1R,2S-methoxamine, also known as L-erythro-methoxamine

CAS 13699-29-1

Molecular Weight, 211.26, C₁₁ H₁₇ N O₃

HYDROCHLORIDE

(1R,2S)-isomer HCl salt of 1 -(2,5-dimethoxyphenyl)-2-amino-1 -propanol also called as (1R, 2S)methoxamine hydrochloride

CAS  16122-04-6

Used as a pressor agent, as a vasoconstrictor, as a nasal decongestant, in ophthalmology and also found very effective in the treatment of faecal incontinence.

treatment of relief of fecal incontinence and anal itch (pruritis ani) , particularly for patients who have had a major bowel resection and reanastomosis .

Anal or fecal incontinence is the inability to voluntarily control the passage of feces or gas through the anus. It may occur either as fecal soiling or as rare episodes of incontinence for gas or watery stools. It is a very distressing condition that can result in self-inflicted social isolation and despair.

Conventional treatments for fecal incontinence include drug therapy to improve stool consistency, such as morphine, loperamide and codeine phosphate to reduce gut motility, and laxatives to soften stools and relieve constipation. Biofeedback training is another treatment which involves muscle strengthening exercises to improve anal canal resting pressure, and squeeze pressure, and to teach symmetry of anal canal function. The most common form of treatment however, is surgical repair, such as the creation of a neo-sphincter which involves grafting on muscle from other parts of the anus, or a colostomy. (Gastroenterology in Practice, Summer 1995, pl8- 21; Dig Dis 1990; 8:179-188; and The New England Journal of Medicine, April 1992, pl002-1004) . In mild cases of anal leakage, the patient will often try and plug the anus with a ball of cotton wall.

In Gut, 1991, 32, p.345-346 it was reported that two thirds of patients with idiopathic faecal incontinence had a decreased anal resting pressure resulting from an abnormal internal sphincter function. In many incontinent patients, the internal anal sphincter was found to be abnormally thin, while others had an external anal sphincter defect. It has also been reported that in vi tro contractile response of the internal anal sphincter to noradrenaline is decreased in incontinence, (Br. J. Surg. 1992, vol 79, August, p829-832; Digestive Diseases and Sciences, vol 38, no. 11, Nov. 1993, pl961-1969) . A further discussion of the innervation and control of the internal anal sphincter and drugs which can increase or decrease the normal anal resting pressure, is discussed in the text book Coloproctology and the Pelvic Floor (Butterworths) , second edition, 1992, at chapter 3 p37-53; Automic Control of Internal Anal Sphincter; and Journal of Clinical Investigation 1990, 86: p424-429.

In Surgery 1990; 107: p311-315 sodium valproate was found to be useful in the treatment of minor incontinence after ileoanal anastomosis.

It has now surprisingly been found that fecal incontinence and anal itch can be resolved by treatment with α adrenergic agonists, nitric oxide synthase inhibitors, prostaglandins F_2α, dopamine, morphine, β-blockers such as propranolol, and 5-Hydroxytryptamine (5-HT) .

This is surprising since it was always thought that once an anal sphincter began functioning abnormally, the patient would require major surgery.

In this way the anal leakage is reduced or eliminated without the patient having to undergo major surgery.

Accordingly in a first aspect of the invention there is provided use of a physiologically active agent selected from an α adrenergic agonist, nitric oxide synthase inhibitor, prostaglandin F_2α, dopamine, morphine, β-blockers, and 5- Hydroxytryptamine in the preparation of a medicament for the treatment or prophylaxis of fecal incontinence or anal itch.

The agents of the invention appear to at least partially treat the incontinence by increasing the resting pressure of the internal anal sphincter. Preferred agents are _λ adrenergic agonists, nitric oxide synthase inhibitors, and prostaglandins F_2α.

Examples of suitable a_λ adrenergic agonists are nor- adrenalin, methoxamine, but particularly preferred is phenylephrine .

Examples of suitable F_2α prostaglandin are dinoprost and carboprost.

Examples of suitable NO synthase inhibitors are

N^G-monnoommeetthhyyll–LL–aarrggiinn:ine (L-NMMA) , and N^G-nitro-L-arginine methyl ester ( -NAME)

The medicament can contain a single active agent or a combination of any of the above active agents.

Nitric Oxide (NO) synthase inhibitors such as LNMMA have previously been suggested for the therapeutic treatment of septic shock.

The prostaglandins, along with thromboxanes and leukotrienes are all derived from 20 -carbon polyunsaturated fatty acids and are collectively termed eicosanoids. F_2α prostaglandins are derived in vivo from the endoperoxide prostaglandin H₂which is in turn derived from leukotrienes. Clinically, F_2α prostaglandins such as dinoprost and carboprost are used as uterine stimulants in the termination of pregnancy, missed abortion or the induction of labour.

Phenylephrine (an α_x adrenergic agonist) is used as a mydriatic in ophthalmology, and as a decongestant , for example, in cold and flu remedies.

However there has been no suggestion to the inventors knowledge of using any of these active agents to treat fecal incontinence or anal itch. As used herein “fecal incontinence” includes all types of anal leakage from minor leakage or ‘spotting’ through moderate leakage, to major instances of faecal incontinence, and includes neurogenic, active, urge and passive incontinence.

More particularly the class of incontinent patients who will benefit most from the present invention are those with idiopathic incontinence and those whose incontinence is at least partly due to a weakness of either the internal or external anal sphincter, especially those with a normal or low maximum anal pressure and a structurally intact internal anal sphincter muscle, such as with an abnormally thin sphincter. However patients with minor structural damage such as a fragmented sphincter would still benefit from the invention. Not only incontinent patients with a damaged or abnormal internal sphincter can be treated, but also patients with a damaged or abnormal external sphincter since the increase in the internal anal resting tone induced by the invention will compensate for a poorly functioning external sphincter.

Another class of patients who particularly benefit from the invention are post-surgical patients who have had major bowel resection and reanastomosis . For example patients with ileoanal pouch (restorative proctocolectomy) , coloanal (with or without colonic pouch) anostomosis, lower anterior resection, and colectomy with ileorectal anastomosis.

The damage to the sphincter could be caused by trauma, such as experienced in child birth, surgical operations, or road traffic accidents. Furthermore it is also believed that incontinence caused by primary internal anal degeneration can also be relieved by the invention.

Anal leakage also often leads to pruritis of the anus and therefore by reducing or eliminating the leakage, the pruritis or anal itch is also relieved or prevented. Furthermore, as a result of the increased anal resting pressure, the patient no longer has the discomfort of distended anal sphincter muscles.

Methoxamine contains two chiral carbons and thus exists in four isomeric forms. Of all the isomeric forms, the studies revealed (1R,2S)- isomer to be therapeutically active.

US patent 2359707 describes the process for the synthesis of racemic β-(2,5-dimethoxy phenyl)-P-hydroxy-isopropyl amine in neutral, acid salt and its derivative from 2,5- dimethoxy propiophenone by treatment with methylnitrite in diethyl ether medium to obtain 2,5-dimethoxy-a-isonitrosopropiophenone hydrochloride. It is further reduced with palladium on carbon to yield β-(2,5-dimethoxyphenyl)-p-ketoisopropylamine hydrochloride and then with platinum black to get p-(2,5-dimethoxyphenyl)-β- hydroxyisopropyl amine hydrochloride. The described process for di-methoxamine HC1 is not cost-effective, due to the use of two expensive catalysts (platinum black and palladium carbon), solvent diethyl ether and involves more number of steps. The other drawback being it is racemic mixture and cannot be used directly as drug. The process described did not specify the quality of the product.

In US patent 3284490 the processes for racemic N-alkyl derivatives of methoxamine are described from dl-methoxamine.

JP 63165348 describes process for production of optically active l-(2,5- dimethoxyphenyl)-2-aminophenol by resolving racemic compound with the use of optically active L-N-acetylleucine as resolving agent. The disadvantages of the process are less yield, low quality and use of expensive naturally occurring amino acid, which prevents from employing this method on commercial scale.

WO 03/055474 A1 discloses mainly, the use of (1R, 2S)-methoxamine in the treatment of faecal incontinence at low doses without local or systemic side effects when used topically. The patent also described the synthesis of (1R, 2S)-methoxamine, from L- alanine, by protecting the amino group using methylchloroformate, converting carboxy
group of the N-protected alanine into an acid chloride insitu followed by reaction with an amine to produce an N-protected (S)-alanine amide and coupling that compound with a brominated 2,5-dimethoxybenzene in the presence of n-butyllithium or a magnesium based reagent to give (S)-amino-l-(2,5-dimethoxy-phenyl)-l-propanone, the amino group of which is protected .The reduction of the N-protected propanone was carried out using dimethylphenylsilane and the protecting group was removed by treatment with potassium hydroxide. Other method adopted in the patent to isolate (1R,2S)methoxamine is by separation of racemic methoxamine using chiral column.

The prior art suffers with some of the disadvantages like using n-butyllithium, which is pyrophoric, expensive and causes hazards to commercial scale. Also, the separation of racemic Methoxamine using chiral column mentioned in the patent can be considered for
isolating small quantities of the required isomer for analytical purposes but cannot be adopted on commercial scale for production of the drug.

US Patent 5962737 described stereospecific synthesis of the racemic threo isomers of 2- nitro-1 -phenylpropanols by reacting benzaldehyde derivative with nitroalkane in the presence of a tertiary amine and reducing 2-nitro-l-phenylpropanols with lithium aluminium hydride to 2-amino-l-phenylpropanols. Also described is phase transfer resolution of racemic mixtures of 2-amino-l-phenylpropanol and its derivatives into their optically pure isomers by reacting with the mono alkali metal salt of tartaric acid ester in a two phase system of a hydrocarbon and water. The specification further describes optically pure isomer D-threo 2-amino-( 1 -dialkoxy or alkoxy)phenylpropanol by resolution of dl- threo 2-amino-( 1 -dialkoxy or alkoxy)phenylpropanol by using dibenzoyltartaric acid. The synthesis of the product (lS,2S)-threo 2-amino-(l-dialkoxy or alkoxy) phenyl propanol involves the use of expensive and hazardous chemicals like LAH making the process technically and commercially difficult for implementation.

Paper

Journal of the American Chemical Society (1984), 106(16), 4629-30

http://pubs.acs.org/doi/pdf/10.1021/ja00328a062

PATENT

http://www.google.com/patents/EP2275099A1?cl=en

EXAMPLE 3Synthesis of 1R,2S-Methoxamine(S)-N-Methoxycarbonyl alanine

To a stirred solution of L-alanine (300g, 3.37 mol sodium hydroxide (1N, 1800 cm³) at 0°C in an ice bath was added dropwise, over 2 hours, methyl chloroformate (274 cm³, 3.54 mol). The pH of the solution was maintained at 9 by the addition of sodium hydroxide (5N). The reaction mixture was stirred at 0°C for 3 hours whereupon it was acidified to pH 1 by the addition of phosphoric acid solution (15%) and extracted with diethyl ether (5 x 1000 cm³). The combined organic extracts were dried (MgSO₄) and concentrated under reduced pressure to yield the product as a viscous green oil (386 g, 78%). ¹H NMR (250 MHz; C²HCl₃) 1.48 (3H, d, J7.25, CH₃), 3.72 (3 H, s, COCH₃), 4.40 (1 H, quintet, J7.25, CH), 5.31 (1 H, bs, NH).

(S)-N-Methoxycarbonyl alaninedimethylamide

To a stirred solution of MeOC-alanine (227 g, 1.54 mol) and dimethylformamide (DMF) (25 cm³) in dry dichlorourethane (DCM) (2000 cm³) at 0°C was added dropwise oxalyl chloride (146 cm³, 1.62 mol) over a period of 2 hours. The solution was stirred at 0°C until the evolution of gasses ceased whereupon a basic solution of dimethylamine (676 g, 7.70 mol) in NaOH (3 N, 2000 cm³) was added. The aqueous layer was extracted with diethyl ether (2 x 500 cm³) and the combined organic layers dried (MgSO₄) and concentrated under reduced pressure to give the product as a white crystalline solid which required no further purification (230 g, 86%). ¹H NMR (250 MH_z; C²HCl₃) 1.33 (3 H, d, J6.75, CH₃), 2.99 3 H, s, OCH₃) 3.08, (3 H, s, OCH₃), 3.66 (3 H, s, COCH₃), 4.66 (H, quintet, J7.00, CH), 5.75 (1 H, d, J5.75, NH).

(S)-2-[(Methoxycarbonyl)amino]-1-(2,5-dimethoxyphenyl)-1-propanone.

To a THF (1000 cm³) solution of bromo-2,5-dimethoxybenzene (55 g, 0.25 mol) at -20°C under nitrogen was addedn-butyl lithium (100 cm³, 2.5 M in hexanes, 0.25 mol). The mixture was stirred at -20°C for 0.75 hours, whereupon a THF (100 cm³) solution of amide (30 g, 0.17 mol) was added via cannula. The solution was stirred at -20°C for 2 hours and was then allowed to warm to room temperature over 1 hour and quenched by the addition of ammonium chloride solution (700 cm³). The solution was diluted with diethyl ether (1000 cm³) and the organic layer was dried (MgSO₄) and concentrated under reduced pressure to give a yellow oil. The product was purified by dry flash chromatography on silica (eluant 4:1 hexane/ethyl acetate then 3:2 hexane/ethyl acetate) to give the product as a white crystalline solid (45 g, 98%). ¹H NMR (250 MHz; C²HCl₃) 1.36 (3 H, d, J7.0, CH₃), 3.70 (3 H, s, COCH₃), 3.82 (3 H, s, OCH₃), 3.92 (3 H, s, OCH₃), 5.43 (1 H, quintet, J 7.3, H-2), 5.80 (1 H, bs, NH), 6.94 (1 H, d, J 9.0, ArH), 7.10 (1 H, dd, J 9.0, 3.3, ArH), 7.32 (1 H, d, J 3.3, ArH).

(1R,2S)-2-[(Methoxycarbonyl)amino]-1-(2,5-dimethoxyphenyl)-1-propanol.

To a stirred solution of ketone i.e. (S)-2-[(methoxycarbonyl)amino]-1-(2,5-dimethoxyphenyl)-1-propanone (20 g, 74.9 mmol) and dimethylphenyl silane (10.7 g, 78.6 mmol) in dry DCM (500 cm³) at 0°C in an ice bath was added dropwise trithioroacetic acid (TFA) (50 cm³). The solution was stirred at 0°C for 1 h and then quenched by the addition of sodium hydroxide (500 cm³, 1 N). The organic layer was dried and concentrated under reduced pressure to give a yellow oil which solidified on standing. This solid was crystallized from ether/hexane to give the product as a white crystalline solid (15.6 g, 75%).¹H NMR (250 MHz; C²HCl₃) 1.03 (3 H, d, J7.0, CH₃), 3.04 (1 H, d, J4.3, OH), 3.68 (3 H, s, COCH₃), 3.78 (3 H, s, OCH₃), 3.80 (3 H, s, OCH₃), 3.94-3.99 (1 H, m, H-2), 5.05-5.15 (2 H, m, H-1 and NH), 6.72-6.85 (2 H, m, ArH) 6.97 (1 H, d, J 2.0, ArH).

(1,R,2S)-Methoxamine.

To a stirred solution of methoxycarbonyl (MeOC) protected alcohol i.e. (1R,2S)-2-[(methoxycarbonyl)amino]-1-(2,5-dimethoxyphenyl)-1-propanol (4.0 g, 14.9 mmol) in methanol (175 cm³) was added a solution of KOH (4.06 g, 72.8 mmol in water (60 cm³). The solution was cooled and acidified with phosphoric acid (15% v/v). The solution was extracted with DCM (2 x 50 cm³) and the aqueous layer basified by the addition of K₂CO₃. The aqueous layer was extracted with diethyl ether (5 x 50 cm³) and the combined ethereal extracts dried (MgSO₄) and concentrated under reduced pressure to give the product as a clear yellow oil (1.9 g, 61%), ¹H NMR (250 MHz; C²HCl₃) 0.84 (3 H, d, J 7.0, CH₃), 3.19-3.22 (1 H, m, H-2), 3.71 (6 H, s, 2 x OCH₃), 4.67 (1 H, d, J 5.0, H-1), 6.66-6.72 (2 H, m, ArH), 6.92 (1 H, d, J 2.5, ArH).

(1R, 2S)-Methoxamine hydrochloride.

To an ice cooled solution of (1R,2S)-methoxamine (1.9 g, 9.00 mmol) in anhydrous diethyl ether (30 cm³) was passed a stream of dry HCl gas for 45 mins. The resultant precipitate was filtered by suction, washed with cold diethyl ether and dried under nitrogen to yield the title compound as a white solid. (1.5 g, 68%). ¹H NMR (250 MHz; [C²H₃]₂SO) 0.89 (3 H, d, J 6.8, CH₃), 3.37-3.42 (1 H,m,H-2), 3.71 (3 H, s, OCH₃), 3.75 (3 H, s, OCH₃), 5.12 (1 H, s, H-1), 5.92 (1 H, d, J 4.3, OH), 6.84 (1 H, dd, J 8.8, 3.0, ArH), 6.92-7.00 (2 H, m, ArH); HPLC.

Analytical Method for the Analysis of Methoxamine

The following method was used to analyse methoxamine samples.

Method

• Column :	Cyclobond I RSP 250 x 4.6 mm
  Column temperature :	23°C
  Mobile phase :	0.1% Tetraethylammonium pH 4.1*
  95%v/v
  :	Acetonitrile 5%v/v
  Flow rate :	0.6 ml/min
  Solution Concentration :	5 mg/l
  Injection volume :	2.5 µl to 20 µl
  Detection :	UV 230 nm
  *Tetraethylammonium acetate pH 4.1 was prepared fresh daily.

Example 2 above allows the complete assignment of the methoxamine isomers as shown below:

PATENT

INDIAN 1020/CHE/2011

BY

The Managing Director of Malladi Drugs & Pharmaceuticals, Prashant Malladi (left), with the Chief Executive Officer, V. N. Gopalakrishnan

The present invention further provides an improved process for the preparation of (JS, 2S)-Methoxamine HC1 of formula (6) from (1R, 2S)-methoxamine by treating with acetic anhydride in toluene medium followed by acid hydrolysis and basification to obtain (IS, 2S)-Methoxamine base which is further acidified to form (1S,2S)- Methoxamine HC1 (6).

The present invention further provides an improved process for the preparation of (1R, 2R)-Methoxamine HC1 of formula (5) from its diastereomer (1S, 2R)-methoxamine HC1 of formula (2) by treating with acetic anhydride in toluene medium followed by acid hydrolysis and basification to obtain (1R, 2R)-Methoxamine base which is further acidified to form (1R, 2R)-Methoxamine HC1 (5).

The following examples illustrate the invention.

EXAMPLES

Example 1
Preparation of l-(2,5-Dimethoxyphenyl)propan-l-one (8)
Aluminium chloride (127.4 g; 0.955 mol) was added to dichloromethane (420 mL) in a round bottomed flask under nitrogen atmosphere. The reaction mixture was cooled to -5 °C; 1,4-dimethoxybenzene (100 g; 0.724 mol) was added slowly within 15-30 minutes. Propionic chloride (87 g; 0.94 mol) dissolved in dichloromethane (245 mL) was added slowly within 2 hours. The reaction mass was allowed to stir for 2 hours and then was quenched in crushed ice (1 kilo) and HC1 (75 mL) at 0 – 5 °C. Separated the layers and the organic layer was washed with 5% sodium hydroxide solution, dried and concentrated (140 g; colorless liquid); Purity by HPLC : 99.04%

Spectroscopic interpretation

The structure of the product, l-(2,5-Dimethoxyphenyl)propan-l-one was confirmed with the help of the following spectroscopic data.

a) IR (cm-1) (KBr)
Aromatic C-H stretch at 3071, aliphatic C – H stretch at 2938, C = O stretch at 1674, benzenoid bands at 1609 and 1584, C – O stretch at 1223, C – H out of plane bending of tri-substituted benzene ring at 814,719.

b) 1H NMR(CDCb, 300 MHz) (δH)
1.16 (3H, t, -CH2-CH3), 3.0 (2H, q, -CH2-CH3), 3.78 (3H, s, -OCH3), 3.85 (3H, s, -OCH3), 6.83 – 7.72 (3H, m, aromatic protons)

c) 13C NMR (CDCb, 300 MHz) (δC)
8.44 (-CH2-CH3), 37.03 (-CH2-CH3), 55.74 (-OCH3), 56.01 (-OCH3), 113.09 – 153.41 (aromatic carbons), 202.96 (C=O)

d) Mass spectrum (ESI, methanol)
[M+Na]+ at m/z 217 (9), [M+H]+ at m/z 195 (100).

Example 2
Preparation of l-(2,5-Dimethoxyphenyl)-2-nitrosopropan-l-one (9) l-(2,5-Dimethoxyphenyl)propan-l-one (100 g; 0.515 mol) was added to dichloromethane (660 mL) in a round bottomed flask under nitrogen atmosphere. Butylnitrite (46.6 g; 0.52 mol) was slowly added in about 30 minutes at 30 – 35 °C. Diethyl ether (60.2 mL) was added to the reaction mixture and dry HC1 gas was purged for about 4 hours at 30 – 35 °C. The reaction mass was maintained for 12 hours and then concentrated under vacuum The residue obtained (60 g; Pale yellow crystalline powder); Purity by HPLC: 99.81%; mp: 104-107 °C

Spectroscopic interpretation

The structure of the product, l-(2,5-Dimethoxyphenyl)-2-nitrosopropan-l-one was confirmed with the help of the following spectroscopic data

a) IR (cm1) (KBr)
O-H stretch at 3250 (broad), aromatic C-H stretch at 3024, aliphatic C – H stretch at 2934, C = O stretch at 1688, C = N stretch at 1645, benzenoid bands at 1589 and 1504, C-O stretch at 1231, C-H out of plane bending of tri-substituted benzene ring at 745,702.

b) 1H NMR(CDCb, 300 MHz) (δh)
2.07 (3H, s, -C-CH3), 3.72 (3H, s, -OCH3), 3.76 (3H, s, -OCH3), 6.84-6.99 (3H, m, aromatic protons), 8.89 (1H, bs, OH)

c) 13C NMR (CDCb, 300 MHz) (δC)
9.16 (-C-CH3), 55.81 (-OCH3), 56.34 (-OCH3), 113.09 – 153.27 (aromatic carbons), 157.07 (C=N-OH); 193.32 (CO)

d) Mass spectrum (ESI, methanol) [M+H]+ at m/z 224 (100)

Example 3
Preparation of dl-erythro-methoxamine HC1 (10)
Raney nickel (50 g); iso-propyl alcohol (250 mL) were added to the autoclave. l-(2,5- Dimethoxyphenyl)-2-nitrosopropan-1 -one (100 g; 0.448 mol) was added slowly at 50 – 55 °C by simultaneously purging the flask with hydrogen at 2-3 Kilo pressure. When hydrogen consumption ceases, the catalyst was filtered and the filtrate was concentrated. iso-Propyl alcohol (200 mL) was added to the concentrated mass followed by acidification with HC1 to obtaindl-erythro-methoxamine HC1 (70 g; white crystalline solid)

Spectroscopic interpretation
The structure of the product, dl-erythro-methoxaxmne HC1 was confirmed with the help of the following spectroscopic data.

a) IR (cm1) (KBr)
O-H stretch at 3409, aromatic C-H stretch at 3010, aliphatic C – H stretch at 2914, HN-H str. at 2574 and 2467, benzenoid bands at 1615 and 1569, C-N stretch at 1279, C-O stretch at 1216, C-H out of plane bending of 1,2,4-tri- substituted benzene ring at 812.

b) 1H NMR (DMSO-d6, 300 MHz) (δH)
1.0 (3H,d, -CH-CH3), 3.74 (3H, s, -OCH3), 3.77 (3H, s, -OCH3), 4.89 (1H, q, -CH-CH3),6.1 (1H, d, -CH-OH), 6.87-7.01 (3H, m, aromatic protons), 8.06 (3H, bs, HN-H) The -OH proton appears to have exchanged with the solvent.

c) 13C NMR (DMSO-d6, 300 MHz) (δc)
14.75 (-CH-CH3), 52.12 (-OCH3), 55.70 (-OCH3), 55.70 (-CH-CH3), 67.25 (CH-OH), 111.89 – 153.16 (aromatic carbons)

d) Mass spectrum (ESI, methanol)
[M+H)+ at m/z 212 (100), [M-H2O]+ at m/z 194 (56).

Example 4
Preparation of(JR,2S)-Metboxamine HC1 (1) and (1S, 2R)-Methoxamine HC1 (2) dl-erythro-methoxamine HC1 (117g; 0.47 mol) was dissolved in water (350 mL) at 30-35 °C. The clear solution obtained was basified using 50% sodium hydroxide solution. dl-erythro-Methoxaumne (3) was extracted into dichloromethane (150 mL) and concentrated. Mixture of methanol/DMSO (4:1; 1650 mL) was added and the mass was heated to 50 °C. L-(+)-Tartaric acid (71.1g; 0.47mol) was added slowly and the temperature of the mass was further raised to 70 °C for complete dissolution. The mass was cooled to 35 °C and maintained for 48 hours. (IR,2.S)-Methoxamine tartrate complex (80 g) precipitated was filtered. From the filtrate on concentration was obtained (1S,2R)- methoxamine tartrate complex (82 g) (IR,25)-Methoxamine tartrate complex was added to water (250 mL) at 35 °C, basified to 12 – 13 pH with 50% sodium hydroxide solution. Dichloromethane (200 mL) was added and stirred for 30 min. Separated the org layer, dried over sodium sulphate and concentrated completely under vacuum at 45° C. Iso-Propyl alcohol (150 mL) was added, charcaolized and filtered. The clear filtrate was acidified with 20%IPA HC1 to yield (1R, 2S)-Methoxamine HC1 which was filtered and dried (48 g); White crystalline powder; Purity by HPLC : 100%; Chiral purity : 100 %; mp : 172-175 °C; [α]D: -47.94° (c = 2% in MeOH)

Spectroscopic interpretation

The structure of the product, (1R,2S)-Methoxamine HC1 was confirmed with the help of the following spectroscopic data.

a) IR (cm1) (KBr)
O-H stretch at 3300, aromatic C-H stretch at 3065, aliphatic C-H stretch at 2938, HN-H str. at 2693 and 2580, benzenoid bands at 1609 and 1578, C-N stretch at 1277, C-O stretch at 1217, C-H out of plane bending of 1,2,4-tri- substituted benzene ring at 818.

b) 1H NMR (DMSO-d6 300 MHz) (δH)
0.91 (3H,d, -CH-CH3), 3.71 (3H, s, -OCH3), 3.75 (3H, s, -OCH3), 5.14 (1H, m, -CH- NH3+), 5.95 (1H, d, -CH-OH), 6.83-7.01 (3H, m, aromatic protons), 8.25 (3H, bs, HN-H) The -OH proton appears to have exchanged with the solvent.

c) 13C NMR (DMSO-d6, 300 MHz) (δC)
II. 44 (-CH-CH3), 49.22 (-OCH3), 55.24 (-OCH3), 55.70 (-CH-CH3), 66.49 (CH-OH),

III. 41 – 153.03 (aromatic carbons)

d) Mass spectrum (ESI, methanol)
[M+H]+ at m/z 212 (100), [M-H2O]+ at m/z 194 (15).
(IS, 2i?)-Methoxamine tartrate complex was added to water (275 mL) at 35 °C, basified

to 12 – 13 pH with 50% sodium hydroxide solution. Dichloromethane (250 mL) was added and stirred for 30 min. Separated the organic layer, dried over sodium sulphate and concentrated completely under vacuum at 45 °C. Iso-Propyl alcohol (175 mL) was added, charcaolized and filtered. The clear filtrate was acidified with 20%IPA HC1 to yield (1S, 2R)-Methoxamine HC1 which was filtered and dried (51 g) White crystalline powder; Purity by HPLC : 99.99%; Chiral purity . 100 %; mp . 172-175 °C;[α]D : + 47.9° (c = 2% in MeOH)

Spectroscopic interpretation

The structure of the product, (1S, 2R)-Methoxamine HC1 was confirmed with the help of the following spectroscopic data.

a) m (cm1) (KBr)
O-H stretch at 3265, aromatic C-H stretch at 3059, aliphatic C-H stretch at 2997, HN-H str. at 2658 and 2567, benzenoid bands at 1611 and 1587,
C-N stretch at 1294, C-O stretch at 1217, C-H out of plane bending of 1,2,4-tri- substituted benzene ring at 818.

b) 1H NMR (DMSO-d6,300 MHz) (δH)
0.91 (3H,d, -CH-CH3), 3.71 (3H, s, -OCH3), 3.75 (3H, s, -OCH3), 5.14 (1H, m, -CH- NH3+), 5.97 (1H, d, -CH-OH), 6.83-7.01 (3H, m, aromatic protons), 8.19 (3H, bs, HN-H) The -OH proton appears to have exchanged with the solvent.

c) 13C NMR (DMSO-d6,300 MHz) (δc)

II. 46 (-CH-CH3), 49.18 (-OCH3), 55.23 (-OCH3), 55.68 (-CH-CH3), 66.45 (CH-OH),

III. 42 – 153.02 (aromatic carbons)

d) Mass spectrum (ESI, methanol)
[M+H]+ at m/z 212 (100), [M-H2O]+ at m/z 194 (15).

Example 5
Preparation of dl-threo-methoxamine HC1 (11)
dl-erythro-methoxamine HC1 (120g; 0.48 mol) was dissolved in DM water (500 mL) at 30 – 35 °C and cooled to 10 – 15 °C. The clear solution was basified using 50 % sodium hydroxide solution and extracted in dichloromethane (250 mL). The organic layer was separated and concentrated under vacuum. The residue thus obtained was dissolved in toluene (200 mL) and was added slowly to acetic anhydride (120 g; 1.17mol) at 65 – 70 °C. The reaction mass was maintained under stirring and further cooled to 10 – 20 °C. Conc.Sulphuric acid (57.6g; 0.58mol) was added to the reaction mass slowly by maintaining the reaction mass at 10 – 200 C. The reaction mass was heated to 35 – 400 C for 3 hours and concentrated under vacuum at below 80 °C.

The reaction mass was cooled to 10 – 15 °C and was dissolved in DM water (250 mL). The mass was maintained for 3 h at reflux temperature and again cooled to 10 – 15 °C.

The pH was adjusted to 12 – 13 using 50% sodium hydroxide solution and extracted the d/-threo-Methoxamine base in dichloromethane (250 mL). Separated the organic layer and concentrated under vacuum. The concentrated mass was triturated with iso-Propyl alcohol (150 mL); acidified using 20% HC1 in iso-propyl alcohol. Distilled the iso- propyl alcohol completely to the final traces and acetone (300 mL) was added. The material precipitated, crude dl-threo-methoxamine HC1 was filtered. (85 g) Off white powder; Purity by HPLC: 99.4%; mp: 221-223 °C Spectroscopic interpretation

The structure of the product, di-threo-methoxamine HC1 was confirmed with the help of the following spectroscopic data.

a) IR (cm”1) (KBr)
O-H stretch at 3401, aromatic C-H stretch at 3005, aliphatic C-H stretch at 2924, HN-H str. at 2581 and 2490, benzenoid bands at 1609 and 1578, C-N stretch at 1277, C-0 stretch at 1215, C-H out of plane bending of 1,2,4-tri- substituted benzene ring at 802.

b) NMR (DMSO-d6,300 MHz) (δH)
1.2 (3H,d, -CH-CHs), 3.72 (3H, s, -OCH3), 3.75 (3H, s, -OCH3), 4.87 (1H, q, -CH-CH3),6.3 (1H, d, -CH-OH), 6.83-6.99 (3H, m, aromatic protons), 8.03 (3H, bs, HN-H) The -OH proton appears to have exchanged with the solvent.

c) 13C NMR (DMSO-d6, 300 MHz) (δC)
14.76 (-CH-CH3), 52.15 (-OCH3), 55.89 (-OCH3), 67.34 (CH-OH), 111.96 – 153.21 (aromatic carbons)

d) Mass spectrum (ESI, methanol)
[M+H]+ at m/z 212 (100), [M-H2O]+ at m/z 194 (52).

Example 6
Preparation of (1S,2S)- Methoxamine HC1 (6)
(IR, 2S)-Methoxamine HC1 (120 g; 0.48 mol) was dissolved in DM water (500 mL) at 30 -35 °C and cooled to 10 – 15 °C. The clear solution was basified using 50 % sodium hydroxide solution and extracted in dichloromethane (250 mL). The organic layer was separated and concentrated under vacuum. The residue thus obtained was dissolved in toluene (200 mL) and was added slowly to acetic anhydride (120 g; 1.17 mol) at 65 – 70 °C. The reaction mass was maintained under stirring and further cooled to 10 – 20 °C. Conc.sulphuric acid (57.6 g; 0.58 mol) was added to the reaction mass slowly by maintaining the reaction mass at 10 – 20 °C. The reaction mass was heated to 35 – 40 °C for 3 hours and concentrated under vacuum at below 80 °C.

The reaction mass was cooled to 10-15°C and was dissolved in DM water (250 mL). The mass was maintained for 3 h at reflux temperature and again cooled to 10 – 15 °C. The pH was adjusted to 12-13 using 50% sodium hydroxide solution and extracted the (1S, 2S)-Methoxamine base in dichloromethane (250 mL). Separated the organic layer and concentrated under vacuum The concentrated mass was triturated with iso-Propyl alcohol (150 mL); acidified using 20% HC1 in iso-propyl alcohol. Distilled the iso- propyl alcohol completely to the final traces and acetone (300 mL) was added. The material precipitated, crude (IS, 2S)-methoxamine HC1 was filtered. (86 g); White crystalline powder; Purity by HPLC . 99.8%; Chiral purity : 99.7%; mp : 172-175 °C; [α]D: + 30.739° (c = 2% in MeOH)

Spectroscopic interpretation
The structure of the product, (IS, 2S)-methoxamine HC1 was confirmed with the help of the following spectroscopic data.

a) IR (cm1) (KBr)
O-H stretch at 3356, aromatic C-H stretch at 3080, aliphatic C-H stretch at 2999, HN-H str. at 2641 and 2583, benzenoid bands at 1611 and 1506, C-N stretch at 1302, C-O stretch at 1229, C-H out of plane bending of 1,2,4-tri- substituted benzene ring at 812.

b) 1H NMR (DMSO-d6 300 MHz) (δH)
1.04 (3H,d, -CH-CH3), 3.72 (3H, s, -OCH3), 3.75 (3H, s, -OCH3), 4.90 (1H, m, -CH- CH3),6.07 (1H, d, -CH-OH), 6.84-7.01 (3H, d, aromatic protons), 8.15 (3H, bs, HN-H)
The -OH proton appears to have exchanged with the solvent.

c) 13C NMR (DMSO-d6, 300 MHz) (δC)
14.75 (-CH-CH3), 52.18 (-OCH3), 55.21 (-OCH3), 55.69 (-CH-CH3), 67.32 (CH-OH), 111.38 -153.01 (aromatic carbons)

d) Mass spectrum (ESI, methanol)
[M+H]+ at m/z 212 (100), [M-H2O]+ at m/z 194 (48).

Example 7
Preparation of (1R, 2R)-Methoxamine HC1 (5)
(IS, 2R)Methoxamine HC1 (120g; 0.48 mol) was dissolved in DM water (500 mL) at 30 – 35 °C and cooled to 10 – 15 °C. The clear solution was basified using 50 % sodium hydroxide solution and extracted in dichloromethane (250 mL). The organic layer was separated and concentrated under vacuum. The residue thus obtained was dissolved in toluene (200 mL) and was added slowly to acetic anhydride (120 g; 1.17mol) at 65 – 70 °C. The reaction mass was maintained under stirring and further cooled to 10 – 20 °C. Cone.Sulphuric acid (57.6g; 0.58mol) was added to the reaction mass slowly by maintaining the reaction mass at 10 – 20 °C. The reaction mass was heated to 35 – 40 °C for 3 hours and concentrated under vacuum at below 80 °C.

The reaction mass was cooled tol0-15°C and was dissolved in DM water (250 mL). The mass was maintained for 3 h at reflux temperature and again cooled to 10 – 15 °C. The pH was adjusted to 12-13 using 50% sodium hydroxide solution and extracted the (IR, 2i?)-Methoxamine base in dichloromethane (250 mL). Separated the organic layer and concentrated under vacuum. The concentrated mass was triturated with iso-Propyl alcohol (150 mL); acidified using 20% HC1 in iso-propyl alcohol Distilled the iso- propyl alcohol completely to the final traces and acetone (300 mL) was added. The material precipitated, crude (1R, 2R)-methoxamine HC1 was filtered. (90 g) White crystalline powder; Purity by HPLC: 99.1%, Chiral purity. 100%; mp: 172-175 °C;[α]D: -29.04° (c – 2% in MeOH)

Spectroscopic interpretation

The structure of the product, (1R, 2R)methoxamine HC1 was confirmed with the help of the following spectroscopic data.

a) IR (cm1) (KBr)
O-H stretch at 3356, aromatic C-H stretch at 3078, aliphatic C-H stretch at 2999, HN-H str. at 2619 and 2500, benzenoid bands at 1611 and 1508, C-N stretch at 1302, C-O stretch at 1229, C-H out of plane bending of 1,2,4-tri- substituted benzene ring at 812.

b) 1H NMR(DMSO-d6 300 MHz) (δH)
I. 04 (3H,d, -CH-CHa), 3.72 (3H, s, -OCH3), 3.75 (3H, s, -OCH3), 4.90 (1H, m, -CH- CH3),6.07 (1H, d, -CH-OH), 6.83-7.01 (3H, d, aromatic protons), 8.13 (3H, bs, HN-H) The -OH proton appears to have exchanged with the solvent.

c) 13C NMR (DMSO-d6 300 MHz) (δe)
II. 41 (-CH-CH3), 52.16 (-OCH3), 55.22 (-OCH3), 55.70 (-CH-CH3), 67.32 (CH-OH), III. 39-153.15 (aromatic carbons)

d) Mass spectrum (ESI, methanol)
[M+H]+ at m/z 212 (100), [M-H2O]+ at m/z 194 (44).

PATENT

http://www.google.com/patents/US8491931

(1,R,2S)-Methoxamine

To a stirred solution of methoxycarbonyl (MeOC) protected alcohol i.e. (1R,2S)-2-[(methoxycarbonyl)amino]-1-(2,5-dimethoxyphenyl)-1-propanol (4.0 g, 14.9 mmol) in methanol (175 cm³) was added a solution of KOH (4.06 g, 72.8 mmol in water (60 cm³). The solution was cooled and acidified with phosphoric acid (15% v/v). The solution was extracted with DCM (2×50 cm³) and the aqueous layer basified by the addition of K₂CO₃. The aqueous layer was extracted with diethyl ether (5×50 cm³) and the combined ethereal extracts dried (MgSO₄) and concentrated under reduced pressure to give the product as a clear yellow oil (1.9 g, 61%), ¹H NMR (250 MHz; C²HCl₃) 0.84 (3H, d, J 7.0, CH₃), 3.19-3.22 (1H, m, H-2), 3.71 (6H, s, 2×OCH₃), 4.67 (1H, d, J 5.0, H-1), 6.66-6.72 (2H, m, ArH), 6.92 (1H, d, J 2.5, ArH).

(1R,2S)-Methoxamine hydrochloride

To an ice cooled solution of (1R,2S)-methoxamine (1.9 g, 9.00 mmol) in anhydrous diethyl ether (30 cm³) was passed a stream of dry HCl gas for 45 mins. The resultant precipitate was filtered by suction, washed with cold diethyl ether and dried under nitrogen to yield the title compound as a white solid. (1.5 g, 68%). ¹H NMR (250 MHz; [C²H₃]₂SO) 0.89 (3H, d, J 6.8, CH₃), 3.37-3.42 (1H,M,H-2), 3.71 (3H, s, OCH₃), 3.75 (3H, s, OCH₃), 5.12 (1H, s, H-1), 5.92 (1H, d, J 4.3, OH), 6.84 (1H, dd, J 8.8, 3.0, ArH), 6.92-7.00 (2H, m, ArH); HPLC.

//1R,2S-methoxamine

RACEMIC

Title: Methoxamine CAS Registry Number: 390-28-3 CAS Name: a-(1-Aminoethyl)-2,5-dimethoxybenzenemethanol Additional Names: a-(1-aminoethyl)-2,5-dimethoxybenzyl alcohol; 2-amino-1-(2,5-dimethoxyphenyl)-1-propanol; b-hydroxy-b-(2,5-dimethoxyphenyl)isopropylamine; b-(2,5-dimethoxyphenyl)-b-hydroxyisopropylamine; 2,5-dimethoxynorephedrine Molecular Formula: C11H17NO3 Molecular Weight: 211.26 Percent Composition: C 62.54%, H 8.11%, N 6.63%, O 22.72% Literature References: a1-Adrenergic agonist. Prepn: Baltzly et al., US 2359707 (1944 to Burroughs Wellcome). Metabolism: A. Klutch, M. Bordun, J. Med. Chem. 10, 860 (1967). Clinical pharmacology: N. T. Smith, C. Whitcher, Anesthesiology 28, 735 (1967); P. D. Snashall et al., Clin. Sci. Mol. Med. 54, 283 (1978). HPLC determn in plasma: I. A. Al-Meshal et al., J. Liq. Chromatogr. 12, 1589 (1989). Therapeutic use: P. M. C. Wright et al., Anesth. Analg. 75, 56 (1992); L. Cabanes et al., N. Engl. J. Med. 326, 1661 (1992). Comprehensive description: A. M. Al-Obaid, M. M. El-Domiaty, Anal. Profiles Drug Subs. 20, 399-431 (1991). Derivative Type: Hydrochloride CAS Registry Number: 61-16-5 Trademarks: Vasoxine (Burroughs Wellcome); Vasoxyl (Burroughs Wellcome); Vasylox (Burroughs Wellcome) Molecular Formula: C11H17NO3.HCl Molecular Weight: 247.72 Percent Composition: C 53.33%, H 7.32%, N 5.65%, O 19.38%, Cl 14.31% Properties: Crystals, mp 212-216°. pKa (25°C) 9.2. Very sol in water: One gram dissolves in 2.5 ml water, in 12 ml ethanol. Practically insol in ether, benzene, chloroform. pH of a 2% aq soln between 4.5 and 5.5. Melting point: mp 212-216° pKa: pKa (25°C) 9.2 Therap-Cat: Antihypotensive. Keywords: a-Adrenergic Agonist; Antihypotensive.

PLECANATIDE;  UNII-7IK8Z952OK;  (3-Glutamic acid(D>E))human uroguanylin (UGN); 467426-54-6;

April 19, 2016

Novel Chronic Idiopathic Constipation Drug Under FDA Review

http://www.empr.com/drugs-in-the-pipeline/novel-chronic-idiopathic-constipation-drug-under-fda-review/article/490799/

Plecanatide is a once-daily, oral, uroguanylin analog

Synergy Pharmaceuticals announced the Food and Drug Administration (FDA) has accepted for review the New Drug Application (NDA) for plecanatide for the treatment of chronic idiopathic constipation (CIC).

The NDA submission was based on data from two double-blind, placebo-controlled Phase 3 trials and one open-label long term safety study in over 3,500 patients with CIC.

RELATED: NDA Submitted for Chronic Idiopathic Constipation Drug Plecanatide

The FDA has set a Prescription Drug User Fee Act (PDUFA) target action date of January 29, 2017 to make a decision on the NDA.

Plecanatide is a once-daily, oral, uroguanylin analog currently under development for the treatment of CIC and irritable bowel syndrome with constipation (IBS-C). It is designed to replicate the function of uroguanylin, a naturally occurring GI peptide, by working locally in the upper GI tract to stimulate digestive fluid movement and support regular bowel function.

PATENT

CN 104628827

http://www.google.com/patents/CN104628827A?cl=en

Prica exenatide Synergy Pharmaceuticals developed by the United States for the GC-C receptor in development of drugs, administered orally Limited.Currently underway include chronic idiopathic constipation (CIC) and constipation irritable bowel syndrome (IBS-C), including the phase III clinical trials. It is expected to receive US FDA clearance to market in recent years. Prica that peptides CAS: 467426-54-6 English name plecanatide, structural formula is as follows:

Preparation Prica that peptides from Shenzhen Han Yu medicine was first reported (CN103694320A), using a solid-phase synthesis of linear peptides in solution and then the two-step method to get into the ring, respectively. Since the method to form a ring carved in solution twice, the solution of complex composition, separation and purification difficult, the method should be improved.

Example 1

 Weigh the degree of substitution of 0. 51mmol / g of Fmoc-Leu- Wang resin 10g (5. Lmmol), added to the solid phase reactor, DMF washing 3 times, the swelling 3h. The volume ratio of 1: 4 piperidine: DMF was added to the reactor the reaction, after the reaction was washed with DCM and washed twice, DMF 4 times. Weigh Fmoc-Cys (Acm) -OH 6. 34g, H0Bt 2. 07g, DIC 2. 37mL was dissolved in DMF, added to the reactor uniformly mixed, the reaction at room temperature 2h. Ninhydrin color reaction control endpoint, the resin was colorless indicates the end of the reaction, the reaction is continued if the color to colorless. After completion of the reaction, DCM was washed twice, DMF and washed 4 times.

 Repeat the above steps, in accordance with the order of the sequence, followed by deprotection, coupling Fmoc-Gly-OH, Fmoc-Thr (tBu) -OH, Fmoc-Cys- (Mmt) -OH, Fmoc-Ala-OH, Fmoc- Val-OH, Fmoc-Asn (Trt) -〇H, Fmoc-Val-OH, Fmoc-Cys (Acm) -OH, Fmoc-Leu-OH, Fmoc-Glu (OtBu) -OH, Fmoc-Cys (StBu) -OH, Fmoc-Glu (OtBu) -OH, Fmoc-Asp (OtBu) -OH, Boc-Asn (Trt) -〇H〇

 To a prepared peptide resin reactor volume percentage of 15% DMF solution of mercapto ethanol, reaction 2h; then DCM was added a solution of 20-fold amount DTNP reaction lh; was added after washing 1% TFA containing TIS 5% of DCM solution reaction 20min.

Preparation of peptide resin obtained after sufficiently washed with DMF, DMF was added 10 times the amount in the reaction solution 12 lh. Full wash sash.

After the preparation of the peptide resin was added in a volume ratio of 95/2/2/1 TFA / TIS / EDT / H lysis reagent 20 is added in an amount 20mL / g, the reaction ice bath lh, stirring was continued at room temperature 5h, then filtration.After lysis reagent suction filtrate using a rotary evaporator until no overflow TFA, precipitated reagent was added standing; Pulika centrifugation the precipitated crude peptide was peptide to give 8. 67g〇

The preparation of the crude peptide was obtained Pulika peptide using preparative HPLC system, wavelength 214nm, C18 reversed-phase column packing for the separation, the mobile phase of water and acetonitrile were used, with a gradient elution method to collect the target polypeptide The absorption peak. Using rotary evaporation at 30 ° C to remove most of the acetonitrile, were freeze-dried to obtain a purified Prica exenatide refined products.

Example 2

Weigh the degree of substitution of 0. 2mmol / g of Fmoc-Leu- Wang resin 10g (2mmol), added to the solid phase reactor. DMF washing 3 times, the swelling 3h. The volume ratio of 1: 4 piperidine: DMF was added to the reactor the reaction, after the reaction was washed with DCM and washed twice, DMF 4 times. Weigh Fmoc-Cys (Acm) -OH1. 24g, HOBtO. 406g, DIC 0 • 465mL dissolved in DMF solution, after mixing into the reactor at room temperature the reaction 2h.Ninhydrin color reaction control endpoint, the resin was colorless indicates the end of the reaction, the reaction is continued if the color to colorless. After completion of the reaction, DCM was washed twice, DMF and washed 4 times.

Repeat the above steps, in accordance with the order of the sequence, followed by deprotection, coupling Fmoc-Gly-OH, Fmoc-Thr (tBu) -OH, Fmoc-Cys- (Mmt) -OH, Fmoc-Ala-OH, Fmoc- Val-OH, Fmoc-Asn (Trt) -〇H, Fmoc-Val-OH, Fmoc-Cys (Acm) -OH, Fmoc-Leu-OH, Fmoc-Glu (OtBu) -OH, Fmoc-Cys (StBu) -OH, Fmoc-Glu (OtBu) -OH, Fmoc-Asp (OtBu) -OH, Boc-Asn (Trt) -〇H〇

[0053] To illustrate the preparation of the present embodiment obtained peptide resin reactor volume percent of a DMF solution of 30% mercaptoethanol, reaction 4h; then 5-fold amount DTNP in DCM reaction lh; was added after washing 1% TFA containing TIS 5% in DCM reaction 20min.

 Preparation of peptide resin obtained after sufficiently washed with DMF, 20 times the amount of DMF was added in the reaction solution 12 lh. Full wash sash.

Peptide Resin [0055] Preparation was added volume ratio of 82. 5/5/5/5/2. 5 TFA / thioanisole / H20 / phenol / EDT cleavage reagents, added in an amount 10mL / g, the reaction ice bath 0 After. 5h, stirring was continued at room temperature for lh, then suction filtered. After lysis reagent suction filtrate to the non-use of force blowing TFA overflow, adding precipitation reagent standing; centrifugation precipitated Prica exenatide crude peptide to give 1. 52g.

 The preparation of the crude peptide was obtained Pulika peptide using preparative HPLC system, wavelength 214nm, C18 reversed-phase column packing for the separation, the mobile phase of water and acetonitrile were used, with a gradient elution method to collect the target polypeptide The absorption peak. Using rotary evaporation at 30 ° C to remove most of the acetonitrile, were freeze-dried to obtain a purified Prica exenatide refined products.

 Example 3

 Weigh the degree of substitution of 0. 6mmol / g of Fmoc-Leu- Wang resin 10g (6mmol), added to the solid phase reactor, DMF washing 3 times, the swelling 3h. The volume ratio of 1: 4 piperidine: DMF was added to the reactor the reaction, after the reaction was washed with DCM and washed twice, DMF 4 times. Weigh Fmoc-Cys (Acm) -OH 7. 46g, H0Bt2. 44g, DIC 2. 79mL was dissolved in DMF, added to the reactor uniformly mixed, the reaction at room temperature 2h.Ninhydrin color reaction control endpoint, the resin was colorless indicates the end of the reaction, the reaction is continued if the color to colorless. After completion of the reaction, DCM was washed twice, DMF and washed 4 times.

 Repeat the above steps, in accordance with the order of the sequence, followed by deprotection, coupling Fmoc-Gly-OH, Fmoc-Thr (tBu) -OH, Fmoc-Cys- (Mmt) -OH, Fmoc-Ala-OH, Fmoc- Val-OH, Fmoc-Asn (Trt) -〇H, Fmoc-Val-OH, Fmoc-Cys (Acm) -OH, Fmoc-Leu-OH, Fmoc-Glu (OtBu) -OH, Fmoc-Cys (StBu) -OH, Fmoc-Glu (OtBu) -OH, Fmoc-Asp (OtBu) -OH, Boc-Asn (Trt) -〇H〇

 To the prepared peptide resin reactor volume percentage of 25% DMF solution of mercapto ethanol, reaction 3h; then 10-fold amount DTNP in DCM reaction lh; was added 1% TFA washed containing TIS5% DCM solution Reaction 20min〇

 Preparation of peptide resin obtained after sufficiently washed with DMF, 15 times the amount of DMF was added in the reaction solution 12 lh. Full wash sash.

 Preparation of the peptide resin was added in a volume ratio of 90/5/3/2 TFA / thioanisole / anisole / EDT cleavage reagents, added in an amount 20mL / g, the ice bath was reacted 0.lh, stirring was continued at room temperature The reaction 10h, then filtration. After lysis reagent suction filtrate using a rotary evaporator until no overflow TFA, precipitated reagent was added standing; Pulika centrifugation the precipitated crude peptide was peptide to give 8. 46g.

 The preparation of the crude peptide was obtained Pulika peptide using preparative HPLC system, wavelength 214nm, C18 reversed-phase column packing for the separation, the mobile phase of water and acetonitrile were used, with a gradient elution method to collect the target polypeptide The absorption peak. Using rotary evaporation at 30 ° C to remove most of the acetonitrile, were freeze-dried to obtain a purified Prica exenatide refined products.

Although the above has been described with general, specific embodiments and test, the present invention has been described in detail, but on the basis of the present invention, it may make some changes or improvements, which the skilled artisan It is obvious. Thus, the present invention without departing from the spirit on the basis of these modifications or improvements made, belong to the scope of the invention as claimed.

PATENT

CN 104211777

http://www.google.com/patents/CN104211777A?cl=en

The pickup exenatide (Plecanatide) is a synthetic analogue of guanylin urine (urine guanylin is a natriuretic hormone, can regulate gastrointestinal transport of ions and liquid), pickup exenatide enter After in vivo and guanylate gastrointestinal tract endothelial cells cyclase C binding and activation, activation of the cystic fibrosis transmembrane conductance regulator (CFTR), to promote chloride and water into the intestine, thereby promoting bowel motility, improve constipation symptoms.

Synergy company announced its pick in the research of new drugs that peptide (code: SP304) on October 6, 2010 the treatment of gastrointestinal disorders II a clinical experimental results. The study, conducted in patients with chronic constipation showed that the drugs can improve bowel function in patients, promote intestinal motility and reduce abdominal discomfort shape. In the experiment, there was no diarrhea and other adverse reactions, at the doses tested did not detect the pickup system that peptides are absorbed. The drug is expected for the treatment of chronic constipation (CC), constipation-predominant irritable bowel syndrome (IBS-C) and other gastrointestinal disorders. CC and IBS-C is a common gastrointestinal disease that can cause serious impact on the work and the quality of life of patients. Synergy will continue to conduct clinical trials of other pickups that peptide.

The structure of the peptide pickup that is:

H-Asn-Asp-Asp-Cys-Glu-Leu-Cys-Val-Asn-Val-Ala-Cys-Thr-Gly-C ys-Leu-〇H (4-12 disulfide, 7- 15)

Example 30:

 H-Asn-Asp-Asp-Cys-Glu-Leu-Cys-Val-Asn-Val-Ala-Cys-Thr-Gly-C ys-Leu-〇H (4-12 disulfide, 7- 15) Preparation of

 embodiments will be prepared by the method of Example 18 H-Asn (Trt) -Asp (OtBu) -Asp (OtBu) -Cys (mmt) -Glu (Ot Bu) -Leu-Cys (StBu) -Val-Asn ( Trt) -Val-Ala-Cys (mmt) -Thr (tBu) -Gly-Cys (StBu) -Leu-CT C resin (IOOmmol, 472. 88g) disposed cracking reactor to 10ml / g resin ratio Add lysis reagent (TFA: EDT: water = 95: 2 5:.. 2 5 (V / V)), stirred at room temperature 2h. The reaction was filtered with sand core funnel, and then added a small amount of TFA The resin was washed in the funnel, collecting the filtrate, the combined filtrate was concentrated. Frozen in dry diethyl ether was added (100ml / g peptide purpose tree months) and the solution was precipitated, centrifuged to remove the precipitate was washed with diethyl ether after dry ether three times, and dried in vacuo to give a white solid powder was approximately 180g, i.e., H-Asn-Asp-Asp -Cys-Glu-Leu-Cys (StBu) -Val-Asn-Val-Ala-Cys-Thr-Gly-Cy s (StBu) -Leu-OH. The solid was dissolved with water to lmg / ml solution. Was added an aqueous solution of 1% by volume of H2O2, the reaction was stirred at room temperature 30min, to prepare H-Asn-Asp-Asp-Cys-Glu-Leu-Cys (StBu) -Val-Asn-Val-Ala-Cys-Thr-Gl y-Cys (StBu) -Leu-OH (disulfide 4-12) was treated with a rotary evaporator after drying the compound containing 500ml 20% β- mercaptoethanol and 0. IM N- methylmorpholine were dissolved in water, followed by stirring After 12h the reaction, the reaction solution was diluted with water to 3mg / ml was about 60L, dissolved in ethanol was added with IL 300mmol I2 solution, the reaction was stirred at room temperature 2h. Adding an appropriate amount Vc remove excess I2, until the color of the reaction solution was transparent, i.e., to give H-Asn-Asp-Asp-Cys-Glu-Leu-Cys-Val-As n-Val-Ala-Cys-Thr-Gly-Cys-L eu_0H (disulfide bonds 4-12, 7-15).

PATENT

WO 2014197720

CN 103694320

WO 2012118972

WO 2012037380

WO 2011069038

US 20100152118

WO 2010065751

///Plecanatide,  普卡那肽 ,  ليكاناتيد , плеканатид, 467426-54-6, Chronic Idiopathic Constipation, NDA, SP 304, SYNERGY, PEPTIDE,

C[C@H]1C(=O)N[C@H]2CSSC[C@@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@@H](CSSC[C@H](NC(=O)CNC(=O)[C@@H](NC2=O)[C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)O)C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N1)C(C)C)CC(=O)N)C(C)C)CC(C)C)CCC(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC(=O)N)N

OR

O=C(N[C@@H](CC(=O)O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H]1CSSC[C@@H]2NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CCC(=O)O)NC1=O)CC(C)C)CSSC[C@H](NC(=O)CNC(=O)[C@@H](NC2=O)[C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)O)C(C)C)C(C)C)[C@@H](N)CC(N)=O

Polmacoxib (Acelex) is a nonsteroidal anti-inflammatory drug (NSAID) used to treat osteoarthritis. It was developed as CG100649 and approved for use in South Korea in February 2015.^[1] It inhibits the enzymes carbonic anhydrase and COX-2. A study in healthy volunteers showed drug effects on urinary prostaglandin metabolites for both CG100649 and celecoxib that suggest a similar cardiovascular risk profile.^[2] Further work by this group developed dose-exposure relationsships of CG100649 to guide clinical development strategies. ^[3]

5-Aryl-2,2-dialkyl-4-phenyl-3(2H)furanone derivatives were studied as a novel class of selective cyclooxygenase-2 inhibitors with regard to synthesis, in vitro SAR, antiinflammatory activities, pharmacokinetic considerations, and gastric safety. 1f, a representative compound for methyl sulfone derivatives, showed a COX-2 IC₅₀ comparable to that of rofecoxib. In case of 20b, a representative compound for sulfonamide derivatives, a potent antiinflammatory ED₅₀ of 0.1 mg kg^-1 day^-1 was observed against adjuvant-induced arthritis by a preventive model, positioning20b as one of the most potent COX-2 inhibitors ever reported. Furthermore, 20b showed strong analgesic activity as indicated by its ED₅₀ of 0.25 mg/kg against carrageenan-induced thermal hyperalgesia in the Sprague−Dawley rat. 3(2H)Furanone derivatives showed due gastric safety profiles as selective COX-2 inhibitors upon 7-day repeat dosing. A highly potent COX-2 inhibitor of the 3(2H)furanone scaffold could be considered suitable for a future generation COX-2 selective arthritis medication with improved safety profiles.

PATENT

WO 2015080435 

non-steroidal anti-inflammatory drugs (nonsteroidal ant i- inf lammatory drug, NSAID) has a problem that causes serious side effects such as renal toxicity or distress Gastrointestinal. NSAID is to inhibit the activity of the enzyme cyclo-oxy-related prostaglandin G / H synthesis to tyrosinase (cyclooxygenase, COX) inhibits the biosynthesis of prostaglandins in the stomach and kidney, as well as inflammation. C0X is present in the two types of C0X C0X-1 and-2.

C0X-1 is induced by the other hand to adjust the height of the above features and is expressed in normal cells, it is C0X-2 mitogen or inflammation occurred in inflammation and other immune banung cytokines. To avoid the toxicity of the NSAID due to the inhibitory action of coexisting C0X-1 which, has been the selective inhibitors of the study C0X-2.

To 4- (3- (3-fluoro-phenyl) -5, 5-dimethyl-4-oxo-4, 5-dihydro-furan-2-yl) benzenesulfonamide represented by the general formula (1), such as 4, 5- diaryl-3- (0-furanones and derivatives thereof are compounds, wherein the by-1 do not inhibit the C0X standing substantially inhibit only C0X-2 selectively – represents a reduced gastrointestinal side effects while showing the inflammatory effect.

In addition, the compound of Formula 1 has C0X-2, as well as CA carbonic anhydrase) in inhibitory effect shown, in the CA-rich than C0X-2 tissues such as the gastrointestinal tract is to neutralize the inhibitory activity of C0X-2 gastrointestinal bleeding, such as side effects and more while the reduction, the less the distribution of the CA, such as joint tissue has a characteristic showing the effect to inhibit only C0X eu 2. Thus, 4, 5-diaryl-3- (0-furanones derivatives compared to conventional NSAIDs significantly reduced gastrointestinal side effects having an anti-inflammatory substance is useful as a.

Compounds and their derivatives of the formula (1) are of various inflammatory diseases; Pain accompanying diseases; viral infection; It is useful in the relief of inflammation, pain and fever, and the like accompanying surgery; diseases such as diabetes. Sikimyeo compounds and their derivatives of the formula (1) and they also inhibit the growth of cancer, including colorectal cancer C0X- parameter, reducing the infarction area of reperfusion injuries to (reperfusion injury) caused by the stroke, treatment of neurodegenerative diseases, including Alzheimer’s disease it is useful. Diabetes accompanying retinopathy (retinopathy) in the treatment of useful and eu C0X-mediated vascularization (angiogenesis) to engage it (Mart in SG et al., Oral surgery oral medicine oral pathology, 92 (4), 2001, 399; James RH et al., oral surgery oral medicine oral pathology, 97 (2), 2004, 139; RE Harris et al., Inflammopharmacology, 12,2009, 55;

K. Oshima et al. , J. Invest. Surg. , 22 (4), 2009, 239; The Journal of

Pharmacology and Experimenral Therapeutics, 318 (3), 2006, 1248; JM. SL et al. , Int. J. Geriatr. Psychiatry, 2011; Jennifer L. et al. , Invest.

Ophthalmol. Vis. Sci. March, 44 (3), 2003, 974; K. M. Leahy et al. , Current Medicinal Chemistry, 7, 2000, 1163).

Method for producing a compound of formula I is disclosed in the International Patent Publication W0 00/615 sign, are incorporated herein by reference in their entirety.However, using the -78-butyllithium, which discloses in the above production method ^° banung in C is not a m- chloroperoxybenzoic acid not suitable for commercial use it is difficult to practically carried out, as well as the yield for each step to be low, there are also overall yield is very low, so that problems 2.22%. ”

Therefore, the way to mass production of a compound of formula 1 without problems, such as the high yield and a low cost has been desired still.

o provide the production method ol compound represented by Formula 1:

[Formula 4]

[Formula 5]

[Formula 8]

[Formula 9]

4- (3- (3-fluorophenyl) -5,5-dimethyl-4-oxo-4, 5-dihydro-furan-2-yl) -benzenesulfonamide The total yield by the method represented by Reaction Scheme 1 It is very easy to about 46% of the high yield and can be economically mass-produced:

Or less, on the basis of the example embodiments The invention will be described in more detail. The following examples are not be the only, and the scope of the invention to illustrate the present invention be limited to these.

Example 1: 2- (3-fluorophenyl) Preparation of the acetyl chloride

2- (3-fluorophenyl) acetic acid (305.5 g, 1.98 mol), thionyl chloride (500 mL, 6.85 mol) to dissolve by stirring the solution in a catalytic amount of dimethylformamide (2.1 mL, 25.83让ol) to the It was. This solution banung 110 ^° and heated to sikimyeo C was stirred under reflux for 3 hours. After nyaenggak banung the solution to room temperature, the excess thionyl chloride under reduced pressure using a concentrator was removed by distillation. The stage was distilled off under reduced pressure to about 5mm¾ burgundy red oily objective compound (323 g, 94.4%) was obtained.

Example 2: 2- (3-fluorophenyl) -1- [4- (methylthio) phenyl] ethanone discussed prepared

Aluminum chloride (225 g, 1.91 mol) in dichloromethane (2500 mL), and then the suspension to 5 ^° C a solution banung 2- (3-fluorophenyl) acetyl chloride (305 g in cooling,

It was added 1.77 mol). The reaction was stirred for about 5 minutes after the common compounds, the liquid Ndo of banung

5 ^° while keeping the C was added dropwise the thio Enigma sol (237 g, 1.91 mol). After stirring for 3 hours banung common compounds at room temperature, it was slowly poured into cold aqueous hydrochloric acid solution. After separation the organic layer was washed with saturated aqueous sodium bicarbonate solution and brine and dried over anhydrous magnesium sulfate. After removing the anhydrous magnesium sulfate by filtration chest and diluted to a concentration under reduced pressure to concentrate the nucleic acid (1,000 mL). The diluted solution was 10 ^° after the nyaenggak C to crystallize, it was stirred for 1 hour and then filtered and washed with a nucleic acid (1,000 mL). The filtered solid 50 ^° and vacuum-dried for 2 hours in the target compound C (406 g, 88.3%) was obtained.

mp: 94.5 – 95.5 ^° C

¾-NMR (CDCls, 300 MHz): δ 2.52 (s, 3H), 4.23 (s, 2H), 6.95-7.05 On, 3H), 7.25-7.30 (m, 3H), 7.92 (d, J = 8.7 Hz , 2H)

Example 3: 2,2-dimethyl-eu 4- (3-phenyl pool Luo) -5- [4- (methylthio) phenyl] -3 () – furanyl discussed prepared

Eu 2 (3-fluorophenyl) – 1- [4- (methylthio) phenyl] was cooled 30 minutes with stirring at ice-water was dissolved ethanone (512 g, 1.97 mol) in tetrahydrofuran (3,900 mL) . Sodium hydride in the reaction solution (60%, 180 g, 7.5 mol) was added to the subdivision for at least 15 minutes, the common banung compounds was stirred for 30 minutes at room temperature. The reaction common compounds 5 ^° after nyaenggak in C, the 2-bromo butyryl cattle feeders cyanide (403 g, 2.29 mol) was added dropwise while maintaining the temperature. After the addition the solution was slowly stirred for 5 hours banung to room temperature. Banung ^ the compounds 5 ^° and cooled to C, and then slowly added to de-ionized water and neutralized with acetic acid (122 g). After concentration under reduced pressure the banung solution was extracted with dichloromethane (2, 500 mL) and deionized water (2, 000 mL). The organic layer was washed with brine and then dried over anhydrous magnesium sulfate and filtered.

Filtered and concentrated under reduced pressure then gave a precipitate is dissolved with stirring in methanol (700 mL). After filtering the precipitate is washed with acid and methane. The filtered solid 50 ^° and vacuum-dried for 2 hours at C, to give the desired compound (534.7 g, 82.8%). mp: 106 ^° C

NMR-¾ (CDCI ₃ , 300 MHz): δ 1.55 (s, 6H), 2.50 (s, 3H), 6.97-7.11 (m, 3H), 7.18 (d, J = 9.0 Hz, 2H), 7.26-7.36 (m, 1H), 7.55 ( d, J = 9.0 Hz, 2H)

Example 4: [4- (3- (3-fluoro-phenyl) -5, 5-dimethyl-4-oxo-4, 5-dihydro-furan-2-yl) phenylsulfonyl] Preparation of methyl acetate

2,2-dimethyl-eu eu eu 4 (3_ fluorophenyl) _5- [4- (methylthio) phenyl] -3 (0 furanones (5.5 Kg) and acetonitrile (27.2 Kg) and dichloromethane (45.43 Kg) after heunhap dissolved in a solvent, the compounds banung common -5 ^° was cooled to C. to binary dissolved in acetic acid solution to the other reaction by injecting a peracetic acid (18%) and injection of dichloromethane and 23.4 Kg 13.9 Kg acetonitrile a common hapaek was prepared. hapaek prepared common to -5 ^° keeping the C and slowly 0-5 was added to the reaction common compounds for 2 h ^° and stirred for 30 to 90 minutes in the C. and the reaction common compounds with purified water 109.2 L separating the washed organic layer was then washed with aqueous sodium thiosulfate and aqueous sodium bicarbonate solution. the organic layer is concentrated 4- (3-fluorophenyl eu) eu 2,2-dimethyl-5- (4-eu

(Methyl sulfinyl) phenyl) furan -3 (2H) – one to give the as an oil form.

NiP: 143-144 ^° C

¾-NMR (CDCls, 300 腿 ζ): δ 1.58 (s, 6Η), 2.76 (s, 3H), 7.26-7.08 (m, 3H), 7.30-7.38 (111, 1H), 7.65 (d, J = 8.2 Hz, 2H), 7.80 (d, J = 8.2 Hz, 2H)

After the thus obtained compound was dissolved in acetic anhydride (42.3 Kg) was added anhydrous sodium acetate (5.1 Kg). A liquid banung 130 ^° under reflux for 12 hours at C and then cooled to room temperature after stirring. By filtration, washed with acetic anhydride solution banung the filtrate was 55 ^° and concentrated in C. 63.5 Kg of purified water to the acid concentrate and 20.7

Injecting L and 10 ^° after a nyaenggak C, it was added oxone 32.3 Kg followed by stirring for 3 hours. A liquid banung 50 ^° and then concentrated in C until the residual liquid was added ½ and purified water (89.5 L) was stirred for 3 hours. The precipitated compound was filtered and then, washed with purified water and heptane and 50 ^°followed by drying for 12 hours at C, to give the desired compound (6.4 Kg, 91.3%).

_{¾ -赚(DMS0-d 6} (300 MHz): δ 8.01 (d, 2H), 7.83 (d, 2H), 7.43 (q, 1H), 7.20 (t, 1H), 7.07 (q, 1H), 5.47 (s, 2H), 2.06 ( s, 3H), 1.52 (s, 6H)

Example 5: Preparation of sodium 4- (3- (3-fluorophenyl) -5,5-dimethyl-4-oxo-4,5-dihydro-2-yl) Preparation of benzene sulfinate

[4- (3- (3-fluoro-phenyl) -5, 5-dimethyl-4-oxo-eu 4, 5-dihydro-furan-2-yl) phenylsulfonyl] methyl acetate (6.4 Kg) in tetrahydrofuran was dissolved in (34.3 Kg) and ethanol (15.3 Kg), the liquid temperature banung 0 ^° was cooled to C. It was dissolved in sodium hydroxide (0.7 Kg) in purified water (16.1 L) to the other reaction section was prepared the solution cooled to C. It was added slowly for 5 hours, the prepared aqueous sodium hydroxide solution to the reaction solution, further stirring the reaction solution after about 1 hour and concentrated at 45 ° C. After concentration is completed, when added to absolute ethanol (10.0 Kg) and the toluene (11.0 Kg) was dissolved in concentrated 5C C. When concentration is complete, and then the absolute ethanol (10.0 Kg) was dissolved was added to toluene (10.1 Kg) and concentrated in 5C C. When the concentration is completed with absolute ethanol (7.7 Kg) was dissolved in 50 was added to toluene (8.4 Kg) ^° was repeated in the course of concentration C twice. After re-concentrated solution of absolute ethanol (4.6 Kg) and the dissolution was added to toluene (5.1 Kg) to 50 ^° and concentrated in C. Rouen (20.7 When the concentrate is completed,

Kg) was added and the resultant mixture was stirred for 2 hours, filtered and the washed with toluene (12.5 Kg). Was added to 20.7 Kg of toluene to the obtained solid was filtered after stirring for one to two hours. The filtered solid to a toluene (11.9 Kg) and washed with heptane (11.9 Kg) and then 45 ^° was obtained in a quantitative and dried for 12 hours in C.

¾- 赚 (DMSO-de, 300 MHz): δ 7.52 (s, 4H), 7.40 (m, 1H), 7. 19-7.02

^‘ (M, 3H), 1.49 (s, 6H) _.

Example 6: 4- (3- (3-fluoro-phenyl) -5, 5-dimethyl-4-oxo-4, 5-dihydro-furan-2-yl) Preparation of benzenesulfonamide

Sodium 4- (3 eu (3_-fluorophenyl) -5, 5-dimethyl-4-oxo-4, 5-dihydro-furan-2-yl eudi) after the benzene sulfinate (6.0 Kg) was dissolved in dichloromethane – 5 ^° and cooled to C. After stirring for another part banung ^ the combined dichloromethane (6.0 Kg) and sulfonic sulfuryl chloride (2. 1 Kg), 0 to the reaction solution obtained in the above ^° was added slowly for 1 hour under C. A common banung hapaek eu 5 ^° and after stirring for 4 hours at C and the organic layer was separated and washed with brine. After filtering the organic layer was dried over sodium sulfate (4.2 Kg), the filtrate was 40 ^° and concentrated in C or less to give the intermediates of sulfonyl chloride compounds.

Tetrahydrofuran (36.3 Kg) and aqueous ammonia (16.9K the other part banung _g were combined for common) was nyaenggak to 0 ° C. By dissolving the obtained sulfonic ponal chloride compound in 8.9 Kg of tetrahydrofuran 5 ^° , while maintaining the below C was added slowly to the prepared aqueous ammonia solution for 1 hour.This solution banung -5 ^° was concentrated after stirring for 30 to 120 minutes in the C. Once completed, the concentrated, purified water 40.2 L

It was added and stirred for 1 to 2 hours. Filtered and the resulting solid was then washed with purified water (16.9 L) and heptane (11.4 Kg). The filtered solid 45 ^°followed by drying for 12 hours at C, to give the desired compound (4.3 Kg, 73%).

mp: 204-205 ^° C

¾-NMR (CDCls, 300 MHz): δ 1.57 (s, 6H), 4.96 (br s, 2H), 6.78 (m,

1H), 6.82 (m, 2H), 7.78 (d, J = 8.7 Hz, 2H), 7.96 (d, J = 8.7 Hz, 2H) IR (cm- ¹ ): 3267, 1686, 1218, 1160

Example 7: Preparation of 2-bromo butyryl cattle feeders cyanide

Was added trimethylsilyl cyanide (283.4 g, 2.86 mol) in 2-bromo cattle feeders butyryl bromide (557 g, 2.24 mol). This solution banung 90 ^° After stirring at C for 3 hours to nyaenggak to room temperature. Banung completed under reduced pressure (79画¾), 66 to 75 ^° to fractional distillation under a C, to give the desired compound (384 g, 90.04%).

-醒(CDC1 ₃₎ 300 MHz): δ 1.97 (s, 6H)

PATENT

WO 2000061571

References

Polmacoxib

Systematic (IUPAC) name
4-(3-(3-Fluorophenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)-benzenesulfonamide
Clinical data
Trade names	Acelex
Identifiers
CAS Number	301692-76-2
PubChem	CID 9841854
ChemSpider	8017569
UNII	IJ34D6YPAO
ChEMBL	CHEMBL166863
Synonyms	CG100649
Chemical data
Formula	C12H16FNO4S
Molar mass	361.3914 g/mol

///////Polmacoxib, CG-100649, 301692-76-2

CC1(C(=O)C(=C(O1)C2=CC=C(C=C2)S(=O)(=O)N)C3=CC(=CC=C3)F)C

WO2016055918) NOVEL STABLE POLYMORPHS OF ISAVUCONAZOLE OR ITS SALT THEREOF

WOCKHARDT LIMITED [IN/IN]; D-4, MIDC Area, Chikalthana, Aurangabad 431006 (IN)

KHUNT, Rupesh Chhaganbhai; (IN).
RAFEEQ, Mohammad; (IN).
MERWADE, Arvind Yekanathsa; (IN).
DEO, Keshav; (IN)

The present invention relates to novel stable novel stable polymorphs of Isavuconazole or its salt thereof, having purity more than 90 % when measured by HPLC. In particular the present invention directs process for the preparation of solid amorphous and crystalline form of Isavuconazole base. In a further embodiment present invention directs to crystalline form Isavuconazole Hydrobromide salt and oxalate salt of 2-(2,5-difluoro- phenyl)-1-[1,2,4]triazol-1-yl-butane-2,3-diol.

Isavuconazole, Isavuconazonium, Voriconazole, and Ravuconazole are azole derivatives and known as antifungal drugs for treatment of systemic mycoses as reported in US 5,648,372, US 5,792,781, US 6,300,353 and US 6,812,238.

The US patent No. 6,300,353 discloses Isavuconazole and its process. It has chemical name [(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl)]-l -(lH-l,2,4-triazol-l-yl)-2-(2,5-difluorophenyl)43utan-2-ol; and has the structural formula I:

Formula I

The ‘353 described the process for the preparation Isavuconazole, involve the use of 2-(2,5-difluoro-phenyl)-l-[l ,2,4]triazol-l-yl-butane-2,3-diol (referred herein after “diol base”) in an oil form, which is difficult to isolate and purify. The use of 2-(2,5-difluoro-phenyl)-l-[l ,2,4]triazol-l-yl-butane-2,3-diol base, without purification, reflects the purity of Isavuconazole and Isavuconazonium sulfate. However, the reported process not feasible industrially.

Thus, an object of the present invention is to provide simple, cost effective and industrially feasible processes for preparation of Isavuconazole or its salt thereof in enhanced yield as well as purity. In a particular present invention directs to novel stable polymorphs of Isavuconazole or its salt thereof.

Examples

Example-1: Preparation of Amorphous Isavuconazole

In a round bottomed flask charged ethanol (250 ml), thioamide compound (25.0 gm) and 4-cyano phenacyl bromide (18.4 gm) under stirring. The reaction mixture were heated to 70 °C. After completion of reaction the solvent was removed under vacuum distillation and water (250 ml) and Ethyl acetate (350 ml) were added to reaction mass. The reaction mixture was stirred and its pH was adjusted between 7 to 7.5 by 10 % solution of sodium bicarbonate. The layer aqueous layer was discarded and organic layer was washed with saturated sodium chloride solution (100 ml) and concentrated under vacuum to get residue. The residue was suspended in methyl tert-butyl ether (250 ml) and the reaction mixture was heated to at 40°C to make crystals uniform and finally reaction mass is cooled to room temperature filtered and washed with the methyl tert-butyl ether. The product was isolated dried to get pale yellowish solid product.

Yield: 26.5 gm

HPLC purity: 92.7%

Example-2: Preparation of crystalline Isavuconazole Base

Charged methylene dichloride (250 ml) and 25.0 gm Isavuconazole Hydrobromide compound of formula-II into 1.0 L flask and stirred. Added aqueous solution of sodium bi carbonate in to the reaction mass to obtained clear solution. The layers were separated and organic layer was washed with dilute hydrochloric acid solution followed by saturated solution of sodium chloride. Finally, Organic layer was concentrated under vacuum to get titled product.

Yield: 18.5 gm

HPLC Purity: 97%

Example-3: Preparation of crystalline Isavuconazole Hydrobromide

Charged isopropanol alcohol (250 ml) followed by thioamide compound (25.0 gm) and 4-cyano phenacyl bromide (18.4 gm) into 1.0 L flask. The reaction mixture was stirred and heated to 50 C, after completion of reaction the precipitated material was filtered and washed with isopropanol alcohol (25 ml). The wet cake is dried under vacuum for 4-5 hrs at 40 C to obtain off-white solid product.

Yield: 26.5 gm

HPLC Purity: 97.3%

Exaniple-4: Synthesis of 2-(2,5-difluoro-phenyl)-l -[l,2,4]triazol-l-yl-butane-2,3-diol oxalate

Dissolved crude 50 gm 2-(2,5-difluoro-phenyl)-l-[l ,2,4]triazol-l -yl-butane-2,3-diol base compound in 150 ml of ethyl acetate. Oxalic acid dihydrate 25 gm was added into the reaction mixture and stirred. Heat the reaction mixture for 1 hour at 50-55 °C. The reaction mixture was cooled to 25°C to 35°C. Toluene 300 ml was added into the reaction mixture to precipitate the solid. The precipitate was washed with toluene and dried under vacuum to obtain the solid crystalline form of titled compound.

Yield: 58 g

HPLC Purity: 76%

Exaniple-5: Synthesis of 2-(2,5-difluoro-phenyl)-l -[l,2,4]triazol-l-yl-butane-2,3-diol oxalate salt

Exemplified procedure in example 1 with the replacement ethyl acetate solvent with tetrahydrofuran and antisolvent toluene with petroleum ether were used to get the title compound.

Exaniple-6: Synthesis of 2-(2,5-difluoro-phenyl)-l -[l,2,4]triazol-l-yl-butane-2,3-diol oxalate

Exemplified procedure in example 1 with the replacement ethyl acetate solvent with isopropyl acetate and antisolvent toluene with diisopropyl ether were used to get the title compound.

Exaniple-7: Synthesis of 2-(2,5-difluoro-phenyl)-l -[l,2,4]triazol-l-yl-butane-2,3-diol oxalate

Exemplified procedure in example 1 wherein diethyl ether is used in place of ethyl acetate and toluene or heptane was used as antisolvent to get the title compound.

Example-8: Synthesis of 2-(2,5-difluoro-phenyl)-l -[l,2,4]triazol-l-yl-butane-2,3-diol oxalate

Exemplified procedure in example 1 wherein diethyl ether is used in place of ethyl acetate and isolation of the product were done by means of partial removal of the solvent under vacuum.

Example-9: Synthesis of 2-(2,5-difluoro-phenyl)-l -[l,2,4]triazol-l-yl-butane-2,3-diol oxalate

Exemplified procedure in example 1 wherein ethyl acetate is replaced with isopropyl acetate and further, the reaction mass was stirred at lower temperatures to about 10°C to about 15°C for 3-5 hours and subsequently precipitated product was isolated and dried.

Example-10: Synthesis of 2-(2,5-difluoro-phenyl)-l-[l ,2,4]triazol-l-yl-butane-2,3-diol base

Stirring the suspension of 260 ml water and 65 gm 2-(2,5-difluoro-phenyl)-l-[l,2,4] triazol-l-yl-butane-2,3-diol oxalate salt were added. The reaction mixture pH was adjusted by addition of 10 % aqueous sodium carbonate solution. The pH was maintained to about pH 7 to about 8, 300 ml dichloro methane was added into the reaction mixture with stirring. The layers were separated and dichloromethane layer was collected. Aqueous layer was extracted with 150 ml dichloromethane. Dichloromethane layer was combined and washed with water. Dichloromethane was distilled out to get titled compound.

Yield: 35 gm

Purity: 87%

Wockhardt Ltd chairman Habil Khorakiwala.

/////////NEW PATENT, WOCKHARDT LIMITED, WO 2016055918, ISAVUCONAZOLE

1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine fumarate

Vonoprazan (Takecab(®)) is an orally bioavailable potassium-competitive acid blocker (P-CAB) being developed by Takeda for the treatment and prevention of acid-related diseases. The drug is approved in Japan for the treatment of acid-related diseases, including erosive oesophagitis, gastric ulcer, duodenal ulcer, peptic ulcer, gastro-oesophageal reflux, reflux oesophagitis and Helicobacter pylori eradication. Phase III development is underway for the prevention of recurrence of duodenal and gastric ulcer in patients receiving aspirin or NSAID therapy. Phase I development was conducted in the UK for gastro-oesophageal reflux; however, no further development has been reported. This article summarizes the milestones in the development of vonoprazan leading to this first approval for acid-related diseases.

Vonoprazan Fumarate was approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on December 26, 2014. It was co-developed and marketed as Takecab^® by Takeda & Otsuka.
Vonoprazan has a novel mechanism of action called potassium-competitive acid blockers (P-CABs) which competitively inhibits the binding the potassium ions to H⁺, K⁺-ATPase (also known as the proton pump) in the final step of gastric acid secretion in gastric parietal cells. Vonoprazan provides a strong and sustained acid section inhibitory effect. It is indicated for the treatment of gastric ulcer, duodenal ulcer and reflux esophagitis.
Cometriq^® is available as tablet for oral use, containing 10 or 20 mg of free Vonoprazan, and the recommended dose is 20 mg orally once daily for adluts.

Vonoprazan fumarate (Takecab(®)) is a first-in-class potassium-competitive acid blocker that has been available in the market in Japan since February 2015. Vonoprazan is administered orally at 20 mg once daily for the treatment of gastroduodenal ulcer, at 20 and 10 mg once daily for the treatment and secondary prevention of reflux esophagitis, respectively, at 10 mg once daily for the secondary prevention of low-dose aspirin- or non-steroidal anti-inflammatory drug-induced peptic ulcer, and at 20 mg twice daily in combination with clarithromycin and amoxicillin for the eradication of Helicobacter pylori. It inhibits H(+),K(+)-ATPase activities in a reversible and potassium-competitive manner with a potency of inhibition approximately 350 times higher than the proton pump inhibitor, lansoprazole. Vonoprazan is absorbed rapidly and reaches maximum plasma concentration at 1.5-2.0 h after oral administration. Food has minimal effect on its intestinal absorption. Oral bioavailability in humans remains unknown. The plasma protein binding of vonoprazan is 80 % in healthy subjects. It distributes extensively into tissues with a mean apparent volume of distribution of 1050 L. Being a base with pKa of 9.6 and with acid-resistant properties, vonoprazan is highly concentrated in the acidic canaliculi of the gastric parietal cells and elicited an acid suppression effect for longer than 24 h after the administration of 20 mg. The mean apparent terminal half-life of the drug is approximately 7.7 h in healthy adults. Vonoprazan is metabolized to inactive metabolites mainly by cytochrome P450 (CYP)3A4 and to some extent by CYP2B6, CYP2C19, CYP2D6, and SULT2A1. A mass balance study showed that 59 and 8 % of the orally administered radioactivity was recovered in urine as metabolites and in an unchanged form, respectively, indicating extensive metabolism. Genetic polymorphism of CYP2C19 may influence drug exposure but only to a clinically insignificant extent (15-29 %), according to the population pharmacokinetic study performed in Japanese patients. When vonoprazan was co-administered with clarithromycin, the mean AUC from time 0 to time of the next dose (dosing interval) of vonoprazan and clarithromycin were increased by 1.8 and 1.5 times, respectively, compared with the corresponding control values, indicating mutual metabolic inhibition. The mean area under the curve from time zero to infinity obtained from patients with severe liver and renal dysfunction were elevated by 2.6 and 2.4 times, respectively, compared with healthy subjects, with no significant changes in plasma protein binding. Vonoprazan increases intragastric pH above 4.0 as early as 4 h after an oral dose of 20 mg, and the extensive anti-secretory effect is maintained up to 24 h post-dose. During repeated dosing of 20 mg once daily, the 24-h intragastric pH >4 holding time ratios were 63 and 83 % on days 1 and 7, respectively. Because vonoprazan elicited a more extensive gastric acid suppression than the proton pump inhibitor, lansoprazole, it also gave rise to two to three times greater serum gastrin concentrations as compared with lansoprazole. In pre-approval clinical studies for the treatment of acid-related disorders, mild to moderate adverse drug reactions (mostly constipation or diarrhea) occurred at frequencies of 8-17 %. Neither severe liver toxicity nor neuroendocrine tumor has been reported in patients receiving vonoprazan.

Vonoprazan fumarate is a first-in-class potassium-competitive acid blocker. It was approved in the Japanese market in February, 2015.^[1]

Vonoprazan can be used for the treatment of gastroduodenal ulcer, reflux esophagitis, and for some drug-induced peptic ulcers. It can be combined with other antibiotics for the eradication of Helicobacter pylori.^[2]

PATENT

CN102421753B

Route 1

Reference：1. WO2006036024A1 / US8048909B2.

2. WO2007026916A1 / US7498337B2.

3. CN104327051A.

1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -IH- pyrrol-3-yl] -N- methylmethanamine fumarate Takeda single An R & D for the gastric acid secretion inhibitors (codename: TAK-438, generic name: vonoprazan fumarate), the drug belongs to the potassium ion (K +) competitive acid blocker (P-CAB) for a new inhibitors, with a strong, long-lasting inhibition of gastric acid secretion, while the gastric parietal cells in the final stage of gastric acid secretion by inhibiting K + for H +, K + -ATP enzyme (proton pump) binding effect on gastric acid secretion also advance termination action.

Its molecular formula is: C17H16FN3O2S · C4H4O4, MW: 461.46, the chemical structure of formula I as shown.

 

CN101300229A discloses 1- [5- (2_-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1Η- pyrrol -3-yl] -N- methylmethanamine fumarate alone, but not related to its crystalline form.

The present invention discloses a I- [5- (2- fluorophenyl) -I- (pyridin-3-ylsulfonyl) -IH- pyrrol-3-yl] -N- methylmethanamine single rich fumarate A method for preparing a crystalline form. 1- [5- (2_-fluorophenyl) -1- (Batch-3-ylsulfonyl) -IH- pyrrol-3-yl] -N- methylmethanamine fumarate single crystalline form A, according to prepared by the following routes:

Example 1

  A method of preparing polymorph having pyrrole derivatives maleate described in detail below.

Step I: 5- (2- fluorophenyl) -1- (pyridin-3-ylsulfonyl) -IH- pyrrole-3-carbaldehyde Synthesis of

Compound II (260mg) was dissolved in tetrahydrofuran (50ml) was added 60% NaH, the reaction was stirred for 30 minutes at room temperature. Was added 15-crown–5 (I. 5g), the reaction mixture was stirred at room temperature for 1 hour and then pyridine-3-sulfonyl chloride was added, stirred at room temperature for 2 hours until complete reaction was followed by thin layer chromatography, and then was added to the reaction system 20mL saturated brine with ethyl acetate (IOOmLX2) and the combined organic phase was washed with saturated brine 50ml organic phase, an appropriate amount of anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude compound IV (200mg) administered directly in the next reaction.

Synthesis 1_ [5- (2-fluorophenyl) -1- (piperidin-3-sulfonyl batch) -IH- pyrrol-3-yl] -N- methylmethanamine of: Step 2

The brown residue obtained in the previous step IV compound (200mg) was dissolved in 30mL methanol was added 27% -33% methyl amine solution, the reaction was stirred for 1.5 hours. Sodium borohydride (68mg), the reaction was stirred for 20 minutes, was added lmol / LHCl to an acidic aqueous solution, and stirred until complete reaction was followed by thin layer chromatography. To the reaction mixture was added saturated sodium bicarbonate solution until weakly basic system was extracted with ethyl acetate (IOOmLX2), the combined organic phases with saturated brine (50mL), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product ( 208mg, yellow oil). Yield: 100%.

  Step 3: 1_ [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -IH- pyrrol-3-yl] -N- methylmethanamine fumarate single synthesis

Compound V obtained in the previous step was dissolved in 20mL of ethyl acetate, taking the mass fraction of equivalents of fumaric acid was dissolved in 2ml of methanol. Added dropwise with stirring to a solution of compound V in ethyl acetate, stirred for 30 minutes at room temperature. Then warmed to 55-65 degrees reflux one hour, cooled to room temperature and filtered to give an off-white solid was washed with cold ethyl acetate IOml and dried in vacuo to give 170mg of crystalline Compound I, about 20% overall yield. X- ray diffraction spectrum of the crystalline sample is shown in Figure 1. DSC spectrum shown in Figure 2, this polymorph is defined as A crystalline form.

Route 2

Reference：1. CN105085484A.

http://www.google.com/patents/CN105085484A?cl=en

Fumaric Wonuo La Like (TAK-438, Vonoprazan fumarate) is Takeda Pharmaceuticals and Otsuka Pharmaceutical to launch a new type of oral anti-acid drugs. As a potassium ion (K +) competitive acid blocker (P-CAB), Wonuo La Like gastric acid secretion in the gastric parietal cells play a role in the final step, by inhibiting K + for H +, K + -ATP enzyme (proton chestnut) combine to inhibit gastric acid secretion and early termination. Compared to the current power of the proton chestnut inhibitors (PPIs), due to the absence of praise Wonuo La CYP2C19 metabolism, so the performance in clinical trials showing good effect: the treatment of gastric ulcer / duodenal ulcer, reflux esophagitis eradication of H. pylori and other effects are better than lansoprazole, while having a similar security.

  fumarate Wonuo La Like chemical name: I- [5_ (2_ gas) -1- (pyridin _3_ cross-acyl group) -IH- P ratio slightly 3-yl] – N- methylmethanamine fumarate, structured as follows:

  Preparation of fumaric Wonuo La Like synthetic route mainly follows:

  Takeda patent CN200680040789 original study discloses a 5- (2-fluorophenyl) -lH- pyrrole-3-carbaldehyde as a starting material, the solvent is tetrahydrofuran, sodium hydride doing acid binding agent, crown ethers do a phase transfer catalyst, with 3-pyridine sulfonyl chloride to give the intermediate 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -IH- pyrrole-3-carbaldehyde, then to form a Schiff base with methylamine boron sodium hydride reduction to give Wonuo La Like the free base and then fumaric acid salt formation, generate fumaric Wonuo La Chan, the reaction equation is as follows:

  Takeda company disclosed in 2010 it 0 01,080,018,114 in improved synthetic route: Intermediate 5- (2-fluorophenyl) -I- (pyridine-3-ylsulfonyl) -IH–3 formaldehyde synthesis, instead of acetonitrile as solvent, DIEA do acid-binding agent, DMAP as catalyst, but side reactions, tedious post-processing operation, the lower the yield, the overall yield of less than 40%.

CN201080018114 improved synthetic route to 5- (2-fluorophenyl) -IH- pyrrole-3-carbonitrile as a starting material of the synthesis route, but this route is converted to the cyano aldehyde used Raney catalytic hydrogenation, industrial scale there is a big security risk, its reaction equation is as follows:

  Y. Arikawa et J. Med Chem 2012, 55, 4446-4456 reported the following synthetic route.:

In phenyl pyrrole-3-carbaldehyde and methylamine alcohol imine by metal borohydride reduction, to give further protection to give Boc ((5-phenyl -IH- pyrrol-3-yl) -N -) methyl carbamate; the above product with an arylsulfonyl chloride, and then de-Boc protection to give 1- (5-phenyl-1 aromatic sulfonyl -IH- pyrrol-3-yl) – N- methyl methylamine;

Y. Arikawa et al reported that the above process step is prolonged, the probability g [J reacting a corresponding increase in the above reaction scheme conditional optimization, control side reactions is one of the present invention is to solve the problem. On the other hand the above literature after the synthesis process used in chromatography, is not conducive to fumaric Wonuo La Like industrial production. Therefore, the development of fumaric acid Wonuo La Like New synthesis process, simplify the synthesis operations, reduce costs, improve productivity, it has important implications for fumaric Wonuo La Like this one which attract anti-acid drugs.

PAPER

J. Med Chem 2012, 55, 4446-4456

http://pubs.acs.org/doi/abs/10.1021/jm300318t

Discovery of a Novel Pyrrole Derivative 1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine Fumarate (TAK-438) as a Potassium-Competitive Acid Blocker (P-CAB)

In our pursuit of developing a novel and potent potassium-competitive acid blocker (P-CAB), we synthesized pyrrole derivatives focusing on compounds with low log D and high ligand-lipophilicity efficiency (LLE) values. Among the compounds synthesized, the compound 13e exhibited potent H⁺,K⁺-ATPase inhibitory activity and potent gastric acid secretion inhibitory action in vivo. Its maximum efficacy was more potent and its duration of action was much longer than those of proton pump inhibitors (PPIs). Therefore, compound 13e (1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate, TAK-438) was selected as a drug candidate for the treatment of gastroesophageal reflux disease (GERD), peptic ulcer, and other acid-related diseases.

SYNTHESIS

References

References

1: Arikawa Y, Nishida H, Kurasawa O, Hasuoka A, Hirase K, Inatomi N, Hori Y, Matsukawa J, Imanishi A, Kondo M, Tarui N, Hamada T, Takagi T, Takeuchi T, Kajino M. Discovery of a novel pyrrole derivative 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamin e fumarate (TAK-438) as a potassium-competitive acid blocker (P-CAB). J Med Chem. 2012 May 10;55(9):4446-56. doi: 10.1021/jm300318t. Epub 2012 Apr 30. PubMed PMID: 22512618.

2: Kondo M, Kawamoto M, Hasuoka A, Kajino M, Inatomi N, Tarui N. High-throughput screening of potassium-competitive acid blockers. J Biomol Screen. 2012 Feb;17(2):177-82. doi: 10.1177/1087057111421004. Epub 2011 Sep 22. PubMed PMID: 21940711.

3: Shin JM, Inatomi N, Munson K, Strugatsky D, Tokhtaeva E, Vagin O, Sachs G. Characterization of a novel potassium-competitive acid blocker of the gastric H,K-ATPase, 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamin e monofumarate (TAK-438). J Pharmacol Exp Ther. 2011 Nov;339(2):412-20. doi: 10.1124/jpet.111.185314. Epub 2011 Aug 9. PubMed PMID: 21828261; PubMed Central PMCID: PMC3199995.

4: Hori Y, Matsukawa J, Takeuchi T, Nishida H, Kajino M, Inatomi N. A study comparing the antisecretory effect of TAK-438, a novel potassium-competitive acid blocker, with lansoprazole in animals. J Pharmacol Exp Ther. 2011 Jun;337(3):797-804. doi: 10.1124/jpet.111.179556. Epub 2011 Mar 16. PubMed PMID: 21411494.

5: Matsukawa J, Hori Y, Nishida H, Kajino M, Inatomi N. A comparative study on the modes of action of TAK-438, a novel potassium-competitive acid blocker, and lansoprazole in primary cultured rabbit gastric glands. Biochem Pharmacol. 2011 May 1;81(9):1145-51. doi: 10.1016/j.bcp.2011.02.009. Epub 2011 Mar 1. PubMed PMID: 21371447.

6: Hori Y, Imanishi A, Matsukawa J, Tsukimi Y, Nishida H, Arikawa Y, Hirase K, Kajino M, Inatomi N. 1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamin e monofumarate (TAK-438), a novel and potent potassium-competitive acid blocker for the treatment of acid-related diseases. J Pharmacol Exp Ther. 2010 Oct;335(1):231-8. doi: 10.1124/jpet.110.170274. Epub 2010 Jul 12. PubMed PMID: 20624992.

• 1 “Vonoprazan: first global approval. – PubMed – NCBI”. Ncbi.nlm.nih.gov. 2015-09-28. Retrieved 2016-03-30.
• 2

“The First-in-Class Potassium-Competitive Acid Blocker, Vonoprazan Fumarate: Pharmacokinetic and Pharmacodynamic Considerations. – PubMed – NCBI”. Ncbi.nlm.nih.gov. 2015-09-28. Retrieved 2016-03-30.

/////

• Originator Kowa Pharmaceutical
• Class Antihyperlipidaemics
• Mechanism of Action Peroxisome proliferator-activated receptor alpha agonists

• Preregistration Dyslipidaemias

Most Recent Events

• 01 Feb 2016 Kowa Research Institute completes a phase I drug-interaction trial in Healthy volunteers in USA (PO) (NCT02719431)
• 12 Jan 2016 Kowa Research Institute plans the phase III PROMINENT trial for Dyslipidaemia (In patients with diabetes mellitus) in countries worldwide
• 01 Jan 2016 Kowa Research Institute initiates a phase I drug-interaction trial in Healthy volunteers in USA (PO) (NCT02719431)

Pemafibrate, also known as K-877 and (R)-K 13675, is a PPAR alpha agonist. (R)-K-13675 decreases the secretion of inflammatory markers without affecting cell proliferation or tube formation. Peroxisome proliferator-activated receptor-alpha (PPAR-alpha) is a key regulator of lipid and glucose metabolism and has been implicated in inflammation. (R)-K-13675 was associated with the inhibition of inflammatory responses without affecting cell proliferation or angiogenesis, and subsequently may induce an anti-atherosclerotic effect.

Pemafibrate had been filed NDA by Kowa for the treatment of dyslipidemia in the Japan in 2015.

Pemafibrate is in phase II clinical trials for the treatment of dyslipidemia in the US and EU.

Route 1

Reference：1. US2009023944A1.

Route 2

Reference：1. US2009076280A1.

http://www.google.com/patents/US20090076280

Example 5 Synthesis of (R)-2-{3-[N-(benzoxazole-2-yl)-N-(3-(4-methoxyphenoxy)propyl)aminomethyl]phenyloxy}butyric acid (Compound (6))

• Ethyl (R)-2-{3-[N-(benzoxazole-2-yl)-N-(3-(4-methoxyphenoxy)propyl)aminomethyl]phenyloxy}butylate (26.0 g) was dissolved in ethanol (200 mL), and 1.5N NaOH (50 mL) was added to the solution, followed by stirring for 1 hour at room temperature. The reaction mixture was washed with diethyl ether, and the formed aqueous layer was acidified with 4N HCl under ice cooling. The thus-treated aqueous layer was extracted with ethyl acetate, and the extract was washed sequentially with water and saturated brine. The washed extract was dried over sodium sulfate anhydrate and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol=10/1), to thereby yield the target product (21.3 g, 87%, 98% ee).

Optical Purity:

• Measurement conditions: HPLC
• Column: CHIRALPAK AD
• Solvent: n-hexane/IPA/TFA=100/30/0.1
• Flow rate: 2 mL/min
• Retention time: 4.19 min (S-form; 3.68 min)
• ¹H-NMR (400 MHz, CD₃OD) δ ppm: 0.94 (t, J=7 Hz, 3H), 1.81 (m, 2H), 1.99 (quintet, J=6 Hz, 2H), 3.60 (t, J=7 Hz, 2H), 3.61 (s, 3H), 3.85 (t, J=6 Hz, 2H), 4.40 (t, J=6 Hz, 1H), 4.65 (s, 2H), 6.69-6.80 (m, 7H), 6.91 (dt, J=7, 1 Hz, 1H), 7.05 (dt, J=7, 1 Hz, 1H), 7.12-7.18 (m, 4H).

Route 3

Reference：1. Bioorg. Med. Chem. Lett. 2007, 17, 4689-4693.

 

Landmark Trial Entitled “PROMINENT” To Explore The Prevention Of Heart Disease In Diabetic Patients With High Triglycerides And Low HDL-C

Trial will evaluate if lowering triglycerides and increasing functional HDL with Kowa’s potent selective peroxisome proliferator activator receptor-alpha (PPAR-alpha) modulator, K-877 (pemafibrate) can reduce the elevated risk of cardiovascular disease in high-risk diabetic patients who are already taking statins

Jan 12, 2016, 09:00 ET from Kowa Research Institute, Inc.

///////Pemafibrate, NDA,  Kowa, dyslipidemia,  Japan, 2015, phase II clinical trials,  US and EU, K-877, K-13675, (R)-

CC[C@H](C(=O)O)Oc1cccc(c1)CN(CCCOc2ccc(cc2)OC)c3nc4ccccc4o3

CC[C@@H](OC1=CC=CC(CN(C2=NC3=CC=CC=C3O2)CCCOC4=CC=C(OC)C=C4)=C1)C(O)=O

.

http://societyofwomenengineers.swe.org/awards/individual-awards/4153-global-leadership

The Global Leadership Award honors a person with at least fifteen (15) years professional experience who has worked in and led an internationally based engineering, scientific or technology-based business or organization, and in doing so, serves as a role model to women engineers and technologists worldwide. A maximum of three (3) awards may be presented annually.

“This award is a recognition of Biocon’s significant role in harnessing the potential of Biotechnology to provide affordable access to highly complex bio-pharmaceuticals like Insulins and monoclonal antibodies for the benefit of patients the world over.” – Kiran Mazumdar-Shaw

//////Kiran Mazumdar Shaw,  ‘The Global Leadership in Engineering 2016’ , Award by USC

Lobeglitazone (trade name Duvie, Chong Kun Dang) is an antidiabetic drug in the thiazolidinedione class of drugs. As an agonistfor both PPARα and PPARγ, it works as an insulin sensitizer by binding to the PPAR receptors in fat cells and making the cells more responsive to insulin.^[3]

Lobeglitazone sulfate was approved by the Ministry of Food and Drug Safety (Korea) on July 4, 2013. It was developed and marketed as Duvie^® by Chong Kun Dang Corporation.

Lobeglitazone is an agonist for both PPARα and PPARγ, and it works as an insulin sensitizer by binding to the PPAR receptors in fat cells and making the cells more responsive to insulin. It is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

Duvie^® is available as tablet for oral use, containing 0.5 mg of free Lobeglitazone. The recommended dose is 0.5 mg once daily.

Lobeglitazone which was reported in our previous works belongs to the class of potent PPARα/γ dual agonists (PPARα EC₅₀:  0.02 μM, PPARγ EC₅₀:  0.018 μM, rosiglitazone; PPARα EC₅₀:  >10 μM, PPARγ EC₅₀:  0.02 μM, pioglitazone PPARα EC₅₀:  >10 μM, PPARγ EC₅₀:  0.30 μM). Lobeglitazone has excellent pharmacokinetic properties and was shown to have more efficacious in vivo effects in KKA^y mice than rosiglitazone and pioglitazone.¹⁷ Due to its outstanding pharmacokinetic profile, lobeglitazone was chosen as a promising antidiabetes drug candidate.

Medical uses

Lobeglitazone is used to assist regulation of blood glucose level of diabetes mellitus type 2 patients. It can be used alone or in combination with metformin.^[4]

Lobeglitazone was approved by the Ministry of Food and Drug Safety (Korea) in 2013, and the postmarketing surveillance is on progress until 2019.^[4][5]

SYNTHESIS

PAPER

Org. Process Res. Dev. 2007, 11, 190-199.

Process Development and Scale-Up of PPAR α/γ Dual Agonist Lobeglitazone Sulfate (CKD-501)

http://pubs.acs.org/doi/abs/10.1021/op060087u

A scaleable synthetic route to the potent PPARα/γ dual agonistic agent, lobeglitazone (1), used for the treatment of type-2 diabetes was developed. The synthetic pathway comprises an effective five-step synthesis. This process involves a consecutive synthesis of the intermediate, pyrimidinyl aminoalcohol (6), from the commercially available 4,6-dichloropyrimidine (3) without the isolation of pyrimidinyl phenoxy ether (4). Significant improvements were also made in the regioselective 1,4-reduction of the intermediate, benzylidene-2,4-thiazolidinedione (10), using Hantzsch dihydropyridine ester (HEH) with silica gel as an acid catalyst. The sulfate salt form of lobeglitazone was selected as a candidate compound for further preclinical and clinical study. More than 2 kg of lobeglitazone sulfate (CKD-501, 2) was prepared in 98.5% purity after the GMP batch. Overall yield of 2 was improved to 52% from 17% of the original medicinal chemistry route.

Silica gel TLC R_f = 0.35 (detection:  iodine char chamber, ninhydrin solution, developing solvents:  CH₂Cl₂/MeOH, 20:1); mp 111.4 °C; IR (KBr) ν 3437, 3037, 2937, 2775, 1751, 1698, 1648, 1610, 1503, 1439, 1301, 1246, 1215, 1183 cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 3.09 (m, 4H), 3.29 (m, 1H), 3.76 (s, 3H), 3.97 (m, 2H), 4.14 (m, 2H), 4.86 (m, 1H), 6.06 (bs, 1H), 6.86 (m, 2H), 7.00 (m, 2H), 7.13 (m, 4H), 8.30 (s, 1H), 11.99 (s, NH); ¹³C NMR (100 MHz, CDCl₃) δ 37.1, 38.2, 53.7, 53.8, 56.3, 62.2, 65.8, 86.0, 115.1, 116.0, 123.0, 129.8, 131.2, 145.7, 153.4, 157.9, 158.1, 161.1, 166.5, 172.4, 172.5, 176.3, 176.5; MS (ESI)m/z (M + 1) 481.5; Anal. Calcd for C₂₄H₂₆N₄O₉S₂:  C, 49.82; H, 4.53; N, 9.68; S, 11.08. Found:  C, 49.85; H, 4.57; N, 9.75; S, 11.15.

PATENT

WO03080605A1.

References

Lobeglitazone

Systematic (IUPAC) name
5-[(4-[2-([6-(4-Methoxyphenoxy)pyrimidin-4-yl]-methylamino)ethoxy]phenyl)methyl]-1,3-thiazolidine-2,4-dione
Clinical data
Trade names	Duvie
Routes of administration	Oral
Legal status
Legal status	Rx-only in South Korea
Pharmacokinetic data
Protein binding	>99%[1]
Metabolism	liver (CYP2C9, 2C19, and 1A2)[1]
Biological half-life	7.8–9.8 hours[2]
Identifiers
CAS Number	607723-33-1
PubChem	CID 9826451
DrugBank	DB09198
ChemSpider	8002194
Synonyms	CKD-501
Chemical data
Formula	C24H24N4O5S
Molar mass	480.53616 g/mol
SMILES CN(CCOC1=CC=C(C=C1)CC2C(=O)NC(=O)S2)C3=CC(=NC=N3)OC4=CC=C(C=C4)OC

///Lobeglitazone Sulfate, CKD-501, Duvie^®,  Approved KOREA, Chong Kun Dang, A dual PPARα and PPARγ agonist , type 2 diabetes.

CN(CCOC1=CC=C(C=C1)CC2C(=O)NC(=O)S2)C3=CC(=NC=N3)OC4=CC=C(C=C4)OC.OS(=O)(=O)O

Patent

WO 2010052013

http://www.google.co.in/patents/WO2010052013A1?cl=en

Examples:

1. CD19xCD3 bispecific single chain antibody

The generation, expression and cytotoxic activity of the CD19xCD3 bispecific single chain antibody has been described in WO 99/54440. The corresponding amino and nucleic acid sequences of the CD19xCD3 bispecific single chain antibody are shown in SEQ ID NOs. 1 and 2, respectively. The VH and VL regions of the CD3 binding domain of the CD19xCD3 bispecific single chain antibody are shown in SEQ ID NOs. 7 to 10, respectively, whereas the VH and VL regions of the CD19 binding domain of the CD19xCD3 bispecific single chain antibody are shown in SEQ ID NOs 3 to 6, respectively.

PATENT

http://www.google.com.ar/patents/WO2010052014A1?cl=en

PATENT

WO 2015006749

http://www.google.com/patents/WO2015006749A2?cl=un

PATENT

CN 104861067

http://www.google.com/patents/CN104861067A?cl=zh

References

Blinatumomab

Monoclonal antibody
Type	Bi-specific T-cell engager
Source	Mouse
Target	CD19, CD3
Clinical data
Trade names	Blincyto
Pregnancy category	US: C (Risk not ruled out)
Routes of administration	intravenous
Legal status
Legal status	US: ℞-only
Pharmacokinetic data
Bioavailability	100% (IV)
Metabolism	degradation into small peptides and amino acids
Biological half-life	2.11 hours
Excretion	urine (negligible)
Identifiers
CAS Number	853426-35-4
ATC code	L01XC19 (WHO)
ChemSpider	none
UNII	4FR53SIF3A
Chemical data
Formula	C2367H3577N649O772S19
Molar mass	54.1 kDa

///////

Istradefylline (KW-6002) is a selective antagonist at the A_2A receptor. It has been found to be useful in the treatment of Parkinson’s disease.^[1] Istradefylline reduces dyskinesia resulting from long-term treatment with classical antiparkinson drugs such as levodopa. Istradefylline is an analog of caffeine.

Kyowa Hakko Kirin is developing istradefylline, a selective adenosine A2A receptor antagonist, for the once-daily oral treatment of Parkinson’s disease (PD). Adenosine A2A receptors are considered to be present particularly in the basal ganglia of the brain; the degeneration or abnormality observed in PD is believed to occur in the basal ganglia, which is recognized to play a significant role in motor control.

Commercially available dopamine replacement therapies effectively treat the early motor symptoms of PD; however, these agents are associated with development of motor complications, limiting usefulness in late stages of the disease. Istradefylline is proposed to possess a clearly distinct action site from existing agents which act on dopamine metabolism or dopamine receptors. Kyowa Hakko Kirin has received approval for istradefylline in the adjunctive treatment of PD in Japan. A New Drug Application was filed in the USA, but the FDA issued a non-approvable letter in February 2008.

PATENT

US5484920A

http://www.google.co.in/patents/US5484920

PAPER

http://www.sciencedirect.com/science/article/pii/S0960894X13003983

PATENT

http://www.google.com/patents/CN103254194A?cl=en

Specific synthetic route is as follows:

the above reaction is a synthetic Parkinson’s disease clinical drug KW-6002 against a yield of 83%.

Example 26 (a new synthetic method for anti-Parkinson’s disease in clinical drug KW-6002):

In addition to use in place of 3,4-dimethoxy-styryl boronic acid (0.4mmol, i.e., in formula IV, R5 is 3,4_-dimethoxy-styryl) benzene boronic acid in Example 23 and 1,3 – two-ethyl-8-phenylthio-9-methyl-xanthine (0.4mmol, i.e., Formula I, R1 is methyl, R2 and R3 are ethyl, R4 is a phenyl group) in place of Example 23 in 1 , 3,9-trimethyl xanthine -8- phenylthio, the remaining steps in Example 23 to give a white solid, yield 83%, mp = 101~103 ° C I1H NMR (⑶CI3, 600MHz): δ 7.71 (d, J = 15.6Hz, 1H), 7.17 (dd, J = 8.2,1.9Hz, 1H), 7.07 (d, J = L 9Hz, 1H), 6

• 88 (d, J = 8.2Hz, 1H), 6.74 (d, J = 15.8Hz, 1H), 4.19 (q, J = 7Hz, 2H), 4.07 (q, J = 7Hz, 2H), 4.03 (s , 3H), 3.93 (s, 3H), 3.90 (s, 3H), 1.36 (t, J = 7Hz, 3H), 1.23 (t, J = 7Hz, 3H); 13C NMR (150MHz, CDCl3): 155.1, 150.8,150.4,150.2,149.2,148.2,138.2,128.6,121.2, 111.2,109.5,109.3,108.0,56.0,55.9,38.4,36.3,31.5,13.4,13.4; HRMS: calcd for C20H25N4O4 (M + H) +385.187

6, Found385.1879. It indicates that the white solid was 8- (3,4-dimethoxy-styryl) structural formula shown KW-6002 (E) -1,3_ diethyl-7-methylxanthine.

 In contrast, KW-6002 is a new drug to treat Parkinson’s disease developed by Kyowa Hakko in Japan, Japan and the United States is currently the second phase of clinical trials. Literature (. J.Hockemeyer, JCBurbiel andC.E.Muller, J.0rg.Chem, 2004,69,3308) through the following synthetic route:

The synthetic route requires five steps, with a total yield of 33%, and there is the use of environmentally unfriendly halogenated solvent methylene chloride, the reaction requires high pressure high temperature (170~180 ° C) and other shortcomings. By comparison, the present invention starting from 8- phenylthio xanthine coupling reaction catalyzed by palladium simple, a yield of 83% was synthesized KW6002, it is currently the most efficient synthesis route KW-6002’s. In particular, the multi-step synthesis route to avoid the complex operation of the reactor, but under relatively mild conditions (60 ° C) conduct, simple operation, suitable for scale synthesis.

PATENT

http://www.google.com/patents/CN104744464A?cl=en

itraconazole theophylline (Istradefylline, KW6002), the chemical name 8 – [(E) -2- (3, 4- dimethoxyphenyl) ethenyl] -1,3-diethyl -7 – methyl-purine-2,6-dione, CAS number: 155270-99-8, structural formula shown below.

 itraconazole Theophylline is a selective adenosine A2a receptor antagonist, by changing the activity of neurons in Parkinson’s disease patients to improve motor function, for the treatment of Parkinson’s disease and Parkinson’s disease improve early dyskinesia.

The invention and JPH0940652A European Patent 0,590,919 discloses a method for preparing itraconazole and theophylline. WO 2004/099207 published good solubility stability of a particle size of less than 50 micrometers 8 – [(E) -2- (3, 4- dimethoxyphenyl) ethenyl] -1,3- diethyl-7-methyl-purine-2,6-dione crystallites.

Example 1 Preparation of theophylline itraconazole  Example

ships equipped with a mechanical stirrer, a thermometer, a 2L 4-neck flask was added 30g8 – [(E) -2- (3, 4- dimethoxyphenyl) ethenyl] -1,3-diethyl- -7- hydrogen – purine-2,6-dione (Intermediate A), 400mL N, N- dimethylformamide and 15g of potassium carbonate, and 25g of methyl iodide and heated to 80 ° C after the reaction was stirred 8h, added 200mL water, cooled to room temperature, and stirring was continued crystallization 2h. The resulting suspension was suction filtered, washed with water after the cake was 800mL sash, 50 ° C under blast drying 24h, 32g give a pale yellow solid, for each polymorph of itraconazole theophylline preparation example the following examples.

References

//////Istradefylline, KW-6002, Nouriast^®, Approved, A selective adenosine A2A receptor antagonist, Parkinson’s disease,

O=C2N(c1nc(n(c1C(=O)N2CC)C)\C=C\c3ccc(OC)c(OC)c3)CC

Reslizumab was approved by the U.S. Food and Drug Administration (FDA) on March 23, 2016. It was developed and marketed as Cinqair^® by Teva.

Reslizumab is an interleukin-5 antagonist, which binds to human IL-5 and prevents it from binding to the IL-5 receptor, thereby reducing eosinophilic inflammation. It is indicated for the maintenance treatment of patients with severe asthma in patients aged 18 years and older.

Cinqair^® is available as injection for intravenous infusion, containing 100 mg of reslizumab in 10 mL solution in single-use vials. The recommended dose is 3 mg/kg once every four weeks.

• Originator Celltech R&D; Schering-Plough
• Developer Celltech R&D; Teva Pharmaceutical Industries
• Class Antiasthmatics; Monoclonal antibodies
• Mechanism of Action Interleukin 5 receptor antagonists

• Orphan Drug Status Yes – Oesophagitis

• 23 Mar 2016 Registered for Asthma in USA (IV) – First global approval
• 04 Mar 2016 Pooled efficacy data from two phase III trials in Asthma presented at the 2016 Annual Meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI-2016)
• 10 Dec 2015 Preregistration for Asthma in Canada (IV)

Reslizumab (trade name Cinqair) is a humanized monoclonal antibody intended for the treatment of eosinophil-meditated inflammations of the airways, skin and gastrointestinal tract.^[1] The FDA approved reslizumab for use with other asthma medicines for the maintenance treatment of severe asthma in patients aged 18 years and older on March 23, 2016. Cinqair is approved for patients who have a history of severe asthma attacks (exacerbations) despite receiving their current asthma medicines.^[2]

Teva Announces FDA Acceptance of the Biologics License Application for Reslizumab

The U.S. Food and Drug Administration today approved Cinqair (reslizumab) for use with other asthma medicines for the maintenance treatment of severe asthma in patients aged 18 years and older. Cinqair is approved for patients who have a history of severe asthma attacks (exacerbations) despite receiving their current asthma medicines.

Asthma is a chronic disease that causes inflammation in the airways of the lungs. During an asthma attack, airways become narrow making it hard to breathe. Severe asthma attacks can lead to asthma-related hospitalizations because these attacks can be serious and even life-threatening. According to the Centers for Disease Control and Prevention, as of 2013, more than 22 million people in the U.S. have asthma, and there are more than 400,000 asthma-related hospitalizations each year.

“Health care providers and their patients with severe asthma now have another treatment option to consider when the disease is not well controlled by their current asthma therapies,” said Badrul Chowdhury, M.D., Ph.D., director of the Division of Pulmonary, Allergy, and Rheumatology Products in the FDA’s Center for Drug Evaluation and Research.

Cinqair is administered once every four weeks via intravenous infusion by a health care professional in a clinical setting prepared to manage anaphylaxis. Cinqair is a humanized interleukin-5 antagonist monoclonal antibody produced by recombinant DNA technology in murine myeloma non-secreting 0 (NS0) cells. Cinqair reduces severe asthma attacks by reducing the levels of blood eosinophils, a type of white blood cell that contributes to the development of asthma.

The safety and efficacy of Cinqair were established in four double-blind, randomized, placebo‑controlled trials in patients with severe asthma on currently available therapies. Cinqair or a placebo was administered to patients every four weeks as an add-on asthma treatment. Compared with placebo, patients with severe asthma receiving Cinqair had fewer asthma attacks, and a longer time to the first attack. In addition, treatment with Cinqair resulted in a significant improvement in lung function, as measured by the volume of air exhaled by patients in one second.

Cinqair can cause serious side effects including allergic (hypersensitivity) reactions. These reactions can be life-threatening. The most common side effects in clinical trials for Cinqair included anaphylaxis, cancer, and muscle pain.

Cinqair is made by Teva Pharmaceuticals in Frazer, Pennsylvania.

References

• 1Walsh, GM (2009). “Reslizumab, a humanized anti-IL-5 mAb for the treatment of eosinophil-mediated inflammatory conditions”. Current opinion in molecular therapeutics 11 (3): 329–36. PMID 19479666.
• 2http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm491980.htm
• http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm491980.htm

/////////CDP-835,  CEP-38072,  CTx-55700,  SCH-5570,  SCH-55700,  TRFK-5, Reslizumab, Cinqair^®, teva, interleukin-5 (IL-5) antagonist, severe asthma, FDA 2016, Orphan Drug StatuS

Daratumumab (Darzalex) is an anti-cancer drug. It binds to CD38.^[1] Daratumumab was originally developed by Genmab, but it is now being jointly developed by Genmab along with the Johnson & Johnson subsidiary Janssen Biotech, which acquired worldwide commercialization rights to the drug from Genmab.^[2]

Clinical trials

Encouraging preliminary results were reported in June 2012 from a Phase 1/2 clinical trial in relapsed multiple myeloma patients.^[3]Updated trial results presented in December 2012 indicate daratumumab is continuing to show promising single-agent anti-myeloma activity.^[4] A 2015 study compared monotherapy 8 and 16mg/kg at monthly to weekly intervals.^[5]

In November 2015, the U.S. Food and Drug Administration approved daratumumab for treatement of multiple myeloma.^[6]

Interference with blood compatibility testing

Daratumumab can also bind to CD38 present on red blood cells and interfere with antibody testing. Patients will show a panreactive antibody panel, including a positive auto-control. Treatment of the antibody panel cells with dithiothreitol (DTT) and repeating testing will effectively negate the binding of daratumumab to CD38 on the RBC surface; however, DTT also inactivates/destroys many antigens on the RBC surface by disrupting disulfide bonds. Fortunately, the only antigen system affected that is associated with common, clinically significant antibodies is Kell, making K-negative RBCs a reasonable alternative when urgent transfusion is indicated.^[7]

Daratumumab is a human IgG1k monoclonal antibody (mAb) that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. It is believed to induce rapid tumor cell death through programmed cell death, or apoptosis, and multiple immune-mediated mechanisms, including complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity.

Daratumumab is approved in the United States for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.

In May 2013, daratumumab received Fast Track Designation and Breakthrough Therapy Designation from the US FDA for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy including a PI and an immunomodulatory agent or who are double refractory to a PI and an immunomodulatory agent.  Breakthrough Therapy Designation is a program intended to expedite the development and review of drugs to treat serious or life-threatening diseases in cases where preliminary clinical evidence shows that the drug may provide substantial improvements over available therapy. Daratumumab has also received Orphan Drug Designation from the US FDA and the EMA for the treatment of multiple myeloma.

Five Phase III clinical studies with daratumumab in relapsed and frontline settings are currently ongoing. Additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant diseases on which CD38 is expressed, such as smoldering myeloma and non-Hodgkin’s lymphoma.

Genmab announced a global license and development agreement for daratumumab with Janssen Biotech, Inc. in August 2012.  The agreement became effective in September 2012.

References

1.  World Health Organization (2009). “International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 101” (PDF). WHO Drug Information 23 (2).
2.  “‘Janssen Biotech Announces Global License and Development Agreement for Investigational Anti-Cancer Agent Daratumumab'”. Janssen Biotech. Retrieved 2013-01-31.
3.  “ASCO: Drug Shows Promise in Myeloma”. MedPage Today.
4.  “‘Daratumumab Continues To Show Promise For Relapsed/Refractory Myeloma Patients (ASH 2012)'”. The Myeloma Beacon. Retrieved 2013-01-31.
5.  Lokhorst, Henk M.; Plesner, Torben; Laubach, Jacob P.; Nahi, Hareth; Gimsing, Peter; Hansson, Markus; Minnema, Monique C.; Lassen, Ulrik; Krejcik, Jakub (2015-09-24). “Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma”. The New England Journal of Medicine 373 (13): 1207–1219. doi:10.1056/NEJMoa1506348. ISSN 1533-4406. PMID 26308596.
6.  http://www.medscape.com/viewarticle/854548?nlid=91686_3663&src=wnl_edit_newsal&uac=78316PX&impID=890536&faf=1
7.  Chapuy, CI; Nicholson, RT; Aguad, MD; Chapuy, B; Laubach, JP; Richardson, PG; Doshi, P; Kaufman, RM (June 2015). “Resolving the daratumumab interference with blood compatibility testing.”. Transfusion 55 (6 Pt 2): 1545–54. PMID 25764134.

Daratumumab

Monoclonal antibody
Type	Whole antibody
Source	Human
Target	CD38
Legal status
Legal status	US: ℞-only
Identifiers
CAS Number	945721-28-8
ATC code	none
ChemSpider	none
UNII	4Z63YK6E0E
Chemical data
Formula	C6466H9996N1724O2010S42
Molar mass	145,391.67 g·mol−1

////Daratumumab

Idarucizumab

(Praxbind^®) Approved

An antidote for rapid reversal of dabigatran-induced anticoagulation indicated for emergency surgery (urgent procedures) and life-threatening or uncontrolled bleeding in patients treated with dabigatran.

BI-655075

CAS No.1362509-93-0

1- 225-Immunoglobulin G1, anti-(dabigatran) (human-Mus musculus γ1-chain) (225→219′)-disulfide with immunoglobulin G1, anti-(dabigatran) (human-Mus musculus κ-chain)

Other Names

• BI 655075
• Idarucizumab
• Praxbind

Protein Sequence

Sequence Length: 444, 225, 219multichain; modified (modifications unspecified)

Idarucizumab, sold under the brand name Praxbind, is a monoclonal antibody designed for the reversal of anticoagulant effects ofdabigatran.^[1][2]

This drug was developed by Boehringer Ingelheim Pharmaceuticals. A large study sponsored by the manufacturer found that idarucizumab effectively reversed anticoagulation by dabigatran within minutes.^[3] It was FDA approved in October 2015.^[4] In the United States the wholesale cost is $3500 US.^[5]

On October 16, 2015, the U. S. Food and Drug Administration granted accelerated approval to idarucizumab (Praxbind  Injection, Boehringer Ingelheim Pharmaceuticals, Inc.) for the treatment of patients treated with dabigatran (Pradaxa) when reversal of the anticoagulant effects of dabigatran is needed for emergency surgery/urgent procedures, or in life-threatening or uncontrolled bleeding.

The approval was based on three randomized, placebo-controlled trials enrolling a total of 283 healthy volunteers who received either dabigatran and idarucizumab or dabigatran and placebo.  The primary endpoint in healthy volunteer trials was the reduction of unbound dabigatran to undetectable levels after the administration of 5 g idarucizumab.  This reduction of dabigatran plasma concentration was observed over the entire 24 hour observation period.

These trials are supported by an ongoing open-label trial in which data from 123 patients receiving dabigatran who had life-threatening or uncontrolled bleeding, or who required emergency surgery/urgent procedures was available for evaluation.  This open-label trial continues to enroll and follow patients. The primary endpoint is the reversal of dabigatran’s anticoagulant effect (measured by ecarin clotting time or dilute thrombin time) in the first four hours after administration of 5 g idarucizumab. In these 123 patients, the anticoagulant effect of dabigatran was completely reversed in more than 89% of patients within four hours of receiving idarucizumab.  Between 12 and 24 hours after idarucizumab administration, elevated coagulation parameters have been observed in a limited number of patients.

Safety data were evaluated in 224 healthy volunteers who received at least one dose of idarucizumab and 123 patients who received idarucizumab. Headache was the most common adverse event reported in more than 5% of healthy volunteers.  Among the 123 patients treated with idarucizumab in the ongoing open-label trial, adverse events reported in more than 5% of patients were hypokalemia, delirium, constipation, pyrexia and pneumonia.

Praxbind is the first approved reversal agent. It is specific for dabigatran.

Continued approval for this indication may be contingent upon the results of completion of the ongoing open-label trial.

The recommended dose for idarucizumab is 5 g (2.5g per vial) administered intravenously as two consecutive 2.5 g infusions or bolus injection by injecting both vials consecutively one after another via syringe.

References

1.  Statement On A Nonproprietary Name Adopted By The USAN Council – Idarucizumab, American Medical Association.
2.  World Health Organization (2013). “International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 109” (PDF). WHO Drug Information 27 (2).
3.  Pollack, Charles V.; Reilly, Paul A.; Eikelboom, John; Glund, Stephan; Verhamme, Peter; Bernstein, Richard A.; Dubiel, Robert; Huisman, Menno V.; Hylek, Elaine M. (2015-08-06).“Idarucizumab for Dabigatran Reversal”. The New England Journal of Medicine 373 (6): 511–520. doi:10.1056/NEJMoa1502000. ISSN 1533-4406. PMID 26095746.
4.  “Press Announcements – FDA approves Praxbind, the first reversal agent for the anticoagulant Pradaxa”. http://www.fda.gov. Retrieved 2015-10-17.
5.  Elia, Joe. “Dabigatran-Reversal Agent Price Set”. Retrieved 20 October 2015.

Idarucizumab

Monoclonal antibody
Type	Fab fragment
Source	Humanized (from mouse)
Target	Dabigatran
Clinical data
Trade names	Praxbind
Identifiers
CAS Number	1362509-93-0
ATC code	V03AB37 (WHO)
IUPHAR/BPS	8298
ChemSpider	none
Chemical data
Formula	C2131H3299N555O671S11
Molar mass	47.8 kg/mol

/////Idarucizumab

> Asfotase Alfa Sequence
LVPEKEKDPKYWRDQAQETLKYALELQKLNTNVAKNVIMFLGDGMGVSTVTAARILKGQL
HHNPGEETRLEMDKFPFVALSKTYNTNAQVPDSAGTATAYLCGVKANEGTVGVSAATERS
RCNTTQGNEVTSILRWAKDAGKSVGIVTTTRVNHATPSAAYAHSADRDWYSDNEMPPEAL
SQGCKDIAYQLMHNIRDIDVIMGGGRKYMYPKNKTDVEYESDEKARGTRLDGLDLVDTWK
SFKPRYKHSHFIWNRTELLTLDPHNVDYLLGLFEPGDMQYELNRNNVTDPSLSEMVVVAI
QILRKNPKGFFLLVEGGRIDHGHHEGKAKQALHEAVEMDRAIGQAGSLTSSEDTLTVVTA
DHSHVFTFGGYTPRGNSIFGLAPMLSDTDKKPFTAILYGNGPGYKVVGGERENVSMVDYA
HNNYQAQSAVPLRHETHGGEDVAVFSKGPMAHLLHGVHEQNYVPHVMAYAACIGANLGHC
APASSLKDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV
KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE
KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKDIDDDD
DDDDDD

STRENSIQ is a formulation of asfotase alfa, which is a soluble glycoproteincomposed of two identical polypeptide chains. Each chain contains 726amino acids with a theoretical mass of 161 kDa. Each chain consists of the catalytic domain of human tissue non-specific alkaline phosphatase (TNSALP), the human immunoglobulin G1 Fc domain and a deca-aspartatepeptide used as a bone targeting domain. The two polypeptide chains are covalently linked by two disulfide bonds.

STRENSIQ is a tissue nonspecific alkaline phosphatase produced byrecombinant DNA technology in a Chinese hamster ovary cell line. TNSALP is a metallo-enzyme that catalyzes the hydrolysis of phosphomonoesters with release of inorganic phosphate and alcohol. Asfotase alfa has a specific activity of 620 to 1250 units/mg. One activity unit is defined as the amount of asfotase alfa required to form 1 μmol of p-nitrophenol from pNPP per minute at 37°C.

STRENSIQ (asfotase alfa) is a sterile, preservative-free, nonpyrogenic, clear, slightly opalescent or opalescent, colorless to slightly yellow, with few small translucent or white particles, aqueous solution for subcutaneous administration. STRENSIQ is supplied in glass single-use vials containing asfotase alfa; dibasic sodium phosphate, heptahydrate; monobasic sodium phosphate, monohydrate; and sodium chloride at a pH between 7.2 and 7.6. Table 5 describes the content of STRENSIQ vial presentations.

Table 5: Content of STRENSIQ Vial Presentations

REFERNCES

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003794/WC500194340.pdf

1. Whyte MP: Hypophosphatasia – aetiology, nosology, pathogenesis, diagnosis and treatment. Nat Rev Endocrinol. 2016 Apr;12(4):233-46. doi: 10.1038/nrendo.2016.14. Epub 2016 Feb 19. [PubMed:26893260 ]
2. Whyte MP, Rockman-Greenberg C, Ozono K, Riese R, Moseley S, Melian A, Thompson DD, Bishop N, Hofmann C: Asfotase Alfa Treatment Improves Survival for Perinatal and Infantile Hypophosphatasia. J Clin Endocrinol Metab. 2016 Jan;101(1):334-42. doi: 10.1210/jc.2015-3462. Epub 2015 Nov 3. [PubMed:26529632 ]
3. Whyte MP, Greenberg CR, Salman NJ, Bober MB, McAlister WH, Wenkert D, Van Sickle BJ, Simmons JH, Edgar TS, Bauer ML, Hamdan MA, Bishop N, Lutz RE, McGinn M, Craig S, Moore JN, Taylor JW, Cleveland RH, Cranley WR, Lim R, Thacher TD, Mayhew JE, Downs M, Millan JL, Skrinar AM, Crine P, Landy H: Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl J Med. 2012 Mar 8;366(10):904-13. doi: 10.1056/NEJMoa1106173. [PubMed:22397652 ]

//////Asfotase alfa, Strensiq, treat hypophosphatasia, ALXN-1215,  ENB-0040,  sALP-FcD-10, FDA 2015

Albutrepenonacog alfa

recombinant factor IX

(Idelvion^®)Approved, 2016-03-04 USFDA

A recombinant albumin-human coagulation factor IX (FIX) fusion protein indicated for the treatment and prevention of bleeding in patients with hemophilia B.

Research Code CSL-654

CAS 1357448-54-4

Blood- coagulation factor IX (synthetic human) fusion protein with peptide (synthetic linker) fusion protein with serum albumin (synthetic human)

Type	Recombinant coagulation factor
Source	Human
Molecular Formula	C5077H7846N1367O1588S67
Molecular Weight	~125000

Other Names

• Albutrepenonacog alfa

Protein Sequence

Sequence Length: 1018modified (modifications unspecified)

• Originator CSL Behring
• Class Albumins; Antihaemorrhagics; Blood coagulation factors; Recombinant fusion proteins
• Mechanism of Action Blood coagulation factor replacements; Factor X stimulants

• Orphan Drug Status Yes – Haemophilia B

//////Albutrepenonacog alfa, CSL-654,  Idelvion; Recombinant factor IX – CSL Behring,  Recombinant factor IX fusion protein linked with human albumin,  rFIX-FP – CSL Behring; rIX-FP, Orphan Drug Status,  Haemophilia B, recombinant factor IX , FDA 2016

Lurasidone

Lurasidone hydrochloride, Jubilant Life Sciences Ltd, WO 2016059649, New patent

An improved process for the preparation of lurasidone hydrochloride

Jubilant Life Sciences Ltd

WO 2016059649

JUBILANT GENERICS LIMITED (FORMERLY JUBILANT LIFE SCIENCES DIVISION) [IN/IN]; Plot 1A, Sector 16 A, NOIDA Uttar Pradesh 201301 (IN)

MISHRA, Vaibhav; (IN).
DUBEY, Shailendr; (IN).
SINGH, Kumber; (IN).
CHOUDHARY, Alka Srivastava; (IN).
VIR, Dharam; (IN)

Disclosed herein is an improved process for the preparation of Lurasidone and its pharmaceutically acceptable salts via novel intermediate and use thereof for the preparation of an antipsychotic agent useful for the treatment of schizophrenia and bipolar disorder. Further, present invention provides a cost effective and eco-friendly process for producing Lurasidone hydrochloride of formula (I) substantially free of residual solvent(s) at industrial scale.

Improved process for preparing lurasidone or its hydrochloride, substantially free of residual solvent, useful for treating schizopherenia and bipolar disorder. Also claims novel intermediate of lurasidone eg ((R,R)-cyclohexane-1,2-diyl)bis((1H-imidazol-1-yl)methanone) and its preparation method.

In April 2016, Newport Premium™ reported that Jubilant Life Sciences was capable of producing commercial quantities of lurasidone and lists the drug as a molecule available under research and development on the company’s website.

This is  the first patenting to be seen from Jubilant Life Sciences that focuses on lurasidone – it having been developed and launched by Sumitomo Dainippon Pharma and EU licensee Takeda, for treating schizophrenia.

May 2, 2014

Neeraj Agrawal: Took charge of API business for Jubilant Life Sciences at the age of 31

Position: CEO Generics, Jubilant Life Sciences

Education: IIIM-C, MBA, 1998; IIT, Bombay, Electrical Engg., 1995.

Previous Jobs: Associate-Business Strategy, Operations Improvement, McKinsey & Co.

Claim to Fame: Took charge of the API business for Jubilant when he was just 31-years-old

Management mantra: It revolves around trust, freedom and teams. I like my team to think and act like an entrepreneur – assess business risks and rewards suitably and then take decisions.

Lurasidone and its pharmaceutically acceptable salts like lurasidone hydrochloride is chemically, (3a ?,45,7 ?,7a5)-2-{ (1 ?,2 ?)-2-[4-(l,2-benzisothiazol-3-yl)piperazin-lyl-methyl] cyclohexylmethyl }hexahydro-4,7-methano-2H-isoindole- 1 ,3 -dione hydrochloride and has the structure represented by the Formula (I):

Formula-I

Lurasidone hydrochloride is marketed in the United States under the trade name Latuda®. Lurasidone and its pharmaceutically acceptable salts as well as process for their preparation was first disclosed in US patent no. 5,532,372. The patent discloses the preparation of lurasidone hydrochloride using racemic trans 1,2-cyclohexane dicarboxylic acid. Racemic trans 1,2-cyclohexane dicarboxylic acid on reduction with lithium aluminium hydride in THF at reflux temperature forms l,2-bis(hydroxymethyl)cyclohexane which is converted into racemic iran5-l,2-bis(methanesulfonyloxymethyl)cyclohexane by reaction with methane sulfonyl halide. l-(l,2-benzisothiazol-3-yl)piperazine on reaction with trans-l, 2-b (methanesulfonyloxymethyl)cyclohexane in the presence of sodium carbonate and acetonitrile forms iran5-3a,7a-octahydroisoindolium-2-spiro- -[4′-(l,2-benzisothiazol-3-yl)]piperazine methanesulfonate which on reaction with bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide in the presence of potassium carbonate, dibenzo-18-crown-6-ether and xylene on refluxing forms racemic lurasidone free base. The compound is obtained by column chromatography and then treated the resulting lurasidone free base with IPA.HCl in acetone to obtain racemic lurasidone hydrochloride. Resolution of racemic lurasidone hydrochloride is carried out using tartaric acid as resolving agent. The process involves use of lithium aluminium hydride which is highly pyrophoric reagent and is not to utilize the same on commercial scale due to its handling problems associated with its reactivity. Also, the use of the column chromatography for purification is not viable on commercial scale. Further the process involves the usage of dibenzo-18-crown-6-ether as a phase transfer catalyst which is costly material and in turn increases the cost of production. Carrying out the resolution in the last stages is difficult due to the presence of six chiral centres in lurasidone and is also not suitable for an industrial scale preparation as it affects the overall yield and cost of the manufacturing process.

Chinese patent application no. CN102731512 discloses a process for preparation of lurasidone which comprises reaction of racemic irans-l,2-bis(methanesulfonyloxymethyl) cyclohexane and l-(l,2-benzisothiazol-3-yl)piperazine in toluene in the presence of sodium carbonate or potassium carbonate having particle size less than 200 micron and tetrabutyl ammonium bromide to give the intermediate /rans-3a,7a-octahydroisoindolium-2-spiro- -[4′-(l,2-benzisothiazol-3-yl)]piperazinemethanesulfonate which on reaction with bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide in toluene using potassium carbonate having particle size less than 200 micron forms racemic lurasidone free base. The racemic free base is converted into racemic hydrochloride salt using acetone and cone, hydrochloric acid. Racemic lurasidone hydrochloride is resolved by following the method disclosed in US patent no. 5,532,372. The process involves resolution of product in the last stage which is not commercially viable as it affects the overall yield and cost of the manufacturing process.

Japanese patent no. JP4219696 discloses the resolution of trans 1,2-cycloheaxne dicarboxylic acid using (lS,2R)-(+)-norephedrine or (lR,2S)-(-)norephedrine to provide (R,R)-trans 1 ,2-cyclohexanedicarboxylic acid. The (R,R)-iran,sl,2-cyclohexane dicarboxylic acid obtained was esterified with ethanol and the obtained ester compound was reduced with vitride to provide (R,R)-l,2-bis(hydroxymethyl)cyclohexane followed by treatment with methane sulfonyl chloride to form (R,R)-1,2-bis(methanesulfonyloxymethyl)cyclohexane. The process requires large quantity of reducing agent viz., for reducing one lg of compound about 5g of reducing agent is required which is not conducive for industrial production.

Chinese patent application no. CN 102952001 discloses a process for the preparation of (lR,2R)cyclohexane-l,2-dimethanol by the reduction of (lR,2R)cyclohexane-l,2-

dicarboxylic acid using sodium borohydride or potassium borohydride and boron triflouoride diethyl ether in THF or diethyl ether as solvent. Boron triflouoride diethyl ether is used in large quantity and quite expensive which makes the process commercially unviable.

International publications no. WO 2012/131606 and WO 2014/037886 disclose a process for preparation of lurasidone which involves separating the racemic transl,2-cyclohexane dicarboxylic acid into its (R,R) trans and (S,S) trans isomers and then using the desired trans (R,R) isomer for the preparation of lurasidone hydrochloride using the chemistry disclosed in US patent no. 5,532,372 for preparation of racemic lurasidone hydrochloride. In these publications diisobutyl aluminium hydride (DIBAL) is used as the reducing agent for the preparation of (1R,2R) cyclohexane 1,2-dimethanol from (1R,2R) cyclohexane 1,2-dicarboxylic acid which is quite expensive. Further the process involves the usage of dibenzo-18-crown-6-ether as a phase transfer catalyst which is costly material and in turn increases the cost of production.

Some of the prior art processes disclose the process for the preparation of lurasidone hydrochloride from l,2-(lR,2R)-bis-(methanesulfonyloxymethyl)cyclohexane using different solvents and bases.

US patent no. 8,853,395 discloses a process for the preparation of lurasidone in which condensation of iran5-l,2-bis(methanesulfonyloxymethyl)cyclohexane with 1-(1,2-benz isothiazol-3-yl)piperazine and condensation of /rans-3a,7a-octahydroisoindolium-2-spiro- -[4′-(l,2-benzisothiazol-3-yl)]piperazine methanesulfonate with bicyclo[2.2.1] heptane-2-exo-3-exo-dicarboximide is carried out using organic bases with a ρ¾ higher than 10 such as l,4-diazabicycloundec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diaza bicyclo[2.2.2] -octane (DABCO). These organic bases are comparatively expensive.

Indian patent application no. IN 2306/MUM/2014 and Chinese patent applications no. CN 102863437 and CN 103864774 disclose the use of dimethyl formamide (DMF), dimethyl sulphoxide (DMSO), dimethyl acetamide (DMA) and N-methyl pyrrolidine (NMP) for the condensation of iran5-3a,7a-octahydroisoindolium-2-spiro- -[4′-(l,2-benzisothiazol-3-yl)] piperazine methanesulfonate with bicyclo[2.2.1] heptane-2-exo-3-exo-dicarboximide to form lurasidone. These solvents have high boiling point so not preferred at commercial scale.

Some of the prior art processes are related to reduction of impurities or quality improvement of lurasidone hydrochloride.

International publication no. WO2011/136383 discloses a process for the preparation of lurasidone hydrochloride in which amount of by products are reduced by increasing the quantity of l-(l,2-benzisothiazol-3-yl)piperazine instead of sodium carbonate or potassium carbonate as base in the reaction mixture. Increasing the amount of l-(l,2-benzisothiazol-3-yl)piperazine causes an increase in cost of production and removal of excess compound makes the process less commercially viable.

International publication no. WO2011/136384 discloses a process for the preparation of lurasidone hydrochloride in which amount of by products are reduced by using dibasic potassium phosphate with a small amount of water as a base instead of sodium carbonate. Use of dibasic potassium phosphate as a base causes an increase in cost of production as dibasic potassium phosphate is expensive.

International publication no. WO2013/014665 discloses various processes for the preparation of lurasidone hydrochloride. In general the process is shown below:

Formula-(I)

In this process iran5-(lR,2R)-2-(aminomethyl)cyclohexyl)methanol of Formula (B) is first reacted with bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide of Formula (A) to form (3aR,4S,7R,7aS)-2-(((lR,2R)-2-(hydroxymethyl)cyclohexyl)methyl)hexahydro-lH-4,7-methanoisoindole-l,3(2H)-dione of Formula (C) which on reaction with methane sulphonyl chloride followed by reaction with l-(l,2-benzisothiazol-3-yl)piperazine of Formula (D) forms lurasidone free base which was converted into lurasidone hydrochloride using acetone and cone, hydrochloric acid.

Some of the prior art processes disclose various combinations of hydrogen chloride and solvent for the preparation of lurasidone hydrochloride from lurasidone free base.

US 7,605,260 discloses use of acetone and aqueous HC1 having strength 1.8-14.4 % for preparing lurasidone hydrochloride. The yield of lurasidone hydrochloride is relatively low (85%) by this method. If the acid concentration during the salt formation is more than 5.0% then acetone quantity as the residual solvent in the reaction product is found to be greater than 0.5% in our hands which is above the ICH limits. If acid concentration during the salt formation is less than 1.8%, then yield is reduced drastically to 65%. Therefore, this method has limitations on the large-scale industrial production.

Chinese patent application no. CN102746289A discloses the process for the preparation of lurasidone hydrochloride by adding a mixture of acetone and aqueous HC1 to a solution of lurasidone free base in acetone. On reproducing this process in laboratory, it was observed that the XRPD of the product obtained does not match with XRPD of lurasidone hydrochloride.

Indian patent application IN 777/MUM/2013 discloses use of IPA, water and 35% Aqueous HC1 for the preparation of lurasidone hydrochloride. The IPA content in the product was found to be more than 5000ppm.

The methods described in the prior art are not suitable for large scale commercial production as the residual solvent is out of the ICH limits and thus the product obtained can’t be used as a drug. In order to keep the residual solvent(s) within ICH limits, repeated crystallization/purification are required which results in reduced yield and make the process quite expensive.

The prior art discloses various processes for the preparation of lurasidone hydrochloride and its intermediates. However, there still remains a need for alternative process for the preparation of lurasidone and its pharmaceutically acceptable salts substantially free of residual solvent(s) which can be used as a drug.

According to another embodiment of the present invention, novel process for the preparation of the compound of Formula (III), their isomers and pharmaceutically acceptable salts thereof, comprises condensing 1,2-cyclohexane dicarboxylic acid of Formula (II), their isomers with carbonyl diimidazole, optionally in a solvent.

(IV)

Formula (III)

NaBH₄ RT /H₂0

Formula (VII)

Scheme-1:

Example-1

Synthesis of trans(R,R)-l,2-cyclo exane dicarboxylic acid

A round bottom flask was charged with methanol (500 mL), IPA (500 mL) and trans (racemic)-l,2-cyclohexane dicarboxylic acid (100 g). In this reaction mass (R)-l-phenylethyl amine (74 mL) was added over a period of 30 minutes and stirred for 2-3 hrs at 30-40 °C. The solid obtained was filtered, washed with methanol and IPA solution (50+50 mL) and dried under reduced pressure to obtain crude salt of iran5(R,R)-l,2-cyclohexane dicarboxylic acid. The obtained salt was stirred in a solution of methanol (500 mL) and IPA (500 mL) at 65-70 °C for 2-3 hours, cooled to room temperature and filtered. The solid was washed with methanol and IPA solution (50+50 mL) and dried under reduced pressure. The solid thus obtained was dissolved in about 2N hydrochloric acid and extracted two times with ethyl acetate (1000 mL+200 mL). Organic layers were combined and washed with brine solution (100 mL). Ethyl acetate was distilled off under vacuum at 50-55 °C and cyclohexane was added to the residue. The solid separated out was filtered and washed with cyclohexane and dried under vacuum at 45-50 °C for 8-10 hours. Yield = 29.4 g

Example-2

Synthesis of ((R,R)-cyclohexane-L2-diyl)bis((lH-imidazol-l-yl)methanone)

To a solution of iran5(R,R)-l,2-cyclohexane dicarboxylic acid (25.0 g) in THF (250 mL), carbonyl diimidazole (60 g) is added and stirred for one hour at 25-30 °C . To the said solution of (R,R)2-(((lH-imidazole-lcarbonyl)oxy)carbonyl)cyclohexanecarboxylic acetic anhydride lH-imidazole (25.0 g) in THF (250 mL) is stirred for one hour at 45-50 °C. The compound obtained is isolated and is characterized by mass and NMR.

[m z = 272.75; 1H-NMR: 8.24 (s, 2H), 7.72 (d, 2H); 7.50 (d, 2H), 3.5 (m, 2H), 2.26-1.50 (m, 8H)]

Example-3

Synthesis of tra»,s(R,R)-l,2- bis(hydroxymethyl)cyclohexane

To a solution of ((R,R)-cyclohexane-l,2-diyl)bis((lH-imidazol-l-yl)methanone) (25 g) in THF (250 mL), sodium borohydride (22.0 g) followed by water (44.0 mL) are added and stirred for one hour. To this reaction mass, 10% solution of acetic acid (500 mL) and dichloromethane (500 mL) are added, stirred and layers separated. The organic layer is washed with 10% sodium bicarbonate solution followed by water. The dichloromethane is distilled off from organic layer under vacuum to give an oily mass. To the oily mass

dichloromethane (100 mL), water (100 mL) and 12.5mL cone, hydrochloric acid (35%) are added, stirred and layers obtained are separated. The dichloromethane is distilled off completely from organic layer at 40 °C to obtain oily mass (15.5 g).

Example-4

One pot process for synthesis of trans(R,R)-l,2- bis(hydroxymethyl)cyclohexane from trans(R,R)-l,2-cyclo exane dicarboxylic acid

To a solution of iran5(R,R)-l,2-cyclohexane dicarboxylic acid (25.0 g) in THF (250 mL), carbonyl diimidazole (60 g) was added and stirred for one hour at 25-30 °C. To the intermediate obtained sodium borohydride (22.0 g) and water (44.0 mL) were added and stirred for one hour. To this reaction mass, 10% solution of acetic acid (500 mL) and dichloromethane (500 mL) were added, stirred and layers separated. The aqueous layer was washed with dichloromethane (250 mL). The organic layer was washed with 10% sodium bicarbonate solution followed by water. The dichloromethane is distilled off from organic layer under vacuum to give an oily mass. To the oily mass dichloromethane (100 mL), water (100 mL) and 12.5mL cone, hydrochloric acid (35%) were added, stirred and layers obtained were separated. The dichloromethane was distilled off completely at 40 °C to obtain oily mass (15.5 g).

Example-5

Synthesis of m¾ns(R,R)- 2-bis(methanesulfonylmethyl) cyclohexane

To a suspension of irafts(R,R)-l,2-bis(hydroxymethyl)cyclohexane (15.0g) in dichloro methane (300 mL), triethyl amine (43.7 mL) followed by methane sulphonyl chloride (17.8 mL) were added over a period of 30-45 minutes. Reaction mass was stirred for 2-3 hrs. Reaction was monitored by HPLC (RI detector). After the completion of reaction, water was added, stirred and layers separated. The organic layer was washed with 10% sodium bicarbonate solution (150 mL) followed by water (150 mL). The dichloromethane was distilled off from organic layer under vacuum at 40-55 °C to give an oily mass. Methanol (30 mL) was added to the oily mass and strip off under vacuum at 40°C, added methanol (150 mL) and stirred for 1 h at 10-15°C and the solid obtained was filtered, washed with methanol (15 mL) and dried under vacuum to get the product (15.8g).

Example-6

Synthesis of ?ran (R,R)-3aJ(¾-octahvdroisoindolium-2-spiro- -r4-(L2-benzoisothiazole-3-yl)l piperazine methanesulfonate:

To a suspension of iran5(R,R)-l,2-bis(methanesulfonylmethyl)cyclohexane (15 g) in acetonitrile (150 mL) l-(l,2-benzisothiazol-3-yl)piperazine (10.95g) and sodium carbonate (7.8 g) were added, heated and stirred for 20 hrs at reflux temperature. Reaction was monitored by HPLC. After the completion of reaction, mass was cooled to 40-45 °C, filtered and washed with acetonitrile (20 mL). The acetonitrile was distilled off under vacuum at 45-50 °C. To the residue acetone (100 mL) was added, stirred for 1 hour, filtered, washed with acetone (10 mL), dried at 50-55°C for 6-8 hours to get the product (12.5 g).

Example-7

Synthesis of Lurasidone

To a suspension of iran5(R,R)-3<3,7(3-octahydroisoindolium-2-spiro- -[4-(l,2-benzo isothiazole-3-yl)]piperazinemethanesulfonate (10 g) in toluene (150 mL), bicycle[2.2.1] heptane-2-exo-3-exo-dicarboximide (5.9 g) and potassium carbonate (4.8 g) were added, heated to 110° C and stirred for 8-10 hours. Reaction was monitored by HPLC. After the completion of reaction, reaction mass was cooled to 20-30 °C, filtered and washed with toluene (10 mL). The toluene was distilled off at 55-60°C. To the residue IPA (100 mL) was added and stirred for 1-2 hours at room temperature. Lurasidone free base obtained was filtered and washed with IPA (10 mL). The solid was suck dried for 30 minutes to obtain lurasidone.

Example-8

Synthesis of Lurasidone hydrochloride

To lurasidone base (5g), acetone (75mL) and water (10 mL) were added. The mixture was heated to 55-60°C followed by the addition of IPA.HCl (10%) (lOmL) and stirred for 1-2 hours, reflux temperature. The clear solution obtained was stirred for 30 min and then 5ml IPA.HCl (10%) was added. The reaction mixture was stirred at reflux temperature for 30 min, cooled and stirred for 60 min. The solid obtained was filtered and washed with acetone (5ml) and dried under vacuum at 60°C for 8 hours.

Acetone: 542 ppm; IPA= 38ppm; Yield=93%

Example-9

Synthesis of Lurasidone hydrochloride

To lurasidone base (5g), acetone (75mL) and water (5 mL) were added. The mixture was heated to 55-60°C followed by the addition of IPA.HCl (10%) (5mL) and stirred for about 1-2 hours. The reaction mixture was stirred for 30 min. at 55-60°C, cooled and stirred for 60 min. The solid obtained was filtered and washed with acetone (5ml) and dried under vacuum at 70-80°C for 8 hours.

Jubilant Generics Limited  

Pharmaceutical Company

Chairman & Managing Director
Jubilant Bhartia Group  Shyam, together with his brother Hari, is founder of Jubilant Bhartia Group (www.jubilantbhartia.com) headquartered in New Delhi, India. The Jubilant Bhartia Group, with 30,000 employees, has a strong presence in diverse sectors like Pharmaceuticals and Life Sciences, Oil and Gas (exploration and production), Agri products, Performance Polymers, Retail, Food and Consulting in Aerospace and Oilfield Services. Jubilant Bhartia Group has four flagships Companies- Jubilant Life Sciences Limited, Jubilant FoodWorks Limited and Jubilant Industries Limited, listed on Indian Stock Exchange and Jubilant Energy NV, listed at AIM market of London Exchange.Shyam, holds a bachelors’ degree in commerce from St. Xavier’s College, Calcutta University, and is a qualified cost and works accountant & a fellow member of the Institute of Cost and Works Accountants of India (ICWAI).Shyam has been associated with various institutions and has served as Member of Board of Governors, Indian Institute of Technology (IIT), Mumbai, and Indian Institute of Management (IIM), Ahmedabad. Shyam has also served as a Member of the Executive Committee of Federation of Indian Chamber of Commerce & Industry (FICCI) & Confederation of Indian Industry (CII) and was also a member of Task Force on Chemicals appointed by the Government of IndiaShyam’s immense contributions have been recognized by various awards. CHEMEXCIL has conferred Lifetime Achievement Award 2010-11 to him. He, along with his brother, was felicitated with the Entrepreneur of the Year Award at the prestigious AIMA Managing India Awards 2013, presented by the President of India. In 2010, the duo also shared the much-covetedErnst & Young Entrepreneur of the Year Award for Life Sciences & Consumer Products category.Shyam serves on the Board of several Public and Private and Foreign companies likes of Chambal Fertilizers and Chemicals Ltd, Putney Inc., CFCL Technologies Limited (Cayman Islands), Tower Promoters, BT Telecom India Pvt Ltd., American Orient Capital Partners India Pvt Ltd, IMACID, Morocco, Safe Food Corporation, etc. He was also a Director on the Board of Air India.Shyam is a regular participant at the World Economic Forum Annual Meeting in Davos and a member of the Chemical Governors Council of the World Economic Forum.Shyam is married to Shobhana, Former Member of Parliament & Chairperson, The Hindustan Times Media Ltd. They have two sons- Priyavrat and Shamit.

ISO Certification

ISO 9001:2008, 14001:2004 & OHSAS 18001:2007 certified

Code of Conduct

Code Of Conduct for Directors and Senior ManagementThis Code of Conduct highlights the standards of conduct expected from the Company’s Directors and Senior Management so as to align these with the Company’s Vision, Promise and Values.Jubilant Life Sciences Ltd. (Jubilant) has a well formulated Vision which drives the business and has the promise of Caring, Sharing, Growing to all the stakeholders–We will, with utmost care for the environment, continue to enhance value for our customers by providing innovative products and economically efficient solutions and for our shareholders through sales growth, cost effectiveness and wise investment of resources.

Director’s Desk

Co-Chairman & Managing Director
Jubilant Bhartia Group
Hari, together with his brother Shyam, is co-founder of Jubilant Bhartia Group (www.jubilantbhartia.com) headquartered in New Delhi, India.The Jubilant Bhartia Group, with 30,000 employees, has a strong presence in diverse sectors like Pharmaceuticals and Life Sciences, Oil and Gas (exploration and production), Agri products, Performance Polymers, Retail, Food and Consulting in Aerospace and Oilfield Services. Jubilant Bhartia Group has four flagships Companies- Jubilant Life Sciences Limited, Jubilant FoodWorksLimited and Jubilant Industries Limited, listed on Indian Stock Exchange and Jubilant Energy NV, listed at AIM market of London Exchange.A Chemical Engineering Graduate from the prestigious Indian Institute of Technology (IIT), Delhi, Hari was conferred the Distinguished Alumni award by his alma mater in 2000. He has been associated in various capacities with the IIT system and with the Ministry of Human Resource Development, Government of India.Hari is a past President of the Confederation of Indian Industry (CII) & a member of several educational, scientific and technological programmes of the Government of India. He is currently the Chairman of the Board of Governors of the Indian Institute of Management (IIM), Raipur and Member of the International Advisory Board of McGill University, Canada.Hari is the Co-Chairman of India-Canada CEO’s Forum appointed by the Prime Minister of India. He is also a member of CEO’s Forum for India-USA, India-France and India-Sri Lanka and Joint Task Force for India-Myanmar & India-UAE. He is a regular participant at the World Economic Forum Annual Meeting in Davos and is a member of the World Economic Forum’s International Business Council and the Health Governors.Hari’s immense contributions have been recognized by various awards. He, along with his brother, was felicitated with the Entrepreneur of the Year Award at the prestigious AIMA Managing India Awards 2013, presented by the President of India. In 2010, the duo also shared the much-coveted Ernst & Young Entrepreneur of the Year Award for Life Sciences & Consumer Products category.Hari serves on the board of several public and private companies like TV 18 Broadcast Ltd., Shriram Pistons & Rings Ltd., Export Credit Guarantee Corporation of India Ltd., BT Telecom India Pvt. Ltd & India Brand Equity Foundation.Hari is married to Kavita, a leading Fashion Designer and Retailer. They have a daughter, Aashti and a son, Arjun.

///////Lurasidone hydrochloride, Jubilant Life Sciences Ltd, WO 2016059649, New patent

Tedizolid phosphate

Suzhou MiracPharma Technology Co Ltd; Zheren Pharmaceutical Nanjing Co Ltd

WO-2016058467   click for patent

SUZHOU MIRACPHARMA TECHNOLOGY CO., LTD [CN/CN]; Room 1305, Building 1 Lianfeng Commercial Plaza, Industrial District Suzhou, Jiangsu 215000 (CN).
ZHEREN PHARMACEUTICAL NANJING CO., LTD [CN/CN]; Qiaolin Industry Park 32-71, Pukou District Nanjing, Jiangsu 211806 (CN)

Disclosed is a method for preparing tedizolid phosphate (I), and the preparation step thereof comprises producing the tedizolid phosphate (I) by means of a coupling reaction of a compound of formula II and a compound of formula III. The preparation method uses easily available raw materials and a simple process, is economical and environmentally friendly, and is suitable for industrial production.

Process for preparing tedizolid phosphate (TD-P), useful for treating bacterial infection. The present filing represents the first PCT and first filing to be seen from Suzhou Miracpharma and Zheren Pharmaceutical, respectively, that focuses on tedizolid; however this case was first seen as a Chinese national filing (assigned to Suzhou Miracpharma), published in February 2015. The drug was developed and launched by Dong-A ST and licensees Cubist Pharmaceuticals and Bayer, for treating acute bacterial skin and skin structure infections.

//////New Patent, Tedizolid phosphate, Suzhou MiracPharma Technology Co Ltd,  Zheren Pharmaceutical Nanjing Co Ltd, WO 2016058467

• This invention relates to steroid compounds and pharmaceutical acceptable salts thereof, a method for preparation thereof, pharmaceutical compositions containing the same as active component, and their use in the preparation of medicines for treating diseases associated with progestogen dependence and for fertility control, abortion or contraception and for anticancer use.
• Mifepristone (11β-[4-(N,N-dimethylamino)phenyl]-17α-(1-propinyl)-17β-hydroxy-4,9-estradiene-3-one) is a steroid compound which is disclosed in French Patent No. 2,497,807 to Rousell-Uclaf, published May 31, 1983. It is the first progesterone receptor antagonist put into clinical application and is a new type of anti-progestin. It binds to progesterone receptor and glucocorticoid receptor, having an affinity with progesterone receptor in rabbit endometrium five-fold higher than that of progesterone and thereby having strong anti-progesterone effect. It causes degeneration of pregnant villus tissue and decidual tissue, endogenous prostaglandin (PG) release, luteinizing hormone decrease, corpus luteum dissolution, and necrosis of embryo sac whose development depends on corpus luteum, leading to abortion. Therefore, it can be used as a non-surgical medicine for stopping early pregnancy. It can also be used, inter alia, in contraception and as an antineoplastic. (The Antiprogestin Steroid Ru486 and Human Fertility Control, 1985, New York: Plenum Press) .
• Onapristone (11β-[4-(N,N-diemthylamino)phenyl]-17α-hydroxy-17β-(3-hydroxypropyl)-13α-4,9-estradiene-3-one), is a steroid compound which is disclosed in German Patent No. 3,321,826 to Schering AG, published Dec. 20, 1984. It has a strong antiprogestin activity and can be used in abortion (American Journal of Obstetrics and Gyencology, 1987, 157:1065-1074), anticancer (Breast Cancer Research and Treatment, 1989, 14:275-288), etc. It was reported that onapristone had toxicity to human liver (European Journal of Cancer, 1999, 35(2):214-218).
• Lilopristone (11β-[4-(N,N-dimethylamino) phenyl]-17α-[3-hydroxy-1(Z)-propenyl]-17β-hydroxy-4,9-estradiene-3-one) is a steroid compound which is disclosed in German Patent No. 3,347,126 to Schering AG, published July 11, 1985. It has a strong antiprogestin activity and can be used in abortion, contraception (American Journal of Obstetrics and Gyencology, 1987, 157:1065-1074), etc. It was reported that the clinical effect of lilopristone in stopping early pregnancy was only equivalent to that of mifepristone (Human Reproduction, 1994, 9(1):57-63).
• ZK112993 (11β-(4-acetylphenyl)-17α-(1-propinyl)-17β-hydroxy-4,9-estradiene-3-one) is as steroid compound which is disclosed in German Patent No. 3,504,421 to Schering AG, published Aug. 7, 1986. It has a potent antiprogestin activity and can be used in, inter alia, anticancer (Anticancer Res., 1990, 10:683-688).
• In European Patent No. 321,010 to Akzo NV, The Netherland published June 21, 1989 are disclosed “11-arylsteroid compounds” having a strong antiprogestin activity.

PATENT

WO 2001018026

http://www.google.com/patents/EP1219632A1?cl=en

The preparation method of the present invention includes the following single- or multi-step procedures:

1. Method for the preparation of 11β-[4-(N-methyl-N-cyclohexylamino)phenyl]-17α-(1-propinyl)-17β-hydroxy-4,9-estradiene-3-one (IV) which includes the following steps:

(1) Preparation of Grignard reagent (III)

4-bromo-N-methyl-N-cyclohexylaniline (II) is reacted with magnesium in tetrahydrofuran (THF) to obtain Grignard reagent of formula (III).

(2) C₁₁ additive reaction

Compound of formula (IV) and the Grignard reagent of formula (III) prepared in step (1) are brought to an additive reaction to obtain compound of formula (V).

(3) Hydrolytic reaction

The compound of formula (V) prepared in step (2) is subjected to a hydrolytic reaction to obtain compound of form (VI).

2. Method for preparation of 11β-[4-(N-cyclohexylamino)phenyl]-17α-(1-propinyl)-17β-hydroxy-4,9-estradiene-3-one (XI) which includes the following steps:

(1) Preparation of Grignard reagent of formula (IX)

4-bromo-N-cyclohexylaniline (VII) is first protected by trimethylchlorosilane, then reacted with magnesium in THF to obtain Grignard reagent of formula (IX).

(2) C₁₁ additive reaction

Compound of formula (IV) and the Grignard reagent of formula (IX) prepared in step (1) are brought to an additive reaction to obtain compound of formula (X).

(3) Hydrolytic reaction

The compound of formula (X) prepared in step (2) is subjects to a hydrolytic reaction to obtain compound of formula (XI).

Example 2:

Preparation of 11β-[4-(N-cyclohexylamino)phenyl]-17α-(1-propinyl)-17β-hydroxy-4,9-estradiene-3-one (XI)(1) Preparation of 4-(N-cyclohexyl-N-trimethylsilylamino)phenyl magnesium bromide (IX)
• 9g 4-bromo-N-cyclohexylaniline (VII) (CA registration number [113388-04-8], see Synthetic Communications, 1986, 16(13): 1641-1645 for its preparation) was placed into a four-necked flask and 15 ml (1.5 mol/L) n-BuLi solution in n-hexane. The mixture was stirred for 30 min at room temperature. Then 8 g trimethylsilyl chloride (Me₃SiCl) was added and the mixture was stirred for 1 hour. Solvent and excessive Me₃SiCl was evaporated under reduced pressure to yield 4-bromo-(N-cyclohexyl-N-trimethylsilylaniline) (VIII) which was formulated into a solution with 7.5 ml anhydrous tetrahydrofuran for further use.
• 1.3 g magnesium was placed into a four-necked flask and a small amount of the above solution was added dropwise and slowly at 40°C. After completion of addition, the temperature was kept for 1 hour to yield a solution of 4-(N-cyclohexyl-N-trimethylsilylamino)phenylmagnesium bromide (IX) in tetrahydrofuran for further use.

(2) Preparation of 3,3-ethylenedioxy-5α,17β-dihydroxy-11β-[4-(N-cylohexylamino)phenyl]-17α-(1-propinyl)-9(10)-estrene(X).

5g 3,3-ethylenedioxy-5,10-epoxy-17α-(1-propinyl)-17β-hydroxy-9(11)-estrene (IV) was placed into a four-necked flask and 10 ml anhydrous tetrahydrofuran and a catalytic amount of cuprous chloride (Cu2Cl2) added. Then solution of 4-(N-cyclohexyl-N-trimethylsilylamino)phenyl magnesium bromide (IX) in tetrahydrofuran was added dropwise and slowly while controlling the temperature below 5°C. After completion of addition, the mixture was allowed to react for 2 hours at room temperature and to stand overnight. Saturated ammonium chloride aqueous solution was added and the tetrahydrofuran layer separated which was washed with saturated ammonium chloride solution. The solution in tetrahydrofuran was washed with saturated saline and dried over anhydrous sodium sulfate. Evaporation of tetrahydrofuran under reduced pressure yielded a residual which was chromatographed on silica gel column using cyclohexane: acetone (5:1) as developing agent to yield 3 g 3,3-ethylenedioxy-5α,17β-dihydroxy-11β-[4-(N-cyclohexylamino)phenyl]-17α-(1-propinyl)-9(10)-estrene(X).

• IR (KBr) cm^-1: 3420 (C₅, C₁₇-OH), 1610, 1510 (benzene backbone), 840, 808 (ArH).
  ¹H NMR (CDCl₃) δ ppm: 0.52(3H, S, C₁₃-CH₃), 2.72(3H, S, N-CH₃), 3.92(4H, m, -O-CH₂CH₂-O-), 4.24(1H, m, C₁₁-H), 6.65-7.00 (4H, ArH).

(3) Preparation of 11β- [4- (N-cyclohexylamino)phenyl] -17α- (1-propinyl) -17β-hydroxy-4,9-estradiene-3-one (XI).

1.5g 3,3-ethylenedioxy-5,17β-dihydroxy-11β-[4-(N-cyclohexylamino)phenyl]-17α-(1-propinyl)-9(10)-estrene (X) and 0.75 g para-toluenesulfonic acid (PTS) were dissolved in 15 ml 90 % ethanol (v/v). The mixture was stirred for 2 hours while controlling the temperature at 40°C-50°C. After completion of the reaction, the reactant was poured into diluted sodium hydroxide aqueous solution, extracted with dichloroethane, washed with water to neutrality, and dried over anhydrous sodium sulfate. Evaporation of the solvent and chromatography on silica gel column using cyclohexane: ethyl acetate (5:1) as developing agent yielded 0.9 g 11β-[4-(N-cyclohexylamino)phenyl]-17α-(1-propinyl)-17β-hydroxy-4,9-estradiene-3-one (XI).

• IR (KBr) cm^-1: 3400 (C₁₇-OH), 1658 (unsaturated ketone), 1613, 1514 (benzene backbone), 865, 810 (ArH).
  ¹H NMR (CDCl₃) δ ppm: 0.50 (3H, S, C₁₃-CH₃), 1.76 (3H, S, C≡C-CH₃), 4.32(1H, S, C₁₁-H), 5.75(1H, S, C₄-H), 6.9-7.10 (4H, ArH).

PATENT

WO 2006063526

PATENT

WO 2007009397

Example 1

Race meters mifepristone synthetic routes:

Epoxy adduct match rice mifepristone

(N- hexylamino methylcyclohexyl) phenyl magnesium bromide (1) 4-

In the four-necked flask, 1.4 g of magnesium into pieces (Mg) and 10 ml of anhydrous tetrahydrofuran (THF), no iodine or add a little change, at about 50 ° C, a solution of 10.86 g of 4-bromo-methyl -N- cyclohexyl aniline (dissolved in 24 ml of anhydrous tetrahydrofuran) dropwise Bi, incubation was continued for 1 hour with stirring to give 4- (N- methyl-cyclohexylamino) phenyl magnesium bromide tetrahydrofuran solution (to be used in the next step an addition reaction ).

(2) 3,3-ethylenedioxy -5 α, 17 β – dihydroxy -11 β – [4- (Ν- methyl -Ν- cyclohexylamino) phenyl] -17 α – (1- propyl block-yl) -9 (10) – Preparation of estra-ene (adduct) of

In the four-necked flask, into 5 g of 3,3-ethylenedioxy-5,10-epoxy -17 α – (1- propynyl) – 17 (3 – hydroxy – 9 (11) – estra-ene (epoxy), 29.1 ml anhydrous tetrahydrofuran (THF) and 0.1 g cuprous chloride (of Cu ₂ of Cl ₂ ), a solution of 4- (N- methyl -N-cyclohexylamino) phenyl magnesium bromide tetrahydrofuran

Nan solution, temperature control 5. C, the drop was completed, the incubation was continued for 5 hours, the reaction was completed, the reaction solution was poured into saturated aqueous ammonium chloride solution, points to the water layer, the organic layer was washed with saturated ammonium chloride solution, the aqueous layer extracted with ethyl acetate number times, the organic layers combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, a silica gel column, eluent cyclohexane: acetone = (5: 1) to give 3,3-ethylene dioxo -5 α, 17 β – dihydroxy -11 β – [4- (- methyl -Ν- cyclohexylamino) phenyl] -17 α – (1- propynyl) -9 (10) – female steroidal women (adduct) solid 6 grams.

IR. ‘KBi cm- ^ SlS OI ^ ^ -OH lS jSlS benzene backbone), 819 (aromatic hydrogen). NMR Ή: (CDC1 ₃ ) ppm by [delta]: 0.47 (3H, the S, the C _IR CH ₃ ), 1.88 (3H, the S, the C ≡ the C-CH ₃ ), 2.72 (3H, the S, the N-CH ₃ ), 6.65- 7.03 (4H, ArH) _O

(3) 11 β – [4- (N- methyl -N- cyclohexylamino) phenyl] -17 α – (1- propynyl) -17 β – hydroxy-estra-4,9-diene – Preparation of 3-one (match rice mifepristone) of

‘2.5 g of p-toluenesulfonic acid (PTS) and 5 grams of 3,3-ethylenedioxythiophene -5 α, 17 β – dihydroxy -11 β – [4- (Ν- methyl cyclohexylamino) phenyl] -17 α – (1- propynyl) -9 (10) – estra-ene (adduct) was dissolved in 50 ml of ethanol 90% (V / V), and at 5 ° C – 40 ° C the reaction was stirred 3 hours, the reaction solution was poured into dilute aqueous sodium hydroxide solution, the precipitated solid was suction filtered, washed with water until neutral, the filter cake was dissolved in 50 ml of ethyl acetate, then with saturated aqueous sodium chloride solution to the water layer was evaporated part of the solvent, the precipitated solid was suction filtered, and dried to give a pale yellow solid 11 β – [4- (Ν- -N- methyl-cyclohexylamino)] -17 α – (1- propynyl) -17 β – hydroxy estra-4,9-dien-3-one (match rice mifepristone) 3 grams.

^ Cm & lt IRCKB ¹ : 3447 (the C _{. 17} -OH), among 1655 (unsaturated ketone), 1607,1513 (benzene backbone), 865,819 (aromatic hydrogen).

NMR ¾: (CDC1 ₃ ) ppm by [delta]: 0.56 (3H, the S ₅ the C ₁₃ -CH ₃ ), 1.89 (3H, the S ₅ -C ≡ the C-the CH3), 2.74 (3H, the S, the N-the CH3), 4.34 ( lH, the S, the C _N -H), 5.75 (lH, the S, the C ₄ -H), 6.68-6.99 (4H, ArH).

PATENT

CN 102107007

PATENT

CN 102106805

PAPER

Volume 878, Issues 7–8, 1 March 2010, Pages 719–723

Determination of cymipristone in human plasma by liquid chromatography–electrospray ionization-tandem mass spectrometry

doi:10.1016/j.jchromb.2010.01.027

Abstract

A rapid, specific and sensitive liquid chromatography–electrospray ionization-tandem mass spectrometry method was developed and validated for determination of cymipristone in human plasma. Mifepristone was used as the internal standard (IS). Plasma samples were deproteinized using methanol. The compounds were separated on a ZORBAX SB C₁₈ column (50 mm × 2.1 mm i.d., dp 1.8 μm) with gradient elution at a flow-rate of 0.3 ml/min. The mobile phase consisted of 10 mM ammonium acetate and acetonitrile. The detection was performed on a triple-quadruple tandem mass spectrometer by selective reaction monitoring (SRM) mode via electrospray ionization. Target ions were monitored at [M+H]⁺m/z 498 → 416 and 430 → 372 in positive electrospray ionization (ESI) mode for cymipristone and IS, respectively. Linearity was established for the range of concentrations 0.5–100 ng/ml with a coefficient correlation (r) of 0.9996. The lower limit of quantification (LLOQ) was identifiable and reproducible at 0.5 ng/ml. The validated method was successfully applied to study the pharmacokinetics of cymipristone in healthy Chinese female subjects.

CHEMICAL ABSTRACTS, vol. 115, no. 25, 23 December 1991 (1991-12-23) Columbus, Ohio, US; abstract no. 270851g, X. ZHAO ET AL.: “Synthesis and terminating early pregnancy effect of mifepristone derivatives” page 117; XP002219009 & ZHONGGUO YAOKE DAXUE XUEBAO, vol. 22, no. 3, 1991, pages 133-136,

//////////Cymipristone, Saimisitong, NDA Filed , china, Shanghai Siniwest Pharmaceutical Chemical Technology Co., Ltd., Shanghai Zhongxi Pharmaceutical Co. Ltd., Xianju Pharmaceutical Co., Ltd,