuno-regulation and anti-malignancy activities.  It can promote the growth of T-lymphocyte subsets, Interleukin-2 and the generation of tumor necrosis factor.  Much research is being conducted on this valuable active constituent, which has exhibited positive physiological and pharmacological effects including vasodilative and hypotensive activities, antihypercholesterolemic activity and anti-inflammatory functions.  In addition to these activities, the 10-HDA in Royal Jelly has been suggested to improve menopausal symptoms.

Other benefits attributed to the qualities of Royal Jelly include relief of bronchial asthma, liver, pancreatic and kidney ailments, stomach ulcers and bone fractures.

Contraindications:
Royal Jelly Nutritional Supplement is a natural bee product and may induce allergic reactions in some people and should, therefore, be tested in very small amounts before continued use.  Symptoms of allergy include breathing problems or tightness in your throat or chest, chest pain, skin hives, rash or itchy or swollen skin.

Cultivation

Royal jelly is secreted from the glands in the heads of worker bees, and is fed to all bee larvae, whether they are destined to become drones (males), workers (sterile females), or queens (fertile females). After three days, the drone and worker larvae are no longer fed with royal jelly, but queen larvae continue to be fed this special substance throughout their development. It is harvested by humans by stimulating colonies with movable frame hives to produce queen bees. Royal jelly is collected from each individual queen cell (honey comb) when the queen larvae are about four days old. It is collected from queen cells because these are the only cells in which large amounts are deposited; when royal jelly is fed to worker larvae, it is fed directly to them, and they consume it as it is produced, while the cells of queen larvae are “stocked” with royal jelly much faster than the larvae can consume it. Therefore, only in queen cells is the harvest of royal jelly practical. A well-managed hive during a season of 5–6 months can produce approximately 500 g of royal jelly. Since the product is perishable, producers must have immediate access to proper cold storage (e.g., a household refrigerator or freezer) in which the royal jelly is stored until it is sold or conveyed to a collection center. Sometimes honey or beeswax are added to the royal jelly, which is thought to aid its preservation.

Composition

The overall composition of royal jelly is 67% water, 12.5% crude protein, including small amounts of many different amino acids, and 11% simple sugars (monosaccharides), also including a relatively high amount (5%) of fatty acids. The main acid is the 10-hydroxy-2-decenoic acid or 10-HDA (about 2 – 3%).It also contains many trace minerals, some enzymes, antibacterial and antibiotic components, pantothenic acid (vitamin B5), vitamin B6 (pyridoxine) and trace amounts of vitamin C,[2] but none of the fat-soluble vitamins, A, D, E and K.[4]

Royalactin

The component of royal jelly that causes a bee to develop into a queen appears to be a single protein that has been called royalactin. Jelly which had been rendered inactive by prolonged storage had a fresh addition of each of the components subject to decay and was fed to bees; only jelly laced with royalactin caused the larvae to become queens.[5] Royalactin also induces similar phenotypical change in the fruitfly (Drosophila melanogaster), marked by increased body size and ovary development.

Epigenetic effects

The honey bee queens and workers represent one of the most striking examples of environmentally controlled phenotypic polymorphism. In spite of their identical clonal nature at the DNA level, they are strongly differentiated across a wide range of characteristics including anatomical and physiological differences, longevity of the queen, and reproductive capacity.[6] Queens constitute the sexual caste and have large active ovaries, whereas workers have only rudimentary, inactive ovaries and are functionally sterile. The queen/worker developmental divide is controlled epigenetically by differential feeding with royal jelly; this appears to be due specifically to the protein royalactin. A female larva destined to become a queen is fed large quantities of royal jelly; this triggers a cascade of molecular events resulting in development of a queen.[3] It has been shown that this phenomenon is mediated by an epigenetic modification of DNA known as CpG methylation.[7] Silencing the expression of an enzyme that methylates DNA in newly hatched larvae led to a royal jelly-like effect on the larval developmental trajectory; the majority of individuals with reduced DNA methylation levels emerged as queens with fully developed ovaries. This finding suggests that DNA methylation in honey bees allows the expression of epigenetic information to be differentially altered by nutritional input.

Uses

Citing various potential health benefits seen in lab studies, royal jelly is collected and sold as a dietary supplement for humans, but the European Food Safety Authority has rejected these claims stating that the current evidence does not support consuming royal jelly will give health benefits in humans.[8] In the United States, both the Federal Trade Commission and the Food and Drug Administration have taken legal action against companies that have used unfounded claims of health benefits to market royal jelly products.[9][10][11][12]

Adverse effects

Royal jelly may cause allergic reactions in humans ranging from hives, asthma, to even fatal anaphylaxis.[13][14][15][16][17][18] The incidence of allergic side effect in people who consume royal jelly is unknown. The risk of having an allergy to royal jelly is higher in people who have other allergies.[13]

The benefits of Royal Jelly are truly extensive. The list of benefits is so extensive that it may actually appear to be ‘too good to be true’ to many of us, myself included. I’m still amazed every time I scan the many studies done on this amazing substance.Royal Jelly is one of the naturally occurring miraculous super foods on the planet that gets very little press!  It packs a powerful health punch and here’s why:Royal Jelly is a substance produced by worker honey bees.  Bee colonies function on a hierarchical system:  Bees all start out as unisex larvae, blank slate bee babies if you will.  Then they break off into 1 of 3 roles within their colony.  The worker bees (females), the drones (males used for reproduction) and The Queen Bee.The workers and drones have a typical life span of 3-4 months, whereas The Queen Been can live for up to 7 years!

What differentiates the role of The Queen Bee from the workers and the drones is quite simply what she is fed!  Keep in mind, she starts off the same as the rest of colony but her diet transforms her into The Queen Bee.  Workers and drones are fed royal jelly when they hatch, followed by pollen and honey for the following 6 days.  The Queen Bee on the other hand, is exclusively fed royal jelly for the entirety of her life- Jelly is one of the naturally occurring miraculous super foods on the planet that gets very little press!  It packs a powerful health punch and here’s why:Royal Jelly is a substance produced by worker honey bees.  Bee colonies function on a hierarchical system:  Bees all start out as unisex larvae, blank slate bee babies if you will.  Then they break off into 1 of 3 roles within their colony.  The worker bees (females), the drones (males used for reproduction) and The Queen Bee.The workers and drones have a typical life span of 3-4 months, whereas The Queen Been can live for up to 7 years!  What differentiates the role of The Queen Bee from the workers and the drones is quite simply what she is fed!  Keep in mind, she starts off the same as the rest of colony but her diet transforms her into The Queen Bee.
 Workers and drones are fed royal jelly when they hatch, followed by pollen and honey for the following 6 days.  The Queen Bee on the other hand, is exclusively fed royal jelly for the entirety of her life- See more at: http://www.collective-evolution.com/2013/06/06/the-royal-benefits-of-royal-jelly/#sthash.DPhCubyY.dpufRoyal Jelly is one of the naturally occurring miraculous super foods on the planet that gets very little press!  It packs a powerful health punch and here’s why:Royal Jelly is a substance produced by worker honey bees.  Bee colonies function on a hierarchical system:  Bees all start out as unisex larvae, blank slate bee babies if you will.  Then they break off into 1 of 3 roles within their colony.  The worker bees (females), the drones (males used for reproduction) and The Queen Bee.The workers and drones have a typical life span of 3-4 months, whereas The Queen Been can live for up to 7 years!  What differentiates the role of The Queen Bee from the workers and the drones is quite simply what she is fed!  Keep in mind, she starts off the same as the rest of colony but her diet transforms her into The Queen Bee.
 Workers and drones are fed royal jelly when they hatch, followed by pollen and honey for the following 6 days.  The Queen Bee on the other hand, is exclusively fed royal jelly for the entirety of her life- See more at: http://www.collective-evolution.com/2013/06/06/the-royal-benefits-of-royal-jelly/#sthash.DPhCubyY.dpufRoyal jelly is a substance that is secreted from the glands of worker bees to feed their larvae and queens. It is thick in texture, milky-white in color, and has been harvested by humans for centuries for its rejuvenating properties. Indeed, it is a fact that queen bees – which are fed royal jelly their entire lives – live approximately 40 times longer than drone or worker bees, largely due to the jelly’s nutritiousness.

Cancer-fighting properties – According to a study published in a 2009 edition of the BMC Complementary and Alternative Medicine, royal jelly fights cancer by suppressing the blood supply to tumors. When the Japanese researchers tested various royal jelly types on umbilical vein tissue cultures, all of them inhibited the formation of blood vessels, especially those richest in caffeic acid, a compound responsible for the greatest suppressive levels. Moreover, since the fatty components of royal jelly contain estrogenic effects – as proved by a study published in the December 2010 edition of PLoS One – it is possible that royal jelly can treat breast and cervical cancer.
Improves blood health – A study published in the November 2008 edition of the Biological and Pharmaceutical Bulletin showed that royal jelly can improve insulin resistance and blood pressure. The researchers fed the jelly to rats suffering from high blood pressure and insulin resistance due to a high-fructose diet. After two months, the rats demonstrated noticeably fewer instances of blood vessel constriction, which resulted in lower triglyceride and insulin levels.

Skincare properties – Although Royal jelly is best-known as a health supplement, it is often used in skincare products because it contains DNA and gelatin, two ingredients that aid collagen production (and thus anti-aging activity). For this reason, many people like to apply royal jelly topically and allow it to nourish and invigorate their skin.

Antibacterial components – According to a study published in the July 1990 edition of the Journal of Biological Chemistry, a protein found in royal jelly – unofficially named royalisin – provides numerous antibacterial and antimicrobial properties, and is effective at dealing with certain bacterial cultures at lower levels.

Rich in nutrients – As with other bee products such as bee pollen and propolis, royal jelly’s biggest attraction is probably its impressive concentration of vitamins and minerals. Indeed, an average serving of royal jelly contains seventeen different amino acids (including all eight essential amino acids, making it a complete protein), most of the B-vitamins (which are used for the production and synthesis of energy), and respectable levels of iron and calcium, which are essential for superior blood and bone Health. Royal jelly also contains vitamins A, C, and E, which are important antioxidants that can neutralize free radical activity, thus guarding us from degenerative diseases.

Infertility treatment – It is not a coincidence that worker bees are infertile, while queen bees can lay up to 2,000 eggs per day throughout their extensive 4 to 6 year lifespan. This is because royal jelly stimulates estrogen production, thereby stabilizing menstrual cycles in women, improving sperm morphology in men, and increasing the libido of both sexes.

Notes

  1. ^ Jung-Hoffmann L: Die Determination von Königin und Arbeiterin der Honigbiene. Z Bienenforsch 1966, 8:296-322.
  2. ^ a b Graham, J. (ed.) (1992) The Hive and the Honey Bee (Revised Edition). Dadant & Sons.
  3. ^ a b Maleszka, R, Epigenetic integration of environmental and genomic signals in honey bees: the critical interplay of nutritional, brain and reproductive networks. Epigenetics. 2008, 3, 188-192.
  4. ^ “Value-added products from beekeeping. Chapter 6.”.
  5. ^ Kamakura, M. (2011). “Royalactin induces queen differentiation in honeybees”. Nature 473 (7348): 478–483. doi:10.1038/nature10093. PMID 21516106. edit
  6. ^ Winston, M, The Biology of the Honey Bee, 1987, Harvard University Press
  7. ^ Kucharski R, Maleszka, J, Foret, S, Maleszka, R (2008). “Nutritional Control of Reproductive Status in Honeybees via DNA Methylation”. Science 319 (5871): 1827–1833. doi:10.1126/science.1153069.
  8. ^ “Scientific Opinion”. EFSA Journal 9 (4): 2083. 2011.
  9. ^ “QVC to Pay $7.5 Million to Settle Charges that It Aired Deceptive Claims”. Federal Trade Commission. March 19, 2009.
  10. ^ “Complaint in the Matter of CC Pollen Company et al.”. Federal Trade Commission. March 16, 1993.
  11. ^ “Federal Government Seizes Dozens of Misbranded Drug Products: FDA warned company about making medical claims for bee-derived products”. Food and Drug Administration. Apr 5, 2010.
  12. ^ “Inspections, Compliance, Enforcement, and Criminal Investigations: Beehive Botanicals, Inc”. Food and Drug Administration. March 2, 2007.
  13. ^ a b Leung, R; Ho, A; Chan, J; Choy, D; Lai, CK (March 1997). “Royal jelly consumption and hypersensitivity in the community”. Clin. Exp. Allergy 27 (3): 333–6. doi:10.1111/j.1365-2222.1997.tb00712.x. PMID 9088660.
  14. ^ Takahama H, Shimazu T (2006). “Food-induced anaphylaxis caused by ingestion of royal jelly”. J Dermatol. 33 (6): 424–426. doi:10.1111/j.1346-8138.2006.00100.x. PMID 16700835.
  15. ^ Lombardi C, Senna GE, Gatti B, Feligioni M, Riva G, Bonadonna P, Dama AR, Canonica GW, Passalacqua G (1998). “Allergic reactions to honey and royal jelly and their relationship with sensitization to compositae”. Allergol Immunopathol (Madr). 26 (6): 288–290.
  16. ^ Thien FC, Leung R, Baldo BA, Weiner JA, Plomley R, Czarny D (1996). “Asthma and anaphylaxis induced by royal jelly”. Clin Exp Allergy 26 (2): 216–222. doi:10.1111/j.1365-2222.1996.tb00082.x. PMID 8835130.
  17. ^ >Leung R, Thien FC, Baldo B, Czarny D (1995). “Royal jelly-induced asthma and anaphylaxis: clinical characteristics and immunologic correlations”. J Allergy Clin Immunol 96 (6 Pt 1): 1004–1007. doi:10.1016/S0091-6749(95)70242-3. PMID 8543734.
  18. ^ Bullock RJ, Rohan A, Straatmans JA (1994). “Fatal royal jelly-induced asthma”. Med J Aust 160 (1): 44.

References

  • Balch, Phyllis A.; Balch, James F. (2000). Prescription for Nutritional Healing, Third Edition. New York: Avery. ISBN 1-58333-077-1.
  • Ammon, R. and Zoch, E. (1957) Zur Biochemie des Futtersaftes der Bienenkoenigin. Arzneimittel Forschung 7: 699-702
  • Blum, M.S., Novak A.F. and Taber III, 5. (1959). 10-Hydroxy-decenoic acid, an antibiotic found in royal jelly. Science, 130 : 452-453
  • Bonomi, A. (1983) Acquisizioni in tema di composizione chimica e di attivita’ biologica della pappa reale. Apitalia, 10 (15): 7-13.
  • Braines, L.N. (1959). Royal jelly I. Inform. Bull. Inst. Pchelovodstva, 31 pp (with various articles)
  • Braines, L.N. (1960). Royal jelly II. Inform. Bull. Inst. Pchelovodstva, 40 pp.
  • Braines, L.N. (1962). Royal jelly III. Inform. Bull. Inst. Pchelovodstva, 40
  • Chauvin, R. and Louveaux, 1. (1956) Etdue macroscopique et microscopique de lagelee royale. L’apiculteur.
  • Cho, Y.T. (1977). Studies on royal jelly and abnormal cholesterol and triglycerides. Amer. Bee 1., 117 : 36-38
  • De Belfever, B. (1958) La gelee royale des abeilles. Maloine, Paris.
  • Destrem, H. (1956) Experimentation de la gelee royale d’abeille en pratique geriatrique (134 cas). Rev. Franc. Geront, 3.
  • Giordani, G. (1961). [Effect of royal jelly on chickens.] Avicoltura 30 (6): 114-120
  • Hattori N, Nomoto H, Fukumitsu H, Mishima S, Furukawa S. [Royal jelly and its unique fatty acid, 10-hydroxy-trans-2-decenoic acid, promote neurogenesis by neural stem/progenitor cells in vitro.] Biomed Res. 2007 Oct;28(5):261-6.
  • Hashimoto M, Kanda M, Ikeno K, Hayashi Y, Nakamura T, Ogawa Y, Fukumitsu H, Nomoto H, Furukawa S. (2005) Oral administration of royal jelly facilitates mRNA expression of glial cell line-derived neurotrophic factor and neurofilament H in the hippocampus of the adult mouse brain. Biosci Biotechnol Biochem. 2005 Apr;69(4):800-5.
  • Inoue, T. (1986). The use and utilization of royal jelly and the evaluation of the medical efficacy of royal jelly in Japan. Proceeding sof the XXXth International Congress of Apiculture, Nagoya, 1985, Apimondia, 444-447
  • Jean, E. (1956). A process of royal jelly absorption for its incorporation into assimilable substances. Fr. Pat., 1,118,123
  • Jacoli, G. (1956) Ricerche sperimentali su alcune proprieta’ biologiche della gelatina reale. Apicoltore d’Italia, 23 (9-10): 211-214.
  • Jung-Hoffmann L: Die Determination von Königin und Arbeiterin der Honigbiene. Z Bienenforsch 1966, 8:296-322.
  • Karaali, A., Meydanoglu, F. and Eke, D. (1988) Studies on composition, freeze drying and storage of Turkish royal jelly. J. Apic. Res., 27 (3): 182-185.
  • Kucharski R, Maleszka, J, Foret, S, Maleszka, R, Nutritional Control of Reproductive Status in Honeybees via DNA Methylation. Science. 2008 Mar 28;319(5871):1827-3
  • Lercker, G., Capella, P., Conte, L.S., Ruini, F. and Giordani, G. (1982) Components of royal jelly: II. The lipid fraction, hydrocarbons and sterolds. J. Apic. Res. 21(3):178-184.
  • Lercker, G., Vecchi, M.A., Sabatini, A.G. and Nanetti, A. 1984. Controllo chimicoanalitico della gelatina reale. Riv. Merceol. 23 (1): 83-94.
  • Lercker, G., Savioli, S., Vecchi, M.A., Sabatini, A.G., Nanetti, A. and Piana, L. (1986) Carbohydrate Determination of Royal Jelly by High Resolution Gas Chromatography (HRGC). Food Chemistry, 19: 255-264.
  • Lercker, G., Caboni, M.F., Vecchi, M.A., Sabatini, A.G. and Nanetti, A. (1992) Caratterizzazione dei principali costituenti della gelatina reale. Apicoltura 8:11-21.
  • Maleszka, R, Epigenetic integration of environmental and genomic signals in honey bees: the critical interplay of nutritional, brain and reproductive networks. Epigenetics. 2008, 3, 188-192.
  • Nakamura, T. (1986) Quality standards of royal jelly for medical use. proceedings of the XXXth International Congress of Apiculture, Nagoya, 1985 Apimondia (1986) 462-464.
  • Rembold, H. (1965) Biologically active substances in royal jelly. Vitamins and hormones 23:359-382.
  • Salama, A., Mogawer, H.H. and El-Tohamy, M. 1977 Royal jelly a revelation or a fable. Egyptian Journal of Veterinary Science 14 (2): 95-102.
  • Takenaka, T. Nitrogen components and carboxylic acids of royal jelly. In Chemistry and biology of social insects (edited by Eder, J., Rembold, H.). Munich, German Federal Republic, Verlag J. Papemy (1987): 162-163.
  • Wagner, H., Dobler, I., Thiem, I. Effect of royal jelly on the peirpheral blood and survival rate of mice after irradiation of the entire body with X-rays. Radiobiologia Radiotherapia (1970) 11(3): 323-328.
  • Winston, M, The Biology of the Honey Bee, 1987, Harvard University Press
    Disclaimer:
    The information presented herein by this post is intended for educational purposes only. These statements have not been evaluated by the FDA and are not intended to diagnose, cure, treat or prevent disease. Individual results may vary, and before using any supplements, it is always advisable to consult with your own health care provider.
    Filed under: AYURVEDA Tagged: 10-Hydroxy-2-Decenoic Acid, AYURVEDA, royal jelly

Levetiracetam Green process construction


Levetiracetam industrial process

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Levetiracetam industrial process

2 pyrolidinone
Inline image 2
ethyl 2 bromo butyrate
Inline image 1
 (R)-(+)-alpha-methyl-benzylamine
Inline image 3
ethyl chloro formate
US4943639.
cut paste
note………….racemic (±)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid is obt by rxn of 2 pyrolidinone with ethyl 2 bromo acetate
+/-)-(R,S)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid methyl ester. CAS# 33978-83-5
EXAMPLE 1 (a) Preparation of the (R)-alpha-methyl-benzylamine salt of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid
8.7 kg (50.8 moles) of racemic (±)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid are suspended in 21.5 liters of anhydrous benzene in a 50 liter reactor. To this suspension is added gradually a solution containing 3.08 kg (25.45 moles) of (R)-(+)-alpha-methyl-benzylamine and 2.575 kg (25.49 moles) of triethylamine in 2.4 liters of anhydrous benzene. This mixture is then heated to reflux temperature until complete dissolution It is then cooled and allowed to crystallize for a few hours. 5.73 kg of the (R)-alpha-methyl-benzylamine salt of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid are thus obtained.
Melting point: 148°-151° C. Yield: 77.1%.
This salt may be purified by heating under reflux in 48.3 liters of benzene for 4 hours. The mixture is cooled and filtered to obtain 5.040 kg of the desired salt. Melting point: 152°-153.5° C. Yield: 67.85%.

(b) Preparation of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid

5.04 kg of the salt obtained in (a) above are dissolved in 9 liters of water. 710 g of a 30% sodium hydroxide solution are added slowly so that the pH of the solution reaches 12.6 and the temperature does not exceed 25° C. The solution is stirred for a further 20 minutes and the alpha-methylbenzylamine liberated is extracted repeatedly with a total volume of 18 liters of benzene.
The aqueous phase is then acidified to a pH of 1.1 by adding 3.2 liters of 6N hydrochloric acid. The precipitate formed is filtered off, washed with water and dried.
The filtrate is extracted repeatedly with a total volume of 50 liters of dichloromethane. The organic phase is dried over sodium sulfate and filtered and evaporated to dryness under reduced pressure.
The residue obtained after the evaporation and the precipitate isolate previously, are dissolved together in 14 liters of hot dichloromethane. The dichloromethane is distilled and replaced at the distillation rate, by 14 liters of toluene from which the product crystallizes.
The mixture is cooled to ambient temperature and the crystals are filtered off to obtain 2.78 kg of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid.
Melting point: 125.9° C. [alpha]D 20 =-26.4° (c=1, acetone). Yield: 94.5%.
(c) Preparation of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide
34.2 g (0.2 mole) of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid are suspended in 225 ml of dichloromethane cooled to -30° C. 24.3 g (0.24 mole) of triethylamine are added dropwise over 15 minutes. The reaction mixture is then cooled to -40° C. and 24.3 g (0.224 mole) of ethyl chloroformate are added over 12 minutes. Thereafter, a stream of ammonia is passed through the mixture for 41/2 hours. The reaction mixture is then allowed to return to ambient temperature and the ammonium salts formed are removed by filtration and washed with dichloromethane. The solvent is distilled off under reduced pressure. The solid residue thus obtained is dispersed in 55 ml toluene and the dispersion is stirred for 30 minutes and then filtered. The product is recrystallized from 280 ml of ethyl acetate in the presence of 9 g of 0,4 nm molecular sieve in powder form.
24.6 g of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide are obtained.
Melting point: 115°-118° C. [alpha]D 25 =-89.7° (c=1, acetone). Yield: 72.3%.
Analysis for C8 H14 N2 O2 in % calculated: C 56.45. H 8.29. N 16.46. found: 56.71. 8.22. 16.48.
The racemic (±)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid used in this synthesis has been prepared in the manner described below.
A solution containing 788 g (19.7 moles) of sodium hydroxide in 4.35 liters of water is introduced over 2 hours into a 20 liter flask containing 3.65 kg (18.34 moles) of ethyl (±)-alpha-ethyl-2-oxo-1-pyrrolidineacetate at a temperature not exceeding 60° C. When this addition is complete, the temperature of the mixture is raised to 80° C. and the alcohol formed is distilled off until the temperature of the reaction mixture reaches 100° C.
The reaction mixture is then cooled to 0° C. and 1.66 liter (19.8 moles) of 12N hydrochloric acid is added over two and a half hours. The precipitate formed is filtered off, washed with 2 liters of toluene and recrystallized from isopropyl alcohol. 2.447 kg of racemic (±)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid, melting at 155°-156° C., are thus obtained. Yield: 78%.
Analysis for C8 H13 NO3, in % calculated: C 56.12. H 7.65. N 8.18. found: 55.82. 8.10. 7.97.

EXAMPLE 2 (a) Preparation of ethyl (S)-4-[[1-(aminocarbonyl)propyl]amino]butyrate

143.6 ml (1.035 mole) of triethylamine are added to a suspension of 47.75 g (0.345 mole) of (S)-2-amino-butanamide hydrochloride ([alpha]D 25 : +26.1°; c=1, methanol) in 400 ml of toluene. The mixture is heated to 80° and 67.2 g (0.345 mole) of ethyl 4-bromobutyrate are introduced dropwise.
The reaction mixture is maintained at 80° C. for 10 hours and then filtered hot to remove the triethylamine salts. The filtrate is then evaporated under reduced pressure and 59 g of an oily residue consisting essentially of the monoalkylation product but containing also a small amount of dialkylated derivative are obtained.
The product obtained in the crude state has been used as such, without additional purification, in the preparation of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide by cyclization.

(b) Preparation of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide

54 g of the crude product obtained in a) above are dissolved in 125 ml of toluene in the presence of 2 g of 2-hydroxypyridine. The mixture is heated at 110° C. for 12 hours.
The insoluble matter is filtered off hot and the filtrate is then evaporated under reduced pressure.
The residue is purified by chromatography on a column of 1.1 kg of silica (column diameter: 5 cm; eluent: a mixture of ethyl acetate, methanok and concentrated ammonia solution in a proportion by volume of 85:12:3).
The product isolated is recrystallized from 50 ml of ethyl acetate to obtain 17.5 g of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide.
Melting point: 117° C. [alpha]D 25 : -90.0° (c=1, acetone). Yield: 41%.

EXAMPLE 3 (a) Preparation of (S)-N-[1(aminocarbonyl)propyl]-4-chlorobutanamide

345.6 g (2.5 moles) of ground potassium carbonate are mixed with 138.5 g (1 mole) of (S)-2-amino-butanamide hydrochloride in 2.5 liters of acetonitrile. The reaction mixture is cooled to 0° C. and a solution of 129.2 g (1.2 mole) of 4-chlorobutyryl chloride in 500 ml of acetonitrile is introduced dropwise. After the addition, the reaction mixture is allowed to return to ambient temperature; the insoluble matter is filtered off and the filtrate evaporated under reduced pressure. The crude residue obtained is stirred in 1.2 liter of anhydrous ether for 30 minutes at a temperature between 5° and 10° C. The precipitate is filtered off, washed twice with 225 ml of ether and dried in vacuo to obtain 162.7 g of (S)-N-[1-(aminocarbonyl)propy]-4-chlorobutanamide.
Melting point: 118°-123° C. [alpha]D 25 : -18° (c=1, methanol). Yield: 78.7%.
The crude product thus obtained is very suitable for the cyclization stage which follows. It can however be purified by stirring for one hour in anhydrous ethyl acetate.
Melting point: 120°-122° C. [alpha]D 25 : -22.2° (c=1, methanol).

(b) Preparation of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide

6.2 g (0.03 mole) of (S)-N-[1(aminocarbonyl)propyl]-4-chlorobutamine and 0.484 g (0.0015 mole) of tetrabutylammonium bromide are mixed in 45 ml of dichloromethane at 0° C. under a nitrogen atmosphere. 2.02 g (0.036 mole) of potassium hydroxide powder are added over 30 minutes, at such a rate that the temperature of the reaction mixture does not exceed +2° C. The mixture is then stirred for one hour, after which a further 0.1 g (0.0018 mole) of ground potassium hydroxide is added and stirring continued for 30 minutes at 0° C. The mixture is allowed to return to ambient temperature. The insoluble matter is filtered off and the filtrate is concentrated under reduced pressure. The residue obtained is recrystallized from 40 ml of ethyl acetate in the presence of 1.9 g of 0,4 nm molecular sieve. The latter is removed by hot filtration to give 3.10 g of (S)-alphaethyl-2-oxo-1-pyrrolidineacetamide.
Melting point: 116.7° C. [alpha]D 25 : -90.1° (c=1, acetone). Yield: 60.7%.

EXAMPLE 4 Preparation of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide……levetiracetam

This example illustrates a variant of the process of Example 3, in which the intermediate 4-chlorobutanamide obtained in situ is not isolated. 84 g of anhydrous sodium sulfate are added to a suspension of 69.25 g (0.5 mole) of (S)-2-amino-butanamide hydrochloride in 600 ml of dichloromethane at ambient temperature. The mixture is cooled to 0° C. and 115 g of ground potassium hydroxide are added, followed by 8.1 g (0.025 mole) of tetrabutylammonium bromide dissolved in 100 ml of dichloromethane. A solution of 77.5 g of 4-chlorobutyryl chloride in 100 ml of dichlorometha is added dropwise at 0° C., wih vigorous stirring. After 5 hours’ reaction, a further 29 g of ground potassium hydroxide are added. Two hours later, the reaction mixture is filtered over Hyflo-cel and the filtrate evaporated under reduced pressure. The residue (93.5 g) is dispersed in 130 ml of hot toluene for 45 minutes. The resultant mixture is filtered and the filtrate evaporated under reduced pressure. The residue (71.3 g) is dissolved hot in 380 ml of ethyl acetate to which 23 g of 0,4 nm molecular sieve in powder form are added. This mixture is heated to reflux temperature and filtered hot. After cooling the filtrate, the desired product crystallizes to give 63 g of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide.
Melting point: 117° C. [alpha]D 25 : -91.3° (c=1, acetone). Yield: 74.1%.

FROM MY OLD POST

(±)-(R,S)-alpha-ethyl-2- oxo-l-pyrrolidineacet-N-(+)-(R)-(l-phenylethyl)-amide a key levetiracetam intermediate

(±)-(R,S)-alpha-ethyl-2- oxo-l-pyrrolidineacet-N-(+)-(R)-(l-phenylethyl)-amide

methyl (±)-(R,S)-alpha-ethyl-2-oxo-l -pyrrolidine acetate with (+)-(R)-(l-phenylethyl)- amine in toluene in the presence of a base such as sodium hydride or methoxide; crystallization- induced dynamic resolution of the resultant (±)-(R,S)-alpha-ethyl-2- oxo-l-pyrrolidineacet-N-(+)-(R)-(l-phenylethyl)-amide

(R)-(+)-1-Phenylethylamine

33978-83-5
1-​Pyrrolidineacetic acid, α-​ethyl-​2-​oxo-​, methyl ester

Ebd414139

1004767-60-5
1-​Pyrrolidineacetamide​, α-​ethyl-​2-​oxo-​N-​[(1R)​-​1-​phenylethyl]​-
(±)-(R.S)-alpha-ethyl-2-oxo-l-pyrrolidineacet-N-(+)-(R)-(l-phenylethyl)-amide

Example 1

(±)-(R,S)-alpha-ethyl-2-oxo-l-pyrrolidineacet-N-(+)-(R)-(l-phenylethyl)-amide.

In a 100 ml reactor equipped with mechanical stirring, thermometer and bubble condenser, 13.4 g of (±)-(R,S)-alpha-ethyl-2-oxo-l-pyrrolidineacetic acid methyl ester (71.6 mmol), 8.8 g of (+)-(R)-(l-phenylethyl)-amine (72.5 mmol) and 45 ml of tetrahydrofuran were charged. 3.4 g of NaH (60% dispersion in mineral oil, 85.6 mmol) was added in small portions under nitrogen atmosphere. Reaction mixture was maintained at room temperature for about 2 h. Then, it was heated up to 350C and kept under stirring overnight. Reaction was controlled by TLC (Rf = 0.5, AcOEt/silica gel).

At reaction completed, one night at 35°C temperature, reaction mixture was cooled to room temperature and 30 ml of water was slowly charged. It was transferred into a separatory funnel and was diluted with 30 ml of water and 80 ml of dichloromethane. Phases were separated and the aqueous one was washed with 50 ml of dichloromethane. Collected organic phases were washed with an aqueous acid solution, dried on Na2SO4, filtered and concentrated under vacuum. 19.5 g of an oil residue was obtained which slowly solidified. Solid was suspended in 20 ml of a hexane/dichloromethane 9/1 v/v mixture. It was then filtered, washed with 10 ml of the same solvent mixture and dried at 400C to give 12.1 g of the title compound (44.1 mmol, 61.6% yield) as dry solid.
1H NMR (400.13 MHz, CDCl3, 25 0C): δ (ppm, TMS)
7.35-7.19 (1OH, m),
6.49 (2H, br s),
5.09-5.00 (2H, m),
4.41 (IH, dd, J = 8.3, 7.4 Hz),
4.36 (IH, dd, J = 8.6, 7.1 Hz),
3.49 (IH, ddd, J = 9.8, 7.7, 6.6 Hz),
3.41 (IH, ddd, J = 9.8, 7.7, 6.2 Hz),
3.30 (IH, ddd, J = 9.6, 8.3, 5.5 Hz),
3.13 (IH, ddd, 9.7, 8.5, 6.1 Hz), 2.47-2.38 (2H, m), 2.41 (IH, ddd, J = 17.0, 9.6, 6.3 Hz), 2.26 (IH, ddd, 17.0, 9.5, 6.6 Hz), 2.10-1.98 (2H, m), 2.01-1.89 (IH, m), 1.99-1.88 (IH, m), 1.98-1.85 (IH, m), 1.88-1.78 (IH, m), 1.75- 1.62 (IH, m), 1.72-1.59 (IH, m), 1.45 (3H, d, J = 7.1 Hz), 1.44 (3H, d, J = 7.1 Hz), 0.90 (3H, t, J = 7.4 Hz), 0.86 (3H, t, J = 7.4 Hz).  

13C NMR (100.62 MHz, CDCl3, 25 0C): δ (ppm, TMS)
176.05 (CO), 176.00 (CO), 169.08 (CO),
168.81 (CO), 143.59 (Cquat),
143.02 (Cquat), 128.66 (2 x CH), 128.55 (2 x CH),
127.33 (CH), 127.19 (CH), 126.05 (2 x CH),
125.80 (2 x CH), 56.98 (CH), 56.61 (CH),
48.90 (CH), 48.84 (CH), 44.08 (CH2),
43.71 (CH2), 31.19 (CH2), 31.07 (CH2), 22.08 (CH3),
22.04 (CH3), 21.21 (CH2), 20.68 (CH2),
18.28 (CH2), 18.08 (CH2), 10.50 (CH3), 10.45 (CH3).

Example 2 (±)-(R.S)-alpha-ethyl-2-oxo-l-pyrrolidineacet-N-(+)-(R)-(l-phenylethyl)-amide (alternative 1).

In a 500 ml reactor equipped with mechanical stirring, thermometer and condenser, 24.2 g of (+)-(R)-(l-phenylethyl)-amine (199.51 mmol) and 40 ml of toluene were charged. By keeping the reaction mixture at 00C temperature under nitrogen atmosphere, 9.5 g of NaH (60% mineral oil suspension, 237.50 mmol) was added in small portions. At the same temperature, 190.0 g of a toluene solution of (±)-(R,S)- alpha-ethyl-2-oxo-l-pyrrolidineacetic acid methyl ester (19.28% equal to 36.63 g, 197.77 mmol) was charged. Reaction mixture was then heated up to 35°C and maintained in that condition till complete disappearing of methyl ester reagent (about 14 h; checked by HPLC).
At reaction completed, reaction mixture was cooled and when room temperature was reached, 100 ml of water was slowly charged. Aqueous phases were separated and extracted with toluene (2 x 75 ml). Collected organic phases were treated with acid water till neuter pH. Solvent was evaporated and residue was suspended in about 100 ml of heptane for about 30 minutes. Product was isolated by filtration and dried in oven at 400C temperature under vacuum overnight to give 45.2 g of the title compound (164.54 mmol, 83.2% yield, d.e. 0.0%) as white dusty solid.

Example 3

(±)-(R,S)-alpha-ethyl-2-oxo-l-pyrrolidineacet-N-(+)-(R)-(l-phenylethyl)-amide (alternative 2).
In a 500 ml reactor equipped with mechanical stirring, thermometer and Dean-Stark distiller, 24.2 g of (+)-(R)-(l-phenylethyl)-amine (199.51 mmol) and 40 ml of toluene were charged. By keeping the reaction mixture at 00C temperature, 42.7 g of sodium methoxide (30% solution in methanol, 237.14 mmol) was added under nitrogen atmosphere. At the same temperature, 190.0 g of a toluene solution of (±)- (R,S)-alpha-ethyl-2-oxo-l-pyrrolidineacetic acid methyl ester (19.28% equal to 36.63 g, 197.77 mmol) was charged. Reaction mixture was then heated up to 65- 700C and maintained in that condition till complete disappearing of methyl ester reagent (about 4 h; checked by HPLC). After a work-up carried out according to the procedure described in example 2, 40.2 g of the title compound (146.53 mmol, 74.1% yield, d.e. 0.0%) as white dusty solid was obtained.
ANTHONY MELVIN CRASTO

THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D
amcrasto@gmail.com

MOBILE-+91 9323115463
GLENMARK SCIENTIST ,  INDIA

Filed under: PROCESS Tagged: industrial process, LEVETIRACETAM

(2S)-2- Oxopyrrolidin-1-yl)butanoic acid………….Key Levetiracetam intermediate

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(2S)-2- Oxopyrrolidin-1-yl)butanoic acid………….Key Levetiracetam intermediate

(s)-2-(2-oxopyrrolidin-1-yl)butanoic Acid
CAS No.: 102849-49-0
Synonyms:
Formula: C8H13NO3
Exact Mass: 171.09000

1H NMR PREDICT

1H NMR (CDCl3, 400 MHz): δ 0.93 (t, J = 7.7 Hz, 3H), 1.67–1.76 (m, 1H), 1.99–2.13 (m, 3H), 2.49 (t, J = 7.7 Hz, 2H), 3.37 (m, J = 8.7, 5.8 Hz, 1H), 3.52-3.58 (m, 1H), 4.64 (dd, J = 10.6, 4.8 Hz, 1H);
Journal of Chemical and Pharmaceutical Research, 2012, 4(12):4988-4994

(S)-2-(2-Oxopyrrolidin-1-yl)butanoic acid NMR spectra analysis, Chemical CAS NO. 102849-49-0 NMR spectral analysis, (S)-2-(2-Oxopyrrolidin-1-yl)butanoic acid H-NMR spectrum
13 C NMR PREDICT
13C NMR (CDCl3, 125 MHz) : δ 10.8, 18.2, 21.9, 30.8, 43.9, 55.4, 173.7, 177.2;
Journal of Chemical and Pharmaceutical Research, 2012, 4(12):4988-4994
(S)-2-(2-Oxopyrrolidin-1-yl)butanoic acid NMR spectra analysis, Chemical CAS NO. 102849-49-0 NMR spectral analysis, (S)-2-(2-Oxopyrrolidin-1-yl)butanoic acid C-NMR spectrum

Cosy predict.BELOW

SYNTHESIS AS IN PAPER

Asymmetric synthesis of chiral amines by highly diastereoselective 1,2-additions of organometallic reagents to N-tert-Butanesulfinyl Imines

Chandra Babu K1,2*, Buchi Reddy R3 , Mukkanti K2 , Madhusudhan G1 and Srinivasulu P1
1 Inogent Laboratories (A GVK BIO Company), 28A, IDA, Nacharam, Hyderabad 500 076, India 2Centre for Pharmaceutical Sciences, JNT University, Kukatpally, Hyderabad 500 072, India
3Orchid Chemicals & Pharmaceuticals Ltd, 476/14, R&D Centre, Chennai -600 119, India __________________________________________________________________________
http://jocpr.com/vol4-iss12-2012/JCPR-2012-4-12-4988-4994.pdf

ABSTRACT We report an asymmetric synthesis of chiral amines (4S,5S)-Cytoxazone, Taxol side chain moiety and (S)- Levetiracetam starting from versatile new chiral N- sulfinimine (4). The key step, stereoselective 1,2-addition of Grignard reagent to chiral N-sulfinimine derived from (R)-glyceraldehyde acetonide and (S)-t-BSA gave the corresponding sulfonamide in high diastereoselectivity. Subsequent reactions yielded the targeted biological active and pharmaceutical important compounds with high purity (>99%) and yield

Journal of Chemical and Pharmaceutical Research, 2012, 4(12):4988-4994

(S)-2-(2-oxopyrrolidin-1-yl)butanoic acid, 16 Potassium hydroxide (1.0 g, 0.017 mol)) was dissolved into water (18.0 ml). Tetra-n-butyl ammonium bromide (0.2 g, 0.0062 mol)) and (S)-15 (1.0 g, 0.0063 mol)) in methylene chloride (10 ml) were charged in 30 min. charged Potassium permanganate (1.5 g, 0.094 mol)). After completion of reaction filtered through a celite bed and washed with water (10.0 ml). The aqueous layer pH was adjusted to 3 using hydrochloric acid (2 ml). Added sodium phosphate (2.5 g, 0.0152 mol) and toluene (25.0 ml). The reaction mixture extracted with dichloromethane (5 x 25 ml). The organic solution was dried with (Na2SO4) distilled under vacuo to give compound 16 as oil. To the residue toluene (10 ml) was added and stirred at 0 °C for about 30 min. The solid was filtered and washed with toluene (5 ml) afford the pure compound 16 (0.83g, 76%);

Mp: 124–125 °C; [α] 25 D = – 24.3 (c l.0, acetone);

1H NMR (CDCl3, 400 MHz): δ 0.93 (t, J = 7.7 Hz, 3H), 1.67–1.76 (m, 1H), 1.99–2.13 (m, 3H), 2.49 (t, J = 7.7 Hz, 2H), 3.37 (m, J = 8.7, 5.8 Hz, 1H), 3.52-3.58 (m, 1H), 4.64 (dd, J = 10.6, 4.8 Hz, 1H);

13C NMR (CDCl3, 125 MHz) : δ 10.8, 18.2, 21.9, 30.8, 43.9, 55.4, 173.7, 177.2;

IR (CHCl3) ν max : 2975, 1731, 1620 cm–1; ESI-MS: m/z 170.0 [M- +1].

Orchid Chemicals & Pharmaceuticals Ltd

Centre for Pharmaceutical Sciences, JNT University

Inogent Laboratories (A GVK BIO Company)

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.



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Filed under: PROCESS, spectroscopy Tagged: (2S)-2- Oxopyrrolidin-1-yl)butanoic acid.............Key Levetiracetam intermediate, 2S)-2- Oxopyrrolidin-1-yl)butanoic acid, LEVETIRACETAM

(S)-2-amino-butanamide hydrochloride………. Key intermediate of Levetiracetam

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(S)-2-amino-butanamide hydrochloride………. Key intermediate of Levetiracetam

(S)-2-amino-butanamide hydrochloride

Key intermediate of Levetiracetam

  • CAS Number 7682-20-4
  • Linear Formula CH3CH2CH(NH2)CONH2 · HCl
  • Displaying
Stage B
(S)-2-aminobutyramide hydrochloride Preparation

Into the above (S)-2-aminobutyric acid methyl ester hydrochloride is added Isopropanol is then added, followed by the introduction of ammonia gas at a pressure about 60 psi (413 kPa) until the reaction is complete. After filtering to remove formed ammonium chloride, the solvent is partially evaporated and isopropanol hydrochloride is added. The mixture is stirred while solid product forms, then the solid is separated by filtration and washed with isopropanol.

The product was characterized by the following 1H NMR data (200 MHz, DMSO-d6): 0.9-1.0(t,3H), 1.8-1.9(Q,2H), 3.7-3.8(t, 1H), 7.5-7.7(Br,NH2), 8.0-8.2(Br,NH2)
1H NMR PREDICT
  • (2S)-2-aminobutanamide,hydrochloride NMR spectra analysis, Chemical CAS NO. 7682-20-4 NMR spectral analysis, (2S)-2-aminobutanamide,hydrochloride H-NMR spectrum

………..

13C NMR PREDICT

(2S)-2-aminobutanamide,hydrochloride NMR spectra analysis, Chemical CAS NO. 7682-20-4 NMR spectral analysis, (2S)-2-aminobutanamide,hydrochloride C-NMR spectrum

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.



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COCK SAYS MOM CAN TEACH YOU NMR

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Filed under: spectroscopy Tagged: (S)-2-amino-butanamide hydrochloride, intermediate, LEVETIRACETAM

Methyl (S)-aminobutyrate hydrochloride…..Levetiracetam intermediate

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Methyl (S)-aminobutyrate hydrochloride…..Levetiracetam intermediate

(s)-2-aminobutyric Acid Methyl Ester
PATENT

http://www.google.im/patents/WO2003014080A2?cl=en

(S)-amino butyric acid
Step 1 – Synthesis of methyl (S)-aminobutyrate hydrochloride
……………………………(23) …………………………………………………….(24)
5.0g of (S)-amino butyric acid (23) was suspended in 50 ml of methanol and stirred at 0-5°C. 6.35g of thionyl chloride was added dropwise over 45 min to form a clear solution. After stirring for 20 hours at room temperature, the reaction was concentrated under reduced pressure to dryness and the almost colourless residue solidified to give the required product which was dried in an oven at 50°C under vacuum (7.6g; 102% crude yield). The same reaction was scaled-up from 200g of the amino acid and provided 296g (99.5% yield) of product (24). Analysis gave the following results:
1H NMR (DMSO-de) : d 0.94 (3H, t) 1.88 (2H, q) 3.75 (3H, s) 3,9 (1H, m) 8,8
(3H, m). m.p. : 107°C-110°C IR : 2876 cm 1, 1742 cm 1.
TLC : Si02, 20%MeOH/80%EtOAc/ l%NH OH, UV & IR. (TLC is an abbreviation for thin layer chromatography).
logo
1H NMR PREDICT
(S)-2-aminobutyric acid methyl ester NMR spectra analysis, Chemical CAS NO. 15399-22-1 NMR spectral analysis, (S)-2-aminobutyric acid methyl ester H-NMR spectrum
13C PREDICT
logo
(S)-2-aminobutyric acid methyl ester NMR spectra analysis, Chemical CAS NO. 15399-22-1 NMR spectral analysis, (S)-2-aminobutyric acid methyl ester C-NMR spectrum
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.




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Filed under: PROCESS, spectroscopy Tagged: intermediate, LEVETIRACETAM, Methyl (S)-aminobutyrate hydrochloride

LINEZOLID

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Skeletal formula of linezolid

LINEZOLID

N- [[(5S) – 3 – [3 -Fluoro-4- (4-morpholinyl)phenyl] -2-oxo- 5 -oxazolidinyl] methyl] acetamide and marketed by Pfizer in US under brand name Zyvox. Linezolid is a synthetic antibacterial agent of the oxazolidinone class. It is used for the treatment of infections caused by multi-resistant bacteria including streptococci and methicillin-resistant Staphylococcus aureus.


(S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl] acetamide.

N-[[(5s)-3-(3-fluoro-4-morpholin-4-ylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide
PRODUCT PATENT

US 5688792 (1997 to Pharmacia & Upjohn)

CAS No.: 165800-03-3
Synonyms:
View More
Formula: C16H20FN3O4
Exact Mass: 337.14400

13C

1H NMR AND 13C PREDICT

1H NMR PREDICT

N-[[(5S)-3-(3-fluoro-4-morpholin-4-ylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide NMR spectra analysis, Chemical CAS NO. 165800-03-3 NMR spectral analysis, N-[[(5S)-3-(3-fluoro-4-morpholin-4-ylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide H-NMR spectrum

13C NMR PREDICT

N-[[(5S)-3-(3-fluoro-4-morpholin-4-ylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide NMR spectra analysis, Chemical CAS NO. 165800-03-3 NMR spectral analysis, N-[[(5S)-3-(3-fluoro-4-morpholin-4-ylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide C-NMR spectrum

COSY
PREDICT

HMBC

ORIGINAL 1H NMR…………...http://www.selleckchem.com/products/Linezolid(Zyvox).html

INTERMEDIATES USED

Arkivoc, , vol. 2012, # 6 p. 45 – 56

WO2011/137222 A1, ;


Union Quimico Farmaceutica, S.A. (UQUIFA) Patent: EP2163547 A1, 2010 ; Location in patent: Page/Page column 11 ;

THE REGENTS OF THE UNIVERSITY OF CALIFORNIA; GARG, Neil K.; RAMGREN, Stephen D.; SILBERSTEIN, Amanda L.; QUASDORF, Kyle W. Patent: WO2012/94622 A2, 2012 ; Location in patent: Page/Page column 31-32 ;

Lianhe Chemical Technology Co., Ltd. Patent: EP2388251 A1, 2011 ; Location in patent: Page/Page column 11 ;

Tammana, Rajesh; Vemula, Kiran Kumar; Guruvindapalli, Ramadasu; Yanamandr, Ramesh; Gutta, Madhusudhan Arkivoc, 2012 , vol. 2012, # 6 p. 45 – 56

Union Quimico Farmaceutica, S.A. (UQUIFA) Patent: EP2163547 A1, 2010 ; Location in patent: Page/Page column 10 ;


Song, Lirong; Chen, Xiaobei; Zhang, Shilei; Zhang, Haoyi; Li, Ping; Luo, Guangshun; Liu, Wenjing; Duan, Wenhu; Wang, Wei Organic Letters, 2008 , vol. 10, # 23 p. 5489 – 5492

Union Quimico Farmaceutica, S.A. (UQUIFA) Patent: EP2163547 A1, 2010 ; Location in patent: Page/Page column 10 ;

JUBILANT LIFE SCIENCES LIMITED; BISWAS, Sujay; PANDA, Atulya, Kumar; GUPTA, Ashish, Kumar; SINGH, Shishupal; TIWARI, Praveen; VIR, Dharam; THOMAS, Saji Patent: WO2013/111048 A1, 2013 ; Location in patent: Page/Page column 24; 25 ;


Perrault, William R.; Pearlman, Bruce A.; Godrej, Delara B.; Jeganathan, Azhwarsamy; Yamagata, Koji; Chen, Jiong J.; Lu, Cuong V.; Herrinton, Paul M.; Gadwood, Robert C.; Chan, Lai; Lyster, Mark A.; Maloney, Mark T.; Moeslein, Jeffery A.; Greene, Meredith L.; Barbachyn, Michael R. Organic Process Research and Development, 2003 , vol. 7, # 4 p. 533 – 546


US6362334 B1, ; Example 13 ;

NMR OF INTERMEDTIATES

………….
…….
………
……………
……………
  • Linezolid is a pharmaceutically active compound useful as an antibacterial agent, e.g. for the treatment of diabetic food infections caused by Gram-positive bacteria. It is represented by the formula (I),
    Figure imgb0001
  • [0003]
    The marketed pharmaceutical compositions are a sterile isotonic solution for an i.v. infusion, a tablet for oral administration and an aqueous suspension for oral administration. They are marketed, i.e., under brand name ZYVOX by Pfizer.
  • [0004]
    The molecule of linezolid has one asymmetric carbon in the molecule allowing for 2 enantiomers; the marketed compound is the (S)-enantiomer. In the above-marketed compositions, linezolid is present as a free base.
  • [0005]
    Hereinunder, the name linezolid will be used as the generic name for N-(3-(3-fluoro-4-(morpholin-4-yl)phenyl)-2-oxooxazolidin-5(S)-ylmethyl)acetamide, unless indicated to the contrary.
  • [0006]
    Linezolid was first disclosed in WO 95/07271 ( EP 0717738 US 5,688,792 ) of the Upjohn Company.
  • [0007]
    Various processes for making linezolid are known in the art. In particular, the important ones are these, the final step of which comprises acetylation of an amine precursor of the formula (II) with an acetylhalide or acetic anhydride (see, e.g., WO 2005 099353 ),
    Figure imgb0002
  • [0008]
    This amine precursor (II) may be made from various starting materials, e.g.:
    1. a) By a reduction of an azide compound of formula (III) by a suitable reductant ( WO2006/091731 , WO 95/07271 , US 5837870 , WO2009/063505 US 7291614 ),
      Figure imgb0003

      The starting compound (III) may be made from the corresponding tosylate or chloride of general formula (VII) below ( WO 2005/099353 ).

    2. b) By a decomposition of a phthalimide compound of formula (IV), e.g. by methylamine ( WO95/07271 ) or by hydrazine ( US 5837870 ),
      Figure imgb0004

      The starting compound (IV) may be made from the same tosylate or chloride as sub a) ( WO2005/099353 ) or by a cyclization of the oxazolidine ring ( WO 99/24393 , WO2006/008754 ).

    3. c) From a sulfonate compound of formula (V),
      Figure imgb0005

      by treatment with ammonium hydroxide in isopropanol or THF ( WO 95/07271 ) or by treatment with ammonia under enhanced pressure ( WO 97/37980 ).

    4. d) By a reduction of an imine (VI),
      Figure imgb0006

      wherein R2 is a chlorophenyl, bromophenyl or 2,4,-dichlorophenyl moiety ( WO 2007/116284 ).

  • [0009]
    Except of the imine (VI), each of the preceded synthetic approaches is based on a step of converting a starting material of the general formula (VII),
    Figure imgb0007

    wherein L is a suitable leaving group, for instance a halogen or an alkyl-or aryl sulfonyloxy group,
    by a reaction with a nitrogen nucleophile (an azide salt, phthalimide salt, ammonia or ammonium hydroxide), followed, if necessary, by a next step of conversion of the formed reaction intermediate (e.g., compound (III) or compound (IV)) into the amino/compound (II). Apparently, making the starting amine-compound (II) in a good yield and purity is the key aspect of commercial success of any of the above synthetic routes yielding linezolid. However, the known approaches have various drawbacks, for instance serious toxicity and explosion hazard of the azide salts, long reaction times and hazardous agents (hydrazine, methyl amine) in using the phthalimide intermediate, low yields and many side products at the ammonium hydroxide approach, or harsh reaction conditions in reaction with ammonia.

Linezolid [(S)-N-[[3-(3-Fluoro-4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide] is an antimicrobial agent. Linezolid is an oxazolidinone, having the empirical formula C16H20FN3Oand the following structure (1):
Figure US20060252932A1-20061109-C00001
Linezolid (1) is described in The Merck Index (13th edition, Monograph number: 05526, CAS Registry Number: 165800-03-3) as white crystals, with a melting point of 181.5-182.5°. Linezolid (1), as well as a process for its preparation, is disclosed in U.S. Pat. No. 5,688,792 (Example 5), European Patent No. 717738, Israeli Patent No. 110,802, Canadian Patent No. 2,168,560, and International Patent Publication WO 95/07271.
U.S. Pat. No. 5,688,792 discloses the antibacterial agent linezolid as well as a process for its preparation. EXAMPLE 5 reports the linezolid produced had a mp of 181.5-182.5°.
There are many other disclosures of processes to prepare linezolid. J. Med. Chem., 39(3), 673-9 (1996) reports the linezolid was, “recrystallized from ethyl acetate and hexanes . . . white crystals, m.p. 181.5-182.5C.” It also sets forth the IR spectrum as “3284, 3092, 1753, 1728, 1649, 1565, 1519, 1447, 1435”.
Tetrahedron Lett., 40(26), 4855 (1999) discloses linezolid and a process to prepare linezolid. However, this document does not set forth the melting point or IR spectrum of the linezolid prepared.
U.S. Pat. No. 5,837,870 (International Publication WO97/37980 of PCT/US97/03458) discloses a process to prepare linezolid. Linezolid is described in EXAMPLE 18, which does not set forth the melting point or IR spectrum of the linezolid prepared.
International Publication WO99/24393 of PCT/US98/20934 discloses a process to prepare linezolid. Linezolid is described in EXAMPLES 8, 9 and 12 which do no set forth the melting point or IR spectrum of the linezolid prepared.
The form of linezolid being used in the clinical trials to support the filing of the NDA is Form II.
Linezolid (1) is marketed in the United States by Pfizer, Inc. as an injection, tablets, and oral suspension under the name ZYVOX®. Its main indications are nosocomial pneumonia, skin and skin-structure infections, and vancomycin-resistant Enterococcus faecium infections.
U.S. Pat. No. 5,688,792 claims linezolid (1) and its use for the treatment of microbial infections. This patent also discloses, but does not claim, the following method of preparation:
Figure US20060252932A1-20061109-C00002
This method of preparation was also disclosed in Bricker, et al., J. Med. Chem., 39 673 -679 (1996), where it was stated that the above route avoids the use of phosgene to make the carbamate precursor of the oxazolidinone ring. The authors also disclose that the use of NaNcan be avoided by using potassium phthalimide, followed by deblocking of the phthalimide with aqueous methyl amine.
In the above-described synthesis, the intermediate amine, S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (2)
Figure US20060252932A1-20061109-C00003

is reacted without isolation with acetic anhydride as an oily product, or in solution, to produce the acetamide, linezolid (1). This is followed by procedures for isolating the linezolid (1) such as those described in U.S. Pat. No. 5,688,792, at col. 15, 11. 22-28 (chromatography and separation of the desired fraction, followed by evaporation and trituration of the product to obtain pure linezolid (1)).

In the above-described syntheses, the intermediate azide R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide (3)
Figure US20060252932A1-20061109-C00004

is reduced to its corresponding amine, S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (2) in the solvent ethyl acetate by hydrogenation using hydrogen gas and a palladium/carbon catalyst. These reaction conditions lead to the production of an undesirable level of reaction by-products, and, following the acetylation of the intermediate amine (2) to linezolid (1), to undesirably high levels of bis-linezolid (4)

Figure US20060252932A1-20061109-C00005

http://www.google.com/patents/US20060252932

FIG. 1 shows the 1H-NMR spectrum of bis-linezolid (4)
FIG. 2 shows the 13C-NMR spectrum of bis-linezolid (4)
FIG. 3 shows the IR spectrum of bis-linezolid (4)

A Novel Synthesis of Oxazolidinone Derivatives (A Key Intermediate of Linezolid)

Pingili Krishna Reddy1,2, K. Mukkanti2 and Dodda Mohan Rao1*
1Symed Research Centre, Plot No. 89/A, Phase-I, Shapoornagar, IDA Jeedimetla, Hyderabad, Andhra Pradesh, India
2Center for Pharmaceutical sciences, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad, India

http://www.orientjchem.org/vol29no3/a-novel-synthesis-of-oxazolidinone-derivatives-a-key-intermediate-of-linezolid/

Reddy P. K, Mukkanti K, Rao D. M. A Novel Synthesis of Oxazolidinone Derivatives (A Key Intermediate of Linezolid). Orient J Chem 2013;29(3). doi : http://dx.doi.org/10.13005/ojc/290322

N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (7a):

IR (KBr, cm-1): 3338 (N-H stretching), 3117, 3066 (aromatic C-H stretching), 2971, 2863, 2818 (aliphatic C-H stretching), 1738, 1662 (C=O stretching), 1545, 1516,1453 (aromatic C=C stretching), 1425 (C-N stretching), 1381 (aliphatic C-H bending), 1334 (C-F stretching), 1274 (C-O stretching), 1198, 1177 (C-N bending), 1117, 1081 (aromatic C-H bending).

1H NMR (CDCl3) δ ppm: 7.44 (m, 1H), 7.26 (m, 1H), 6.99 (m, 1H), 6.01 (t,1H), 4.76 (m, 1H), 4.02 (m, 2H), 3.80 (m, 4H), 3.61(m, 2H), 3.05 (m, 4H), 2.02 (t, 3H):

C13NMR(CDCl3) δppm: 171.33, 156.87, 154.44, 136.40, 132.84, 118.67, 113.81, 107.52, 71.96, 66.76, 50.79, 47.46, 41.68, 22.81. MS: 338 (M++H);

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ARKIVOC 2012 (vi) 45-56 Page 45 ©ARKAT-USA, Inc.

An expeditious construction of 3-aryl-5-(substituted methyl)-2- oxazolidinones: a short and efficient synthesis of Linezolid

Rajesh Tammana,a,b Kiran Kumar Vemula,a Ramadasu Guruvindapalli,a Ramesh Yanamandra,c and Madhusudhan Gutta* a
aDepartment of Research & Development, Inogent Laboratories Pvt. Ltd.,

A GVK BIO Company, 28A, IDA, Nacharam, Hyderabad 500 076, Andhra Pradesh, India

bCentre for Pharmaceutical Sciences, Institute of Science and Technology, Jawaharlal Nehru Technological University, Hyderabad 500 072, Andhra Pradesh, India

cDepartment of Analytical Research & Development, GVK Biosciences Pvt. Ltd., 28A, IDA, Nacharam, Hyderabad 500 076, Andhra Pradesh, India

E-mail: madhusudhan.gutta@inogent.com

http://www.arkat-usa.org/get-file/42622/
N-(((S)-3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide 1 (Linezolid) 1 was prepared according to the method described in literature.12,15

Mp 182-183 °C, (lit.12a 181.5- 182.5 °C); enantiomeric purity 99.9% (by chiral HPLC);

IR (KBr): ν 3343 (NH), 3075 (Ar-H), 2967 (CH), 1741 (C═O), 1660 (C═O) cm-1 ;

1H NMR (CDCl3): δ 2.03 (s, 3H), 3.04-3.07 (t, 4H), 3.56-3.77 (m, 3H), 3.86-3.89 (t, 4H), 4.00-4.06 (t, 1H), 4.74-4.79 (m, 1H), 5.96 (s, 1H), 6.90- 6.96 (t, 1H), 7.06-7.10 (d, 1H), 7.43-7.48 (d, 1H).

13C NMR (DMSO-d6): δ 22.4, 41.4, 47.3, 50.6, 66.1, 71.5, 106.4, 114.0, 119.1, 133.3, 135.5, 154.0, 156.2, 170.0;

ESI-MS (C16H20FN3O4): m/z (%) 338.18 (100, M+ +1).

12. (a) Brickner, S. J.; Hutchinson, D. K.; Barbachyn, M. R.; Manninen, P. R.; Ulanowicz, D. A.;
Garmon, S. A.; Grega, K. C.; Hendges, S. K.; Toops, D. S.; Ford, C. W.; Zurenko, G. E. J.
Med. Chem. 1996, 39, 673. (b) Barbachyn, M. R.; Brickner, S. J.; Hutchinson, D. K. U.S.
patent 5688792; 1997; Chem. Abstr. 1995, 123, 256742. (c) Dhananjay, G. S.; Nandu, B. B.;
Avinash, V. N.; Kamlesh, D. S.; Anindya, S. B.; Tushar, A. N. PCT Int. Appl. 063505, 2009;
Chem. Abstr. 2009, 150, 515152.
13. (a) Imbordino, R. J.; Perrault, W. R.; Reeder, M. R. PCT Int. Appl. 116284, 2007; Chem.
Abstr. 2007, 147, 469356. (b) Pearlman, B. A.; Perrault, W. R.; Barbachyn, M. R.;
Manninen, P. R.; Toops, D. S.; Houser, D. J.; Fleck, T. J. U.S. Patent 5837870, 1998; Chem.
Abstr. 1998, 130, 25061. (c) Perrault, W. R.; Pearlman, B. A.; Godrej, D. B.; Jeganathan, A.;
Yamagata, K.; Chen, J. J.; Lu, C. V.; Herrinton, P. M.; Gadwood, R. C.; Chan, L.; Lyster, M.
A.; Maloney, M. T.; Moeslein, J. A.; Greene, M. L.; Barbachyn, M. R. Org. Proc. Res. Dev.
2003, 7, 533.
14. (a) Yu, D. S.; Huang, L.; Liang, H.; Gong, P. Chin. Chem. Lett. 2005, 16, 875. (b) Pearlman,
B. A. PCT Int. Appl. 9924393, 1999; Chem. Abstr. 1999, 130, 338099. (c) Weigert, F. J. J.
Org. Chem. 1973, 38, 1316.
15. (a) Wang, M.; Tong, H. CN patent 101220001, 2008. (b) Mohan Rao, D.; Krishna Reddy, P.
PCT Int. Appl. 099353, 2005; Chem. Abstr. 2005, 143, 440395. (c) Mohan Rao, D.; Krishna
Reddy, P. PCT Int. Appl. 008754, 2006; Chem. Abstr. 2006, 144, 170978.

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Org. Proc. Res. Dev.20037 (4), pp 533–546
DOI: 10.1021/op034028h

Organic Process Research and Development, 2003 , vol. 7, # 4 p. 533 – 546

http://pubs.acs.org/doi/abs/10.1021/op034028h

Abstract Image
Since 1993, a significant process research and development effort directed towards the large-scale synthesis of oxazolidinone antibacterial agents has been ongoing in both Early Chemical Process Research and Development, and Chemical Process Research and Development at Pharmacia. This work has led to the successful development of the current commercial process to produce Zyvox (linezolid), recently approved by the FDA as an antibacterial. While this synthesis is appropriate for the preparation of linezolid in particular, a more convergent and versatile synthesis was developed for the rapid preparation of numerous other oxazolidinone analogues. Toward this end, economical methods for the large-scale preparation of N-[(2S)-2-(acetyloxy)-3-chloropropyl]acetamide and tert-butyl [(2S)-3-chloro-2-hydroxypropyl]carbamate 27 from commercially available (S)-epichlorohydrin via the common intermediate (2S)-1-amino-3-chloro-2-propanol hydrochloride 2a were developed. Also, general methods for coupling these reagents with N-aryl carbamates to giveN-aryl-5(S)-aminomethyl-2-oxazolidinone derivatives in one step were developed. These reagents and procedures have proven widely applicable in the preparation of a diverse array of oxazolidinone analogues such as 23 and 28 in both process and medicinal chemistry research.

(S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo- 5-oxazolidinyl]methyl]acetamide: Linezolid: Zyvox

HPLC analyses showed the first and second crops to be 98.9 and 94.6 wt % linezolid, respectively, with <0.2% enantiomer in each; also, an additional 9.7% yield of linezolid was detected in the filtrate by external standard HPLC (total ) 80.6%). Analysis data for 1st crop material: mp ) 73-76 °C;

1 H NMR (CDCl3, 400 MHz)
δ 7.43 (dd, J ) 14.4, 2.4 Hz, 1H), 7.07 (dd, J ) 8.8, 2.0 Hz, 1H), 6.91 (t, J ) 8.8 Hz, 1H), 6.43 (br t, 1H), 4.77 (m, 1H), 4.02 (t, J ) 9.2 Hz, 1H), 3.86 (t, J ) 4.4 Hz, 4H), 3.76 (dd, J ) 8.8, 6.8 Hz, 1H), 3.66 (m, 2H), 3.05 (t, J ) 4.8 Hz, 4H), 2.02 (s, 3H);

13C NMR (CDCl3, 100 MHz)
δ 23.07 (q), 41.93 (t), 47.66 (t), 51.00 (t), 66.95 (t), 71.99 (d), 107.56 (dd, JC-F ) 26.16 Hz), 113.97 (dd, JC-F ) 3.02 Hz), 118.85 (dd, JC-F ) 4.03 Hz), 132.90 (sd, JC-F ) 4.03 Hz), 136.58 (sd, JC-F ) 9.06 Hz), 154.42 (s), 155.50(sd, JC-F ) 246.53 Hz), 171.19 (s)

MS (EI) m/z (relative intensity) 337 (90), 293 (81), 209 (100);

[R]25D ) -16 (c ) 1.05, ethanol).

Anal. Calcd for C16H20FN3O4: C, 56.97; H, 5.97; N, 12.46; found: C, 56.86; H, 6.05; N, 12.44

HPLC (99.0 wt %, 98.9 area % linezolid, tR 1.60 min) conditions: InertsilODS-2 5.0 µm 150 mm × 4.6 mm, flow rate ) 2.0 mL/ min, gradient elution from 40:60 A:B to 80:20 A:B over 10 min; A ) acetonitrile; B ) water. External standard HPLC analysis of the filtrate showed
d 12.9% and 7.6% yield of linezolid and 8, respectively.
SEE HPLC AT   http://file.selleckchem.com/downloads/hplc/S140801-Linezolid-Zyvox-HPLC-Selleck.pdf
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http://www.google.com/patents/WO2007064818A1?cl=en

Linezolid [(S)-N-[[3-(3-Fluoro-4-morpholinyl)phenyl]-2-oxo-5- oxazolidinyljmethyl] acetamide} is an antimicrobial agent. Linezolid is an oxazolidinone, having the empirical formula C16H20FN3O4 and the following structure:
Figure imgf000002_0001

Linezolid

Linezolid is described in The Merck Index (13th edition, Monograph number: 05526, CAS Registry Number: 165800-03-3) as white crystals, with a melting point of 181.5-182.50C. Linezolid, as well as a process for its preparation, is described in U.S. Patent No. 5,688,792 (Example 5), European Patent No. 717738, Israeli Patent No. 110,802, Canadian Patent No. 2,168,560, and International Patent Publication WO 95/07271. Linezolid is marketed in the United States by Pfizer, Inc. as an injection, as tablets, and as an oral suspension under the name ZYVOX®. Its main indications are nosocomial pneumonia, skin and skin-structure infections, and vancomycin-resistant Enterococcus faecium infections.
U.S. Patent No. 5,688,792 describes linezolid and its use for the treatment of microbial infections. This patent also describes the following method for the preparation of linezolid:
Figure imgf000003_0001
This method of preparation was also described in Bricker, et al., J. Med. Chem., 39, 673 — 679 (1996), where it was stated that the above route avoids the use of phosgene to make the carbamate precursor of the oxazolidinone ring. The authors also disclose that the use OfNaN3 can be avoided by using potassium phthalimide, followed by deblocking of the phthalimide with aqueous methyl amine.
An analysis of the commercial tablet ZYVOX® shows the presence of desfluoro linezolid as an impurity of linezolid. An HPLC chromatogram of ZYVOX® is depicted in Figure 1. The desfluoro linezolid haviong a relative retention time (RRT) of 0.69 compared to the retention time of linezolid.
desfluoro linezolid of the following structure:
Figure imgf000008_0001
Desfluoro linezolid
As illustrated in Figure 1, this impurity is ideal for use as a reference standard since it is detectable by HPLC, and yet it is present in much less amounts than linezolid, having a RRT of 0.69 compared to the retention time of linezolid.
The isolated desfluoro linezolid is pure. Preferably it has about 95% purity by weight with respect to other compounds, including linezolid. Preferably, the desfluoro linezolid is isolated in about 99.3% purity by weight. Thus, the isolated desfluoro linezolid contains less than about 5%, preferably less than about 2%, and even more preferably less than about 1%, by weight, linezolid.
The isolated desfluoro linezolid of the present invention can be characterized by data selected from: 1H NMR (400MHz, DMSO-d6) δ (ppm): 1.8a (s), 3.04 (brt), 3.40 (t), 3.68 (m), 3.72 (brt), 4.04 (t), 4.67 (m), 6.95 (d), 6.95 (d), 737 (d), 7.37 (d) and 8.21 (t); 13C NMR (lOOMHz, DMSO-d6) δ (ppm): 22.8, 41.9, 48.0, 49.2, 66.5, 71.7, 115.9, 115.9, 119.9, 119.9, 130.9, 148.0, 154.7, 170.0; EI+m/z (MH+): 319; and IR spectra on KBr at 1523, 1555, 1656, 1731, 2830, 2926, 2968 and 3311 cm‘1.
The isolated desfluoro linezolid of the present invention may be characterized by a 1H NMR, substantially as depicted in figure 2. The isolated desfluoro linezolid of the present invention may be characterized by 13C NMR, substantially as depicted in figure 3. The isolated desfluoro linezolid of the present invention may be characterized by an IR spectrum substantially as depicted in figure 4. The isolated, desfluoro linezolid of the present invention may be characterized by an Mass spectrum substantially as depicted in figure 5. The isolated desfluoro linezolid of the present invention may be prepared by performing the process described in U.S. Patent No. 5,688,792, with l-fluoro-4- nitrobenzene instead of 3,4-difluoronitrobenzene, according to the following scheme:
Figure imgf000009_0001

Desfluoro Linezolid

The desfluoro linezolid of the present invention is isolated by a process comprising the following steps; a) combining (5R)-[[3-[4-(4-morpholinyl)phenyl]-2- oxo-5-oxazolidinyl]methyl]azide with an organic solvent, preferably a C1-C4 alkyl ester or a C6 to C12 aromatic hydrocarbon, more preferably toluene or ethylacetate, most preferably toluene, and hydrogen gas in the presence of a catalyst to obtain a reaction mixture containing (5S)-[[3-[4-(4-morpholinyl)phenyl]-2-oxo-5- oxazolidinyl]methyl] amine; b) filtering the reaction mixture to obtain a solution containing (5S)-[[3-[4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl}methyl]amine; c) adding acetic anhydride to the solution to obtain a precipitate; and d) recovering and drying the precipitate to obtain isolated desfluoro linezolid. Preferably, recovering of the precipitate in step d) is carried out by filtering or decanting. Preferably, the catalyst in step a) is selected from the group consisting of Pd/C, Raney Nickel, and noble metal catalysts, more preferably the catalyst is Pd/C. The isolated desfluoro linezolid of the present invention is useful as a reference marker for linezolid. As such, it may be used in order to detect the desfluoro linezolid impurity in a linezolid sample.
Step 7. Preparation of N-rr(5S)-3-r4-(4-moφholinyl)phenyl1-2-oxo-5- oxazolidinyl]methyl1acetamide (des-fluoro-linezolid). In a IL reactor, 6 g (5R)-[[ 3-(4-morpholinyl)phenyl]-2-oxo-5- oxazolidinyl]methyl]azide were charged with 0.7L toluene followed by 0.6 g Pd/C (10% Pd/C containing 52% water). The system was bubbled with ammonia (gas) during 2 h, and then flushed three times with nitrogen and 3 times with hydrogen. The pressure of hydrogen was set to 1.5 arm. The reaction mixture was stirred at RT and the reaction followed up until completion. The reaction mixture was filtered and the solution was treated with 60 ml acetic anhydride at RT. The precipitate was filtered and dried to obtain 3.3 g of desfluoro linezolid (purity: 99.3%). Desfluorolϊnezolid 1H-NMR and 13C-NMR identification
Figure imgf000015_0001
Figure imgf000015_0002
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HTTP://WWW.GOOGLE.COM/PATENTS/US6559305

 
Example 1 Preparation of Crystal Form II of Linezolid
Linezolid with better than 99.8% enantiomeric purity, less than 0.2% of the R enantiomer, (1.99 grams) is mixed with ethyl acetate (100 mL). The flask is stoppered and heated to 65° with constant stirring in a temperature controlled oil bath. The linezolid is completely dissolved and the mixture is stirred for an additional 10 minutes. The temperature is maintained at 55° in the flask and one neck of the flask is unstoppered to allow slow evaporation of the solvent. A gentle stream of nitrogen is blown across the open neck to aid in evaporation. Solids spontaneously precipitated from solution and the volume is reduced by about 25% of the initial volume. The flask is sealed and mixed for 90 minutes while maintaining the mixture at 55°. The mixture was then cooled to about 23° while being stirred. The solids are isolated by vacuum filtration using a sintered glass funnel to give linezolid in crystal form. Analysis by powder X-ray diffraction indicates that the solids are linezolid crystal Form II.
 
 
 
 
 
 
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HTTP://WWW.GOOGLE.COM/PATENTS/US7989618

 
Example 1 Linezolid Dihydrochloride
20 g of linezolid are dissolved in 750 ml of acetone at about 30° C. The solution is kept at about 30° C. and 8 ml of concentrated hydrochloric acid (37% w/w aqueous solution) are added, thus immediately causing linezolid dihydrochloride to precipitate as a white solid. The mixture is kept under stirring at about 30° C. for approximately 30 minutes, then refluxed under stirring for about 2 hours. The mixture is left to cool to room temperature, then cooled on ice-water bath, under stirring, for about 2 hours. A white solid precipitates which is filtered with suction, washed with 30 ml of acetone and dried under vacuum at about 50° C.
A solid water-soluble crystalline product is obtained, characterized by an XRPD spectrum substantially as reported in FIG. 3, wherein the most intense diffraction peaks fall at 13.9; 18.2; 19.1; 19.7; 22.2; 22.9; 23.6; 25.3; 27.1; 28.4±0.2° in 2θ; and by a DSC thermogram substantially as reported in FIG. 4, characterized by an exothermic peak around 178±2° C. The acid-base potentiometric titre is double while the argentimetric one is 17.71% (theor. dihydrochloride 17.77%). Purity 99.8% as determined by HPLC.
1H NMR (300 MHz, DMSO-d6), ppm: 8.37 (bt, 1H), 7.50 (dd, 1H, J=15.3 Hz, J=2.7 Hz), 7.10 (m, 2H), 4.68 (m, 1H), 4.05 (t, 1H, J=9.0 Hz), 3.70 (m, 5H), 3.36 (t, 2H, J=5.1 Hz), 3.07 (t, 4H, J=4.5 Hz), 1.80 (s, 3H).

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http://www.google.com/patents/EP2690100A1?cl=en

Example 3

  • [0034]
    To a 25 ml, round-bottomed flask equipped with a magnetic stirring bar was charged “amine” (0.49 g) followed by water (8.30 ml). A heterogeneous mixture was stirred and hydrochloric acid (0.12 mL, 35 %) was added. A homogenous solution was obtained. The solution was cooled down in an ice-water bath to 0°C. Acetic anhydride (0.31 mL) was added followed by sodium bicarbonate (0.45 g). Carbon dioxide was immediately released and a formation of white precipitate was observed. The precipitate was filtered off and the filter cake was washed with water (10 ml). The filter cake was collected and dried (100 mbar) at 70°C overnight. An off-white solid linezolid (0.26 g) was isolated.

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PATENT

http://www.google.com/patents/WO2007116284A1?cl=en

Example 3 Preparation of (S)~N-[3-(3-fiuoro~4~morpholin-4-yI-ρhenyI)~2-oxo- oxazolidin-5~ylmethyl]-acetarnide (Linezo!id)
Figure imgf000011_0001
Method A
To (S)-5-{[(4-chloro-benzylidene)-amino]-methyl}-3-(3-fluoro-4-morpholin-4-yl- phenyl)-oxazolidin-2-one (129.5g, 31 mmol, 1.0 eq.) is added ethyl acetate (935 mL) and water (935 mL). To the heterogeneous mixture is added 12M aq. HCl (51.58 mL, 620 mmol, 2.0 eq.). Within minutes, the solid went into solution and the reaction mixture is biphasic. After stirring the emulsion at ambient temperature for 2 hours, HPLC assay showed the hydrolysis reaction to be complete (HPLC conditions: YMC 5μ ODS-AM 150 nm X 4.6 nm column, eluting with CH3CN /water + 0.1% TFA from 20% CH3CN to 80% CH3CN in 8 min at 0.5 mL/min, detecting at 254nm, Retention time of (S)-N-[3-(3-fluoro-4-morpholin-4-yl- phenyl)-2-oxo-oxazolidin-5-ylmethyl]-amine is 3.2 min). The phases are separated, the organic layer is discarded, and the aqueous layer is washed with ethyl acetate (500 mL). CH2Cl2 (900 mL) is added and the pH is adjusted to 6.7 with ~ 25 mL aq. 50% aq. NaOH. With constant stirring, Ac2O (58.49 mL, 620 mmol, 2.0 eq.) is added in one portion and the pH dropped to 2. The pH is then readjusted to 6 using 50% aq. NaOH. The pH is adjusted to ca. 7.1 with 50% aq. NaOH and the phases separated. The aqueous phase is extracted with CHiCl2 (800 mL) and the organics are combined and concentrated to ~1L in volume. Ethyl acetate (IL) is added and the volume is reduced to 1.5 L under vacuum. Another IL of ethyl acetate is added and volume is reduced again to IL under vacuum. The resultant slurry is cooled to 00C and the precipitate collected by vacuum filtration. The resulting solid is washed with ethyl acetate (250 mL). The crude product is dried under vacuum at 500C for 2 hours to give the title compound as Hnezolid crystalline Form I.
Figure imgf000012_0001
Following the general procedure of method A and making non-critical variations, but substituting (S)-5- { [2,4-dichloro-benzylidene)-amino]-methyl } -3-(3-fluoro-4-morphoIin-4-yl- phenyl)-oxazolidin-2-one (example 11) for (S)-5-{[(4-chloro-benzylidene)-amino]- methyl}-3-(3-fluoro-4-morρholin-4-yl-phenyl)-oxazolidin-2-one, the title compound is obtained.
Figure imgf000012_0002
Following the general procedure of method B and making non-critical variations, but substituting (S)-5-{ [4-bromo-benzylidene)-amino] -methyl }-3-(3-fluoro-4-morpholin-4-yl~ phenyl)-oxazolidin-2-one (example 9) for (S)-5-{[(4-chloro-benzylidene)-amino]- methyl}-3-(3-fluoro-4-morph.olin-4-yl-phenyl)-oxazoIidin-2-one, the title compound is obtained.

Example 4 Trituration (convert linezolid crystalline Form I to linezolid crystalline Form E) The product from Example (89.18 g) is transferred to a 3L round bottom flask equipped with a mechanical stirrer, thermocouple and heating mantel. Ethyl acetate (2.23 L, 15 mL/g) is added and seeded with Linezolid form II crystals and the slurry is heated to ca. 500C. A slight exotherm of 30C is observed. After 30 minutes of heating the form change is observable as the solid is changing to long needles. Stirring is continued for 2 hours at 500C, at which time the contents are cooled to ambient temperature and stirred for an additional 30 minutes. The contents are then cooled to 30C for 1.5 hours, filtered and washed with cold ethyl acetate (300 mL total). The resultant solids are dried under vacuum at 50°C for 18 hours to give Linezolid (78.12 g) Form II by XRD, 99.8 wt%, 99.9% ee. HPLC conditions: YMC 5μ ODS-AM 150 nm X 4.6 nm column, etuting with CH3CN /water + 0.1% TFA from 20% CH3CN to 80% CH3CN in 8 min at 0.5 mL/min, detecting at 254nm. TR (Linezolid) = 4.4 min; HPLC conditions: Chiralcel OJ-H 250 nm X 4.6 nm column, eluting with 90% CO2/ 10%MeOH at 3.0 mL/min, detecting at 255 nm. TR [title compound] = 3.6 min; TR (enantiomer of title compound) = 4.1 rain
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http://www.google.com/patents/EP2516408A1?cl=en

The polymorphic form obtained by following process disclosed in U.S. Pat. No. 5,688,792 is designated as Form I. Figure- 1 depicts the PXRD graph of Form I obtained by following prior art process. [15] Disadvantage of the process disclosed in U.S. Pat. No. 5,688,792 is that it involves use of n-butyl lithium. Due to its explosive nature it is difficult to handle at plant scale. Also, the said reaction is carried out at temperature of -78°C, which is difficult to attain during commercial production. Further the intermediate obtained requires purification by column chromatography. Column chromatography is a cumbersome technique and difficult to practice during commercial scale production.
The process for the preparation of Linezolid is also disclosed in Journal of Medicinal Chemistry (1996), 39(3), 673-9, U.S. Pat. Nos. 6,492,555, 5,837,870, 6,887,995, 7,307,163, 7,429,661, etc.

Linezolid was first disclosed in U.S. Pat. No. 5,688,792. The process for synthesis is as disclosed in Scheme-I

The synthetic reaction scheme of the present invention is as shown below.
Figure imgf000013_0001
Scheme-ll
Example 6: Synthesis of Linezolid Crude.
[140] Ethyl acetate (3500ml) and 10% palladium on carbon catalyst (6.0g) are added in autoclave having (R)- [N- 3 – (3 -Fluoro-4-morpholinylphenyl) -2-oxo- 5 -oxazolidinyl] methyl azide (lOOg) at 20-30°C. Cool the reaction mass & maintain 2-3kg hydrogen pressure at 15-20°C for 6-7 hrs. Filter it & wash the hyflo bed by Ethyl acetate
(100mlx2). Then add the Triethyl amine (35. lg) & Acetic anhydride (29.9g) slowly at 25-30°C under stirring. Cool the mix, filter it and wash the solid with chilled (0-5°C) Ethyl acetate (100 ml) followed by water (100mlx2). Finally product is dried at 55-60° C. Yield: 0.85.: Percentage 81%w/w.
[141]
[142] Example 7: Synthesis of Linezolid Pure
[143] Reflux the Acetone (1020ml) and Linezolid crude (lOOg) at 55-60°C for the 30
minutes. Filter the hot turbid solution & wash it with hot (55-60°C) acetone (50ml). Cool the reaction mixture at -5 to 0°C for 1 hour, wash the solid with chilled (-5 to 0°C) acetone (50ml). After drying the Linezolid semi pure (77g) add n-Propanol (308ml) reflux it at 95-100°C for 30 min & filter it by hot solution through hyflo bed. Cool the mix to 0-5°C for 1 hour and wash the solid with chilled (0-5°C) n-Propanol (77ml). Dry the material at 55-60°C. Yield: 0.73.: Percentage 73%w/w.
[144]
[145] Example 8: Synthesis of Linezolid
[146] Ethyl acetate (3500ml) and 10% palladium on carbon catalyst (6.0g) are added in autoclave having (R)- [N- 3 – (3 -Fluoro-4-morpholinylphenyl) -2-oxo- 5 -oxazolidinyl] methyl azide (lOOg) at 20-30°C. Cool the reaction mass & maintain 2-3kg hydrogen pressure at 15-20°C for 6-7 hrs. Filter it & wash the hyflo bed by Ethyl acetate. Distill out ethyl acetate at 75-90°C and then cool the reaction mass to 0-5°C. Add acetone (1000ml) & acetic anhydride (29.9g) at 0-5°C. Further, add Triethyl amine (37.8g) slowly at 0-5°C under stirring. Maintain the reaction mass at 0-5°C for 1-2 hrs. Heat the reaction mass to reflux at 65-75°C for 1 hr. Again cool the reaction mass to 0-5°C fori hr. Filter the solid wash it with acetone and water and dry it at 55-60C. Yield: 0.80.: Percentage 80 w/w.
 Example 9: Synthesis of Linezolid Form I
[149] Reflux n-propanol (400ml) and Linezolid (lOOg) at 95-100°C till all solid gets
dissolved. Add activated charcoal (2.0g) and heat for 30 mins. Filter thro hyflo bed. Heat the filtrate and concentrate the solution by partially removing n-propanol. Cool to 0-5°C and filter the solid and dry it at 55-60°C under vacuum. Yield: 0.9. : Percentage 90 w/w.

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https://acs.confex.com/acs/green08/techprogram/P52019.HTM

Wednesday, June 25, 2008 – 2:00 PM
New York (Capital Hilton)
128

Convergent Green Synthesis of Linezolid (Zyvox)

William R. Perrault, James B. Keeler, William C. Snyder, Christian L. Clark, Michael R. Reeder, Richard J. Imbordino, Rebecca M. Anderson, Nabil Ghazal, Stephen L. Seacrest, and Bruce A. Pearlman. Pfizer, Kalamazoo, MI
Pfizer has developed a novel, convergent, green, second generation synthesis of Linezolid (the active ingredient in ZyvoxTM). The second generation process will replace the launch process after approval by appropriate regulatory agencies and has numerous green chemistry benefits: overall yield is increased by 8%; total waste is reduced by 56%; non-recycled w is eliminated. At current volumes, total waste will be reduced 1.9 million kilograms per year and 1.7 million kg per year non-recyclable waste will be eliminated. The improved process utilizes a highly efficient low dilution convergent synthesis to replace the more dilute linear synthesis utilized in the launch process. The key chlorohydrin imine reagent 1 contains both the chiral center and the key 5-S-aminomethyl moiety of linezolid. In the launch process, S-1-chloro-2,3-propanediol was utilized to install the oxazolidinone functionality. However, this yielded a 5-S-hydroxymethyl group which required activation as the 3-nitrobenzenesulfonate and displacement with excess ammonia to generate the corresponding aminomethyl group of linezolid. The second generation process affords the oxazolidinone imine 3 in the convergent step. The penultimate 5-S-aminomethyl oxazolidinone 4 is then easily formed via hydrolysis with stoichiometric hydrochloric acid. Acylation of this amine with acetic anhydride, utilizing an improved Schotten Baumann reaction, affords high purity linezolid.

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http://www.google.com/patents/EP2072505A2?cl=en

    • WO 95/07271 , which specifically describes the synthesis of linezolid, namely [(S)-N-[[3-(3-fluoro-4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide], according to the following scheme:
      Figure imgb0001
    • [0003]
      Other synthetic routes for the preparation of linezolid are reported for example in US 6107519 and in Tetrahedron Letters, Vol 37, N° 44, pages 7937-7940, wherein the chiral compound shown below is used instead of glycidyl butyrate as a synthon containing the molecule stereocenter.
      Figure imgb0002
    • [0004]
      It should be appreciated that all of the known approaches to the preparation of linezolid make use of chiral synthons for the construction of the stereocenter. These are small molecules characterized by a high cost, therefore they are not suitable for the production of the compound on an industrial scale.
    • [0005]
      There is therefore the need for an alternative synthesis which provides oxazolidinone derivatives, linezolid included, from inexpensive starting materials, and which does not require a chiral synthon for the construction of the molecule, so that it can be used for the industrial preparation of such derivatives.

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http://pubs.rsc.org/en/content/articlelanding/2010/md/c0md00015a/unauth

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RSC Adv., 2013,3, 24946-24951

DOI: 10.1039/C3RA45186K



http://pubs.rsc.org/en/content/articlelanding/2013/ra/c3ra45186k#!divAbstract

Graphical abstract: Concise asymmetric synthesis of Linezolid through catalyzed Henry reaction
A new asymmetric synthesis of the antibiotic Linezolid was performed through a copper-catalyzed Henry reaction as the key step. The use of camphor-derived aminopyridine ligands helped to improve the yields of the chiral precursor and to obtain Linezolid in good overall yield and enantiomeric excess.

Linezolid 1. Mp: 181–182 C [lit. 181.5–182.5 C];
1 H-NMR (300 MHz; CDCl3) d 2.02 (s, 3H), 3.06 (t, J ¼ 4.7 Hz, 4H), 3.61– 3.78 (m, 3H), 3.87 (t, J ¼ 4.7 Hz, 4H), 4.03 (t, J ¼ 9.0 Hz, 1H), 4.72–4.82 (m, 1H), 6.17 (bt, 1H, exch. with D2O), 6.93 (t, J ¼ 9.0 Hz, 1H), 7.08 (dd, J1 ¼ 9.0 Hz, J2 ¼ 2.5 Hz, 1H), 7.44 (dd, J1 ¼ 14.4 Hz, J2 ¼ 2.5 Hz, 1H); ee ¼ 71%;

HPLC (Daicel CHIRALPAK-IA, hexane/i-PrOH ¼ 70 : 30, ow rate 0.8 mL min 1 , l ¼ 254 nm); tR (major) ¼ 14.1 min; tR (minor) ¼ 16.4 min. A true sample of (S)-Linezolid (ee > 98%) under the same HPLC conditions gave a tR ¼ 14.1 min.

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http://www.slideshare.net/vishwajeeta/introduction-new-ppt

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http://www.slideshare.net/pushechnikov/linezolid-case-study

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http://pubs.rsc.org/en/content/articlelanding/2011/cc/c1cc15503b#!divAbstract

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http://www.mdpi.com/1424-8247/3/7/1988/htm

Pharmaceuticals 03 01988 g001 1024

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Numbered structure of linezolid, showing the pharmacophore required for good activity (in blue) and desirable structural features (in orange).

Title: Linezolid
CAS Registry Number: 165800-03-3
CAS Name: N-[[(5S)-3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
Manufacturers’ Codes: PNU-100766; U-100766
Trademarks: Zyvox (Pharmacia & Upjohn); Zyvoxid (Pharmacia & Upjohn)
Molecular Formula: C16H20FN3O4
Molecular Weight: 337.35
Percent Composition: C 56.96%, H 5.98%, F 5.63%, N 12.46%, O 18.97%
Literature References: Prototype of the oxazolidinone antimicrobials; inhibits bacterial mRNA translation. Prepn: M. R. Barbachyn et al., WO 9507271 (1995 to Upjohn); eidem, US 5688792 (1997 to Pharmacia & Upjohn); S. J. Brickner et al., J. Med. Chem. 39, 673 (1996).
Antibacterial spectrum: C. W. Ford et al., Antimicrob. Agents Chemother. 40, 1508 (1996). Mechanism of action study: D. L. Shinabarger et al., ibid. 41, 2132 (1997).
 HPLC determn in plasma: C. Buerger et al., J. Chromatogr. B 796, 155 (2003). Clinical comparison with vancomycin, q.v., for MRSA infections: D. L. Stevens et al., Clin. Infect. Dis. 34, 1481 (2002).
Review of pharmacology: L. D. Dresser, M. J. Rybak, Pharmacotherapy 18, 456-462 (1998); and clinical experience: R. Norrby, Expert Opin. Pharmacother. 2, 293-302 (2001).
Properties: White crystals from ethyl acetate and hexanes, mp 181.5-182.5°. [a]D20 -9° (c = 0.919 in chloroform).
Melting point: mp 181.5-182.5°
Optical Rotation: [a]D20 -9° (c = 0.919 in chloroform)
Therap-Cat: Antibacterial.
Keywords: Antibacterial (Synthetic); Oxazolidinones.
Linezolid
Skeletal formula of linezolid
Linezolid-from-xtal-2008-3D-balls.png
Systematic (IUPAC) name
(S)-N-({3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide
Clinical data
Trade names Zyvox, Zyvoxam, Zyvoxid
AHFS/Drugs.com monograph
MedlinePlus a602004
Licence data US FDA:link
  • AU: C
  • US: C
Intravenous infusion, oral
Pharmacokinetic data
Bioavailability ~100% (oral)
Protein binding Low (31%)
Metabolism Hepatic (50–70%, CYPnot involved)
Half-life 4.2–5.4 hours (shorter in children)
Excretion Nonrenal, renal, and fecal
Identifiers
165800-03-3 Yes
J01XX08
PubChem CID 441401
DrugBank DB00601 
ChemSpider 390139 Yes
UNII ISQ9I6J12J Yes
KEGG D00947 Yes
ChEMBL CHEMBL126 Yes
NIAID ChemDB 070944
Chemical data
Formula C16H20FN3O4
337.346 g/mol
Cited Patent Filing date Publication date Applicant Title
WO1995007271A1 * Aug 16, 1994 Mar 16, 1995 Michael R Barbachyn Substituted oxazine and thiazine oxazolidinone antimicrobials
AU2001100437A4 * Title not available
EP0963980A2 * Mar 10, 1999 Dec 15, 1999 The Wellcome Foundation Limited 1,2,4-Triazine derivative, its preparation and its use as reference marker for testing purity and stability of “lamotrigine”
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2 * [Online] June 1995 (1995-06), XP002388489 Retrieved from the Internet: URL:www.emea.eu.int/pdfs/human/ich/38195en .pdf> [retrieved on 2006-07-03]
3 * DATABASE CA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; LIU, JUN ET AL: “Preparation of oxazolidone derivatives as antibacterial agents” XP002429969 retrieved from STN Database accession no. 2003:576097 -& CN 1 355 165 A (INSTITUTE OF MEDICAL AND BIOLOGICAL TECHNOLOGY, CHINESE ACADEMY OF MED) 26 June 2002 (2002-06-26)
4 * GLEAVE D M ET AL: “Synthesis and antibacterial activity of [6,5,5] and [6,6,5] tricyclic fused oxazolidinones” BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 8, no. 10, 19 May 1998 (1998-05-19), pages 1231-1236, XP004137053 ISSN: 0960-894X
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S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.



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Filed under: GENERIC DRUG, Uncategorized Tagged: LINEZOLID, ZYVOX

A surprising source of serotonin could affect antidepressant activity

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Originally posted on lyranara.me:

This schematic drawing of a serotonergic neuron shows exocytotic release of serotonin from vesicles (red arrow) and the nonexocytotic release described by Mlinar and colleagues (blue arrow). Reuptake of serotonin (green arrow) is blocked by SSRI antidepressants, increasing the extracellular serotonin concentration. Credit: Adell 2015

Depression affects an estimated 350 million people worldwide and poses a major public health challenge, according to the World Health Organization. Researchers have discovered an unconventional way that serotonin is released from neurons that could play an important role in the mechanism through which antidepressant drugs work. The Journal of General Physiology study is highlighted in the April issue.

Serotonin is a chemical in the brain that plays a key role in regulating various emotions and behaviors. Like other neurotransmitters, which relay signals between neurons, serotonin is stored in small sacs called vesicles in the presynaptic terminal of one neuron and released into the synapse…

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Overview about API manufacturing for the European market

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Originally posted on DRUG REGULATORY AFFAIRS INTERNATIONAL:

EudraGMDP provides some interesting information about the API manufacturing sites as well as about importers, distributors of APIs to be used as starting material in Medicinal Products for human use in Europe. Please read more about the API registrations in EudraGMDP.

http://www.gmp-compliance.org/enews_04767_Overview-about-API-manufacturing-for-the-European-market_9188,S-WKS_n.html

EudraGMDP provides some interesting information about the API manufacturing sites as well as about importers, distributors of APIs to be used as starting material in Medicinal Products for human use in Europe. Although the database is still not complete (not all competent authorities in Europe have established a system to make sure that all registration data will be entered into EudraGMDP in a timely manner) the current information is already very interesting.

Currently (as per 19 March 2015) the database counts 3.275 API manufacturing sites, importers or distributors located outside Europe. On the other side 936 API manufacturing sites, importers or distributors are located in EEA countries (EU Member states…

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New EU GMP Annex 15 Revision published – Valid as of 1 October 2015

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Originally posted on DRUG REGULATORY AFFAIRS INTERNATIONAL:

In February 2014 the draft for the revision of Annex 15 was published. Compared with the currently valid version the changes were partly significant. Now the draft was published as final document and will be valid as of 1 October 2015. Read more about the Changes in Annex 15.

http://www.gmp-compliance.org/enews_04792_New-EU-GMP-Annex-15-Revision-published—Valid-as-of-1-October-2015_9184,9266,9185,9322,Z-QAMPP_n.html

In February 2014 the draft for the revision of EU GMP Annex 15 was published (see the GMP-News from 11 February 2014 “Revision of the EU GMP Annex 15 for Qualification and Validation published“). Compared with the currently valid version the changes were significant in some parts (see also the GMP-News from 21 March 2014 “Detailed Analysis of Annex 15 Draft“. Now the draft was published as final document and will be valid as of 1 October 2015.

What will change? Following you will find an overview about the changes.

With 16 pages the document is much…

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Ozonization of Pharmaceutical Water and the Biocidal Products Regulation

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With the new biocidal products regulation from 2013 in-situ generated ozone now also falls into the scope of this directive. Ozone generation systems with a biocide application (such as disinfection of pharma water) thus require an approval after the transitional period expires in the September 2017. The ozone registration group is active for this purpose. Read more about the Ozonization of Pharmaceutical Water and the Biocidal Products Regulation.

http://www.gmp-compliance.org/enews_04756_Ozonization-of-Pharmaceutical-Water-and-the-Biocidal-Products-Regulation_9200,9122,9340,9251,Z-PEM_n.html

With the new biocidal products regulation from 2013 in-situ generated ozone now also falls into the scope of this regulation. Ozone generation systems with a biocide application (such as disinfection of pharma water) thus require an approval after the transitional period expires in the September 2017. We already reported about the impact of the new Biocidal Products Regulation – please see the GMP News “Pharmaceutical Water: Uncertainty caused by the New Biocidal Products Regulation” from 21 May 2014.

Admission will take place in two stages. In the first step, ozone is certified as an active ingredient and registered in the list of active substances authorised in the EU. In the second step, the ozone generation system is approved as a biocidal product. The major manufacturers of ozone generation systems have joined forces for this in the ozone registration group (ORG). It aims at relieving users of ozone systems from the registration procedure. That means the documents should be provided to the users. The access to the marketing authorisation dossier is supposed to be assured through a Letter of Access (LoA). One of the open questions seems to be resolved now: the question whether an authorisation document will be required for each ozone precurser (i.e. water, oxygen or air). As this seems to be unnecessary, only one authorisation document is currently being processed.

The question with regard to how reasonable it is to include ozone from pharmaceutical water systems in the biocidal products regulation cannot be clarified at this point. The same is true with regard to the question on who is supposed to control pharmaceutical companies and whether their ozone comes from approved ozone systems.

You can find more information on the page Ozone registration group.

 


Filed under: GMP, Regulatory Tagged: biocide application, GMP, oxone, Ozone generation system, REGULATORY

Susan Mayne, Ph.D. Director of FDA’s Center for Food Safety and Applied Nutrition

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Susan Mayne

Susan Mayne, Ph.D.

Susan Mayne, Ph.D. Director of FDA’s Center for Food Safety and Applied Nutrition

Susan Mayne (@STMYale) | Twitter

www.linkedin.com/pub/susan-mayne/a/881/452/en

http://www.researchgate.net/profile/Susan_Mayne

She is  passionate about food safety and nutrition and their role in public health. I especially enjoy the intersection of science and policy, leading me to recently relocate to the FDA.

Education

ELAM (Executive Leadership for Academic Medicine)

 

 

Experience

Director, Center for Food Safety and Applied Nutrition

FDA

January 2015 – Present College Park, Maryland

C.-E.A. Winslow Professor of Epidemiology

Yale University School of Medicine

1988 – January 2015 (27 years)Yale School of Public Health

Susan T. Mayne joined the U.S. Food and Drug Administration (FDA) as the new director of the Center for Food Safety and Applied Nutrition (CFSAN), replacing her predecessor Michael Landa, who led the center for more than four years.

Susan T. Mayne is C.-E.A. Winslow Professor of Epidemiology with tenure and Chair, Department of Chronic Disease Epidemiology at the Yale School of Public Health.

Dr. Mayne is also Associate Director of the Yale Comprehensive Cancer Center, being responsible for Population Sciences.

She also directs a pre-doctoral training program at Yale in Partnership with the U.S. National Cancer Institute, to train students in modern methodologies for evaluating lifestyle determinants of human cancer risk, with an emphasis on nutritional, environmental, and occupational determinants, including their interactions with genetic factors.

Dr. Mayne earned a Ph.D. in nutritional biochemistry from Cornell University, with minors in biochemistry and toxicology, and a B.A. in chemistry from the University of Colorado.

Dr. Mayne is a fellow of the American College of Epidemiology, and of the Executive Leadership in Academic Medicine (ELAM) Program for Women. She has authored or co-authored over 180 articles/book chapters.

She also has served on several editorial boards including the Journal of Nutrition, Cancer Epidemiology, Biomarkers and Prevention, and Nature Reviews Clinical Oncology.

Dr. Mayne has served on several National Academy of Sciences committees, including most recently the Committee that established Dietary Reference Intakes for Vitamin D and Calcium.

She is currently on the Food and Nutrition Board of the National Academy of Sciences, and recently completed a 5-year term on the Board of Scientific Counselors for the U.S. National Cancer Institute. Her research emphasizes lifestyle determinants of human cancer risk.

Mayne certainly boosts the academic credentials of an Ivy League scholar. CFSAN’s new director has researched the role of food, nutrition and obesity as risks for chronic disease, and she is the author or co-author of more than 200 scientific publications, according to FDA. She received a B.A. in chemistry from the University of Colorado, and went on to earn a Ph.D. in nutritional sciences, with minors in biochemistry and toxicology, from Cornell University.

“While I make no claims as an expert on food safety, I studied toxicology while earning my Ph.D., and have conducted research into relationships between chemical contaminants and cancer risk, as well as studying microbes and their role in human cancer,” Mayne said in the Q&A. “Thus, I think about things from the perspective of both benefits and risks, and am equally interested in both areas.”

Mayne grew up in rural Colorado. She understands agriculture and comes from a health-conscious family. She said her grandmother lived to be one year shy of age 100 and produced most of her food on a farm in rural Pennsylvania. Mayne’s dad had a small ranch in Colorado where he raised cattle. She characterized her 80-something-year-old mom as “the image of successful aging.”

“She chooses healthy foods, is physically active daily, and frequently sends me pictures of her hikes in the Colorado mountains,” Mayne wrote.

Susan Mayne, PhD

C.-E.A. Winslow Professor of Epidemiology (Chronic Diseases)

Susan T. Mayne, Ph.D., an expert in the lifestyle determinants of cancer risk, has been named the C.-E.A. Winslow Professor of Epidemiology at the Yale School of Public Health (YSPH).

Mayne’s research has emphasized the role of dietary factors in the etiology of several major cancers. She also studies other lifestyle factors, such as tobacco and alcohol use, and their interaction with genetics in cancer risk.

Recently, Mayne co-authored a study that found that indoor tanning significantly raises the risk of an increasingly common form of skin cancer in young people. Mayne and colleagues at the School of Public Health reported online in the Journal of the American Academy of Dermatology in December that people under the age of 40 who had tanned indoors had a 69 percent increased risk of early-onset basal cell carcinoma. The team found that the association was strongest among women, and that the risk increased with years of tanning use.

Mayne is head of the Division of Chronic Disease Epidemiology, which includes 28 faculty members. She is also associate director of Yale Cancer Center, where she is responsible for Population Sciences. Mayne, who earned her doctorate from Cornell University, has led Yale’s Cancer Prevention and Control Research Program for 17 years to record-high levels of National Institutes of Health (NIH) funding and productivity. She developed the Yale-National Cancer Institute partnership, which gives faculty and students access to important national cohort studies for research, as well as an NIH-funded training program in cancer epidemiology and genetics, now entering its ninth year. She has received the Distinguished Teaching Award at YSPH.

A member of several editorial boards, Mayne is a fellow of the American College of Epidemiology and of the Executive Leadership in Academic Medicine Program for Women. She has authored or co-authored over 170 articles and book chapters.

The C.-E.A. Winslow Memorial Fund was established in 1958 by an anonymous donor to support the work of a professor in the Department of Public Health (a precursor to YSPH). It recognizes Charles-Edward Amory Winslow, M.S., Dr.Ph., who served as chair of the department from its founding in 1915 until his retirement in 1945. A scholar with an international reputation and a firm belief in the philosophy of disease prevention, Winslow profoundly influenced both Yale’s department and the burgeoning field of public health.

From the New CFSAN Director: Reflections on My First Two Months

By: Susan Mayne, Ph.D.

I have been the director of FDA’s Center for Food Safety and Applied Nutrition (CFSAN) for two months now. What I have enjoyed the most about this new job has been getting to know the people in CFSAN, who come from incredibly varied and interesting backgrounds. I am truly impressed by their commitment to excellence and dedication to our mission to protect and promote public health.


I have also been struck by the depth and breadth of expertise involved in every initiative CFSAN undertakes. So many scientific disciplines are involved: We rely on the insights of our medical officers, toxicologists, epidemiologists, biologists, chemists, behavioral scientists, and nutritionists. Working with our scientists are our policy and communications experts, economists and lawyers. We all have the same goal: to give the safety of food and cosmetics and nutrition issues the thorough and careful consideration they deserve.

We stand on two legs: strong science and our ability to create policy and regulatory solutions to address public health concerns. The scientific fields in which we work, from genomics to toxicology, are advancing rapidly. The use of new technologies can make our science better and help us to get the information we need more quickly. Yet the constant evolution and adoption of new scientific methods can also pose unique challenges — for example, in interpreting trends in food safety and foodborne illness.

When considering the science of food and cosmetic safety, we assess the scientific certainty, severity, and likelihood of any given risk, and identify those people who would be most vulnerable. We consider what additional research can be undertaken to better clarify the science for decision-making, and use what we currently understand to determine whether the risk can be avoided.

For each issue, we need to examine the full range of options, ranging from consumer education to regulation to enforcement. For regulatory options we work with our legal teams to consider what is possible within our authorities. What are we empowered to do and how does our work intersect with that of other federal agencies? If we take an action, what is the international context, and are there foreign trade implications? What are the views of groups that will be most affected by our decisions, on both the consumer and industry sides? What are the costs and benefits? Have we thoughtfully considered how to ensure high levels of compliance?

I have observed with a great sense of satisfaction how we work together with other federal partners. For example, leaders from the Centers for Disease Control and Prevention (CDC) visited our center recently to share information and discuss how we can best support each other in our joint commitment to food safety. In the brief time I have been here, I have also observed interactions with the U.S. Department of Agriculture, the National Institutes of Health, and the Environmental Protection Agency.

CFSAN’s work is funded by taxpayers and affects people’s lives every day. Our work has real consequences for consumers, businesses, and industry. I have learned the importance of engaging in meaningful conversations with those outside of government, who are affected by our decisions. As we talk to our industry stakeholders, we benefit from their expertise and better understand the real-world constraints they face, and that ultimately helps us to put forth more effective policy. Similarly, we value hearing the perspectives of consumers, medical groups, and the scientific community, which often highlight areas where additional FDA focus is needed to protect public health. In our communications, we strive to accurately convey the risks and/or benefits of any food or product, and to rapidly communicate any emerging health concerns.

I have observed an amazing array of public health issues coming across my desk at CFSAN over the past two months. I am energized by the diverse breadth and depth of activity, and look forward to the challenges and opportunities ahead, and to sharing my thoughts and experiences with you on Twitter and in future blog posts.

Susan Mayne is the Director of FDA’s Center for Food Safety and Applied Nutrition

– See more at: http://blogs.fda.gov/fdavoice/#sthash.gt9fjQow.dpuf

http://blogs.fda.gov/fdavoice/

 

From left to right: Avery LaChance, Leah Ferrucci, Lisa Davis, Susan Mayne

 

 

College Park (Maryland)

 

 

 

University of Maryland, College Park

 

 

 

    1. Map of college park maryland

Filed under: SPOTLIGHT Tagged: fda, Susan Mayne

TELMISARTAN PART 2/3

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 Figure imgf000002_0001

4′-[[4-methyl-6-(1-methyl-1h-benzimidazol-2-yl)-2-propyl-1h-benzimidazol-1yl]methyl]biphenyl-2-carboxylic acid (telmisartan)

PART 1……..http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-13.html

PART 2……..http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-23.html

                   OR  http://newdrugapprovals.org/2015/04/06/telmisartan-part-23/

PART3……   http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-33.html

GENERAL DESCRIPTION

Telmisartan is currently available as oral tablets in 20, 40, and 80 mg strengths for use in the treatment of hypertension. It is also marketed as Micardis® HCT which is a fixed dose combination with Hydrochlorothiazide (HCTZ) in 40/12.5, 80/12.5, 80/25 mg/mg strengths, and Twynsta® its fixed dose combination with Amlodipine in 40/5, 80/5, 40/10, 80/10 mg/mg strengths.

In 2009, Boehringer Ingelheim (Boehringer) gained approval to extend the market authorised indication of the Telmisartan 80 mg strength to include reducing the risk of myocardial infarction, stroke or death from cardiovascular disorders.  

The Telmisartan molecule was discovered and developed by Boehringer, and was launched in Europe and the US in 1998. Boehringer has co-marketing agreements with Bayer Schering Pharma and GlaxoSmithKline in certain countries.

Displaying image001.png

Telmisartan (1) is an angiotensin II receptor antagonist useful in the treatment of hypertension, heart diseases, heart strokes, and bladder diseases.1 Telmisartan (1) is currently available in the market as an antihypertensive drug2 under the brand name of MICARDIS. The first reported synthetic method3 for this molecule consists of 8 steps (Scheme 1) involving condensation of 4-amino-3-methyl benzoic acid methyl ester (2) with butyryl chloride (3) in chlorobenzene to yield 4. Nitration of 4 followed by reduction of the resulting 5-substituted nitro compound 5 over Pd-C in methanol yielded amine 6. Cyclisation of 6 in acetic acid reflux affords the monobenzimidazole derivative 7, which upon further hydrolysis yielded an acid intermediate 8 by a saponification process. Condensation of compound 8 with diamine derivative 9 in polyphosphoric acid yielded the dibenzimidazole compound 10, which was further alkylated with 4′-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (11)4 to afford product 12. Finally, hydrolysis of ester12 in trifluoracetic acid yielded telmisartan (1) in an overall yield of around 21% with several impurities. This process suffers from disadvantages such as (a) a multistep synthesis for compound 8 (3 steps from compound 5); (b) the solvents dimethyl formamide (DMF) or dimethylsulfoxide (DMSO) used in the penultimate stage are unrecoverable, while the use of potassium tert-butoxide resulted in high organic volatile impurities (OVI) in telmisartan; (c) deprotection of the tert-butyl group using trifluoroacetic acid in DMF lead to the formation of several byproducts; (d) residue on ignition (ROI) in API obtained from this process is always >1.0% (ICH limit <0.1%), and there is no specified process mentioned in the literature to control the ash content. This is mainly due to very poor solubility of the telmisartan in most of the solvents including water; and (e) the overall yield (21%) of this process is discouraging, which makes the process less viable for commercial production.

(1) (a) Battershill, A. J.; Scott, L. J. Drugs 2006, 66 (1), 51-83. (b) Norbert, H.; Berthold, N.; Uwe, R.; Jacobus, C. A.; Van, M.; Wolfgang, W.; Michael, E. U.S. Patent 5,591,762, 1997. (c) Ruth, R. W.; William, J. C.; John, D. I.; Michael, R. C.; Kristine, P.; Ronald, D. S.; Pieter, B. M. W. M. T. J. Med. Chem. 1996, 39 (3), 625-656.

(2) http://www.rxlist.com/cgi/generic2/telmisartan.htm.

(3) (a) Uwe, J. R.; Gerhard, B. N.; Kai, M. H.; Helmut, W.; Michael, E.; Jacobus, C. A.; Van, M.; Wolfgang, W.; Norbert, H. H. J. Med. Chem. 1993, 36, 4040-4051. (b) Merlo

(4) Carini, D. J.; Dunicia, J. V. Eu. Patent 2,53,310, 1988. (5) Venkataraman, S.; Mathad, V. T.; Kikkuru, S. R.; Neti, S.; Chinta, R. R.; Arunagiri, M.; Routhu, L. K PCT WO 06/044754A2, 2006.

(6) The intermediate 9 is prepared via monomethylation of o-nitroaniline (15) using dimethylsulfate followed by hydrogenation over Pd-C catalyst in methanol with 75% of overall yield. Of the several methylating agents such as CH3I, DMS, HCOOH, and H2CO explored

(7) Structures of these impurities were tentatively proposed based on MS-MS data and a probable reaction mechanism and then synthesized as shown in Scheme 3. These impurities were characterized by NMR, mass, and IR techniques and further confirmed to be present in the sample by HPLC coinjection and spiking methods (0.1%). (8) Shen, J.; Li, J.; Yan, T.; Li, H.; Ji, R. CN 1,344,712, 2002.

(9) Several brominating agents such as molecular bromine, N-bromosuccinimide (NBS), and 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) resulted in 13 along with the dibromo impurity 26. The formation of the dibromo impurity 26 is varying from 20-45% by HPLC. The content of 26 is nearly 45% in the case of NBS bromination, whereas the same is in the range of 15%- 20% in the case of DBDMH. Hence, DMDBH has been utilized as the brominating agent in the process. However impurity 26 did not participated in the next step and was easily washed out to a nondetected level during the isolation of 14 in the condensation step.

(10) Robert, E. D.; Peter, S.; Herbert, N.; Kenneth, S.; William, I. F. D. J. Pharm. Sci. 2000, 89 (11), 1465-1479.

Whilst patent protection for Telmisartan molecule, DE4103492A, has expired in Canada, it is still in force in the US until January 2014, receiving the longer term based on 17 years from the issue date for patents filed prior to June 8 1995. The equivalent European patent, EP0502314 (‘314), has been extended by SPC in France, Germany, Spain and the UK until December 2013 (see Figure 3).

Boehringer, seeking to protect its Telmisartan franchise, has also filed SPC applications for its Telmisartan-HCTZ and Telmisartan-Amlodipine products, for the basic patent ‘314, in France, Germany, Spain and the UK, potentially extending protection until January 2017 (see Figure 3). GenericsWeb’s proprietary SPC analyser has identified the basic patent as a ‘C3’ category, suggesting the claims of the basic patent do not protect the combinations and therefore the SPC may be invalid. The response by the national IPOs in respect to the invalidity of SPCs for the Telmisartan combinations has varied. The French SPC application (FR02C0028) for Telmisartan-HCTZ was initially rejected by the Institut National de la Propriété Industrielle (INPI) in December 2010, finding the claims of the basic patent did not protect a medicine comprising Telmisartan in association with HCTZ. The Paris Court of Appeal upheld INPI’s decision in June 2012, denying Boehringer’s request for appeal. Similarly, on June 2012, the Juzgado de lo Mercantil de Pamplona (the Court) held the Spanish SPC (C20020018) for Telmisartan-HCTZ invalid following a revocation suit filed by Cinfa and Actavis against Boehringer in April 2010. The Court’s decision relied on the ECJ’s findings in the ‘Medeva’ decision relating to SPCs for combination products, which concluded that to satisfy article 3(a) of SPC regulation 469/2009 the wording of the claims of the basic patent had to specify all active ingredients. Therefore, the Court found the SPC to be invalid on the grounds of article 15.1(a) in regard to 3(a), finding ‘314 did not specify a composition of Telmisartan in association with HCTZ. In February 2013, revocation proceedings were filed in the Bundespatentgericht for the German SPC (DE10299029) for Telmisartan-HCTZ. This raises the question of whether the SPC will prevent a generic Telmisartan-HCTZ product in Germany until conclusion of the revocation proceedings or will generic companies launch their products ‘at risk’ upon expiry of the SPC for Telmisartan, therefore assuming invalidity based on the ‘Medeva’ decision and similar findings by other PTOs and Courts in the matter.

The French (FR11C0008), German (DE122011000013) and Spanish (C201100010) SPCs for the Telmisartan-Amlodipine combination have been withdrawn. However, the UKIPO has granted the SPCs for both combination products (see Figure 3). No litigation proceedings have been detected in the UK. This may be due to amendments, under section 27 of the Patents Act 1977, of the specification for the UK designation of ‘314, in 2004 and 2011. The amendments were in the form of amended claim pages which included a pharmaceutical composition comprising HCTZ or a calcium channel blocker. Patents in the family with priority GB9722026A protect authorised indicated uses of the 80 mg dosage form of Telmisartan for reducing cardiac tissue damage associated with myocardial infarction and prevention or treatment of stroke, so are considered to be a constraint only for those indicated uses.

The family with the priority DE19901921A protects the crystalline form used in the commercially available product but are not considered to be a constraint to generic competition because the protected technology is likely to be circumvented. Families AU2002242676A, DE10301371A and EP04026234A protect Telmisartan combination products (see Figure 2). AU2002242676A and EP04026234A claim bilayer tablets comprising Telmisartan and HCTZ or Amlodipine, respectively. They are not considered to be a constraint to generic competition because the protected technologies are likely to be circumvented by generic reformulation. However, patents in the family DE19901921A expiring in July 2024, claiming composition of Telmisartan and several other drugs, including Amlodipine, are considered to be a constraint to generic competition for the Telmisartan-Amlodipine product. The family was deemed key due to its Canadian member 2534006 being listed on Health Canada’s patent register. Equivalent patents in the US have not been granted yet, but claims listed in the image wrapper in USPTO appear to limit the claims to a currently unauthorised use of Telmisartan and Amlodipine, therefore may not be a constraint for generic entry in the US.
Amongst the US approvals, Watson is the only company to have obtained tentative market approvals for all dosage strengths for the Telmisartan tablets and the fixed dose combination of Telmisartan and HCTZ. Lupin has gained a tentative approval for the Telmisartan and Amlodipine fixed dose combination. No generics are currently on the market in the UK due to unexpired patent protection, however several companies including Egis, Sandoz and Glenmark have obtained market authorisation for Telmisartan tablets in all dosage strengths. Actavis and Teva have obtained market authorisations via the centralised procedure. Dr Reddy’s Lab and Krka hold generic authorisations for both Telmisartan and Telmisartan-HCTZ fixed dose combination tablets. These generic approvals are suggestive of the competition Micardis® will face across Europe upon molecule patent expiry. Currently no generic Telmisartan-Amlodipine approvals have been identified in Europe. This is due to data exclusivity previsions in Europe, preventing the filing of generic market authorisation until October 2018, and a further 2 year market exclusivity period could prevent the launch of a generic equivalent until October 2020. In Canada, Mylan was one of the generic competitors to launch Telmisartan and Telmisartan-HCTZ following molecule patent expiry. This is likely to be mirrored in other territories upon expiry of the molecule patent.

Figure 4: Marketing Authorisations for products containing Telmisartan in Key Countries

In summary, patent protection remains a significant barrier to generic entry for the Telmisartan products in most major markets due to the molecule patent being in force. Boehringer’s lifecycle management attempts to maintain a monopoly for their blockbuster drug, including combination products and extensions of indications. Patent protection for its products, apart from the molecule patent, include a ‘use’ patent and combination patents which may pose a barrier to generic competition and may see Boehringer retain some of their market share. SPCs for the Telmisartan-HCTZ combination have been the subject of litigation in France and Spain, resulting in their invalidation, a revocation proceeding is on-going in Germany. Data exclusivity provisions in Europe will prevent the launch of a generic Telmisartan-Amlodipine fixed dose combination. In Canada, generic competition for Telmisartan and Telmisartan-HCTZ entered the market shortly after the expiry of the molecule patent. This is likely to be mirrored in other territories with generic companies already holding market authorisations for both products.

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PATENT

WO 2010018441

http://www.google.im/patents/WO2010018441A2?cl=en

Telmisartan is chemically named as 4′-[(1,4′-Dimethyl-2I-propyl[2l6′-bi-1H- benzimidazol]-1′-yl)methyl][1 ,1′-biphenyl]-2-carboxylic acid; or 4′-[[4-methyl-6-(1-methyl-2- benzimidazolyO^-propyl-i-benzimidazolyllmethyll^-biphenylcarboxylic acid.

The key raw material used to prepare Telmisartan is Bltyl, chemically named as 1,7′- dimethyl-2′-propyl-2,5′-bi-1H-benzimidazole, also known by other names, i.e 2-Propyl-4- methyl-6-(1 -methylbenzimidazol-2-yl)benzimidazole; 4-Methyl-6-(1 -methyl benzimidazol-2- yl)-2-propylbenzimidazole, and the structure shown as below:

BIM WO2006136916 describes substantially pure micronized particles of Telmisartan or a pharmaceutically acceptable salt, ester or derivative. The “substantially pure” is further defined as “Telmisartan or pharmaceutically acceptable salt, ester or derivative thereof having a purity of greater than or equal to about 98%, preferably a purity of greater than or equal to about 99% and more preferably a purity of greater than or equal to about 99.5%.° The substantially pure Telmisartan or a pharmaceutically acceptable salt, ester or derivative has an effective average particle size of less than about 300 microns.

A Journal of http://www.IP.com (2005), 5(7B), 4 – describes a process for purification of 4′-(2-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazol-1-ylmethyl)biphenyl-2- carboxylic acid (Telmisartan). The pure compound was isolated by filtration under reduced pressure.

US20060276525 claims Telmisartan form A having HPLC purity > 99.5 %. It further provides a process for preparing Telmisartan form A by crystallization from a polar organic solvent selected from the group consisting of dimethyl sulfoxide, DMF, N.N-dimethyl acetamide, N-methyl 2-pyrrolidone, water and mixtures thereof. The process provides Telmisartan with a limit of DMSO at a level of < 1000 ppm. The process uses high boiling solvent in the last step for getting required purity, and which is also an extra purification step, which limits its commercial application.

US5591762 ( column-37,38 ) described the general process for the preparation of compound of formula-V

wherein bromine in structure IV is leaving group. There are several other leaving groups such as chlorine, iodine, a substituted sulphonyloxy group, e.g. a methane sulphonyloxy, phenylsulphonyloxy or p-toluenesulphonyloxy group are reported.

US5591762 describes preparation of Telmisartan from Telmisartan tert. butyl ester using trifluoroacetic acid in DMF as a solvent in 63.9 % yield. (Example-9) The resulting product had a melting point of 261-2630C.

The process for the preparation of tert. Butyl ester of Telmisartan is not commercially viable and deprotection involving the use of trifluoro acetic acid is not eco-friendly.

US 6385986 describes polymorphs of 4′-[2-n-propyl-4-methyl-6-(1-methylbenzimid- azol-2-yl) benzimidazol-1-ylmethyl] biphenyl-2-carboxylic acid (Telmisartan) i.e. polymorphic form B, mixtures of the polymorphs. The processes for preparing Telmisartan containing form B and the use for preparing a pharmaceutical composition. US ‘986 further describes that Telmisartan obtained process of as described in EP502314B1 to give a solid in the form of long needles which is difficult to filter, wash and isolate. It is further characterized that it requires a long time for drying due to the presence of solvent which forms large and hard fragments during the drying process. The fragments on grinding produce a dry powder which exhibits strong tendency to electrostatic charging and is virtually impossible to pour. The polymorphic form B of Telmisartan shows virtually no tendency to electrostatic charging and easy for suction filtration, centrifuge, washing, drying and is free-flowing even without being ground up.

Therefore, as a consequence of the alleged unsuitability of Telmisartan form A for pharmaceutical use, only a mixture of crystalline Telmisartan form A and form B is claimed in the ‘986 patent, wherein Telmisartan form A is characterized by having an endothermic maximum at 269±2°C, and Telmisartan form B is characterized by having an endothermic maximum at 183±2°C.

Apparently Telmisartan form A is similar to the original form characterized by its’ melting point in the ‘762 patent. The differences between the DSC value and the measured melting point may be attributed to the different methodologies used-the DSC maxima can be slightly different than the visually observed melting point.

Hence, the prior art teaches a lengthy, complicated and industrially disadvantageous process for obtaining crystalline Telmisartan form A. The need to further reprocess the re- crystallized Telmisartan, as taught in the examples of the ‘986 patent, shows that the product was not highly-pure and/or that it contained residual solvents, because the solvents used therein have high boiling point. JMC-1993, vol-36, No25 pg-4040-4051 describes preparation of Telmisartan tert. butyl ester using BIM and 2-(4’bromomethyl phenyl) tert. butyl benzoate using pot. Tert butoxide as a base in DMSO as solvent.

Formula 6

The preparative details for compound of formula-VII on page-4049, coloumn-3, compound 33, paragraph-4; line1-4 reads as follows.

Potassium tert-butoxide was added to the solution of BIM in DMSO at room temperature followed by the addition of the compound of formula Vl. Upon stirring for 14 hrs, the mixture was poured into water and extracted with ethyl acetate, the combined extract was dried on MgSO4 and evaporated. Residue was purified by silica gel column chromatography to give compound of formula-VII. The above mentioned process uses chromatographic purification, which is generally cumbersome and time consuming process and also requires solvents in high volume.

US20060094883 describes a process for the preparing Telmisartan, wherein Telmisartan alkyl ester – a

compound of formula-ll is prepared , comprising the steps of :

(a) combining i.y-dimethyl^’-propyl-IH.S’H-p.S1 ] bibenzimidazole (referred to as BIM) of formula III,

Formula 3 with 4′-bromomethyl-biphenyl-2-carboxylic acid alkyl ester (referred to as BMBP alkyl ester) of formula IV1

Formula 4 an inorganic base and a low boiling point organic solvent, to obtain a mixture;

(b) heating the mixture obtained in step (a) to a temperature of about 55°C. to about 1200C;

(c) maintaining the mixture obtained in step (b) for about 1 hour to about 8 hours, to obtain Telmisartan alkyl ester of formula II; and

(d) recovering Telmisartan alkyl ester of formula II, wherein, R is a straight or branched chain C1-C4 alkyl.

WO2005108375 describes process for the preparation of Telmisartan, characterized in that 1H-Benzimidazole-2-n-propyl-4-methyl-6-(1 ‘-methyl benzimidazole- 2’yl) of formula (II) and methyl-4- (bromo methyl)biphenyl 2-carboxylate of formula (III) are subjected to

WO 2007/010558 describes a method for the preparation of Telmisartan involving

Telmisartan dihydrochloride which comprises, i) condensing 4-Methyl-2-n-propyl-IH- benzimidazole-6-carboxylic acid with N-Methyl- O-phenylene diamine dihydrochloride to yields 4-methyl-6 (1 -methyl benzimidazol-2- yl)-2-n-propyl IH- benzimidazole, ii) treating 4- methyl-6-(l -methyl benzimidazol-2-yl)-2-n-propyl-IH-benzimidazole with

4*– (bromomethyl)-2-biphenyl-2-carboxylate in presence of a base in an organic solvent and isolating the ester as acid addition salt, iii) converting ester acid addition salt to Telmisartan dihydrochloride and iv) converting Telmisartan dihydrochloride to Telmisartan. CN1344712 describes method comprising reaction of 4-methyl-6-(1-methyl-2(1H)- benzimidazolyl)-1H-benzimidazole with 4′-bromomethyl-biphenyl-2-carboxylic acid alkyl ester [wherein alkyl is methyl or ethyl] in solvent i.e. DMF, DMSO, THF, dioxane, chloroform, dichloroethane, etc. in the presence of base [such as Na alcoholate, triethylamine, tributylamine, tripropylamine, KOH, NaOH, CsOH, Ba(OH)2 etc.] as acid capturer at 20- 1000C for 8-10 hrs, and then hydrolyzing with acid (such as H2SO4, HCI, HBr, HOAc, etc) at room temp, to reflux temp, or with base in Ci-5 alc.-water at 20-1600C for 1-10 hour. WO 2006/125592 describes a new process for the preparation of saltans 2-butyl-3- [[2″-[1 -(triphenylmethyl)-i H- tetrazol-5-yl][1 , 1 ‘-biphenyl]-4-yl]methyl]-1 ,3-diazaspiro[4.4] non- 1-en-4-one is disclosed, which proceeds via novel intermediate, 4-[(2-butyl-4-oxo-1 ,3- diazaspiro[4.4]non-1-en-3-yl)methyl]phenylboronic acid (Formula (H)) or its analogs. Compound (II) reacts with 5-(2-bromophenyl)-1-(triphenylmethyl)-1H-tetrazole (III) in the presence of catalyst, using conditions of Suzuki reaction, to give trityl irbesartan (I), whereas analogs to compound (II) may give candesartan, valsartan, Telmisartan, losartan and olmesartan.

WO 2006/050509 describes the amorphous form of Telmisartan sodium and the preparation thereof. Also provided are the Telmisartan sodium polymorph crystal Forms 0 to

XIII and XV to XX and preparations thereof. Also provided are pharmaceutical composition of amorphous and polymorphic forms of Telmisartan sodium or mixtures thereof, and methods of treatment of a mammal in need thereof.

WO 2006/044754 describes a process for preparing Telmisartan and intermediates formed in the process.

WO 2004/087676 describes a novel method for the production of Telmisartan by reacting 2-n-propyl-4-methyl-6-(1′-methylbenzimidazol-2′-yl)-benzimidazol with a compound of general formula (IV)1 in which Z is a leaving group, wherein the compound 2-cyano-4′-[2″- n-propyl-4″-methyl-6″-(1 ‘”-methylbenzimidazol-2l“-yl)benzimidazol-1 “-ylmethyl]biphenyl is obtained, and subsequently conducting hydrolysis of the nitrile to acid function.

WO2000/043370 describes polymorphs of 4′-[2-n-propyl-4-methyl-6(1 -methyl benzimidazol -2-yl) benzimidazol -1-ylmethyl] biphenyl-2-carboxylic acid (INN: Telmisartan), and in particular the polymorphous form B of formula (I), characterized by an endothermic peak at 183 ± 2°C during thermal analysis by differential scanning calorimetry. The invention also relates to mixtures of said polymorphs, methods for producing Telmisartan containing form B and to the use thereof in the preparation of a medicament.

Example-5 : Preparation of 4′-[[2-n-propyl-4methyl-6-(1-methylbenzimidazol-2-yl)- benzimidazol-1-yl]-methyl] biphenyl carboxylic acid [Telmisartan]

90 gm of ethyl-4′-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol- 1-yl]-methyl] biphenyl carboxylate was stirred with 810 ml aq. HCI [32-35 % wt/ vol] at 95±2°C for about 8-10 hours. The reaction mixture was cooled to 25-300C. 180 ml of Dichloromethane and 1350 ml of water were added, pH of the reaction mixture was adjusted to -9.0 to 10.0 using 20 % aq. NaOH. The reaction mixture was stirred at 30-350C for about 30 minutes and the layer was allowed to separate. 1800 ml of MDC was added to aqueous phase at 25-300C. pH of the solution was adjusted to ~3 to 3.5 with acetic acid. The mixture was stirred for about 20 minutes and the layer was allow to separate. The aqueous layer was extracted with 900 ml DCM and organic layer was separated and washed with 2 X 900 ml water. The organic phase was dried over anhy. Sodium sulfate and charcoalized followed by distillation to remove about 80-85 % of DCM at 40-420C. The reaction mixture was slowly cooled to 80C and stirred at 8-120C for about 1Hr. 2700 ml of acetone (100C was slowly added and temperature is maintained at 8-12°C.The reaction mixture was stirred for 2 hours with slow RPM. The mixture was filtered at 8-120C and washed with 2×180 ml of acetone. The product was obtained through suction drying for 30-45 minutes, and under vacuum at 85-900C. 70.0 gm of Telmisartan is obtained having purity of 99.84%.

…………………………

PATENT

WO2009006860A2

http://www.google.im/patents/WO2009006860A2?cl=en

Telmisartan (I) is produced in accordance with the original patent of Boehringer Ingelheim (US 5 591 762) from telmisartan tert-butyl ester (II). The hydrolysis is carried out using of trifluoroacetic acid in the toxic solvent N,N-dimethylformamide.

According to another patent applied by the same company (US 2004 236113) the manufacture was problematic and this is why this procedure was replaced with hydrolysis of the corresponding nitrile (III). However, during the hydrolysis, which is carried out with potassium hydroxide in ethylene glycol, a high temperature (160 0C) is used, which causes browning of the product, which must be subsequently purified by means of activated carbon. Also, the energy demands of several-ton production would be considerably high.

In a newer application of Cipla (WO 2005/10837) the last two synthetic steps (iii+iv) are combined and telmisartan is isolated after alkaline hydrolysis by acidifying of the reaction mixture in water or extraction with dichloromethane and precipitation with acetone. Both the ways of isolation are unsuitable for industrial production. In the case of telmisartan of crystalline form A its isolation from water or aqueous solutions of organic solvents is very difficult since a hardly filterable product is formed. Extraction of the product with dichloromethane and precipitation with acetone brings a well-filterable product, but the use of dichloromethane is virtually impossible from the point of view of environment protection.

Another method has been described by Dr. Reddy (WO 2006/044754), which starts from telmisartan methylester hydrochloride, which is hydrolyzed to produce the potassium salt of termisartan, which is further acidified in aqueous acetonitrile; after isolation it crystallizes from a dichloromethane/methanol mixture and finally from methanol alone, and wherein a pressure apparatus is used for the dissolution in methanol at a temperature above its boiling point (80 °C). The result of this complex procedure, which manifests the already above mentioned shortcomings, is a low yield of the product.

The method of Teva (WO 2006/044648) is in many aspects similar to the above mentioned procedure of Cipla, wherein the last two steps of the synthesis are also combined. The method comprises phase separations, which lead to low yields (69 % – 80 %) besides increased tediousness. Matrix starts from telmisartan tert-butyl ester (II), which is first converted to telmisartan dihydrochloride, which in turn, by action of aqueous ammonia in methanol, provides telmisartan with a low total yield of 73%.

http://www.google.im/patents/WO2009006860A2?cl=en

Example 1

4′-[[4-methyl-6-(l-methyl-lH-benzimidazol-2-yl)-2-proρyl-lH-benzimidazol- lyl]methyl]biphenyl-2-carboxylic acid (telmisartan)

Telmisartan methylester (VI) (40 g) was refluxed in methanol (440 ml) with potassium hydroxide (14.9 g) for 24 hours. To the boiling solution, methanol (240 ml) and then acetic acid (45.5 g) were added. While boiling, the mixture was stirred for another 1 hour, after cooling to 4°C the product was aspirated within 1 hour and washed with methanol (2 x 80 ml). After drying at the laboratory temperature (24 h) 35.18 g (90 %) of the product were obtained.

Analytic assessment: HPLC purity: 99.90 %,

Content of residual solvents: methanol (below the detection limit) acetic acid (360 ppm) Titration content: 100.9 % Sulfate ash content: 0.04 % DSC: form A

Example 2

4′-[[4-Methyl-6-(l-methyl-lH-benzimidazol-2-yl)-2-propyl-lH-benzimidazol- lyl]methyl]biphenyl-2-carboxylic acid (telmisartan)

Telmisartan methylester (VI) (20 g) was refluxed in methanol (300 ml) with potassium hydroxide (7 g ) for 24 h. After addition of formic acid (17 g) and after cooling to 4 °C the product was aspirated within 1 hour and washed with methanol (2 x 80 ml). After drying at the laboratory temperature (24 h) 18.7 g (96 %) of the product were obtained.

Example 3

4′-[[4-methyl-6-(l-methyl-lH-benzimidazol-2-yl)-2-propyl-l/J-benzimidazol- lyl]methyl]biρhenyl-2-carboxylic acid (telmisartan)

Telmisartan methylester (VT) (20 kg) was refluxed in methanol (400 1) with potassium hydroxide (7 kg) for 24 h. After addition of acetic acid (20 kg) and cooling to 4 °C the product was aspirated within 1 hour and washed with methanol (2 x 80 1). After drying at the laboratory temperature (24 h) 18.5 kg (95 %) of the product were obtained. Example 4

4′-[[4-methyl-6-(l-methyl-lH-benzimidazol-2-yl)-2-propyl-lH-benzimidazol- lyl]methyl]biphenyl-2-carboxylic acid (telmisartan)

Telmisartan methylester (40 g) was refluxed in methanol (240 ml) with potassium hydroxide (14.9 g) for 24 h. To the boiling solution methanol (240 ml) and then acetic acid (45.5 g) were added. After cooling to 4 °C the product was aspirated within 1 hour and washed with methanol (2 x 80 ml). After drying at the laboratory temperature (24 h) 36 g (92%) of the product were obtained.

…………………………..

PAPER

Displaying image002.png

Org. Process Res. Dev., 2007, 11 (1), pp 81–85
DOI: 10.1021/op060200g
Abstract Image

Telmisartan (1), a substituted dibenzimidazole derivative, is an antihypertensive drug, essentially used to control blood pressure. An improved, cost-effective, and impurity-free process for telmisartan (1) suitable for large-scale production is described here by addressing various process development issues. The overall yield obtained from this newly developed process is around 50% (over five steps) compared to the literature reported process (21%, over eight steps).

4′-[(1,4′-Dimethyl-2′-propyl-[2,6′-bi-1H-benzimidazol]- 1′-yl)methyl]-[1,1′-biphenyl]-2-carboxylic Acid (1).

Telmisartan (1) as a white crystalline powder. Yield 7 g (77%); purity by HPLC 99.9%; mp 260- 262 °C; Pd content not detected; Heavy metals <10 ppm; MS m/z 515 (M+ + H);

1 H NMR (CDCl3) δ 12.8 (s, 1H), 7.05-7.5 (m, 14H), 5.60 (s, 2H), 3.82 (s, 3H), 2.97 (t, J ) 7.5, 2H), 2.63 (s, 3H), 1.88 (q, J ) 7.3, 2H), 1.04 (t, J ) 7.3, 3H);

13C NMR (DMSO-d6) δ 13.5, 16.7, 20.6, 27.6, 32.7, 47.1, 51.7, 112.0, 112.7, 114.7, 118.6, 125.3, 125.7, 125.8, 127.0, 127.4, 128.6, 129.3, 130.4, 130.6, 131.5, 132.3, 133.1, 133.7, 134.5, 140.2, 140.5, 150.2, 157.3, 168.1.

Anal. Calcd for C33H30N4O2: C, 77.02; H, 5.88; N, 10.89; O, 6.22. Found: C, 77.0; H, 5.82; N, 10.89; O, 6.20.

………………….

PATENT

EP1719766A2

http://www.google.im/patents/EP1719766A2?cl=en

he present invention provides a process for the preparation of a compound of formula (I) or a salt thereof

comprising the reaction of a compound of formula (II) or a salt thereof

with a synthon of formula (III) or a salt thereof

prepared by reaction of a compound of formula (IV)

with a compound of formula (V)

  • Telmisartan, 4′-[(1,7′ -dimethyl-2′ -propyl[2,5′ -bis-l H-benzimidazol]-3′-yl)methyl][1,1′-biphenyl]-2-carboxylic acid is a known ACE inhibitor useful in therapy as antihypertensive agent. Its preparation is disclosed inEP 502314 and comprises the alkylation of 4-methyl-6-(1-methyl-benzimidazol-2-yl)-2-propylbenzimidazole (A) with t-butyl 4′-(bromomethyl)biphenyl-2-carboxylate (B)

  • However, compound (B) is not commercially available and its synthesis requires a number of steps, among them the protection of the carboxylic function which is finally removed by hydrolysis. There is therefore the need for an alternative synthesis for the industrial preparation of telmisartan, which makes use of commercially available or easy to prepare intermediates and which, if possible, avoids the additional steps of protection and deprotection of the carboxylic function.

Example 4. 4′-[[4-Methyl-6-(1-methyl-2-benzimidazolyl)-2-propyl-1-benzimidazolyl]methyl]-2-biphenylcarboxylic acid (telmisartan)

  • (4′-Methyl-2′-propyl-1H-benzimidazol-6′-yl)-1-methyl benzimidazole (3.0 g, 9.8 mmol), 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzyl methanesulfonate (3.12 g, 10 mmol), tetrahydrofuran (15 ml) and potassium carbonate (1.38 g, 10 mmol) are loaded into a round-bottom flask equipped with magnetic stirrer, condenser and under nitrogen atmosphere. The mixture is stirred at room temperature for 8 hours, then 10% hydrochloric acid is added to pH=2.
  • THF is evaporated off, which causes precipitation of boronic acid. After recrystallization from ethyl acetate, 4.2 g of product are obtained.
  • The boronic acid (3.5 g, 8.0 mmol), ethyl 2-bromoacetate (1.83 g, 8.0 mmol), sodium hydroxide (1.28 g, 32 mmol), water (5 ml), tetrahydrofuran (20 ml), triphenylphosphine (315 mg, 1.2 mmol) and palladium acetate (90 mg, 0.4 mmol) are loaded into a round-bottom flask equipped with magnetic stirrer and condenser. All the residual air is removed with nitrogen and then the mixture is heated at 60°C for 18 hours, thereafter is cooled, added with water (30 ml) and tetrahydrofuran is evaporated off. Ethyl acetate is added (30 ml) and the mixture is acidified with acetic acid to pH=5. The product is filtered and washed with water, to obtain 2.8 g of crude telmisartan, which is purified by dissolution in concentrated ammonia (2 ml), addition of acetone and reprecipitation with acetic acid.

……………………

PATENT

http://www.google.im/patents/EP2305650A1?cl=en

  • Telmisartan and its physiologically acceptable salts have valuable pharmacological properties. Telmisartan is an angiotensin-II-antagonist, which may be used to treat hypertension and cardiac insufficiency, ischaemic peripheral circulatory disorders, myocardial ischaemia (angina). Furthermore, Telmisartan may be used to prevent the progression of cardiac insufficiency after myocardial infarct, to treat diabetic neuropathy, glaucoma, gastrointestinal diseases and bladder diseases. Telmisartan is also suitable for treating pulmonary diseases, e. g. lung oedema and chronic bronchitis, for preventing arterial restenosis after angioplasty, for preventing thickening of blood vessel walls after vascular operations, and for preventing arteriosclerosis and diabetic angiopathy. In view of the effects of angiotensin on the release of acetyl-choline and dopamine in the brain, Telmisartan is also suitable for alleviating central nervous system disorders, e. g. depression, Alzheimer’s disease, Parkinson syndrome, bulimia and disorders of cognitive function.
  • Telmisartan is a compound of formula (I)

    chemically known as 4′-((1,7′-dimethyl-2′-propyl-1H,3′H-2,5′,-bibenzo[d]imidazol-3′-yl)methyl)biphenyl-2-carboxylic acid, which is disclosed in EP 502314 B1 and marketed under the trade name Micardis®.

  • Several methods have been used to prepare Telmisartan.
  • The process described inEP 502314 B1 comprises the alkylation of 4-methyl-6-(1-methyl-benzimidazol-2-yl)-2-propylbenzimidazole (III)

    with t-butyl 4′-(bromomethyl)biphenyl-2-carboxylate and subsequently hydrolysis to Telmisartan. t-Butyl 4′-(bromomethyl)biphenyl-2-carboxylate is not commercially available and its synthesis requires a number of steps, among them the protection of the carboxylic function which is finally removed by hydrolysis.

  • The patent application WO 2006044648 relates to a method for the production of Telmisartan by reacting 4-methyl-6-(1-methyl-benzimidazol-2-yl)-2-propylbenzimidazole (III) with 4′-(bromomethyl)biphenyl-2-carboxylic acid alkyl ester and subsequently hydrolysis.
  • The patent application WO 2004087676 relates to a method for the production of Telmisartan by reacting 4-methyl-6-(1-methyl-benzimidazol-2-yl)-2-propylbenzimidazole (III) with 4-bromomethyl-2′-cyanobiphenyl and subsequently hydrolysis of the nitrile to the acid function.
  • The patent application EP 1719766 relates to a method for the production of Telmisartan, by coupling with a Suzuki reaction the N-4-bromobenzyl derivative of the compound of formula (III) with 2-carboxylphenyl boronic acid. As described in EP 1878735 , 2-carboxyphenyl boronic acid requires a very laborious process to separate it, since it is extremely soluble in water, making the process unattractive for an industrial application. Thus, the active substance prepared by the process known up till now can only be obtained in a satisfactory quality after running through a number of process steps, wherein additional steps of protection and deprotection of the carboxylic function or additional steps to obtain the carboxylic function are often present.

Example 2 4′-((1,7′-dimethyl-2′-propyl-1H,3′H-2,5′-bibenzo[d]imidazol-3′-yl)methyl)biphenyl-2-carboxylic acid (I)

  • A 2L four-necked glass reactor, fitted with mechanical stirrer, thermometer, dropping funnel, under nitrogen atmosphere, was charged with sodium hydride (60% in mineral oil) (12.5 g, 312 mmol) and toluene (450 mL). The suspension was stirred and trimethylsilanol (31 g, 343 mmol) was added dropwise. After stirring for 15 minutes, methyl 4′-((1,7′-dimethyl-2′-propyl-1H, 3′H-2,5′-bibenzo[d]imidazol-3′-yl)methyl)biphenyl-2-carboxylate (V) (145 g, 274 mmol) was added, the mixture was stirred for 5 hours at about 100°C and monitored by quantitative TLC (elution with 5% MeOH in EtOAc) until complete conversion. The mixture was then cooled at room temperature, water (130 mL) was added, and the mixture was brought at 50°C. The phases were separated and the aqueous phase was stripped under vacuum to remove residual toluene.
    350 g of an aqueous solution were obtained and used as such in the next step.
  • A 1L four-necked glass reactor, fitted with mechanical stirrer, thermometer, dropping funnel, under nitrogen atmosphere, was charged with the aqueous solution in MeOH (600 mL). The mixture was heated under stirring at 40°C until dissolution and charcoal (7 g) was added. The suspension was stirred at 40°C for 30 minutes, filtered through a pad of Celite and the resulting solid was washed with a mixture of MeOH/water 4/1 (100 mL). The filtrate and the washings were combined, the resulting solution was heated to reflux temperature and acetic acid (17.7 g, 295 mmol) was added dropwise over 1 hour. The suspension was then cooled, filtered and the solid was washed with a mixture MeOH/water 4/1 (3 x 50 mL). The collected solid was then dried at 55°C under reduced pressure affording the title compound (130 g) as a white solid.

………………………

PATENT

WO2014067237A1

http://www.google.im/patents/WO2014067237A1?cl=en

Telmisartan is a novel non-peptide angiotensin Π (ΑΤ Π) receptor antagonist, for the clinical treatment of hypertension, its chemical name is 4 ‘- [(1,4′-dimethyl – 2′-propyl [2,6′- two -1Η- benzoimidazol] -Γ–yl) methyl] biphenyl] -2-carboxylic acid, knot

Figure imgf000002_0001

Telmisartan

Telmisartan synthetic route has mainly 3-methyl-4-amino-benzoic acid methyl ester as the starting material by N- acylation, nitration, reduction, cyclization, ester hydrolysis and condensation reaction intermediates 2-n-propyl-4-methyl – 6(1 – methyl-benzimidazol-2-yl) benzimidazole-α), Ϊ with 4′-bromomethyl-biphenyl-2-carboxylate (V) via nucleophilic substitution, hydrolysis reaction to give the final product two Bu telmisartan (reaction formula 1) (J Med Chem, 1993, 36: 4040-4051).

Reaction Scheme 1

Figure imgf000002_0002

After has been reported by 4′-bromomethyl-biphenyl-2-carboxylic acid methyl ester (or ethyl ester) (VI) or 4′-bromomethyl-biphenyl-2-carbonitrile (VII) Preparation of telmisartan (CN01126367 .9, CN01131915.1).

Figure imgf000003_0001
Figure imgf000008_0001
Figure imgf000009_0001
Figure imgf000009_0002

Example 16: Preparation of telmisartan

The title compound of Example 15 (III, R = CN) (24.8g, 0.05mol) was added propylene glycol (100ml) and water (100ml) (or other previously described embodiments will be an aqueous mixed solvent :), potassium hydroxide (or e.g. prior to said other inorganic bases) (0.2mol), was refluxed for 10 hours. After no starting material by TLC was cooled to room temperature, concentrated under reduced pressure to a small volume, was added dropwise hydrochloric acid adjusted to pH 5 to 6, the precipitated solid was filtered, washed with water to obtain telmisartan.

Telmisartan Preparation: 17 Examples

The title compound I (30.4g, 0.10moi>, embodiments of Example 14 4′-chloro-methyl-biphenyl-2-carbonitrile (0.12mol), sodium ethoxide (or other organic bases as previously described) (0.3mol) and DMF (or other solvent as previously described) (200ml) mixed, 65 ° C for about 5 hours. TLC detected no starting material, was added ethylene glycol (100ml and water (50ml) (or other aqueous solvent), and heated to 160 ° C. TLC detected no starting material, concentrated hydrochloric acid under ice cooling to adjust pH to 5-6, to precipitate a solid, the resulting solid was filtered, washed with water to give crude telmisartan, by recrystallization in telmisartan.

Examples 18 to 24: Preparation of telmisartan reference method of Example 8, the title compound of Example 6 to the compound of formula I (10g, leq) and implemented as a reactant, with NaH as a base, the reaction temperature under different conditions the reaction, the reaction solution was subjected to phase detection by conventional post-treatment to give telmisartan (crude), yield was calculated, and the purity of the liquid phase detection telmisartan. The test results are shown in Table 2.

Table 2 compares the reaction conditions

Figure imgf000019_0001
 ……………………..
PATENT
WO2011077444A1

1 Telmisartan ……………………………….2 Impurity B

Table 1 : Preparation of Telmisartan and 2 with reported synthetic schemes

process for the preparation of telmisartan, comprising: condensation of -n-propyl-4-methyl-6-(l’-methylbenzimidazol-2′-yl)benzimidazole (I)

with a compound of general formula II)

wherein Z denotes a leaving group such as a halogen atom, for example, a chlorine, bromine, or iodine atom to obtain the compound 2-cyano-4′-[2″-n-propyl-4″-methyl-6″-( 1 “‘-methylbenzimidazol-2″‘-yl)benzimidazol- 1 “-ylmethyl]biphenyl (III), and subsequent

hydrolysis of nitrile in the presence of excess base and solvent followed by acid/base purification to obtain pure telmisartan.

Scheme-I

EXAMPLES:

Experiment-1: Preparation of 2-cyano-4-[2-n-propyl-4-methyI-6-(l- methylbenzimidazol-2-yl) bnzimidazol-l-ylmethyl] biphenyl.

Add 2-n-propyl-4-methyl-6-(l ‘-methylbenzimidazol-2′-yl) benzimidazole 100 g in 1000ml of acetone and of potassium hydroxide 22.0 g with stirring at 20-25°C. Then of 4-bromomethyl-2′-cyanobiphenyl 92g is added at 20-25°C. Monitor the reaction on thin layer chromatography, after compilation reaction, the crystals are suction filtered, washed with chilled acetone, water, and then dried in a air drying cupboard at 80° C. Yield: 135.0 g (82.82% of theory); melting point: 196° C.-197° C; HPLC: 99.30%. N-3 isomer: 0.08%.

Experiment-2: Preparation of 2-cyano-4-[2-n-propyl-4-methyl-6-(l- methylbenzimidazol-2-yl) benzimidazol-l-ylmethyl] biphenyl.

Add 2-n-propyl-4-methyl-6-( -methylbenzimidazol-2′-yl) benzimidazole 100 g in 1000ml of acetone and of potassium hydroxide 22.0 g with stirring at 20-25°C. Then of 4-bromomethyl-2′-cyanobiphenyl 92g is added at 20-25 °C. Monitor the reaction on thin layer chromatography, after the reaction is completed, cooled to 0 to 5.0° C. and stirred for another hour at this temperature. The material is filtered, washed with chilled acetone, then wash with water, and then dried in a air drying cupboard at 80° C. Yield: 141.50 g (87.73% of theory); melting point: 196° C.-197° C; HPLC: 99.50%. N-3 isomer: 0.16%

Experiment-3: Preparation of Telmisartan.

Add potassium hydroxide 80g in 500ml of ethylene glycol then add 2-cyano-4′- [2-n-propyl-4-methyl-6-( 1 -methyl benzimidazol-2-yl) benzimidazol- 1 -ylmethyl] biphenyl lOOgm at room temperature. Stir the reaction mixture and raise temperature to 150- 155° C. The mixture is stirred for 15 to 18 hours at this temperature and monitor reaction mass by HPLC. After compilation of reaction cool to 30 to 35°C then diluted with 800 ml methanol then telmisartan precipitates by adding of acetic acid at 25 to 30°C and further diluted with water. Then stirred for further 90min at 25 to 30°C. After the crystals have been suction filtered. The wet material dissolve in 500ml methanol with 12gm potassium hydroxide then after treatment of charcoal crystallize the telmisartan to adjusting of pH 6.0 to 6.4 by acetic acid then dilute with 400ml water. Filtered and then dried in a vacuum tray drier at 85°C. Yield: 90g (87.37% of theory); HPLC: 99.91%.

Experiment-4: Preparation of Telmisartan.

Add potassium hydroxide lOOg in 500ml of ethylene glycol then add 2-cyano- 4′-[2-n-propyl-4-methyl-6-(l -methyl benzimidazol-2-yl) benzimidazol- 1 -ylmethyl] biphenyl 1 OOgm at room temperature. Stir the reaction mixture and raise temperature to 150-155° C. The mixture is stirred for 15 to 18 hours at this temperature and monitor reaction mass by HPLC. After compilation of reaction cool to 30 to 35°C then diluted with 800ml methanol then telmisartan crystallize by adding of acetic acid at 25 to 30°C then dilute with 300ml water. Stir for further 90min at 25 to 30°C. Filter and then dried in a vacuum drying cupboard at 85°C. Yield: 101 g (1.03% of theory); HPLC: 99.90%.

Experiment-5: Preparation of pure Telmisartan.

Crude telmisartan 101 g (from example 4) & activated carbon lOg is added in methanol 100ml , dichloromethane 500ml at 25 to 30°C. Stir the reaction mixture then the brown solution is filtered through hyflow bed, Completely distilled out filtrate below 50°C then add 800ml water at that temperature and stir for lhr. The telmisartan is hot filtered and washed with water. The telmisartan is dried at 80° C. in a vacuum drying cupboard. Yield: 90 g (87.37% of theory); HPLC: >99.95%.

Experiment-6: Preparation of Telmisartan.

2-cyano-4′- [2-n-propyl-4-methyl-6-( 1 -methyl benzimidazol-2-yl) benzimidazol- 1 – ylmethyl] biphenyl lOOgm is added in 500ml of ethylene glycol with lOOg of potassium hydroxide powder at 20-25°C. Stir and raise temperature to 160° C. to 165° C. The mixture is stirred for 15 to 18 hours at this temperature and monitor reaction mass by HPLC. After compilation of reaction cool to 70 to 75°C then diluted with methanol and water then telmisartan crystallize by adding of acetic acid to adjust the pH 5.5 to 6.0 at 25 to 30°C. Stir for further 60min at 25 to 30°C. After the crystals have been suction filtered. The wet material dissolve in methanol with potassium hydroxide 12gm then after treatment of charcoal crystallize the telmisartan by adding of acetic acid by adjusting of pH 6.0 to 6.4 then stir for further 60min. The material is filtered and dried in a vacuum drying cupboard at 85°C. Yield: 86.56g (84.03% of theory); HPLC: >99.96%.

Experiment-7: Preparation of Telmisartan.

of 2-n-propyl-4-methyl-6-(r-methylbenzimidazol-2′-yl) benzimidazole 100 g is add in 1000 ml of acetone, and of potassium hydroxide 22 gm with stirring at 20-25° C and then 90.0 g of 4-bromomethyl-2′-cyanobiphenyl is added at 20-25°C. The temperature of the reaction mixture is maintained at 20 to 25° C. Stir for a further 6.0 to 8.0 hours at 20 to 25° C. Monitor the reaction on thin layer chromatography, after compilation reaction distil out acetone. Add ethylene glycol 500ml and potassium hydroxide lOOgm to residue Stir the reaction mixture and raise temperature to 150° C. to 155° C. The mixture is stirred for 15 to 18 hours at this temperature and monitor reaction mass by HPLC. After compilation of reaction cool to 30 to 35°C. Reaction mass diluted with methanol and stir for 30min then telmisartan precipitated by adding of acetic acid to adjust the pH 6.0 to 6.5 at 25 to 30°C. Then dilute with water and filter, wash with of methanol. Wet telmisartan is dissolved in methanolic potassium hydroxide, filtered to remove un dissolved material. Acetic acid is added to adjust the pH 6.0 to 6.4 , water added for complete precipitation of material. Finally telmisartan is suction filter and wash with water at 40 to 45 °C. The telmisartan is dried at 80° C. in a vacuum drying cupboard. Yield: 130g

HPLC: 99.4%.

1H NMR (DMSO-d6) δ 1.0 (t,3H), 1.9 (q, 2H), 2.95 (t, 2H), 2.4 (s, 3H), 3.95 (s, 3H), 5.8 (s, 2H), 7.28 (s,lH),7.80 (s,lH), 7.75 (d, 2H), 7.25 (t, 2H), 7.10 (d, 2H), 7.30 (d, 2H), 7.40 (d, 1H), 7.40 (t, 1H), 7.30 (t, 1H), 7.45 (d, 1H). 12.9 (s, 1H).

m/z 514.7 [ M + H]+.

 …………………
PATENT
US 6358986
EXAMPLE
3185 kg of recrystallised telmisartan (recrystallised from dimethylformamide or dimethylacetamide), 5.6 kg of activated charcoal, 185 l of water, 190.4 kg of formic acid (99-100%) and 185 l of methylethylketone are placed in a 1200 l stirring apparatus. The mixture is stirred for about 1 h at 60-70° C. and then filtered into another 1200 l stirring apparatus and washed with a mixture of 74 l of methylethylketone and 8.3 kg of formic acid (99-100%). About 278 l of solvent are distilled off at 80-100° C. whilst simultaneously 278 l of water are added. The mixture is then cooled to 20-30° C. and precipitated by the metered addition of 281.5 kg of 25% ammonia solution. The product precipitated is centrifuged, washed with water and dried at 120-125° C. Yield: 178 kg of telmisartan (96.2% of theory)
Comparison Example
150 kg of telmisartan (recrystallised from dimethylformamide or dimethylacetamide), 7.5 kg of activated charcoal, 750 l of ethanol and 30 kg of 25% aqueous ammonia solution are placed in a 1200 l stirring apparatus. The mixture is stirred for about 1 h and then filtered into another 1200 l stirring apparatus and washed with 150 l of ethanol. The mixture is heated to 70-80° C., 35 kg of glacial acetic acid are added and the mixture is stirred for a further 1.5-2 h at 75-80° C. The mixture is then cooled to 0-10° C. and stirred for a further 2 h. The product precipitated is centrifuged, washed with 300 l of ethanol and with 300 l of water and dried at 70-90° C. Yield: 135 kg of telmisartan (90% of theory) pure form AIn the preparation process according to the invention, as a result of the partial conversion of the polymorphic form B into the polymorphic form A during the drying process, telmisartan occurs as a pure substance in a mixture of two polymorphic forms. However, this does not affect the properties of the pharmaceutical composition, as in the course of the manufacture of telmisartan tablets, for example, the mixture of the polymorphic forms A and B is dissolved in 0.1 N NaOH solution and converted by spray drying into a homogeneous and totally amorphous granulate which is then subjected to the other tablet making steps. For more detailed information on the use of the products according to the invention for preparing a pharmaceutical composition, cf. EP 502314 B1, the contents of which are hereby referred to.
 …………………………..
PATENT
WO2009006860A2

Telmisartan (I) is produced in accordance with the original patent of Boehringer Ingelheim (US 5 591 762) from telmisartan tert-butyl ester (II). The hydrolysis is carried out using of trifluoroacetic acid in the toxic solvent N,N-dimethylformamide.

According to another patent applied by the same company (US 2004 236113) the manufacture was problematic and this is why this procedure was replaced with hydrolysis of the corresponding nitrile (III). However, during the hydrolysis, which is carried out with potassium hydroxide in ethylene glycol, a high temperature (160 0C) is used, which causes browning of the product, which must be subsequently purified by means of activated carbon. Also, the energy demands of several-ton production would be considerably high.

In a newer application of Cipla (WO 2005/10837) the last two synthetic steps (iii+iv) are combined and telmisartan is isolated after alkaline hydrolysis by acidifying of the reaction mixture in water or extraction with dichloromethane and precipitation with acetone. Both the ways of isolation are unsuitable for industrial production. In the case of telmisartan of crystalline form A its isolation from water or aqueous solutions of organic solvents is very difficult since a hardly filterable product is formed. Extraction of the product with dichloromethane and precipitation with acetone brings a well-filterable product, but the use of dichloromethane is virtually impossible from the point of view of environment protection.

Another method has been described by Dr. Reddy (WO 2006/044754), which starts from telmisartan methylester hydrochloride, which is hydrolyzed to produce the potassium salt of termisartan, which is further acidified in aqueous acetonitrile; after isolation it crystallizes from a dichloromethane/methanol mixture and finally from methanol alone, and wherein a pressure apparatus is used for the dissolution in methanol at a temperature above its boiling point (80 °C). The result of this complex procedure, which manifests the already above mentioned shortcomings, is a low yield of the product.

The method of Teva (WO 2006/044648) is in many aspects similar to the above mentioned procedure of Cipla, wherein the last two steps of the synthesis are also combined. The method comprises phase separations, which lead to low yields (69 % – 80 %) besides increased tediousness. Matrix starts from telmisartan tert-butyl ester (II), which is first converted to telmisartan dihydrochloride, which in turn, by action of aqueous ammonia in methanol, provides telmisartan with a low total yield of 73%.

WO2009006860A2

Example 3

4′-[[4-methyl-6-(l-methyl-lH-benzimidazol-2-yl)-2-propyl-l/J-benzimidazol- lyl]methyl]biρhenyl-2-carboxylic acid (telmisartan)

Telmisartan methylester (VT) (20 kg) was refluxed in methanol (400 1) with potassium hydroxide (7 kg) for 24 h. After addition of acetic acid (20 kg) and cooling to 4 °C the product was aspirated within 1 hour and washed with methanol (2 x 80 1). After drying at the laboratory temperature (24 h) 18.5 kg (95 %) of the product were obtained.

Example 4

4′-[[4-methyl-6-(l-methyl-lH-benzimidazol-2-yl)-2-propyl-lH-benzimidazol- lyl]methyl]biphenyl-2-carboxylic acid (telmisartan)

Telmisartan methylester (40 g) was refluxed in methanol (240 ml) with potassium hydroxide (14.9 g) for 24 h. To the boiling solution methanol (240 ml) and then acetic acid (45.5 g) were added. After cooling to 4 °C the product was aspirated within 1 hour and washed with methanol (2 x 80 ml). After drying at the laboratory temperature (24 h) 36 g (92%) of the product were obtained.

……………………………….
PATENT
WO2010004385

Telmisartan was first disclosed in US 5,591,762. US 5,591,762 also discloses a process for the preparation of Telmisartan by reacting l,4′-dimethyl-2′-propyl[2,6′-bi-lH- benzimidazole (II) with 4′-(bromomethyl)[l,r-biphenyl]-2-carboxylic acid 1,1- dimethylethyl ester (III) in a solvent optionally in the presence of an acid binding agent to produce the intermediate 4′-[(l,4′-dimethyl-2′-propyl[2,6l-bi-lH-benzimidazol]-l- yl)methyl]-[l,l’-biphenyl]-2-carboxylic acid 1,1-dimethylethyl ester (IV), which is further hydrolysed to produce crude Telmisartan. The crude product obtained is purified over a silica gel column and finally crystallized from acetone. The process is shown in Scheme 1 :

Hydrolysis

(I)

The disadvantage with the above process is the use of column chromatography in the purification of Telmisartan. Employing column chromatography technique is tedious and laborious and also involves use of large quantities of solvents, and hence is not suitable for industrial scale operations.

US 6,358,986 describes two crystalline forms of Telmisartan donated as Form A, Form B. In US 6,358,986, the process for preparing crystalline Telmisartan Form A comprises mixing the Telmisartan with ethanol, adding activated charcoal and aqueous ammonia and mixing for one hour, then filtering to another stirring apparatus and washing with ethanol. Resulting solution is heated to 70~80°C, adding glacial acetic acid and stirring for further 1.5-2 hours at the same temperature, cooling to 0-10°C, stirring for further 2 hours, isolating the product by centrifugation, washing with ethanol then with water and drying at 70-90°C. According to the detailed description given in the US ‘986 patent, in addition to the disadvantageously prolonged drying process of the Telmisartan Form A, very hard particles are obtained. The grinding process of these particles produces a dry powder, which has strong tendency to electrostatic charging and which is virtually impossible to pour and manipulate for pharmaceutical preparations. On the other hand, Telmisartan Form B is free from the above-mentioned limitations. However, the inventors of the US ‘986 patent could not obtain pure, dry Form B because upon drying, some of Form B transformed into Form A. According to the teachings of the US ‘986 patent, mixtures of Telmisartan Form A and Form B ranging from 90:10 to 60:40 are suitable for industrial scaling-up, and even a content of 10% of Form B is sufficient to ensure that the product will have the positive qualities required for large-scale production.

US 2006/0276525 Al describes a process for the preparation of crystalline solid of Telmisartan Form A by dissolving Telmisartan in a polar solvent such as dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), ΛζiV-dimethylacetamide (DMA)5 iV-methyl-2-pyrrolidone (ΝMP) and cooling the solution for sufficient time to produce Telmisartan Form A crystals, which are filtered and dried.

EXAMPLE-8

PREPARATION OF 4′-[[4-METHYL-O-(I-METHYL-Z-BENZIMIDAZOLYL) ^- PROPYL-1-BENZIMIDAZOLYL] METHYL]-Z-BIPHENYLCARBOXYLIC

ACID [TELMISARTAN]

Powdered sodium hydroxide (6.83 g) was added in N,N~dimethylformamide (175 ml) at 4°C followed by 4-methyl-6-(l-methyl-2-benzimidazolyl)-2 -propyl- 1- benzimidazole monohydrate (50 g) and stirred for 5 min. Thereafter, methyl-2-[4′- (bromomethylphenyl)]benzoate (54.76 g) was added at 0°C and stirred to the reaction mass till completion of the reaction. Methylene chloride (250 ml) was added, followed by water (500 ml) at 20C and stirred for 10 min. The aqueous layer was separated and extracted with methylene chloride (50 ml). The combined organic extract was washed with water (250 ml) to obtain 380 ml of the organic solution containing Telmisartan methyl ester. 320 ml of this organic layer was concentrated at ambient pressure to collect 210 ml of the distillate. Methanol (120 ml) was added to the concentrated mass and distilled to collect 96 ml of the distillate. The concentrated mass was diluted with 160 ml of methanol at 5O0C. Thereafter, aqueous sodium hydroxide solution (17.4 g of NaOH in 40 ml of water) was added at 5O0C and heated to reflux at 69-7O0C and stirred at reflux temperature till completion of hydrolysis reaction. Thereafter, the reaction mass was concentrated under reduced pressure at 60-650C till no more solvent distils. Water (600 ml) and methylene chloride (200 ml) was added to this solution. pH was adjusted to 4 with hydrochloric acid (22 ml, 35% w/w) at 27-28°C. The aqueous layer was separated and extracted with methylene chloride (40 ml). The combined organic layer was washed with water (80 ml) to obtain 280 ml of the organic solution. This is divided in to four parts and taken for isolation of Telmisartan as given below.

Part-1 The organic layer (70 ml) as obtained above was diluted with N,N-dimethylformamide (500 ml) at 27°C and seeded with Telmisartan form-A. The solution was left on standing without stirring for 30 min. The resulting suspension was stirred at 27-28°C for 30 min at this temperature. Solid was filtered, washed with precooled N5N- dimethylformamide (15 ml, -5°C) followed by precooled ethanol (10 ml, -2°C) and dried at 85-900C under reduced pressure to afford 10.1 g of Telmisartan.

Part-2

The organic layer (70 ml) as obtained above was diluted with N,N-dimethylformamide (50 ml) at 27°C and seeded with Telmisartan form-A. The solution was left on standing without stirring for 30 min. The resulting suspension was concentrated under reduced pressure at 65-700C to collect 30 ml of the distillate. Thereafter, the concentrated mass was cooled to -5°C and stirred for 30 min at this temperature. Product was filtered, washed with precooled N,N-dimethylformamide (15 ml, -3°C) followed by precooled ethanol (10 ml, -2°C) and dried at 85-900C under reduced pressure to afford 11.4 g of Telmisartan.

Part-3

The organic layer (70 ml) as obtained above was diluted with N,N-dimethylformamide (60 ml) at 27°C and seeded with Telmisartan form-A. The solution was left on standing without stirring for 30 min. The resulting suspension was concentrated under reduced pressure at 65-70°C to collect 50 ml of the distillate. Thereafter, stirred at 30°C for 15 min, cooled to -5°C and stirred for 30 min at this temperature. Product was filtered, washed with precooled N,N-dimethylformamide (15 ml, -5°C) followed by precooled ethanol (10 ml, -20C) and dried at 85-900C under reduced pressure to afford 11.7 g of Telmisartan.

Part-4

The organic layer (70 ml) as obtained above was diluted with N,N-dimethylformamide (40 ml) at 27°C arid seeded with Telmisartan form-A. The solution was left on standing without stirring for 30 min. The resulting suspension was concentrated under reduced pressure at 65-700C to collect 45 ml of the distillate. Thereafter, stirred at 300C for 15 min, cooled to -5°C and stirred for 30 min at this temperature. Product was filtered, washed with precooled N,N-dimethylformamide (15 ml, -5°C) followed by precooled ethanol (10 ml, -20C) and dried at 85-900C under reduced pressure to afford 12.3 g of Telmisartan.

…………………………………
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Omeprazole spectral visit

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Omeprazole

CAS NO. 119141-89-8

(RS)-5-methoxy-2-((4-methoxy-3,5-dimethylpyridin-2-yl) methylsulfinyl)-1H-benzo[d]imidazole

Omeprazole
CAS No.: 119141-89-8
Synonyms:
  • ZOLTUM;
  • PRILOSEC;
  • LOSEC;
  • GASTROGARD;
  • ANTRA;
  • OMEPRAL;
  • MEPRAL;
  • H 168/68;
  • GASTROLOC;
  • MOPRAL;
Formula: C17H19N3O3S
Exact Mass: 345.11500

Ome is a chemical substance (C17H19N3O3S), its molecular weight is 345.42g/mol, the color is white, has weak alkaline properties, melts at 156oC

ome 1h nmr

NMR……………http://file.selleckchem.com/downloads/nmr/S138902-Omeprazole-Prilosec-HNMR-Selleck.pdf

NMR………..file:///C:/Users/anthonyc/Downloads/233-434-1-SM.pdf

1H NMR PREDICT

STR

STR 2

OMEPRAZOLE NMR spectra analysis, Chemical CAS NO. 119141-89-8 NMR spectral analysis, OMEPRAZOLE H-NMR spectrum

13C NMR PREDICT

OMEPRAZOLE NMR spectra analysis, Chemical CAS NO. 119141-89-8 NMR spectral analysis, OMEPRAZOLE C-NMR spectrum

COSY

COSY NMR prediction (7)

HMBC

HMBC, HSQC NMR prediction (1)

Image

………………………………..

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ARKIVOC 2006 (v) 5-11

The structure of Omeprazole in the solid state: a 13C and 15N NMR/CPMAS study

Rosa M. Claramunt,a Concepción López,a and José Elguerob *

a Departamento de Química Orgánica y Bio-Orgánica, Facultad de Ciencias, UNED, Senda del Rey 9, E-28040 Madrid, Spain

b Instituto de Química Médica, CSIC, Juan de la Cierva, 3. E-28006 Madrid, Spain

E-mail: iqmbe17@iqm.csic.es

http://www.arkat-usa.org/get-file/22955/

Abstract

The 13C and 15N CPMAS spectra of a solid sample of Omeprazole have been recorded and all the signals assigned. The sample consists uniquely of the 6-methoxy tautomer. For analytical purposes, the signals of the other tautomer, the 5-methoxy one, were estimated from the data in solution (Magn. Reson. Chem. 2004, 42, 712).

Keywords: Omeprazole, NMR, 13C, 15N, CPMAS, tautomerism, benzimidazole

Displaying image008.png

Omeprazole, 5(6)-methoxy-2-{(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl}-1H-benz – imidazole [1(2)], is an important ulcer drug,1 that has been classified amongst the blockbuster drugs.2 This compound presents two sources of structural differentiation. First, Omeprazole is chiral (a vs. b) 3 since it has a stereogenic center on the sulfur atom but the commercial form has been sold, until recently, as a racemate. In 2001, Esomeprazole magnesium, the S enantiomer was approved.4 The second source of diversity is that these compounds present tautomerism (1 vs. 2). We have already devoted a paper to the tautomerism of Omeprazole in solution using 1 H and 13C NMR spectroscopy.5 In this paper a complete assignment of the signals was carried out and the tautomeric equilibrium constant, KT = [2]/[1], was determined in THF at 195 K, to be 0.59 in favor of the 6-methoxy tautomer 2.

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References

1. Carlsson, E.; Lindberg, P.; von Unge, S. Chem. Brit. 2002, 38, 42 and references therein.

2. Berkowitz, B. A.; Sachs, G. Mol. Interventions 2002, 2, 6.

3. von Unge, S.; Langer, V.; Sjölin, L. Tetrahedron: Asymmetry 1997, 8, 1967.

4. Olbe, L.; Carlsson, E.; Lindberg, P. Nature Reviews Drug Discovery 2003, 2, 132.

5. Claramunt, R. M.; López, C.; Alkorta, I.; Elguero, J.; Yang, R.; Schulman, S. Magn. Reson. Chem. 2004, 42, 712.

6. Elguero, J.; Katritzky, A. R.; Denisko, O. Adv. Heterocycl. Chem. 2000, 76. 1.

7. Allen, F. H. Acta Crystallogr. Sect. B 2002, 58, 380.

8. Braga, S. S.; Ribeiro-Claro, P.; Pillinger, M.; Gonçalves, I. S.; Fernandes, A. C.; Pereira, F.; Romåo, C. C.; Correia, P. B.; Teixeira-Dias, J. J. C. J. Incl. Phenom. Macro. Chem. 2003, 47, 47.

9. Berger, S.; Braun, S. 200 and More NMR Experiments. Wiley-VCH, Weinheim, 2004.

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DSC OF OMEPRAZOLE

UV

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UV Study: The Ultraviolet spectrum was recorded from 200 nm to 400 nm, with API concentration of 0.0015% in methanol. The spectrum showed two λmax at 207 and 301 nm. As seen below.

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FTIR Study The FTIR of spectrum of Omeprazole was recorded by preparation of pellet with KBr.

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NMR

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13 C NMR

 

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mass

The mass spectrum of Omeprazole was recorded on 4000-Q trap LCMSMS system. The sample is introduced into the system through HPLC by bypassing the column. The ESI +ve ionization spectrum of Omeprazole displayed a protonated molecular ion at m/z= 346 which corresponds to the molecular formula C17H17N3O3S. The fragmentation pattern was observed with product ion scan.

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Raman

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Title: Omeprazole
CAS Registry Number: 73590-58-6
CAS Name: 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole
Manufacturers’ Codes: H-168/68
Trademarks: Gastrogard (Merial); Losec (AstraZeneca); Mopral (AstraZeneca); OmeLich (Winthrop); Omelind (Lindopharm); Omepral (AstraZeneca); Omeprazen (Malesci); Osiren (Probiomed); Parizac (Lacer); Pepticum (Grñenthal); Prilosec (AstraZeneca); Zegerid (Santarus); Zoltum (AstraZeneca)
Molecular Formula: C17H19N3O3S
Molecular Weight: 345.42
Percent Composition: C 59.11%, H 5.54%, N 12.16%, O 13.90%, S 9.28%
Literature References: Gastric proton-pump inhibitor. Prepn: U. K. Junggren, S. E. Sjostrand, EP 5129; eidem, US 4255431(1979, 1981 both to AB Hässle). Resolution and activity of enantiomers: P. Erlandsson et al., J. Chromatogr. 532, 305 (1990). Manuf process for optically pure salts: S. Von Unge, US 5693818 (1997 to Astra). Pharmacology: P. Muller et al., Arzneim.-Forsch. 33, 1685 (1983). Mechanism of action study: B. Wallmark et al., Biochim. Biophys. Acta 778, 549 (1984). LC determn in plasma and urine: P. Lagerstrom, B. Persson, J. Chromatogr. 309, 347 (1984). Survey of preclinical data: Scand. J. Gastroenterol. 20, Suppl 108, 1-120 (1985). Toxicological studies: L. Ekman et al., ibid. 53. Clinical trial in Zollinger-Ellison syndrome: C. B. H. W. Lamers et al., N. Engl. J. Med. 310, 758 (1984); in duodenal ulcer: K. Lauritsen et al., ibid. 312, 958 (1985). Veterinary trial in race horses: M. J. Murray et al., Equine Vet. J. 29, 425 (1997). Review of pharmacology and clinical efficacy: H. D. Langtry, M. I. Wilde, Drugs 56, 447-486 (1998).
Properties: Crystals from acetonitrile, mp 156°. Freely sol in ethanol, methanol; slightly sol in acetone, isopropanol; very slightly sol in water. LD50 in mice, rats (g/kg): 0.08, >0.05 i.v.; >4, >4 orally (Ekman).
Melting point: mp 156°
Toxicity data: LD50 in mice, rats (g/kg): 0.08, >0.05 i.v.; >4, >4 orally (Ekman)
Derivative Type: Magnesium salt
CAS Registry Number: 95382-33-5
Trademarks: Antra (AstraZeneca); Gastracid (AWD); Gastroloc (AstraZeneca); Omebeta (Betapharm); Omep (Hexal); Ome-Puren (Alpharma)
Molecular Formula: C34H36MgN6O6S2
Molecular Weight: 713.12
Percent Composition: C 57.26%, H 5.09%, Mg 3.41%, N 11.78%, O 13.46%, S 8.99%
Derivative Type: S-Form
CAS Registry Number: 119141-88-7
Additional Names: Esomeprazole; perprazole
Manufacturers’ Codes: H-199/18
Literature References: LC-MS determn in plasma: H. Stenhoff et al., J. Chromatogr. B 734, 191 (1999).
Properties: Colorless syrup. [a]D20 -155° (c = 0.5 in chloroform).
Optical Rotation: [a]D20 -155° (c = 0.5 in chloroform)
Derivative Type: S-Form magnesium salt
CAS Registry Number: 161973-10-0
CAS Name: (T-4)-Bis[5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazolato]magnesium
Additional Names: esomeprazole magnesium
Trademarks: Nexium (AstraZeneca)
Literature References: Review of clinical experience in acid disorders: D. A. Johnson, Expert Opin. Pharmacother. 4, 253-264 (2003).
Properties: White powder. [a]D20 -128.2° (c = 1 in methanol).
Optical Rotation: [a]D20 -128.2° (c = 1 in methanol)
Therap-Cat: Antiulcerative; in treatment of Zollinger-Ellison syndrome.
Therap-Cat-Vet: Antiulcerative.
Keywords: Antiulcerative; Gastric Proton Pump Inhibitor.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.




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