VIXOTRIGINE

• Molecular FormulaC₁₈H₁₉FN₂O₂
• Average mass314.354 Da
• раксатригин , راكساتريجين , 维索曲静 ,

Vixotrigine (INN, USAN), formerly known as raxatrigine (INN, USAN), is an analgesic which is under development by Convergence Pharmaceuticals for the treatment of lumbosacral radiculopathy (sciatica) and trigeminal neuralgia (TGN).^[1][2][3] Vixotrigine was originally claimed to be a selective central Na_v1.3 blocker, but was subsequently redefined as a selective peripheral Na_v1.7 blocker.^[4]Following this, vixotrigine was redefined once again, as a non-selective voltage-gated sodium channel blocker.^[4] As of January 2018, it is in phase III clinical trials for trigeminal neuralgia and is in phase II clinical studies for erythromelalgia and neuropathic pain.^[5] It was previously under investigation for the treatment of bipolar disorder, but development for this indication was discontinued.^[5]

WO2018085521 , claiming novel dosage regimen, assigned to Biogen Inc and Biogen Ma Inc , naming a different team. Biogen, following the acquisition of Convergence Pharmaceuticals , that previously acquired clinical assets from GlaxoSmithKline , is developing vixotrigine ( phase 2 , in November 2018), a voltage-gated sodium channel 1.7 inhibitor, for treating neuropathic pain associated with trigeminal neuralgia, and small fibre neuropathy

PATENT

WO 2011/029762.

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2011029762

Preparation 1 : Methyl 4-(2-fluorobenzyloxy)benzoate (P1)

Methylparaben (8.85 g, 58.19 mmol) and K₂CO₃ (16.1 g, 1 16.38 mmol) were stirred in acetonitrile (100 mL) for 5 minutes and then 2-fluorobenzyl bromide (10 g, 52.9 mmol) was added. The suspension was heated to 50-55 °C and held for 2 hours. The mixture was then cooled to 20-25 °C, filtered, and the filtrate solution concentrated to a thick residue. The residue was then dissolved in CH₂CI₂, washed with a 1 M Na₂CO₃ solution, dried over Na₂SO₄, and concentrated to a solid. The solid was then stirred vigorously for 1 hour in just enough hexanes to allow for agitation (~40 mL) and then cooled to 0-5 °C. After 15 minutes, the product was isolated by filtration and washed with -25 mL of hexanes. After drying under vacuum, 1 was isolated as a white solid (13.1 g, 87% yield).

¹H NMR (400 MHz, DMSO-d₆) δ 7.96-7.90 (2H, m), 7.57 (2H, apparent td, J = 7.7, 1.8 Hz),

7.48-7.39 (1 H, m), 7.30-7.21 (2H, m), 7.17-7.12 (2H, m), 5.22 (2H, s), 3.81 (3H, s).

¹³C NMR (100 MHz, DMSO-d₆) δ 166.2, 162.4, 160.8 (d, J = 247 Hz), 131.6, 131.1 (d, J = 3.8

Hz), 131.0 (d, J = 8.3 Hz), 124.9 (d, J = 3.4 Hz), 123.5 (d, J = 14.1 Hz), 122.6, 1 15.8 (d, J =

21.0 Hz), 115.0, 64.2 (d, J = 3.4 Hz), 52.2.

LRMS (m/e) : 261.3 [MH]⁺.

Preparation 2: 4-(2-fluorobenzyloxy)benzoic acid (P2).

Methyl 4-(2-fluorobenzyloxy)benzoate (P1 , 10.0 g, 26.9 mmol) was dissolved in methanol (60 mL) and THF (90 mL). A 45 wt% potassium hydroxide solution (20 mL) was then added and

the resulting exotherm was controlled by a water bath. After 1.5 days at 20-25 °C the solution became a thick suspension. Using a water bath to control the exotherm, 20 mL of concentrated HCl was added. The mixture was then concentrated to remove the THF and methanol and 150 mL water was added. The solid was isolated by filtration and washed with 50 mL water. After drying under vacuum, the title compound was isolated as a white crystalline solid (9.4 g, 99% yield).

¹H NMR (400 MHz, DMSO-d₆) δ 7.95-7.89 (2H, m), 7.58 (2H, apparent td, J = 7.5, 1.7 Hz), 7.48-7.41 (1 H, m), 7.30-7.22 (2H, m), 7.16-7.10 (2H, m), 5.22 (2H, s).

¹³C NMR (100 MHz, DMSO-d₆) δ 167.3, 162.1 , 160.8 (d, J = 246 Hz), 131.7, 131.2 (d, J = 3.8 Hz), 131.0 (d, J = 8.3 Hz), 124.9 (d, J = 3.4 Hz), 123.8, 123.6, 115.8 (d, J = 21.0 Hz), 114.9, 64.2 (d, J = 3.4 Hz).

LRMS (m/e) 247.2 [MH]⁺.

Preparation 3: 4-(2-fluorobenzyloxy)-N-methyl-N-methoxybenzamide (P3).

4-(2-fluorobenzyloxy)benzoic acid (P2, 5.5 g, 22.3 mmol) was suspended in thionyl chloride (16.5 mL) and heated to 65 °C and held for 3 hours during which time the reactor was kept under a slow sweep of nitrogen. The mixture was then concentrated to a thick oil under hi vac to remove all traces of residual thionyl chloride. The residue was then diluted in CH₂CI₂ (20 mL) and cooled to 0 °C. In a separate flask, a solution of diaza(1 ,3)bicycle[5.4.0]undecane (DBU, 8.0 mL, 8.15 g, 53.52 mmol) and N-methoxy-N-methyl amine hydrochloride (2.61 g, 26.76 mmol) in CH₂CI₂ (20 mL) was made and slowly added to the solution at 0 °C. After warming to 20-25 °C, the mixture was washed with 1 M HCl and then with a saturated NaHCO₃ solution. After drying over Na₂SO₄, the solution was concentrated to a thick residue. The mixture was then purified by flash column chromatography eluting with 0→ 100% EtOAc/hexanes (gradient). Concentration of the fractions containing the title compound gave an oil that crystallized upon standing (6.0 g, 93% yield).

¹H NMR (400 MHz, DMSO-d₆) δ 7.66-7.62 (2H, m), 7.58 (2H, apparent td, J = 7.5, 1.7 Hz), 7.48-7.41 (1 H, m), 7.30-7.23 (2H, m), 7.12-7.07 (2H, m), 5.20 (2H, s), 3.55 (3H, s), 3.25 (3H, s).

¹³C NMR (100 MHz, DMSO-d₆) δ 168.9, 168.0 (d, J = 246 Hz), 163.0, 131.2 (d, J = 3.8 Hz), 130.9 (d, J = 8.2 Hz), 130.4, 126.9, 124.9 (d, J = 3.4 Hz), 123.8 (d, J = 14.8 Hz), 115.8 (d, J = 21.0 Hz), 114.4, 64.0 (d, J = 3.8 Hz), 60.9, 33.8.

LRMS (m/e) 290.3 [MH]⁺.

Preparation 4: 1-(4-[2-fluorobenzyloxy]phenyl)-2-propen-1-one (P4).

4-(2-fluorobenzyloxy)-N-methyl-N-methoxybenzamide (P3, 6.0 g, 20.7 mmol) was dissolved in THF (100 mL) and cooled to -78 °C. A 1.0 M solution of vinyl magnesium bromide in THF (31 mL, 31 mmol) was added and the cold bath was removed. Upon warming to 20-25 °C, the mixture was poured into a vigorously stirred solution of 1 M HCl. The resulting mixture was extracted twice with CH₂CI₂. The combined organic layers were then washed with 1 M HCl, then with a saturated NaHCO₃ solution, dried over Na₂SO₄, and concentrated to a thick residue. The product was purified by flash column chromatography eluting with 0→ 40% acetone hexanes (gradient). Concentration of the fractions containing 4 gave an oil that crystallized upon standing (4.83 g, 91% yield).

¹H NMR (400 MHz, DMSO-d₆) δ 8.06-8.01 (2H, m), 7.59 (1 H, apparent td, J = 7.5, 1.7 Hz), 7.48-7.38 (2H, m), 7.30-7.22 (2H, m), 7.21-7.16 (2H, m), 6.32 (1 H, dd, J = 17.0, 2.0 Hz), 5.92 (1 H, dd, J = 10.5, 2.0 Hz), 5.26 (2H, s).

¹³C NMR (100 MHz, DMSO-d₆) δ 188.3, 162.6, 160.8 (d, J = 246 Hz), 132.5, 131.3, 131.2 (d, J = 3.8 Hz), 131.0 (d, J = 8.2 Hz), 130.3, 129.7, 124.9 (d, J = 3.1 Hz), 123.6 (d, J = 14.4 Hz), 115.8 (d, J = 21.0 Hz), 115.2, 64.3 (d, J = 3.4 Hz).

LRMS (m/e) 257.3 [MH]⁺.

Preparation 6: Ethyl-5-(4-[2-fluorobenzyloxy]phenyl)-3,4-dihydro-2H-pyrrole-2- carboxylate (P5)

(S)-4-lsopropyl-2-[(S)-2-(diphenylphosphino) ferrocen-1-yl]oxazoline (18.8 mg, 0.039 mmol) and Cu(MeCN)₄PF₆ (14.5 mg, 0.039 mmol) were added to a dried, nitrogen swept reaction vessel. Anhydrous, degassed, BHT inhibited THF (5.0 mL) was then added and the mixture was stirred for 30 minutes at 20-25 °C. The resulting solution was then cooled to -78 °C and a solution of 1-(4-[2-fluorobenzyloxy]phenyl)-2-propen-1-one (P4, 2.0 g, 7.80 mmol) and ethyl N-(diphenylmethylidene)glycinate (2.29 g, 8.58 mmol) in THF (15 mL total volume) was added over 1-2 minutes. After 3-5 minutes, a solution of DBU (5.9 mg, 0.039 mmol) in THF (0.5 mL total volume) was added. The solution was then stirred for 8-12 hours at -78 °C. The reaction mixture was then warmed to 0-5 °C and 1 M H₂SO₄ (aq., 25 mL) was then added. The reaction mixture was then warmed to 20-25 °C and mixed vigorously for 2 hours. The mixture was then poured into a rapidly stirring solution of NaHCO₃ (saturated, enough to bring the pH to≥ 7.0). After 5minut.es of stirring, the mixture was extracted twice with TBME and the organic extracts were pooled, dried over Na₂SO₄, and concentrated to near dryness. The resulting residue was purified by flash column chromatography eluting with 0→ 40% acetone/hexanes (gradient). Concentration of the fractions containing the title compound gave a crystalline solid (2.23 g, 84% yield).

¹H NMR (400 MHz, DMSO-d₆) δ 7.85-7.80 (2H, m), 7.58 (1H, apparent td, J = 7.5, 1.7 Hz), 7.47-7.41 (1 H, m), 7.30-7.22 (2H, m), 7.13-7.09 (2H, m), 5.21 (2H, s), 4.82-4.76 (1 H, m), 4.14 (2H, q, J = 7.1 Hz), 3.13-3.02 (1 H, m), 2.98-2.87 (1 H, m), 2.32-2.21 (1 H, m), 2.09-1.98 (1 H, m), 1.22 (3H, t, J = 7.02 Hz).

¹³C NMR (100 MHz, DMSO-d₆) δ 174.8, 173.1 , 160.8 (d, J = 246 Hz), 160.6, 131.1 (d, J = 3.8 Hz), 130.9 (d, J = 8.3 Hz), 130.0, 127.1 , 124.9 (d, J = 3.1 Hz), 123.9 (d, J = 14.4 Hz), 1 15.8 (d, J = 21.0 Hz), 115.0, 74.2, 64.0 (d, J = 3.8 Hz), 60.7, 35.3, 26.6, 14.4.

LRMS (m/e) 342.4 [MH]⁺.

Preparation 6: 1-{4-[(phenylmethyl)oxy]phenyl}-2-propen-1-one (P6).

1-{4-[(phenylmethyl)oxy]phenyl}-2-propen-1-one may be prepared from N-methyl-N-(methyloxy)-4-[(phenylmethyl)oxy]benzamide using analogous procedures as those described above for the preparation of P4. N-methyl-N-(methyloxy)-4-[(phenylmethyl)oxy]benzamide may be prepared according to procedures known from the literature (Cowart, M. et. al. J. Med. Chem. 2005, 48, 38).

¹H NMR (400 MHz, DMSO-d₆) δ 8.05-8.00 (2H, m), 7.50-7.32 (6H, m), 7.18-7.14 (2H, m),

6.32 (1 H, dd, J = 16.9, 2.1 Hz), 5.92 (1 H, dd, J = 10.5, 2.1 Hz), 5.23 (2H, s).

¹³C NMR (100 MHz, DMSO-d₆) d 188.3, 162.8, 136.8, 132.5, 131.3, 130.1 , 129.6, 128.9,

128.4, 128.2, 115.3, 69.9.

LRMS (m/e) 239.3 [MH]⁺.

Praparation 7a and 7b Ethyl (2R)-2-[(diphenylmethylidene)amino]-5-(4-[2-fluorobenzyloxy]phenyl)-5-oxopentanoate (P7a) and Ethyl (2S)-2-[(diphenylmethylidene)amino]-5-(4-[2-fluorobenzyloxy]phenyl)-5-oxopentanoate (P7b).

The Ligand (according to Table 1 below reported, 0.0084 mmol) and Cu(MeCN)₄PF₆ (3.13 mg, 0.0084 mmol) were added to a dried, nitrogen swept reaction vessel. Anhydrous, degassed, BHT inhibited THF (0.4 mL) was then added and the mixture was stirred for 30 minutes at 20-25 °C. The resulting solution was then cooled to -20 to -21 °C and a solution of 1-{4-[(phenylmethyl)oxy]phenyl}-2-propen-1-one (P6, 100mg, 0.42 mmol) and ethyl N-(diphenylmethylidene)glycinate (123.5 mg, 0.462 mmol) in THF (0.5 mL total volume) was added over 1-2 minutes. After 1-5 minutes, a solution of DBU (1.27 mg, 0.0084 mmol) in THF (0.1 mL total volume) was added. The solution was then stirred for 8-12 hours at -20 to -25 °C. After this time the reactions were complete and an aliquot of each reaction mixture was diluted in 10% iPrOH / hexanes and analyzed by chiral HPLC. An analytically pure sample was obtained by subjecting the concentrated reaction mixture to flash column chromatography eluting with 0→ 40% acetone hexanes (gradient). Concentration of the fractions containing 7a and 7b (94:6) gave a thick syrup (187 mg, 88% yield).

¹H NMR (400 MHz, DMSO-d₆) δ 7.91-7.86 (2H, m), 7.54-7.32 (13H, m), 7.13-7.07 (4H, m), 5.20 (2H, s), 4.11-4.05 (2H, m), 4.02 (1 H, dd, J = 8.0, 4.8 Hz), 3.01-2.91 (2H, m), 2.27-2.21 (1 H, m), 2.14-2.08 (1 H, m), 1.16 (3H, t, J = 7.2 Hz).

¹³C NMR (100 MHz, DMSO-d₆) δ 197.3, 171.2, 170.0, 162.1 , 138.8, 136.5, 135.6, 130.5, 130.1 , 129.6, 128.7, 128.6, 128.5, 128.2, 128.1 , 128.0, 127.7, 127.3, 114.6, 69.4, 63.8, 60.5, 33.6, 27.7, 14.0.

Example 1: (5R)-5-(4-[2-fluorobenzyioxy]phenyl)-L-prolinamide (E1)

A mixture of 5% Pt/C (Johnson Mathey B102022-5, 100 mg) was added to a solution of Ethyl -5-(4-[2-fluorobenzyloxy]phenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate (P5, obtained as above reported, 1.0 g, 2.93 mmol) in ethanol (12 mL). Acetic acid (1.2 ml.) was then added and the reaction vessel was purged with N₂ and then H₂. The mixture was hydrogenated at 50 psi of H₂ at 15-20 °C for at least 2h. Upon completion of the reaction (monitored by H₂ uptake), the mixture was filtered through celite, then through a 0.2 μm PTFE filter and concentrated to approximately 1.5 mL. The mixture was diluted with 1 :1 iPrOAc/TBME and washed with a saturated solution of NaHCO₃. After concentrating the organics to a thick residual oil (986mg, 98% crude yield; LCMS retention time 2.04 minutes, calculated 344.4 [MH]⁺, found 344.3 [MH]⁺), a solution of ammonia in methanol (ca 7 M) was added in two portions (4 mL initially and then 1 mL after ~10 hrs). After the additions were complete, the reaction stirred for at least 24 hrs at 15-20 °C. Upon completion of the reaction, the mixture was concentrated to dryness. The solid was suspended in a mixture of toluene/TBME 1 :1 (~4 mL) at 18-23 °C with vigorous mixing. After 2hrs at 18-23 °C, the mixture was cooled to 0-5 °C and held for 1 hr. The solid was isolated by filtration and washed with TBME (~4 mL). Drying the solid in a vacuum oven at approximately 40 °C gave the title compound as an off white-solid (720 mg, 78% yield from P5).

Analysis of the sample obtained, performed on CHIRALCEL OJ analytical HPLC column (10% iPrOH/hexanes, 1 mL/min, rt), revealed the presence in minor amounts of (5S)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-D-prolinamide (enantiomer of the title compound); retention times: (5S)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-D-prolinamide 36.3 min (1.2%), E1 41.8 min (98.8%).

¹H NMR (400 MHz, DMSO-d₆) δ 7.55 (1 H, apparent td, J = 7.6, 1.6 Hz), 7.45-7.32 (4H, m), 7.29-7.21 (2H, m), 7.14 (1 H, br. s), 7.00-6.95 (2H, m), 5.12 (2H, s), 4.10 (1 H, dd, J = 9.4, 5.8 Hz), 3.56 (1 H, dd, J = 9.4, 4.4 Hz), 2.14-1.96 (2H, m), 1.92-1.82 (1 H, m), 1.47-1.36 (1 H, m). ¹³C NMR (100 MHz, DMSO-d₆) δ 177.1 , 160.3 (d, J = 246 Hz), 157.0, 137.1 , 130.6 (d, J = 3.8 Hz), 130.3 (d, J = 8.3 Hz), 127.6, 124.5 (d, J = 3.4 Hz), 124.0 (d, J = 14.4 Hz), 115.3 (d, J = 21.0 Hz), 114.4, 63.5 (d, J = 3.8 Hz), 61.7, 59.9, 34.1 , 30.4.

Example 2: (5R)-5-(4-[2-fluorobenzyloxy]phenyl)-L-prolinamide hydrochloride (E2)

To a solution of E1 ( 72 mg, 0.23 mmol) in a mixture of ethyl acetate (1.0 ml) and methanol (1.0 ml) was added 4M HCl in 1 ,4-dioxane (57.5 uL, 0.23 mmol) at 0°C. The mixture was stirred for 1.5h and slowly allowed to warm to room temperature. After evaporating the solvent, the residue was triturated with diethyl ether to afford the title compound as a white solid (75 mg, 93% yield).

¹H NMR (300 MHz, DMSO-d₆) δ 10.89 (1 H, br. s), 8.12 (1 H, s), 8.1 1 (1 H, br. s), 7.73 (1 H, s), 7.60-7.39 (4H, m), 7.30-7.21 (2H, m), 7.13-7.06 (2H, m), 5.18 (2H, s), 4.66-4.56 (1 H, m), 4.36-4.28 (1 H, m), 2.42-1.94 (4H, m).

PATENT

WO-2018213686

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018213686&tab=PCTDESCRIPTION&maxRec=1000

Novel crystalline forms of vixotrigine and their anhydrous form or solvates (designated as Forms A-C), processes for their preparation and composition comprising them are claimed.

The hydrochloride salt of (2S, 5R)-5-(4-((2-fluorobenzyl)oxy)phenyl)pyrrolidine-2-carboxamide, herein referred to as the compound of formula (I):

(I)

is described in WO 2007/042239 as having utility in the treatment of diseases and conditions mediated by modulation of use-dependent voltage-gated sodium channels. The synthetic preparation of (2S, 5R)-5-(4-((2-fluorobenzyl)oxy)phenyl)pyrrolidine-2-carboxamide hydrochloride is described in both WO 2007/042239 and WO 2011/029762.

However, there is a need for the development of crystalline forms of such a-carboxamide pyrrolidine derivatives, which have desirable pharmaceutical properties

Example 1 : (5/?)-5-(4-{[(2-Fluorophenyl)methyl]oxy}phenyl)-L-prolinamide hydrochloride (E1 )

. HCI

The compound of Example 1 may be prepared as described in Example 2,

Procedures 1 to 5 of WO 2007/042239.

Example 2: (5 ?)-5-(4-{[(2-Fluorophenyl)methyl]oxy}phenyl)-L-prolinamide hydrochloride Form 1 (Anhydrous A) (E2)

25.0 mg of Example 1 was added to a 3 mL scintillation vial. THF (2.00 mL) was added and the resulting suspension stirred for 10 minutes. The suspension was filtered through a 0.45 μηι PTFE filter and the filtrate vial placed inside a 20 mL scintillation vial. Hexanes (2 mL) were placed in the outer vial, the entire system sealed and stored at room temperature for 3 days, after which time a crop of colorless crystals was evident in the 3 mL vial. One of these crystals was selected for a single crystal X-ray diffraction experiment. Full characterisation is shown in Figures 1 and 2 and Tables 1 and 2 below

References

External links

Vixotrigine – AdisInsight

Vixotrigine

Clinical data
Synonyms	Raxatrigine; CNV1014802; GSK-1014802; BIIB 074
Routes of administration	By mouth
ATC code	None
Identifiers
IUPAC name[show]
CAS Number	934240-30-9 934240-35-4 (mesylate)
PubChem CID	16046068
ChemSpider	13174481
KEGG	D11179
Chemical and physical data
Formula	C18H19FN2O2
Molar mass	314.354 g/mol
3D model (JSmol)	Interactive image
SMILES[hide] C1CC(NC1C2=CC=C(C=C2)OCC3=CC=CC=C3F)C(=O)N

////////////VIXOTRIGINE, раксатригин , راكساتريجين , 维索曲静 , QQS4J85K6Y, Raxatrigine, UNII:QQS4J85K6Y

FDA approves first treatment Firdapse (amifampridine) for Lambert-Eaton myasthenic syndrome, a rare autoimmune disorder

The U.S. Food and Drug Administration today approved Firdapse (amifampridine) tablets for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults. LEMS is a rare autoimmune disorder that affects the connection between nerves and muscles and causes weakness and other symptoms in affected patients. This is the first FDA approval of a treatment for LEMS.

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/UCM627093.htm?utm_campaign=11282018_PR_FDA%20approves%20treatment%20for%20LEMS&utm_medium=email&utm_source=Eloqua

///////////Priority Review,  Breakthrough Therapy,  Firdapse,  Orphan Drug designation, fda 2018, amifampridine

Selexipag

• Molecular FormulaC₂₆H₃₂N₄O₄S
• Average mass496.622 Da

Selexipag, Uptravi

475086-01-2 CAS

(C₂₆H₃₂N₄O₄S, M_r = 496.6 g/mol)

A prostacyclin receptor (PGI2) agonist used to treat pulmonary arterial hypertension (PAH).

NIPPON SHINYAKU….INNOVATOR

セレキシパグ

Selexipag (brand name Uptravi) is a drug developed by Actelion for the treatment of pulmonary arterial hypertension (PAH). Selexipag and its active metabolite, ACT-333679 (MRE-269) (the free carboxylic acid), are agonists of the prostacyclin receptor, which leads to vasodilation in the pulmonary circulation.^[1]

FDA approves new orphan drug to treat pulmonary arterial hypertension

The US FDA granted it Orphan Drug status^[2] (for PAH). It was approved by the U.S. FDA on 22 December 2015.^[2]

In 2016, the EMA granted marketing authorization in the E.U. for this indication and launch took place shortly after in Germany and the United Kingdom. In Japan, Nippon Shinyaku received approval for the treatment of PAH in 2016.

Selexipag was approved by the U.S. Food and Drug Administration (FDA) on Dec 21, 2015, approved by European Medicine Agency (EMA) on May 12, 2016. It was originally developed by Nippon Shinyaku and then it was licensed to Actelion for co-development. It is marketed as Uptravi^® by Actelion in US and EU.

Selexipag is a prostacyclin receptor (PGI2) agonist, which leads to vasodilation in the pulmonary circulation. It is indicated for the treatment of pulmonary arterial hypertension (PAH).

Uptravi^® is available as tablets for oral use, containing 200, 400, 600, 800, 1000, 1200, 1400, or 1600 mcg of selexipag. The initial dose is 200 mcg twice daily, and increase the dose by 200 mcg twice daily at weekly intervals to the highest tolerated dose up to 1600 mcg twice daily.

ACT-333679 or MRE-269, the active metabolite of selexipag

SYNTHESIS DEPICT

PATENT

US2012/101276

http://www.google.st/patents/US20120101276?hl=pt-PT&cl=en

The present invention relates to a crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide (hereinafter referred to as “compound A”).

BACKGROUND OF THE INVENTION

Compound A has an excellent PGI2 agonistic effect and shows a platelet aggregation inhibitory effect, a vasodilative effect, a bronchodilative effect, a lipid deposition inhibitory effect, a leukocyte activation inhibitory effect, etc. (see, for example, in WO 2002/088084 (“WO ‘084”)).

Specifically, compound A is useful as preventive or therapeutic agents for transient ischemic attack (TIA), diabetic neuropathy, diabetic gangrene, peripheral circulatory disturbance (e.g., chronic arterial occlusion, intermittent claudication, peripheral embolism, vibration syndrome, Raynaud’s disease), connective tissue disease (e.g., systemic lupus erythematosus, scleroderma, mixed connective tissue disease, vasculitic syndrome), reocclusion/restenosis after percutaneous transluminal coronary angioplasty (PTCA), arteriosclerosis, thrombosis (e.g., acute-phase cerebral thrombosis, pulmonary embolism), hypertension, pulmonary hypertension, ischemic disorder (e.g., cerebral infarction, myocardial infarction), angina (e.g., stable angina, unstable angina), glomerulonephritis, diabetic nephropathy, chronic renal failure, allergy, bronchial asthma, ulcer, pressure ulcer (bedsore), restenosis after coronary intervention such as atherectomy and stent implantation, thrombocytopenia by dialysis, the diseases in which fibrosis of organs or tissues is involved [e.g., Renal diseases (e.g., tuburointerstitial nephritis), respiratory diseases (e.g., interstitial pneumonia (pulmonary fibrosis), chronic obstructive pulmonary disease), digestive diseases (e.g., hepatocirrhosis, viral hepatitis, chronic pancreatitis and scirrhous stomachic cancer), cardiovascular diseases (e.g, myocardial fibrosis), bone and articular diseases (e.g, bone marrow fibrosis and rheumatoid arthritis), skin diseases (e.g, cicatrix after operation, scalded cicatrix, keloid, and hypertrophic cicatrix), obstetric diseases (e.g., hysteromyoma), urinary diseases (e.g., prostatic hypertrophy), other diseases (e.g., Alzheimer’s disease, sclerosing peritonitis; type I diabetes and organ adhesion after operation)], erectile dysfunction (e.g., diabetic erectile dysfunction, psychogenic erectile dysfunction, psychotic erectile dysfunction, erectile dysfunction associated with chronic renal failure, erectile dysfunction after intrapelvic operation for removing prostata, and vascular erectile dysfunction associated with aging and arteriosclerosis), inflammatory bowel disease (e.g., ulcerative colitis, Crohn’s disease, intestinal tuberculosis, ischemic colitis and intestinal ulcer associated with Behcet disease), gastritis, gastric ulcer, ischemic ophthalmopathy (e.g., retinal artery occlusion, retinal vein occlusion, ischemic optic neuropathy), sudden hearing loss, avascular necrosis of bone, intestinal damage caused by administration of a non-steroidal anti-inflammatory agent (e.g., diclofenac, meloxicam, oxaprozin, nabumetone, indomethacin, ibuprofen, ketoprofen, naproxen, celecoxib) (there is no particular limitation for the intestinal damage so far as it is damage appearing in duodenum, small intestine and large intestine and examples thereof include mucosal damage such as erosion and ulcer generated in duodenum, small intestine and large intestine), and symptoms associated with lumbar spinal canal stenosis (e.g., paralysis, dullness in sensory perception, pain, numbness, lowering in walking ability, etc. associated with cervical spinal canal stenosis, thoracic spinal canal stenosis, lumbar spinal canal stenosis, diffuse spinal canal stenosis or sacral stenosis) etc. (see, for example, in WO ‘084, WO 2009/157396, WO 2009/107736, WO 2009/154246, WO 2009/157397, and WO 2009/157398).

In addition, compound A is useful as an accelerating agent for angiogenic therapy such as gene therapy or autologous bone marrow transplantation, an accelerating agent for angiogenesis in restoration of peripheral artery or angiogenic therapy, etc. (see, for example, in WO ‘084).

Production of Compound A

Compound A can be produced, for example, according to the method described in WO ‘084, and, it can also be produced according to the production method mentioned below.

Step 1:

6-Iodo-2,3-diphenylpyrazine can be produced from 6-chloro-2,3-diphenylpyrazine by reacting it with sodium iodide. The reaction is carried out in the presence of an acid in an organic solvent (e.g., ethyl acetate, acetonitrile, acetone, methyl ethyl ketone, or their mixed solvent). The acid to be used is, for example, acetic acid, sulfuric acid, or their mixed acid. The amount of sodium iodide to be used is generally within a range of from 1 to 10 molar ratio relative to 6-chloro-2,3-diphenylpyrazine, preferably within a range of from 2 to 3 molar ratio. The reaction temperature varies depending on the kinds of the solvent and the acid to be used, but may be generally within a range of from 60° C. to 90° C. The reaction time varies depending on the kinds of the solvent and the acid to be used and on the reaction temperature, but may be generally within a range of from 9 hours to 15 hours.

Step 2:

5,6-Diphenyl-2-[(4-hydroxybutyl(isopropyl)amino]pyrazine can be produced from 6-iodo-2,3-diphenylpyrazine by reacting it with 4-hydroxybutyl(isopropyl)amine. The reaction is carried out in the presence of a base in an organic solvent (e.g., sulfolane, N-methylpyrrolidone, N,N-dimethylimidazolidinone, dimethyl sulfoxide or their mixed solvent). The base to be used is, for example, sodium hydrogencarbonate, potassium hydrogencarbonate, potassium carbonate, sodium carbonate or their mixed base. The amount of 4-hydroxybutyl(isopropyl)amine to be used may be generally within a range of from 1.5 to 5.0 molar ratio relative to 6-iodo-2,3-diphenylpyrazine, preferably within a range of from 2 to 3 molar ratio. The reaction temperature varies depending on the kinds of the solvent and the base to be used, but may be generally within a range of from 170° C. to 200° C. The reaction time varies depending on the kinds of the solvent and the base to be used and on the reaction temperature, but may be generally within a range of from 5 hours to 9 hours.

Step 3:

Compound A can be produced from 5,6-diphenyl-2-[4-hydroxybutyl(isopropyl)amino]pyrazine by reacting it with N-(2-chloroacetyl)methanesulfonamide. The reaction is carried out in the presence of a base in a solvent (N-methylpyrrolidone, 2-methyl-2-propanol or their mixed solvent). The base to be used is, for example, potassium t-butoxide, sodium t-butoxide or their mixed base. The amount of N-(2-chloroacetyl)methanesulfonamide to be used may be generally within a range of from 2 to 4 molar ratio relative to 5,6-diphenyl-2-[4-hydroxybutyl(isopropyl)amino]pyrazine, preferably within a range of from 2 to 3 molar ratio. The reaction temperature varies depending on the kinds of the solvent and the base to be used, but may be generally within a range of from −20° C. to 20° C. The reaction time varies depending on the kinds of the solvent and the base to be used and on the reaction temperature, but may be generally within a range of from 0.5 hours to 2 hours.

The compounds to be used as the starting materials in the above-mentioned production method for compound A are known compounds, or can be produced by known methods.

PATENT

WO 2002088084

and

http://www.google.fm/patents/WO2009157398A1?cl=en

PAPER

Bioorganic and Medicinal Chemistry, 2007 ,  vol. 15,   21  p. 6692 – 6704

compd 31

PAPER

Bioorganic and Medicinal Chemistry, 2007 ,  vol. 15,   24  p. 7720 – 7725

2a is the drug

N-Acylsulfonamide and N-acylsulfonylurea derivatives of the carboxylic acid prostacyclin receptor agonist 1 were synthesized and their potential as prodrug forms of the carboxylic acid was evaluated in vitro and in vivo. These compounds were converted to the active compound 1 by hepatic microsomes from rats, dogs, monkeys, and humans, and some of the compounds were shown to yield sustained plasma concentrations of 1 when they were orally administered to monkeys. These types of analogues, including NS-304 (2a), are potentially useful prodrugs of 1.

http://www.sciencedirect.com/science/article/pii/S0968089607007614

PATENT

WO 2011024874

A. Preparation of
Compound A Compound A can be produced , for example, by the method described in Patent Document 1, but can also be produced by the production method described below.
[
Step 2]
6-iodo-2,3-diphenylpyrazine can be produced by reacting 6-chloro-2,3-diphenylpyrazine with sodium iodide. This reaction is carried out in an organic solvent (for example, ethyl acetate, acetonitrile, acetone, methyl ethyl ketone, or a mixed solvent thereof) in the presence of an acid. As the acid to be used, for example, acetic acid, sulfuric acid, or a mixed acid thereof can be mentioned. The amount of sodium iodide used is, for example, suitably in the range of 1 mole to 10 moles, preferably in the range of 2 time moles to 3 times the amount of 1 mole of 6-chloro-2,3-diphenylpyrazine . The reaction temperature varies depending on the raw materials used and the type of acid, but is usually carried out within the range of 60 ° C. to 90 ° C. The reaction time varies depending on the starting materials used, the type of acid and the reaction temperature, but it is usually within the range of 9 hours to 15 hours.Step 2
5,6-diphenyl-2- [4-hydroxybutyl (isopropyl) amino] pyrazine can be prepared by reacting 6-iodo-2,3-diphenylpyrazine with 4-hydroxybutyl (isopropyl) amine. This reaction is carried out in an organic solvent (for example, sulfolane, N-methylpyrrolidone, N, N-dimethylimidazolidinone, dimethylsulfoxide or a mixed solvent thereof) in the presence of a base. Examples of the base used include sodium hydrogencarbonate, potassium hydrogen carbonate, potassium carbonate, sodium carbonate, and mixed bases thereof. The amount of 4-hydroxybutyl (isopropyl) amine to be used is, for example, suitably in the range of 1.5 mol to 5.0 mol per 1 mol of 6-iodo-2,3-diphenylpyrazine, It is within the range of 2 mol to 3 mol. The reaction temperature varies depending on the type of raw material and base used, but is usually carried out within the range of 170 ° C. to 200 ° C. The reaction time varies depending on the type of raw materials and base used and the reaction temperature, but it is usually within the range of 5 hours to 9 hours.Step 3
Compound A can be prepared by reacting 5,6-diphenyl-2- [4-hydroxybutyl (isopropyl) amino] pyrazine with N- (2-chloroacetyl) -methanesulfonamide. This reaction is carried out in an organic solvent (N-methylpyrrolidone, 2-methyl-2-propanol or a mixed solvent thereof) in the presence of a base. Examples of the base to be used include potassium t-butoxide, sodium t-butoxide or mixed bases thereof. The amount of N- (2-chloroacetyl) -methanesulfonamide used is, for example, 2 to 4 mol per 1 mol of 5,6-diphenyl-2- [4-hydroxybutyl (isopropyl) amino] It is suitable within the range, and preferably within the range of 2 mol to 3 mol. The reaction temperature varies depending on the type of raw material and base used, but is usually carried out within the range of -20 ° C. to 20 ° C. The reaction time varies depending on the kinds of raw materials and bases used and the reaction temperature, but it is usually within the range of 0.5 hour to 2 hours.Each compound used as a raw material in the above-mentioned production method of compound A is a known compound or can be produced according to a known method.

Example　1 t- butylamine Form I crystal of the salt
Compound A (40 mg) with 0.5mL dimethoxyethane (hereinafter, referred to as. “DME”) was dissolved in, and t- butylamine (1.1 eq) were added, 25 1 ° C. at 8 it was stirred for hours. Thereafter, the reaction solution was added t- butyl methyl ether (1mL), at -20 ° C. 3 and held hours. It was collected by filtration the precipitated crystals produced, under reduced pressure, and dried, I-form crystals of t- butylamine salt ( 3 to afford 9.9mg). B Powder X-ray diffraction spectrum of type I crystal obtained t- butylamine salt using the apparatus shown in Figure 1.
Melting point: 152.5 ℃
elemental analysis (C 3 0 H 4 3 N 5 O 4 S + 0.0 3 H 2 as O)
calculated value (%) C:　6 3 .1 8 H: 7 . 6 1 N: 12 .2 8　measured value (%) C: 6 2. 8 5 H: 7 . 6 4 N: 12.52 1 H-NMR (DMSO-D 6 ): delta 8 .15 (s, 1H), 7 .55 – 7 . 8 0 (M, 2H), 7 .10- 7 . .45 (M, 10H), 4 7 . 0-4 8 5 (M, 1H), 3 . 6 6 (s, 2H), 3 .4 7 (t, 2H), 3 .45 (t, 2H), 2. 7 3 (s, 3 H), 1.50-1. 7 5 (M, 4H), 1.2 3 (s, 9H), 1.22 (D, 6 H)
Example 2　I-form crystal of the potassium salt
Compound A tetrahydrofuran with (40mg) 12mL (hereinafter, referred to as. “THF”) was dissolved in, 0.1M aqueous potassium hydroxide solution (1.1 eq) was added, 40 ℃ It was heated and stirred in for 15 minutes. After that, it was evaporated under reduced pressure, the solvent. The residue it was added ethyl acetate (200μL). While shaking the mixture heated to 50 ° C. 8 was allowed to cool to 25 ℃ over hours. After repeated two more times this step, at -20 ° C. 3 and held hours. The resulting precipitated crystals were collected by filtration under reduced pressure, and dried to obtain Form I crystal of the potassium salt. B Powder X-ray diffraction spectrum of type I crystal of the obtained potassium salt using the apparatus shown in Fig. 1 H-NMR (DMSO-D 6 ): delta 8 .14 (s, 1H), 7 .1 8 – 7 . 3 8 . (M, 10H), 4 7 . 2-4 8 4 (M, 1H) , 3 . 6 5 (s, 2H), 3 .4 7 (t, 2H), 3 .45 (t, 2H), 2. 7 2 (s, 3 H), 1.55-1. 7 0 ( M, 4H), 1.2 3 (D, 6 H)
Example 3　 II-form crystals of the potassium salt
Compound A with (40mg) was dissolved in THF and 12mL, 0.1M aqueous potassium hydroxide solution (1.1 eq) was added and heated with stirring for 15 min at 40 ℃. After that, it was evaporated under reduced pressure, the solvent. The residue it was added ethyl acetate (200μL). While shaking the mixture heated to 50 ° C. 8 was allowed to cool to 25 ℃ over hours. This operation was repeated two more times, at -20 ° C. 3 and held hours. It was collected by filtration the precipitated crystals produced, under reduced pressure, after drying, 40 ℃, relative humidity 7 while 5% of thermo-hygrostat 7 left for days to give crystalline Form II of the potassium salt. B Powder X-ray diffraction spectrum of crystalline Form II of the resulting potassium salt using the apparatus Fig 3 is shown in.

Example 4　III type crystal of the potassium salt
Compound A , in addition to (100mg) acetonitrile (1mL), and stirred with heating, Compound A was dissolved, followed by cooling to 20 ℃. To a solution 3 .5M potassium hydroxide / ethanol solution (1.1 eq) was added and stirred for 200 minutes at 20 ℃. While stirring the mixture 7 after a heated stirring for 1 hour to 0 ° C., and then cooled to 10 ℃ over 10 hours. Further heated while the mixture 6 is heated to 0 ℃, t- butyl methyl ether (0. 3 after adding mL), cooled to 20 ℃ over 10 hours. It was collected by filtration the precipitated crystals produced, under reduced pressure, and dried, III type crystal of the potassium salt ( 7 to afford 5mg). The powder X-ray diffraction spectrum of the type III crystal of the obtained potassium salt using R unit is shown in FIG. Furthermore, in differential scanning calorimetry, of about 7 endothermic peak was observed at around 4 ° C..
Elemental analysis (C 2 6 H 3 1 N 4 O 4 . SK + 0 7 8 H 2 as O)
calculated value (%) C: 5 6 .91　H: 5.9 8 N: 10.21
measured value (%) C: 5 6 . 6 1 H: 5.55 N:. 10 3 6

EXAMPLE 5　IV-type crystal of the potassium salt
Compound A , in addition to (50mg) and ethyl acetate (1mL), and stirred with heating, Compound A was dissolved, followed by cooling to 20 ℃. To a solution 3 .5M potassium hydroxide / ethanol solution (2.2 eq) was added and 2 at 20 ° C. 3 and stirred for hours. It was collected by filtration the precipitated crystals produced, under reduced pressure, and dried to obtain Form IV crystal of the potassium salt (41mg). The powder X-ray diffraction spectrum of crystalline Form IV of the resulting potassium salt using R unit is shown in FIG. Furthermore, in differential scanning calorimetry, an endothermic peak was observed at around approximately 91 ℃.

Paper

J Med Chem 2015, 58(18): 7128

PATENT

WO 2018008042

https://patents.google.com/patent/WO2018008042A1/en

The present invention relates to an improved and novel processes for the preparation of 2- {4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy} -N-(methylsulfonyl) acetamide compound of formula- 1 , which is represented by the following structural formula- l .

Formula-

The present invention also relates to novel crystalline forms of the compound of formula- 1 and process for the preparation thereof.

Background of the Invention:

2- {4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl) acetamide is known as Selexipag. It is developed by Nippon Shinyaku under the brand name of Uptravi®, for the treatment of pulmonary arterial hypertension.

2- {4-[(5,6-diphenylpyTazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl) acetamide was firstly described in US7205302B2 herein after referred as US ‘302. The said patent also describes its process for the preparation. According to this process the final product was obtained with low yield and purity.

US8791 122 (herein after referred as US’ 122) patent describes crystalline form-I, II and III of 2- {4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy} -N-(methylsulfonyl) acetamide. Because of drug compounds having, for example, improved stability, solubility, shelf life and in vivo pharmacology, are consistently sought, there is an ongoing need for new or pure salts, hydrates, solvates and polymorphic forms of existing drug molecules. The novel crystalline forms of 2- {4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy} -N- (methylsulfonyl) acetamide described herein help meet this requirement.

US ‘ 122 patent describes amorphous form of the compound of formula- 1 . This patent does not disclose any detailed process for amorphous form and PXRD pattern of amorphous compound of formula- 1 .

Examples:

Example-1 Preparation of 4-((5₎6-diphenylpyrazin-2-yl)(isopropyl)amino)butan-l-ol compound of formula-8

A mixture of 5-chloro-2,3-diphenylpyrazine (25 gm) compound of formula-7a and 4- (isopropyl amino)butan- 1 -ol (108 gm) was heated to 190-195°C and stirred the reaction i mixture for 10- 12 hours at same temperature. Cooled the reaction mixture to 25-35°C. To this reaction mixture n-heptane followed by water were added slowly at 25-30°C and stirred the reaction mixture for 2 hours at the same temperature. Filter the precipitated solid, washed with water and dried to get the title compound.

Yield: 30 gm.

Example-2: Preparation of tert-butyl 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino) butoxy)acetate

Potassium hydroxide solution (96.6 gm of potassium hydroxide dissolved in 175 ml of water) was added to the mixture of 4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butan- l -ol (25 gm) and toluene ( 175 ml) at 25-30°C and stirred the reaction mixture for 30 minutes at the same temperature. Cooled the reaction mixture to 0-5°C. Tert-butyl bromoacetate (94 gm) was slowly added to the reaction mixture at 0-5°C and stirred the reaction for 60 minutes at same temperature. Raised the temperature of the reaction mixture to 25-30°C and maintained for 60 minutes. Both the aqueous and organic layers were separated. The aqueous layer was extracted with toluene and combined the organic layers. Organic layer was washed with hydrochloric acid solution followed by with aqueous sodium bicarbonate solution. Organic layer was dried with sodium sulphate and distilled off the solvent completely from the organic layer under reduced pressure to get the title compound.

Yield: 29 gm.

Example-3: Preparation of 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy) acetic acid compound of formula-6

Aqueous sodium hydroxide solution (7.5 gm of sodium hydroxide was dissolved in 80 ml of water) was added to the solution of tert-butyl 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl) amino)butoxy)acetate (30 gm) in methanol (290 ml) at 30-35°C. Heated the reaction mixture to reflux temperature and stirred for 3 hours at the same temperature. Distilled off solvent completely from the reaction mixture under reduced pressure and cooled the reaction mixture to 25-30°C. Water was added to the obtained compound and acidified the reaction mixture using diluted hydrochloric acid at the same temperature. Extracted the reaction mixture with ethyl acetate. The organic layer was washed with aqueous sodium chloride solution and dried with sodium sulphate. Distilled off the solvent from the organic layer under reduced pressure. Diisopropyl ether (60 ml) was added to the obtained compound at 25-30°C and stirred for 60 minutes at the same temperature. Filtered the precipitated solid, washed with diisopropyl ether and dried to get the title compound.

Yield: 19 gm.

Example-4: Preparation of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropy.)amino]butoxy}- N-(methylsulfonyl) acetamide compound of formula-1

Triethylamine (9.6 gm) was added to the mixture of 2-(4-((5,6-diphenylpyrazin-2- yl)(isopropyl)amino)butoxy)acetic acid (10 gm), dichloro methane (100 ml), N,N- dicyclohexylcarbodiimide (4.9 gm), hydroxybenzotriazole (3.5 gm) and methane sulfonamide (3.39 gm) at 25-30°C and stirred the reaction mixture for 12 hours at the same temperature. Filtered the unwanted compounds from the reaction mixture and washed with dichloromethane. The organic layer was washed with water, followed by with aqueous citric acid solution and then washed with aqueous sodium chloride solution. Distilled off the solvent from the organic layer under reduced pressure. To this residue ethyl acetate (20 ml) and carbon (1 gm) were added at 25-30°C and stirred the reaction mixture for 30 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with ethyl acetate. The obtained filtrate was slowly added to the mixture of n-heptane and water at 25-30°C and stirred for 10 hours. Filtered the precipitated solid, washed with n-heptane and dried to get the title compound.

Yield: 4.5 gm.

Example-5: Preparation of 2-{4-f(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}- N-(methylsulfonyl) acetamide compound of formula-1

Sodium t-butoxide (96.6 gm) was added to the mixture of n-methy pyrrolidinone (125 ml) and 4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butan-l-ol (25 gm) compound of formula-8 at 0-5°C and stirred the reaction for 20 minutes at the same temperature. 2-chloro- N-(methylsulfonyl)acetamide (23.7 gm) was slowly added to the reaction mixture at 0-5°C and raise the temperature of the reaction mixture to 25-30°C. Stirred the reaction mixture for 10-12 hours at 25-30°C and water was added to it at the same temperature. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium chloride solution and distilled off the solvent from the organic layer under reduced pressure. To this residue ethyl acetate (50 ml) and carbon (2.5 gm) were added at 25-30°C and stirred the reaction mixture for 30 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with ethyl acetate. The obtained filtrate was slowly added to the mixture of n-heptane and water at 25-30°C and stirred for 10 hours. Filtered the precipitated solid, washed with n-heptane and dried to get the title compound.

Yield: 14 gm.

Example-6: Preparation of 2-chIot^*o- -(methylsulfonyl)acetamide

A mixture of methane sulfonamide (100 gm) and chloroacetyl chloride (356.4 gm) was heated to reflux temperature and stirred it for 10 hours at the same temperature. Cooled the reaction mixture to – 10 to -5°C and stirred it for 2 hours at the same temperature. Filtered the precipitated, solid, washed with toluene followed by n-heptane and dried to get the title compound.

Yield: 175 gm.

ExampIe-7: Purification of the compound of formula-1

Methanol (20 ml) was added to the compound of formula-1 (2 gm) at 25-30°C and heated to reflux temperature. Dichloromethane (3 ml) was added to the reaction mixture at reflux temperature and stirred for 15 minutes at the same temperature. Filtered the reaction mixture, distilled off the solvent from the filtrate under reduced pressure to get the title compound. Yield: 2 gm

Example-8: Preparation of N-isopropyI-5,6-diphenylpyrazin-2-amine (Formula-4) Isopropyl bromide (5.5 gm) was added to the mixture of 2-amino -5,6-diphenylpyrazine ( 10 gm), potassium tert-butoxide (9 gm) and dimethylformamide (50 ml) at 25-30°C, slowly heated to 80-85°C and stirred the reaction mixture for 6 hours at same temperature. The reaction mixture was cooled to 10- 15°C, diluted the reaction mixture with water and stirred it for 2 hours at the same temperature. Filtered the obtained solid and dried to get the title compound.

Yield: 9.5 gm

ExampIe-9: Preparation of N-isopropyl-5,6-diphenylpyrazin-2-amine (Formula-4)

A mixture of 5-chloro-2,3-diphenylpyrazine ( 10 gm), isopropyl amine (7.5 gm) and potassium carbonate (10.5 gm) and dioxane (50 ml) were heated to 40-45°C and stirred the reaction mixture for 12 hrs at the same temperature. The reaction mixture was cooled to 10- 15°C, diluted with water and extracted with dichloromethane. Combined the organic layers was washed with aqueous sodium hydrochloride solution and dried over anhydrous sodium sulphate. Distilled off the solvent completely from the organic layer under reduced pressure to provide the title compound.

Yield: 9 gm

Example-10: Preparation of 2-(4-chlorobutoxy)aceticacid (Formula-5a)

2-bromoaceticacid (10 gm) was slowly added to a mixture of l-chlorobutan-4-ol (7.2 gm), potassium carbonate (26.5 gm) and acetonitrile (50 ml) at 25-30°C. The reaction mixture was heated to 75-80°C and stirred the reaction mixture for 6 hours at same temperature. The reaction mixture was cooled to 25-30°C and diluted with , water. Acidified the reaction mixture using diluted hydrochloric acid at 25-30°C. The reaction mixture extracted with dichloromethane. Combined the organic layers was dried over anhydrous sodium sulphate and distilled off the solvent under reduced pressure to provide the title compound.

Yield: 10.5 gm.

Example-11: Preparation of 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino) butoxy)acetic acid (formula-6)

A mixture of N-isopropyl-5,6-diphenylpyrazin-2-amine (8 gm), potassium carbonate (7.5 gm) and acetonitrile (40 ml) was stirred for 1 hr at 25-30°C. A solution of 2-(4-chlorobutoxy) aceticacid (5.4 gm) in acetonitrile (15 ml) was slowly added to the reaction mixture at 25- 30°C. Heated the reaction mixture to reflux and stirred for 12 hours at the same temperature. The reaction mixture was cooled to 10-15°C and diluted with wateT. Acidified the reaction mixture using diluted hydrochloric acid and extracted the reaction mixture using ethyl acetate. Combined the organic layers and dried over sodium sulphate. Distilled off the solvent completely from the organic layer to get the title compound.

Yield: 8.5 gm

Example-12: Preparation of 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyt)amino)butoxy)- N-(methylsulfonyl)acetamide (formula-1)

A mixture of 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid (5 gm), HATU (5.4 gm), triethylamine (1.5 gm) and dimethylformamide (20 ml) was stirred for 1 hr at 5-10°C under nitrogen atmosphere. Methane sulfonamide (5.2 gm) was slowly added to the reaction mixture at 5-10°C and stirred for 12 hrs at the same temperature. The reaction mixture was diluted with water and stirred for 2 hrs. The precipitated solid was filtered and dried to get the title compound.

Yield: 4.5 gm

Example-13: Preparation of 2-(4-((5,6-diphenylpyrazin-2-yl) (isopropyl) amino) butoxy) acetonitrile (Formula-12)

To the mixture of 4-((5,6-diphenylpyrazin-2-yI)(isopropyl)amino)butan-l-ol ( 10 gm), tetrabutyl ammoniumbromide (0.2 gm), potassium carbonate (7.6 gm) and acetone (50 mL), chloroacetonitrile (3.2 gm) was added at 25-30°C. Heated the reaction mixture to reflux temperature and stirred the reaction mixture for 6 hrs at the same temperature. The reaction mixture was cooled to 10- 15°C and filtered the reaction mixture. Distilled off the solvent completely from the filtrate to get the tile compound.

Yield: 9 gm

Example-14: Preparation of 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy) acetic acid (formula-6)

Sodium hydroxide (3.5 gm) was added to a solution of 2-(4-((5,6-diphenylpyrazin-2-yl) (isopropyl) amino) butoxy) acetonitrile (8 gm) in methanol (60 ml) and water (30 ml). The reaction mixture was heated to 65-70°C and maintained for 6 hrs. The reaction mixture was cooled to 10°C, acidified with diluted hydrochloric acid and stirred at same temperature for 2 hr. The obtained solid was filtered and dried to provide the title compound.

Yield: 7.5 gm

Example-15: Preparation of 2-chloro-N-(methylsulfonyl)acetamide (Formula-16)

The mixture of methane sulfonamide (50 gm) and chloroacetyl chloride (92 gm) was heated to 1 10-1 15°C and stirred the reaction mixture for 7 hours at the same temperature. The reaction mixture was cooled to 25-30°C and dichloromethane was added to the reaction mixture at the same temperature. Cooled the reaction mixture to 15-20°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid and washed with dichloromethane. The obtained solid was recrystallized using dichloromethane to get pure title compound. Yield: 80 gm. M.R.: U0- 1 15°C. Purity by HPLC: 98.85%.

Example-16: Preparation of 4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butan-l-ol (Formula-8)

The mixture of 5-chloro-2,3-diphenylpyrazine ( 100 gm) and 4-(isopropylamino)butan-l -ol (245.5 gm) was heated to 190-195°G and stirred the reaction mixture for 12 hours at the same temperature. The reaction was cooled to 25-30°C and n-heptane was added to the reaction mixture. The reaction mixture was further cooled to 10-15°C, water was slowly added to the reaction mixture and stirred for 2 hours at the same temperature. Filtered the precipitated solid and washed with water. Dichloromethane (300 ml) was added to the obtained solid and stirred for 5 minutes. Both the organic and aqueous layers were separated. The organic layer was dried with sodium sulphate, distilled off the solvent from the organic layer completely under reduced pressure and co-distilled with n-heptane. 400 ml of n-heptane was added to the obtained compound at 25-30°C, heated the reaction mixture to 45-50°C and stirred for 30 minutes at the same temperature. The reaction mixture was cooled to 15-20°C and stirred for 2 hours at the same temperature. Filtered the solid, washed with n-heptane and dried to get the title compound.

Yield: 82 gm. M.R.: 100-105°C. Purity by HPLC: 95.4%.

Example-17: Purification of 4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butan-l-ol (Formula-8)

n-Heptane (750 ml) was slowly added to pre-cooled solution of 4-((5,6-diphenylpyrazin-2- yl)(isopropyl)amino)butan- l -ol (100 gm) in acetone (250 ml) was cooled to 0-5°C. Stirred the reaction mixture for 4 hours at the same tempereature. Filtered the precipitated solid, washed with n-heptane and dried to get the pure title compound.

Yield: 54 gm. Purity by HPLC: 99.92%.

Example-18: Preparation of crystalline form-L of compound of formula-1

Melting the compound of formula-1 (10 gm) at 140-145°C under reduced pressure for 15 minutes. The above obtained oily residue was added to 100 ml of pre-cooled n-heptane at 0- 5°C. Stirred the reaction mixture for 6 hr at 0-5°C. Filtered the precipitated solid, washed with n-heptane and dried to get the title compound. Yield: 9 gm; PXRD of the obtained compound is depicted in figure- 10 and DSC thermogram is depicted in figure- 1 1. Example-19: Preparation of crystalline form-P of compound of formula-1

Melting the compound of formula-1 (10 gm) at 140-145°C under reduced pressure for 15 minutes. The above obtained oily residue was added to 100 ml of pre-cooled n-heptane at 0- 5°C. Stirred the reaction mixture for 36 hours at 0-5°C. Filtered the precipitated solid, washed with n-heptane and dried to get the title compound.

Yield: 9 gm; PXRD of the obtained compound is depicted in figure-7, its IR is depicted in figure-8 and its DSC is depicted in figure-9.

Example-20: Preparation of crystalline form-P of compound of formula-1

Melting the compound of formula-1 (10 gm) at 140-145°C under reduced pressure for 15 minutes. The above obtained oily residue was added to 100 ml of n-heptane at 30-40°C.

Stirred the reaction mixture for 36 hours at 30-40°C. Filtered the precipitated solid, washed with n-heptane and dried to get the title compound.

Yield: 9 gm; PXRD of the obtained compound is similar to the figure-7.

Example-21 : Preparation of amorphous form of compound of formula-1

Melting the compound of formula-1 ( 10 gm) at 140- 145°C under reduced pressure for 15 minutes and the above obtained oily residue was cooled to 0-5°C. Unload the obtained compound and dried to get the title compound. Yield: 9 gm; Purity by HPLC: 99.74%. PXRD of the obtained compound is depicted in figure-5 and IR is depicted in figure-6.

Exaniple-22: Preparation of crystalline form-I of compound of formula-1

Melting the compound of formula-1 (5 gm) at 140-145°C under reduced pressure for 15 minutes. 50 ml of n-heptane was added to the above obtained oily residue at 115-120°C.

Stirred the reaction mixture for 20 minutes at 1 15- 120°C. Cooled the reaction mixture to 25-

30°C and stirred for 60 minutes at the same temperature. Further cooled the reaction mixture to 0-5°C and stirred the reaction mixture for 60 minutes at the same temperature. Filtered the precipitated solid, washed with n-heptane and dried to get the title compound.

Yield: 4 gm; Purity by HPLC: 99.68%.

PATENT

CN 108675964

PATENT

CN 106316967

PATENT

WO 2017029594

PATENT

US8791122

Form-I  II  III

https://patents.google.com/patent/US8791122B2/en

PATENT

https://patents.google.com/patent/WO2018022704A1/en

Selexipag has the chemical name 2-{4-[(5,6-diphenylpyrazin-2- yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide. Selexipag has the following chemical structure:

[0004] Selexipag is being developed by Actelion and Nippon Shinyaku for the treatment of arteriosclerosis obliterans, pulmonary hypertension and Raynaud’s disease secondary to systemic sclerosis.

[0005] Selexipag is disclosed in US 7,205,302. US 8,791,122, US 9,284,280 and US 2014- 0155414 disclose polymorphs of Selexipag, denominated forms I, II and III. WO

2017/040872 discloses form IV and V of Selexipag.

xample 1: Preparation of Selexipag

[00126] A. Route 1

[00127] Crude Selexipag can be obtained by any method known in the art, for example by the method described in US 7,205,302 or according to the following.

[00128] B. Route 2

[00129] Step a: Preparation of 4-((5,6-diphenyl-pyrazin-2-yl)(isopropyl)amino)butan-l-ol

[00130] To 50 g (0.161 mol) of 5-bromo-2,3-diphenylpyrazine, 116 g (0.884 mol, 5.5 eq/mol) of 4-(isopropylamino)-butan-l-ol and 13.33 g of KI (0.080 mol, 0.5 Eq/mol) were added. The reaction mixture was stirred, warmed and then heated up to 140°C for about 18- 20 hrs. The reaction was monitored by TLC up to completion (starting material about 1% by TLC). The reaction mixture was cooled down to room temperature. After the reaction was completed, the following work up step was performed:

[00131] Option 1 : Ethyl acetate was added (500 mL, 10 vol) and the organic phase was washed with water (150 mL, 3 vol). The organic phase was separated and aqueous phase was extracted with ethyl acetate (150 mL, 3 vol). The organic phases were joined and washed with water (200 mL, 2 vol) three times.

[00132] The solvent was distilled off under vacuum at not more than (“NMT”) 40°C until 1 vol (oil appearance).

[00133] Option 2: The material (mixture) was dissolved in acetone (250 mL, 5 vol), the solution obtained was cooled down to 0°C to 5°C and anti-solvent / water was added (1000 mL, 20 vol) for 40 minutes, then the suspension was stirred for about 30 minutes at about 0°C-5°C. The solid material was filtered and washed with water (200 mL, 4 vol). Crude wet product was obtained as yellow solid yielding 101.8 % WY (87 % MY), HPLC purity 90.8% on area at this stage.

[00134] The crude material, obtained in either of the above described options, was purified through crystallization from acetone :«-heptane as follows: to a solution of 4-((5,6-diphenyl- pyrazin-2-yl)(isopropyl)amino)butan-l-ol crude in acetone (175 mL, 3.5 vol) at 0°C – 5°C, hexane (600 mL, 12 vol) dropwise in about 120 min was added, then the precipitated mixture was cooled down to about -10°C and stirred for about 60 min. The product was filtered off and washed with hexane (250 mL, 5 vol) and dried under vacuum at 25°C. Pure product was obtained as yellowish solid yielding overall 77.2%, (66.5% MY), HPLC purity 98.2% on area.

[00135] Step b: Preparation (2-bromo-N-(methylsulfonyl)-acetamide)

[00136] To a suspension of 50 g (0.526 mol) of methanesulfonamide in toluene (625 mL, 12.5 vol) and isopropyl acetate (625 mL, 12.5 vol), 159.1 g (0.789 mol) of bromo-acetyl- bromide (“BAB”) was added under nitrogen atmosphere. The reaction mixture was heated up to about 90°C for about 8 hours under a nitrogen stream. The reaction was monitored by TLC up to completion (starting material about 1% by TLC). The reaction mixture was cooled down to about 40°C and concentrated under vacuum until 10 volumes. Subsequently, toluene was added (250 mL, 5 vol) and distilling off solvents is carried out at NMT 30°C until 10 volumes. Then was added dichloromethane (100 mL, 2 vol) and the mixture was cooled down at 0°C and is stirred for 90 min. The solid was filtered and washed with

dichloromethane (100 mL, 2 vol). Crude product was obtained as beige solid material yielding 187% WY (83% MY), HPLC purity 99.2% at this stage. [00137] The crude material (83 g) was purified through re-slurring with dichloromethane (166 mL, 2 vol; preferably 332 mL, 4 vol) by stirring at about 32°C for about 60 min. The crystallization mixture was cooled down to about 0°C-5°C and stirring for 30 min, filtered off and washed with dichloromethane (100 mL, 2 vol). Subsequently, the material was dried at 35°C for 24 hours. Pure and dried material was obtained as white off solid yielding overall 173%, (77% MY), HPLC purity 99.6 % on area.

[00138] Step c: Preparation of (2-[4-[(5,6-diphenyl-2-pyrazinyl)(l- methylethyl)amino]butoxy]-N-(methylsulfonyl)-acetamide) – Selexipag

[00139] To 10 g (0.028 mol) of 4-((5,6-diphenyl-pyrazin-2-yl)(isopropyl)amino) butan-l-ol was added a strong base (6.0 eq/mol), previously suspended in an appropriate solvent, within a range of from -10°C to 40°C under a nitrogen atmosphere and stirred for 60 min. Then, a solution of 17.9 g (3.0 eq/mol) of 2-bromo-N-(methylsulfonyl)-acetamide, previously dissolved in the same solvent, is added dropwise within a range of from 120 tol 80 min, controlling the exothermic temperature. The reaction was monitored by TLC up to completion. Subsequently, the mixture reaction was cooled down around 5°C and water is added by controlling the exotherm (NMT 15°C). Finally, an acetic acid solution was added and the suspension was stirred for about 60 min at 0°C -5°C. The product (crude) was filtered off and washed with water. An amorphous solid was obtained. The crude product was purified by crystallization from ethanol:THF.

[00140] Step d: Purification of Selexipag

[00141] Crude Selexipag can be purified by crystallization in an organic solvent for example alcohols such as ethanol, iso-amyl alcohol, iso-propyl alcohol, butanol; ethers such as tetrahydrofuran, hydrocarbons such as heptane and mixed solvents thereof.

[00142] C. Route 3

[00143] 33.3 g (0.297 mol, 6.0 eq/mol) of potassium tert-butoxide were dissolved in DMF (2.8 vol) in a flask (500 mL) under nitrogen atmosphere and stirred for 15 min. Then, a solution of 17.9 g (0.049 mol, 1.0 eq/mol) of 4-((5,6-diphenyl-pyrazin-2-yl)(isopropyl) amino) butan-l-ol (SLX-4) dissolved in DMF (1.2 vol) was added in one portion. The reaction mixture was stirred for 60 min within a temperature range from 20°C to 25°C at 150 rpm Then, a solution of 32.1 g (0.15 mol, 3.0 Eq/mol) of 2-bromo-N-(methylsulfonyl)- acetamide (SLX-9), previously dissolved in DMF (1.3 vol), was added dropwise for 120 minutes by controlling the temperature (exothermic process).

[00144] The reaction mixture was quenched with cool water (0.33 vol), transferred into a flask of more capacity (1000 mL) and placed in an ice bath. Cool water (38.32 vol) was added to the reaction mixture and the pH was adjusted to 5.0 with AcOH (0.33 vol). The mixture was stirred at 300 rpm for 40 min. Then, the flask with the reaction mixture was stored in the refrigerator at 8°C. After 8h, the solid was filtered and washed with cool water (5 vol, 2 times). The crude product (yellow solid) was drained (i.e. dried) for 30 min and was stored at 8°C.

Example 2: Preparation of crystalline Selexipag Form IV

[00145] A. Route 1

[00146] 3.0 g of Selexipag was dissolved in dimethylformamide (“DMF”) (12 mL, 4 vol). The obtained solution was added dropwise to a pre-cooled acetic acid solution (0.06 M, 120 mL, from 2°C to 8°C) to obtain a suspension. The suspension was stirred within a range of from 2°C to 8°C for 30 min; then the material was filtered, washed with water (10 mL, 3.3 vol) and drained (i.e. dried) for 10 minutes. The solid material (amorphous) was suspended in heptane (25 mL, 7.5 vol) and the obtained suspension was stirred for 30 minutes at room temperature. The material was filtered, washed with heptane (20 mL, 6.6 vol) and drained (i.e. dried) under vacuum for at least 30 minutes at room temperature to obtain the Form IV Crystal.

[00147] B. Route 2

[00148] Crude Selexipag (1.0 g, amorphous solid, obtained from the synthesis) was dissolved in ethyl acetate (5 vol, 5 mL), then water was added (10 vol, 10 mL) into the solution, the mixture was stirred for about 10 minutes and the pH was adjusted to a range of from 8.0 to 9.0 by titration with K2CO₃ solution. The phases were separated; the pH of the aqueous phase was adjusted to a range of from 3.5 to 5.0 by titration with acetic acid. Then, ethyl acetate (10 vol, 10 mL) was added into the aqueous phase, the obtained mixture was stirred and the phases were separated. The organic phase was distilled off under reduced pressure (from 2 to 3 volumes), and a solution was obtained. The obtained concentrated solution was quickly added to a mixture (suspension) of Form IV in ^-heptane (17 mL, 17 vol), over a period of less than 5 minutes, (the suspension temperature was of from 15°C to 25°C), and a suspension was obtained. The obtained suspension was stirred (155rpm) for 90 minutes at a temperature of from 0°C to 5°C. The suspension was filtered, washed with heptane, squeezed for 15 minutes and dried at 25°C, under vacuum, for about 14 hours. The product was analyzed by PXRD – Form IV was obtained.

[00149] The above procedure can be performed by dissolving the crude amorphous starting material in any suitable organic solvent, for example ester solvent. Example 3: Preparation of (2-[4-[(5,6-diphenyl-2-pyrazinyl)(l- methylethyl)amino] butoxy] -N-(methylsulfonyl)-acetamide) – Selexipag

SLX-4 SLX-9 SLX-6

[00150] 9.2 grams (0.082 mol, 5.9 eq/mol) of potassium tert-butoxide were combined with DMF (2.7 vol, 13.5 mL) in a flask (50 mL) under nitrogen atmosphere and a suspension was formed and was stirred for 20 min. Then, 5.0 g (0.014 mol, 1.0 eq/mol) of 4-((5,6-diphenyl- pyrazin-2-yl)(isopropyl)amino)butan-l-ol (SLX-4) as solid powder was added under nitrogen atmosphere. The reaction mixture was stirred for 60 min within a temperature range from 20°C to 25°C and at 170 rpm. Then, a solution of 8.9 g (0.041 mol, 3.0 eq/mol) of 2-bromo- N-(methylsulfonyl)-acetamide (SLX-9), previously dissolved in DMF (1.3 vol, 6.5 mL), was added dropwise for 120 minutes by controlling the temperature (exothermic process). After the end of addition, the reaction was completed, and the reaction mixture was quenched with cold water (0.5 vol, 2.5 mL), subsequently transferred into a flask of more capacity (500 mL) and placed into an ice bath. Cold water (40 vol, 200 mL) was added into the suspension and the pH was adjusted within the range from 4.0 to 5.0 with acetic acid. The obtained mixture was stirred for 120 min. The crude amorphous product was collected by filtration and washed twice with cold water (5 vol, 25 mL). The product was drained (i.e. dried) for 30 min and isolated as a yellow-brown solid which was stored within the range from 2°C to 8°C for approximately 17 hours. Then, the crude amorphous material was dissolved in ethyl acetate (15 vol, 75 mL) and water was added into the solution (30 vol, 150 mL). The pH was adjusted from 8.0 to 9.0 by addition of potassium carbonate solution, the phases were separated and the aqueous phase was washed twice with ethyl acetate (7.5 vol, 37.5 mL). The pH of the final aqueous phase was adjusted to a range from 4.0 to 5.0 with acetic acid. Then, ethyl acetate was added (30 vol, 150 mL) and the phases were separated. The organic phase was washed twice with water (7.5 vol, 37.5 mL). The organic phase was distilled off under reduced pressure (from 6 to 7 volumes, or from 6 to 15 volumes) and a solution was obtained.

[00151] In a different flask (capacity of 250 mL with a PTFE stirrer blade), a suspension of 0.05 g of Selexipag Form IV in ^-heptane (30 volumes, 150 mL) was stirred for 60 minutes within the range 0°C to 5°C and this suspension was added into the above ethyl acetate concentrated solution at room temperature over a period of less than 5 minutes. The final suspension was cooled down to 0°C to 5°C and stirred (220 rpm) for 120 minutes. The solid product was filtered off and washed twice with cold heptane (5 vol, 25 mL). The product was drained (i.e. dried) overnight. The product was analyzed by PXRD – Form VI was obtained, PXRD pattern is depicted in Figure 1.

PATENT

CN105949135

https://patents.google.com/patent/CN105949135A/en

Example 1

[0027] A) Preparation of [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate:

[0028] 4 – [(tert-butoxycarbonyl) (isopropyl) amino] butanol -1_ (20 (^, 0.09111 〇1) and tert-butyl bromoacetate (21 · lg, 0 llmol) solution. The reaction was stirred for 2 hours to burn dichloromethane (90mL), was added tetrabutylammonium chloride (0.72g, 2.6mmol), potassium hydroxide (7.3g, 0.13mol) and water (12.0g), the reaction mixture was 25 ° C The reaction solution was concentrated under reduced pressure and rotary evaporated to dryness and extracted with ethyl acetate, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, a mixed solvent of ethanol and recrystallized from isopropanol to give [4- (tert-butoxycarbonyl) (isopropyl yl) aminobutoxy] acetate, as a pale yellow oil (26.6 g of), a yield of 89.0%, the reaction formula of this step is as follows:

[0029]

[0030] B) Preparation of [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetic acid:

[0031] [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate (26. (^, 0.075! 11〇1) was dissolved in methanol (50 mL), was added sodium hydroxide solution (NaOH = 3 · 3g, 0 · 08mol; water 9 · 0g), was heated to 80 ° C for 6 hours, cooled to room temperature, after treatment and purification, to give [4- (tert-butoxycarbonyl) (isopropyl ) aminobutoxy] acetic acid (20.7 g of), a yield of 95.0%, the reaction formula of this step is as follows:

[0033] C) Preparation of 2- [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide:

[0034] [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetic acid (20 (^, 0.07 11〇1) and a hoot “-.! P sitting carbonyldiimidazole (14.0g, 0.09mo 1 ) was dissolved in tetrahydro-thiopyran Misaki (70 mL), with stirring, was added methyl sulfonamide (7.9g, 0.08mol), the reaction mixture was 90 ° C the reaction stirred for 18 hours, the reaction solution was concentrated by rotary evaporation to dryness, extracted with ethyl acetate, over magnesium sulfate, and concentrated by rotary evaporation to dryness, recrystallized from methanol to give 2- [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide as an off-white solid (21.2 g), yield 83.7%, the reaction formula of this step is as follows:

[0036] D) Preparation of SIPA Seiler: 2- [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide (20 (^, 0.055111〇1. ) and dissolved in methanol (1101 ^), trifluoroacetic acid (6.88,0.06111〇1), 65 ° (: the reaction stirred for 6 hours to complete the reaction, the reaction was added dropwise to a stirred solution of water (200 mL), cooled to 0 ° C crystallization for 3 hours and filtered to give the intermediate compound (2- [4- (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide), and then dissolved in methanol (40 mL), was added 5 – chloro-2,3-diphenyl-pyrazine (16 · 0g, 0 · 06mol), N, N- diisopropylethylamine (15 · 5g, 0 · 12mol), the reaction mixture was stirred reactor 8 100 ° C hours, the reaction was cooled to room temperature, water (40 mL), cooled to -10 ° C crystallization for 3 hours and filtered to give SIPA game music, as a white solid (25.0 g of), a yield of 92.3%, the reaction step formula as follows:

[0037]

[0038] Example 2

[0039] A) Preparation of [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate:

[0040] 4 – [(tert-butoxycarbonyl) (isopropyl) amino] -1-butanol (23 (^, 0.10111 〇1) and tert-butyl bromoacetate (25 · 2g, 0 · 13mol) was dissolved. burning in 1,2-dichloroethane (110mL), was added tetrabutylammonium bromide (1 · lg, 3 · 5mmol), sodium hydroxide (6.4g, 0.16mol) and water (14.0g), the reaction mixture was 30 ° C The reaction was stirred for 3 hours, the reaction solution was concentrated by rotary evaporation to dryness under reduced pressure and extracted with ethyl acetate, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, a mixed solvent of ethanol and recrystallized from isopropanol to give [4- (tert-butoxy butoxycarbonyl) (isopropyl) aminobutoxy] acetate, as a pale yellow oil (30.3 g of), a yield of 88.2%, the reaction of the present step is the same formula as in Example 1;

[0041] B) Preparation of [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetic acid:

[0042] [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate (30. (^, 0.09! 11〇1) was dissolved in ethanol (85 mL), was added potassium hydroxide solution ( 1 (! = 5.78,0.10111〇1 01; 128 water), heated to 75 ° (: 7 hours, cooled to room temperature, after treatment and purification, to give [4- (tert-butoxycarbonyl) (isopropyl ) aminobutoxy] acetic acid, an off-white solid (23.5 g of), a yield of 93.7%, the reaction of the present step is the same formula as in Example 1;

[0043] C) Preparation of 2- [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide:

[0044] [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetic acid (23 (^, 0.08 11〇1) and Chi ^ -! Dicyclohexyl carbodiimide (22. lg, 0. llmol) was dissolved in chloroform (120 mL), with stirring, was added methyl sulfonamide (9.8g, 0. lOmol), the reaction mixture was 80 ° C the reaction stirred for 19 hours, the reaction solution was concentrated by rotary evaporation to dryness, ethyl acetate was added and extracted dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, recrystallized from methanol to give 2- [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide, off-white the solid (24.8 g of), a yield of 85.0%, the reaction of the present step is the same formula as in Example 1;

[0045] D) Preparation of SIPA Seiler: 2- [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide (24 (^, 0.065111〇1. ) and dissolved in ethanol (1601 ^), trifluoroacetic acid (9 (^, 0.08111〇1.), 70 ° (: the reaction was stirred for 7 hours to complete the reaction, the reaction was added dropwise to a stirred solution of water (260 mL of), cooled crystallization to 0 ° C for 3 hours and filtered to give the intermediate compound (2- [4- (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide), and then dissolved in ethanol (90 mL) , 5-chloro-2,3-diphenyl-pyrazine (! 11〇1 21.8 8,0.08), triethylamine (14.98,0.15111〇1), the reaction mixture was 100 ° (: The reaction was stirred for 18 hours, the reaction solution cooled to room temperature, water (40 mL), cooled to -10 ° C crystallization for 3 hours and filtered to give SIPA game music, as a white solid (29.6 g of), a yield of 91.0%, the reaction of the present step is the same formula as in Example 1 .

[0046] Example 3

[0047] A) Preparation of [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate:

[0048] 4 – [(tert-butoxycarbonyl) (isopropyl) amino] -1-butanol (12g, 0.05mol) and t-butyl bromoacetate (12.1g, 0.06mol) was dissolved in chloroform (70mL), was added tetrabutylammonium iodide (0 · 5g, 1 · 3mmol), lithium hydroxide (1 · 7g, 0 · 07mol) and water (6.5 g of), the reaction mixture was stirred 20 ° C for 4 hours, the reaction solution under reduced pressure concentrated by rotary evaporation to dryness, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, a mixed solvent of ethanol and recrystallized from isopropanol to give [4- (tert-butoxycarbonyl) (isopropyl) aminobutyrate oxygen yl] acetate, as a pale yellow oil (15.6 g of), a yield of 86.8%, the reaction of the present step is the same formula as in Example 1;

[0049] B) Preparation of [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetic acid:

[0050] [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate (15.0g, 0.04mol) was dissolved in isopropanol (40mL), was added a solution of lithium hydroxide (LiOH = 1 · 3g, 0 · 05mol; water 6 · 0g), was heated to 70 ° C for 8 hours, cooled to room temperature, after treatment and purification, to give [4- (tert-butoxycarbonyl) (isopropyl) aminobutyrate oxy] acetic acid as an off-white solid (11.7 g), 93.0% yield, this step is the same reaction scheme of Example 1;

[0051] C) Preparation of 2- [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide:

[0052] [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetic acid (11 (^, 0.04! 11〇1) and 1- (3-dimethylaminopropyl) -3- ethylcarbodiimide (8.38,0.05111〇1) was dissolved in acetonitrile (4〇1111 ^), with stirring, was added methyl sulfonamide (5.] ^, 0.05mol), the reaction mixture was 95 ° C the reaction stirred for 22 hours, The reaction solution was concentrated by rotary evaporation to dryness, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, recrystallized from methanol to give 2- [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide as an off-white solid (11.7 g), yield 84.2%, the reaction of the present step is the same formula as in Example 1;

[0053] D) Preparation of SIPA Seiler: 2- [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide (11 (^, 0.03111〇1. ) and dissolved in dichloromethane (601 ^), trifluoroacetic acid (4.48,0.04111〇1), 50 ° (: the reaction was stirred for 10 hours to water (120 mL completion of the reaction, the reaction liquid was added to a stirred), cooled to crystallization 0 ° C for 3 hours and filtered to give the intermediate compound (2- [4- (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide), and then dissolved in tert-butanol (40 mL ), 5-chloro-2,3-diphenyl-pyrazine (9.68,0.036 11〇1), 4-dimethylaminopyridine (8.18,0.07111〇1), the reaction mixture was 110 ° (:! reaction was stirred for 14 hours the reaction was cooled to room temperature, water (15 mL), cooled to -10 ° C crystallization for 3 hours and filtered to give SIPA game music, as a white solid (13.5 g of), a yield of 90.5%, the reaction in this step is the same formula Example 1.

[0054] Example 4

[0055] A) Preparation of [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate:

[0056] 4 – [(tert-butoxycarbonyl) (isopropyl) amino] -1-butanol (15 (^, 0.065111〇1) and t-butyl bromoacetate (17.78,0.09111〇1) was dissolved in toluene (701] 11 ^), was added tetrabutylammonium hydrogen sulfate (0.888,2.61] 11] 1〇1), potassium carbonate (15.2 area, 0.1 lmol) and water (9.5 g of), the reaction mixture was stirred 40 ° C for 1.5 hours, the reaction solution was concentrated under reduced pressure and rotary evaporated to dryness and extracted with ethyl acetate, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, a mixed solvent of ethanol and recrystallized from isopropanol to give [4- (tert-butoxycarbonyl) (isopropyl propyl) aminobutoxy] acetate, as a pale yellow oil (19.6 g of), in the same reaction formula in this step a yield of 87.5% in Example 1;

[0057] B) Preparation of [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetic acid:

[0058] [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate (19 (^, 0.055! 11〇1) was dissolved in tert-butanol (60 mL), hydroxide solution of cesium (CsOH = 11. lg, 0.07mol; water, 8.0 g), the reaction was heated to 75 ° C for 6.5 hours cooled to room temperature, after treatment and purification, to give [4- (tert-butoxycarbonyl) (isopropyl ) aminobutoxy] acetic acid, an off-white solid (15.0 g of), a yield of 94.2%, the reaction of the present step is the same formula as in Example 1;

[0059] C) Preparation of 2- [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide:

[0060] [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetic acid (15.0g, 0.05mol) and diazabicyclo 1,8_

[5.4.0] – | -7- dilute (9.5 region, 0.06111〇1) was dissolved in toluene (8〇1111 ^), with stirring, was added methyl sulfonamide (5.7 region, 0.06mo 1), the reaction mixture was 105 ° C for 16 hours, the reaction solution was concentrated by rotary evaporation to dryness, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, recrystallized from methanol to give 2- [4- (tert-butoxycarbonyl) (isopropyl ) aminobutoxy] -N- (methylsulfonyl) acetamide as an off-white solid (16.6 g of), 87.3% yield, this step is the same reaction scheme of Example 1;

[0061] D) Preparation of SIPA Seiler: 2- [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide (16 (^, 0.04111〇. 1) and dissolved in ethyl acetate (^ 1,301,111), trifluoroacetic acid (5.78,0.051] 1〇1), 80 <€ the reaction was stirred for 5 hours to complete the reaction, the reaction was added dropwise to a stirred solution of water (150 mL), was cooled to 0 ° C crystallization for 3 hours and filtered to give the intermediate compound (2- [4- (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide), then dissolved in isopropanol (50 mL), was added 5-chloro-2,3-diphenyl-pyrazine (13.58,0.05 11〇1!), a hoot dimethylaniline (12.28,0.10111〇1), the reaction mixture was 95 ° (: The reaction was stirred 12 hours, the reaction was cooled to room temperature, water (40 mL), cooled to -10 ° C crystallization for 3 hours and filtered to give SIPA game music, as a white solid (19.7 g of), a yield of 91.0%, the reaction step formula in Example 1.

//////////////

Selexipag (C₂₆H₃₂N₄O₄S, M_r = 496.6 g/mol) ist ein Diphenylpyrazin-Derivat. Es wird in der Leber zum aktiven Metaboliten ACT-333679 (MRE-269) biotransformiert. Selexipag unterscheidet sich strukturell von Prostazyklin und anderen Prostazylin-Rezeptor-Agonisten.

References

• 1 Sitbon, O.; Morrell, N. (2012). “Pathways in pulmonary arterial hypertension: The future is here”. European Respiratory Review 21 (126): 321–327. doi:10.1183/09059180.00004812. PMID 23204120.
• 2 New Drug Approved for Rare Lung Disorder. PPN. 23 Dec 2015 Has link to GRIPHON study results

1. Kuwano et al. NS-304, an orally available and long-acting prostacyclin receptor agonist prodrug. J Pharmacol Exp Ther 2007;322:1181-1188.
2. Kuwano et al. A long-acting and highly selective prostacyclin receptor agonist prodrug, NS-304, ameliorates rat pulmonary hypertension with unique relaxant responses of its active form MRE-269 on rat pulmonary artery. J Pharmacol Exp Ther 2008;326:691-699.
3. Simonneau G, Lang I, Torbicki A, Hoeper MM, Delcroix M, Karlocai K, Galie N. Selexipag, an oral, selective IP receptor agonist for the treatment of pulmonary arterial hypertension Eur Respir J 2012; 40: 874-880
4. Mubarak KK. A review of prostaglandin analogs in the management of patients with pulmonary arterial hypertension. Respir Med 2010;104:9-21.
5. Sitbon, O.; Morrell, N. (2012). “Pathways in pulmonary arterial hypertension: The future is here”. European Respiratory Review 21 (126): 321–327. doi:10.1183/09059180.00004812. PMID 23204120.
6. Publication numberPriority datePublication dateAssigneeTitle
   WO2016193994A12015-05-292016-12-08Megafine Pharma (P) Ltd.Amorphous selexipag and process for preparation thereof

   WO2017040872A12015-09-032017-03-09Teva Pharmaceuticals International GmbhSolid state forms of selexipag

   WO2017042731A12015-09-102017-03-16Lupin LimitedAmorphous form of selexipag and solid dispersion thereof

   WO2017109772A1 *2015-12-202017-06-29Mapi Pharma Ltd.Amorphous form of selexipag

   WO2018008042A1 *2016-07-052018-01-11Maithri Drugs Private LimitedNovel process for the preparation of 2-{4-[(5,6-diphenyl pyrazin-2-yl)(isopropyl)amino]butoxy}-n-(methylsulfonyl)acetamide and novel polymorphs thereof

   WO2018015974A12016-07-202018-01-25Mylan Laboratories LimitedPolymorphic forms and amorphous solid dispersion of selexipag

   WO2018022704A12016-07-262018-02-01Teva Pharmaceuticals International GmbhCrystalline form vi of selexipag

   WO2018078383A12016-10-272018-05-03Cipla LimitedPharmaceutical composition comprising amorphous selexipag

   Family To Family Citations

   WO2009107736A1 *2008-02-282009-09-03日本新薬株式会社Fibrosis inhibitor

   CN106279047A2015-05-132017-01-04上海适济生物科技有限公司Preparation method of prostacyclin receptor agonist

   WO2017029594A1 *2015-08-172017-02-23Dr. Reddy’s Laboratories LimitedProcesses for preparation of selexipag and its amorphous form

   WO2017042828A3 *2015-09-102017-04-27Megafine Pharma (P) Ltd.Process for the preparation of selexipag

   EP3192502A12016-01-152017-07-19Sandoz AgPharmaceutical composition of selexipag

   WO2017168401A1 *2016-04-012017-10-05Honour (R&D)Process for the preparation of diphenylpyrazine derivatives

   CN105949135A *2016-05-102016-09-21湖南欧亚生物有限公司Synthetic method of selexipag

   EP3335699A12016-12-152018-06-20H e x a l AktiengesellschaftSelexipag formulation in liquisolid system

Selexipag

Names
IUPAC name 2-{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}-N-(methanesulfonyl)acetamide
Other names ACT-293987, NS-304
Identifiers
CAS Number	475086-01-2
ChEMBL	ChEMBL238804
ChemSpider	8089417
IUPHAR/BPS	7552
Jmol interactive 3D	Image
KEGG	D09994
PubChem	9913767
UNII	P7T269PR6S
InChI[show]
SMILES[show]
Properties
Chemical formula	C26H32N4O4S
Molar mass	496.6 g·mol−1

//////////ACT-333679,  MRE-269, Selexipag, セレキシパグ , UNII-5EXC0E384L, селексипаг , سيليكسيباق , Orphan Drug, fda 2015, NS 304,  ACT 293987,  Uptravi, EU 2016, 

CC(C)N(CCCCOCC(=O)NS(=O)(=O)C)C1=CN=C(C(=N1)C2=CC=CC=C2)C3=CC=CC=C3

ROLAPITANT HYDROCHLORIDE

• Rolapitant HCl
• Rolapitant hydrochloride
• Sch 619734
• SCH619734
• UNII-57O5S1QSAQ

(5S ,8S)-8-[[(1R)-1-[3 ,5-
Bis(trifluoromethyl)phenyl] ethoxy] methyl]-8-phenyl-1,7-
diazaspiro[4.5]decan-2-one hydrochloride monohydrate.

CAS 914462-92-3

Empirical Formula: C25H26F6N2O2 · HCl · H2O, Molecular Weight:  555

USAN Name: Rolapitant hydrochloride, INN Name:  rolapitantum or rolapitant

CAS Number: 552292-08-7 (rolapitant free base); 914462-92-3 (rolapitant HCl monohydrdate).

Rolapitant

• Molecular FormulaC₂₅H₂₆F₆N₂O₂
• Average mass500.477 Da

It is in late-stage trials of its drug rolapitant, which showed promising mid-stage results in reducing nausea and vomiting in patients undergoing chemotherapy

Rolapitant hydrochloride is a tachykinin neurokinin 1 (NK1) antagonist in phase III clinical trials at Tesaro for the prevention of chemotherapy-induced nausea and vomiting (CINV). Phase II clinical trials are also under way at OPKO for this indication. At Merck & Co., phase II clinical studies were also under way for the treatment of chronic idiopathic cough and for the prevention of chemotherapy-induced nausea; however, no recent developments have been reported for these indications.

NK1 is a G-protein coupled receptor found in the central and peripheral nervous systems. Substance P is the endogenous ligand for this receptor, whose activation leads to the production of inositol triphosphate. NK1 is believed to be involved in the emetic response.

The drug candidate was originally developed by Schering-Plough (now Merck & Co.), and in 2009 it was licensed to OPKO for the prevention of nausea and vomiting related to cancer chemotherapy and surgery. In 2010, rolapitant was licensed by OPKO to Tesaro on a worldwide basis for the prevention of chemotherapy-induced nausea and vomiting.

Rolapitant is a selective, bioavailable, CNS penetrant neurokinin NK1 receptor antagonist that shows behavioral effects in animals models of emesis. In vitro studies indicate that rolapitant has a high affinity for the human NK1 receptor of 0.66 nM and high selectivity over the human NK2 and NK3 subtypes of >1000-fold. Rolapitant is a functionally competitive antagonist, as measured by calcium efflux, with a calculated Kb of 0.17 nM.  (source: Pharmacol Biochem Behav.2012 Mar 31.

Rolapitant is a potent, selective NK1 receptor antagonist that is rapidly absorbed, has a remarkably long half-life (up to180 hours), and appears to have a low potential for drug-drug interactions.  A randomized, multicenter, double-blind, dose-ranging study of rolapitant was conducted with placebo and active control groups. Six hundred nineteen adult women undergoing open abdominal surgery were randomly assigned in equal ratios to 1 of 6 study arms: oral rolapitant in 5-mg, 20-mg, 70-mg, or 200-mg doses; IV ondansetron 4 mg; or placebo, stratified by history of PONV or motion sickness. The primary study endpoint was absence of emetic episodes, regardless of use of rescue medication, at 24 hours after extubation.RESULTS: Groups assigned to rolapitant 20-mg, 70-mg, and 200-mg had a higher incidence of no emesis in comparison with placebo at 24 hours after surgery. A linear relationship between rolapitant dose and primary outcome was seen. The probability of an emetic episode was significantly lower in the rolapitant 70-mg and 200-mg groups in comparison with placebo (P ≤ 0.001 based on the log-rank test). No significant differences were noted between rolapitant and the active control (ondansetron) at 24 hours after surgery, but there was a higher incidence of no emesis (regardless of rescue medication use) in the rolapitant 200- and 70-mg groups at 72 and 120 hours, respectively. CONCLUSION: Rolapitant is superior to placebo in reducing emetic episodes after surgery and reduces the incidence of vomiting in a dose-dependent manner. No differences in side effect profile were observed between rolapitant and placebo.

Rolapitant (INN,^[2] trade name Varubi /vəˈruːbi/ və-ROO-bee in the US and Varuby in Europe) is a drug originally developed by Schering-Plough and licensed for clinical development by Tesaro, which acts as a selective NK₁ receptor antagonist (antagonist for the NK₁ receptor).^[3] It has been approved as a medication for the treatment of chemotherapy-induced nausea and vomiting (CINV) after clinical trials showed it to have similar or improved efficacy and some improvement in safety over existing drugs for this application.^[4][5][6][7

Medical uses

Rolapitant is used in combination with other antiemetic (anti-vomiting) agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy.^[1] The approved antiemetic combination consists of rolapitant plus dexamethasone and a 5-HT₃ antagonist.^[8]

Contraindications

Under the US approval, rolapitant is contraindicated in combination with thioridazine, whose inactivation could be inhibited by rolapitant.^[9] Under the European approval, it is contraindicated in combination with St. John’s Wort, which is expected to accelerate inactivation of rolapitant.^[8]

Side effects

In studies comparing chemotherapy plus rolapitant, dexamethasone and a 5-HT₃ antagonist to chemotherapy plus placebo, dexamethasone and a 5-HT₃ antagonist, most side effects had comparable frequencies in both groups, and differed more between chemotherapy regimens than between rolapitant and placebo groups. Common side effects included decreased appetite (9% under rolapitant vs. 7% under placebo), neutropenia (9% vs. 8% or 7% vs. 6%, depending on the kind of chemotherapy), dizziness (6% vs. 4%), indigestion and stomatitis (both 4% vs. 2%).^[9]

Overdose

Up to eightfold therapeutic doses have been given in studies without problems.^[8]

Interactions

Rolapitant moderately inhibits the liver enzyme CYP2D6. Blood plasma concentrations of the CYP2D6 substrate dextromethorphanhave increased threefold when combined with rolapitant; and increased concentrations of other substrates are expected. The drug also inhibits the transporter proteins ABCG2 (breast cancer resistance protein, BCRP) and P-glycoprotein (P-gp), which has been shown to increase plasma concentrations of the ABCG2 substrate sulfasalazine twofold and the P-gp substrate digoxin by 70%.^[8]

Strong inducers of the liver enzyme CYP3A4 decrease the area under the curve of rolapitant and its active metabolite (called M19); for rifampicin, this effect was almost 90% in a study. Inhibitors of CYP3A4 have no relevant effect on rolapitant concentrations.^[8]

Pharmacology

Pharmacodynamics

Both rolapitant and its active metabolite M19 block the NK₁ receptor with high affinity and selectivity: to block the closely related receptor NK₂ or any other of 115 tested receptors and enzymes, more than 1000-fold therapeutic concentrations are necessary.^[10]

Pharmacokinetics

Rolapitant is practically completely absorbed from the gut, independently of food intake. It undergoes no measurable first-pass effect in the liver. Highest blood plasma concentrations are reached after about four hours. When in the bloodstream, 99.8% of the substance are bound to plasma proteins.^[8]

It is metabolized by the liver enzyme CYP3A4, resulting in the major active metabolite M19 (C4-pyrrolidine-hydroxylated rolapitant) and a number of inactive metabolites. Rolapitant is mainly excreted via the feces (52–89%) in unchanged form, and to a lesser extent via the urine (9–20%) in form of its inactive metabolites. Elimination half-life is about seven days (169 to 183 hours) over a wide dosing range.^[8]

Chemistry

The drug is used in form of rolapitant hydrochloride monohydrate, a white to off-white, slightly hygroscopic crystalline powder. Its maximum solubility in aqueous solutions is at pH 2–4.^[10]

Patents

WO 2003051840

PATENT

WO 2008118328

The preparation of diazaspirodecan-2-ones for example, 8-[{1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one, for example, (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one (the compound of Formula I) has been described in U.S. Pat. No. 7,049,320 (the ‘320 patent), issued May 23, 2006, the disclosure of which is incorporated herein in its entirety by reference.

The compounds described in the ‘320 patent are classified as tachykinin compounds, and are antagonists of neuropeptide neurokinin-1 receptors (herein, “NK-1” receptor antagonists). Other NK₁ receptor antagonists and their synthesis have been described, for example, those described in Wu et al, Tetrahedron 56, 3043-3051 (2000); Rombouts et al, Tetrahedron Letters 42, 7397-7399 (2001); and Rogiers et al, Tetrahedron 57, 8971-8981 (2001) and in published international application no. WO05/100358, each of which are incorporated herein in their entirety by reference.

“NK-1” receptor antagonists have been shown to be useful therapeutic agents, for example, in the treatment of pain, inflammation, migraine, emesis (vomiting), and nociception. Among many compounds disclosed in the above-mentioned ‘320 patent are several novel diazaspirodecan-2-ones, including the compound of Formula I, which are useful in the treatment of nausea and emesis associated with chemotherapy treatments (Chemotherapy-induced nausea and emesis, CINE).

The synthesis method for preparing the compound of Formula I described in the ‘320 patent generally follows Scheme I in the provision of 8-[{1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxyl}-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one compounds.

The process for the preparation of the compound of Formula I described in the ‘320 patent is carried out in 18 individual steps from commercially available starting materials (see the ‘320 patent at col. 43, line 55 to col. 45, line 20; col. 75. line 55 to col. 80, line 21; col. 90 lines 35 to 63; and col. 98, line 1 to col. 99. line 24). In many steps of the process described in the ‘320 patent, intermediate compounds must be isolated or isolated and purified before use in a subsequent step, often utilizing column chromatography for this purpose.

PATENT

US7049320

Examples 72a and 72b

Step 1:

To a solution of crude Compound 53 (19 g) in CH₂Cl₂ (300 ml) at RT, DIEA (15 ml, 0.087 mol) was added, followed by triphosgene (4.34 g, 0.015 mol). The mixture was stirred at RT for 18 h and was filtered through a pad of silica. Solvents were removed in vacuum to give crude Compound 60 as yellow oil which was used in the next reaction without further purifications.

Step 2:

To the crude Compound 60 in THF (200 ml) at 0° C., LiBH₄ (1.26 g, 0.058 mol) was added in small portions. The mixture was stirred at RT for 18 h before quenching with saturated NH₄Cl solution. Water and EtOAc were added to the mixture. Layers were separated and the aqueous layer was extracted with EtOAc (100×2). The combined organic layers were dried (MgSO₄) and filtered. Solvents were removed in vacuum and purification by column chromatography [hexane-EtOAc, 4:1 (v/v)] gave Compound 61 (12.9 g, 62% overall) as white foam.

Step 3:

Oxalyl chloride (4.2 ml, 0.048 mol) was added to a solution of DMSO (6.8 m[, 0.096) in CH₂Cl₂ (300 ml) at −78° C. under N₂. The mixture was stirred at −78° C. for 15 min before a solution of Compound 61 (8.5 g, 0.012 mol) in CH₂Cl₂ (100 ml) was added. The mixture was stirred at −78° C. for a further 1 h and Et₃N (23.5 ml) was added. The cooling bath was removed and the mixture was warmed to RT before it was quenched with saturated NaHCO₃ solution. Layers were separated and the aqueous was extracted with CH₂Cl₂ (150 ml×2). The combined organic layers were dried (MgSO₄) and filtered. Removal of solvents in vacuum gave an aldehyde as yellow oil. To a mixture of NaH (1.44 g, 0.036 mol) in THF at 0° C., methyl diethylphosphonoacetate (6.6 ml, 0.036 mol) was added. The mixture was stirred at 0° C. for 15 min and a solution of aldehyde in THF (100 ml) was added. The cooling bath was removed and the mixture was stirred at RT for 1 h. The reaction was quenched with saturated NH₄Cl solution. Water and EtOAc were added to the mixture. Layers were separated and the aqueous layer was extracted with EtOAc (200 ml×2). The combined organic layers were dried (MgSO₄) and filtered. Solvents were removed in vacuum and purification by column chromatography [hexane-EtOAc, 4:1 (v/v)] gave an ester as white foam. The ester was dissolved in EtOH (100 ml) and a catalytic amount of palladium (1.28 g, 10% on carbon) was added. The mixture was shaken under H₂ (50 psi) for 2 days. Catalytic amount of Pd(OH)₂ (20% on carbon) was then added to the mixture and the mixture was again shaken under H₂ (50 psi) for 5 h. The mixture was filtered through a pad of Celite and solvents were removed in vacuum to give a white foam. The foam was then dissolved in CH₂Cl₂ (200 ml) and TFA (8.9 ml, 0.12 mol) was added. The mixture was stirred at RT for 18 h and was cooled at 0° C. before it was neutralized with saturated NaHCO₃ solution. Water and EtOAc were added to the mixture. Layers were separated and the aqueous layer was extracted with EtOAc (200 ml×2). The combined organic layers were dried (MgSO₄) and filtered. Solvents were removed in vacuum to give a yellow oil. The oil was dissolved in CH₃OH (50 ml) and a catalytic amount of K₂CO₃ (166 mg, 0.0012 mol) was added. The mixture was heated at 60° C. for 2 h. After being cooled to RT, the mixture was filtered through a pad of silica and solvents were removed in vacuum. Purification by column chromatography (EtOAc) gave the mixture of two isomers Example 72a and 72b (2.3 g, 38% overall) as white foam. Separation by HPLC using Chiralcel OD [hexane-isopropanol, 95:5 (v/v)] gave the less polar major isomer Example 72a as white foam. Electrospray MS [M+1]⁺=501.1. Continuous elution with the same solvent system gave the more polar minor isomer Example 72b as colorless oil.

Electrospray MS [M+1]⁺=501.1.

PATENT

US8552191

Example 6 Preparation of Formula I Compound Salt: (5S,8S)-8-({(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}methyl)-8-phenyl-1,7-diazaspiro[4.5]decan-2-one hydrochloride monohydrate

…………………

https://www.google.it/patents/US8552191?hl=it&dq=WO+2008118328&ei=alDCUs-_KYiIrQeg3oCwDw&cl=en

……………

update added

Rolapitant Hydrochloride Hydrate (Varubi)

 

PATENT

https://patents.google.com/patent/CN106866669A/en

⑴ Route A:

[0005] ⑵ Route B:

[0007] (3) Route C:

[0009] Scheme C, wherein the method further comprises synthesizing Via, namely:

Won] now, with respect to the other two routes, from the reaction step, time costs, material costs, product yield and product purity of view, comparing the current line C is respected, it is more suitable for production. But even so, there are still a number of route C the following questions:

[0012] [1], the synthesis of compound V, there is a slow reaction, and the reaction was not complete and so on;

[0013] [2], when Via a salt, the desired product is low chiral purity and yield to be improved;

[0014] [3], when VIII recrystallized grain size to be improved.

CLIP

Rolapitant

Clinical data
Pronunciation	/roʊˈlæpɪtænt/ roh-LAP-i-tant
Trade names	Varubi (US), Varuby (EU)
Synonyms	SCH 619734
AHFS/Drugs.com	varubi
License data	EU EMA: by INN
Routes of administration	By mouth (tablets)
ATC code	A04AD14 (WHO)
Legal status
Legal status	US: ℞-only
Pharmacokinetic data
Bioavailability	nearly 100%
Protein binding	99.8%
Metabolism	CYP3A4
Metabolites	C4-pyrrolidine-hydroxylated rolapitant (major)
Elimination half-life	169–183 hours
Excretion	Feces (52–89%), urine (9–20%)[1]
Identifiers
IUPAC name[show]
CAS Number	552292-08-7
PubChem CID	10311306
IUPHAR/BPS	5749
DrugBank	DB09291
ChemSpider	8486772
UNII	NLE429IZUC
KEGG	D10742
ChEBI	CHEBI:90908
Chemical and physical data
Formula	C25H26F6N2O2
Molar mass	500.476 g/mol
3D model (JSmol)	Interactive image
SMILES[hide] FC(F)(F)c(c4)cc(C(F)(F)F)cc4C(C)OCC3(c2ccccc2)NCC1(CC3)NC(=O)CC1

Eluxadoline

• Molecular FormulaC₃₂H₃₅N₅O₅
• Average mass569.651 Da

5-({[(2S)-2-amino-3-(4-carbamoyl-2,6-dimethylphenyl)propanoyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino}methyl)-2-methoxybenzoic acid

5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid

864821-90-9 CAS

JNJ-27018966

Molecular Formula: C₃₂H₃₅N₅O₅

Molecular Weight: 569.6508

Agents for Irritable Bowel Syndrome, mu-Opioid Agonists, delta-Opioid Antagonists

Eluxadoline

Trade Name: Viberzi®

Research Code: JNJ-27018966, JNJ27018966, JNJ 27018966

Chemical Name: 5 – [[[(2S) -2-amino-3- [4- (aminocarbonyl) -2,6-dimethylphenyl ] -1- oxopropyl] [(1S) -1- (4-phenyl-1H-imidazol-2-yl) ethyl] amino] methyl] -2-methoxybenzoic acid

MOA: mu opioid receptor agonist, Indication: Irritable bowel syndrome with diarrhea (IBS-D)

Approval Date: May 27, 2015 (US)

Originator: Furiex Pharmaceuticals Inc ( Furiex acquired Eluxadoline from Janssen in 2011 )

Developer: Forest Laboratories Inc. (acquired by Actavis PLC in 2014 )

Eluxadoline, sold under the brand names Viberzi (/vaɪˈbɜːrzi/ vy-BUR-zee) in the US and Truberzi in Europe,^[2] is a medication taken by mouth for the treatment of diarrhea and abdominal pain in individuals with diarrhea-predominant irritable bowel syndrome (IBS-D).^[3]It was approved for use in the United States in 2015.^[4] The drug originated from Janssen Pharmaceutica and was developed by Actavis.

Contraindications

This drug is contraindicated in case of having:

• Blockage of the gallbladder or a sphincter of Oddi problem
• Problems with alcohol abuse
• Pancreatitis
• Liver problems
• Chronic or severe constipation^[5]

Adverse effects

Common adverse effects are constipation and nausea, but rates of discontinuation due to constipation were low for both eluxadoline and placebo. Rare adverse effects: fatigue, bronchitis, viral gastroenteritis. Rare serious adverse effects include pancreatitis with a general incidence of 0.3% – higher incidence with 100 mg dose (0.3%) than with 75 mg dose (0.2%).^[6] The risk is even greater in those who do not have a gall bladder and the medication is not recommended in this group.^[7]

In March 2017, the U.S. Food and Drug Administration issued a safety alert for eluxadoline concerning an increased risk of serious pancreatitis in patients without a gallbladder.^[8] An FDA review found that in such patients, spasm of the sphincter of Oddi may lead to severe pancreatitis.^[9] The FDA reported that in some cases symptoms have occurred with just one or two doses at the recommended dosage for patients without a gallbladder (75 mg).^[9] Of two deaths associated with eluxadoline reported up to February 2017, both occurred in patients without a gallbladder.^[8]

Interactions

Elevated concentrations of eluxadoline were observed with co-administration of inhibitors of the transporter protein OATP1B1, such as:

• Cyclosporine
• Gemfibrozil
• Certain antiretrovirals
• Rifampin
• Eltrombopag

Also, concurrent use of other drugs that cause constipation is not preferred, such as:

• Opioids
• Alosetron
• Anticholinergics
• Bismuth subsalicylate, potentially dangerous synergism.^[10]

Eluxadoline increases the concentrations of drugs which are OATP1B1 and BCRP substrates. Also, co-administration of eluxadoline with rosuvastatin may increase the risk of rhabdomyolysis.^[1]

Pharmacology

Mechanism of action

Eluxadoline is a μ- and κ-opioid receptor agonist and δ-opioid receptor antagonist ^[11] that acts locally in the enteric nervous system, possibly decreasing adverse effects on the central nervous system.^[12][13]

Pharmacokinetics

In the in vitro studies, eluxadoline was found to be transported by OAT3 (SLC22A8), OATP1B1 (SLCO1B1) and BSEP (ABCB11) at the highest concentrations tested (400 ng/ml which is 162-fold larger than the observed Cmax of the highest therapeutic dose of 100 mg). However, it was not to be transported by OCT1 POU2F1, OAT1 Organic anion transporter 1, OCT2, OATP1B3 (SLCO1B3), P-gp (P-glycoprotein), or BCRP (ABCG2).

Multidrug resistance-associated protein 2 (MRP2)-vesicular accumulation of eluxadoline was observed, indicating that the drug is a substrate of MRP2. Eluxadoline was not found to inhibit BCRP-, BSEP-, MRP2-, OCT1-, OCT2-, OAT1-, OAT3-, or OATP1B3-mediated transport of probe substrates but inhibited the transport of probe substrates of OATP1B1 and P-gp. Also in the in vitro studies, it was observed that eluxadoline is an in vivo substrate of OATP1B1, OAT3, and MRP2. Finally, no inhibition or induction of cytochrome P450enzymes was observed.^[14]

Following a 100 mg dose of eluxadoline, the C_max was about 2 to 4 ng/ml and AUC was 12-22 ng.h/ml. Eluxadoline has linear pharmacokinetics with no accumulation upon repeated twice daily dosing. Taking eluxadoline with high fat meal decreased the C_max by 50% and AUC by 60%.^[1]

Chemistry

Synthesis

The synthesis of eluxadoline was extensively discussed in the patent No. WO2006099060 A2, with the title : “Process for the preparation of opioid modulators” which was published in Sept. 2006^[15]

A CLIP

5 JAN 2014

Furiex Pharmaceuticals Inc.  more than doubled in its best day of trading after its experimental drug alleviated diarrhea and abdominal pain caused by irritable bowel syndrome in two studies.

The drug eluxadoline met targets for improvements in stool consistency and abdominal pain that were developed in conjunction with U.S. and European regulators, the company said today. Furiex will apply for approval in June, Chairman Fred Eshelman said in an investor call today. He estimated annual sales of $750 million to $1 billion.

“By our math, it looks like a pretty doggone good market,” Eshelman said on the call, noting that there is only one currently approved drug available in the U.S. for the condition.

Diarrhea-predominant irritable bowel syndrome is a chronic disorder that affects about 28 million patients in the U.S. and Europe, Furiex said in the statement.Furiex said it would apply by mid-year for U.S. approval of the drug, eluxadoline, to treat diarrhea-predominant irritable bowel syndrome (IBS-d), a debilitating bowel disorder that affects about 28 million people in the United States and major European markets.

Furiex said it expected to seek European approval in early 2015.

“We believe that there are a lot of patients out there who need this drug. There is a huge unmet need,” Furiex Chief Medical Officer June Almenoff said in a telephone interview.

Currently approved drugs for IBS address constipation associated with the disorder, but there are few options for diarrhea predominant IBS.

Furiex founder and chairman Fred Eshelman said he believes the drug has the potential for blockbuster sales, which he defined as annual sales of between $750 million and $1 billion.

Eluxadoline was tested at two doses against a placebo over the course of 12 weeks to meet requirements by the U.S. Food and Drug Administration, and for 26 weeks for European health regulators, in Phase III studies involving 2,428 patients, Furiex said.

For the combined goal of improvement in abdominal pain and stool consistency for at least half the days in the study, eluxadoline achieved a statistically significant improvement at the 100 milligram and 75 mg doses through 12 weeks in both studies.

On the 26-week measure, the higher dose succeeded in both studies but the lower dose missed statistical significance in one of the two trials, according to initial results released by the company.

The success appeared to be driven by the percentage of patients reporting improvements in diarrhea, which ranged from 30 percent to 37 percent versus 22 percent and 20.9 percent for the placebo groups.

When the composite goal was broken into its two components, researchers found a numerical improvement in pain response rates that did not achieve statistical significance.

The drug appeared to be safe and well-tolerated in both studies, Furiex said. The most commonly reported side effects were constipation and nausea.

The company plans to present a far more detailed analysis of the late stage studies at an upcoming medical meeting.

“We’re very excited about the path ahead and about how this can transform patients’ lives,” Almenoff said.

Mu Delta is a locally active mu opioid receptor agonist and delta opioid receptor antagonist in phase III clinical evaluation at Furiex Pharmaceuticals for the oral treatment of diarrheal predominant irritable bowel syndrome (d-IBS).

The product candidate holds an advantage over currently marketed products for this indication because it acts locally on the enteric nervous system, possibly decreasing adverse effects on the central nervous system. In 2011, fast track designation was assigned in the U.S. for the treatment of d-IBS. In 2011, Mu Delta was licensed to Furiex Pharmaceuticals by Janssen for the treatment of d-IBS, granting an option to Furiex to continue development and commercialization following phase II proof of concept studies.

The opioid receptors were identified in the mid-1970’s, and were quickly categorized into three sub-sets of receptors (mu, delta and kappa). More recently the original three types of receptors have been further divided into sub-types. Also known is that the family of opioid receptors are members of the G-protein coupled receptor (GPCR) super-family. More physiologically pertinent are the well established facts that opioid receptors are found throughout the central and peripheral nervous system of many mammalian species, including humans, and that modulation of the respective receptors can elicit numerous, albeit different, biological effects, both desirable and undesirable (D. S. Fries, “Analgesics”, inPrinciples of Medicinal Chemistry, 4th ed.; W. O. Foye, T. L. Lemke, and D. A. Williams, Eds.; Williams and Wilkins: Baltimore, Md., 1995; pp. 247-269; J. V. Aldrich, “Analgesics”, Burger’s Medicinal Chemistry and Drug Discovery, 5^thEdition, Volume 3: Therapeutic Agents, John Wiley & Sons, Inc., 1996, pp. 321-441). In the most current literature, the likelihood of heterodimerization of the sub-classes of opioid receptors has been reported, with respective physiological responses yet undetermined (Pierre J. M. Riviere and Jean-Louis Junien, “Opioid receptors: Targets for new gastrointestinal drug development”, Drug Development 2000, pp. 203-238).

A couple biological effects identified for opioid modulators have led to many useful medicinal agents. Most significant are the many centrally acting mu opioid agonist modulators marketed as analgesic agents to attenuate pain (e.g., morphine), as well as peripherally acting mu agonists to regulate motility (e.g., loperamide). Currently, clinical studies are continuing to evaluate medicinal utility of selective delta, mu, and kappa modulators, as well as compounds possessing combined sub-type modulation. It is envisioned such explorations may lead to agents with new utilities, or agents with minimized adverse side effects relative to currently available agents (examples of side effects for morphine includes constipation, respiratory depression, and addiction potential). Some new GI areas where selective or mixed opioid modulators are currently being evaluated includes potential treatment for various diarrheic syndromes, motility disorders (post-operative ileus, constipation), and visceral pain (post operative pain, irritable bowel syndrome, and inflammatory bowel disorders) (Pierre J. M. Riviere and Jean-Louis Junien, “Opioid receptors: Targets for new gastrointestinal drug development” Drug Development, 2000, pp. 203-238).

Around the same time the opioid receptors were identified, the enkephalins were identified as a set of endogenous opioid ligands (D. S. Fries, “Analgesics”, inPrinciples of Medicinal Chemistry, 4th ed.; W. O. Foye; T. L. Lemke, and D. A. Williams, Eds.; Williams and Wilkins: Baltimore, Md., 1995; pp. 247-269). Schiller discovered that truncating the original pentapeptide enkephalins to simplified dipeptides yielded a series of compounds that maintained opioid activity (Schiller, P. WO 96/06855). However one potential drawback cited for such compounds is the likelihood of their inherent instability (P. W. Schiller et al., Int. J. Pept. Protein Res. 1993, 41 (3), pp. 313-316).

More recently, a series of opioid pseudopeptides containing heteroaromatic or heteroaliphatic nuclei were disclosed, however this series is reported showing a different functional profile than that described in the Schiller works. (L. H. Lazarus et al., Peptides 2000, 21, pp. 1663-1671).

Most recently, works around morphine related structures were reported by Wentland, et al, where carboxamido morphine derivatives and it’s analogs were prepared (M. P. Wentland et al., Biorg. Med. Chem. Letters 2001, 11, pp. 1717-1721; M. P. Wentland et al., Biorg. Med. Chem. Letters 2001, 11, pp. 623-626). Wentland found that substitution for the phenol moiety of the morphine related structures with a primary carboxamide led anywhere from equal activities up to 40 fold reduced activities, depending on the opioid receptor and the carboxamide. It was also revealed that any additional N-substitutions on the carboxamide significantly diminished the desired binding activity.

Compounds of the present invention have not been previously disclosed and are believed to provide advantages over related compounds by providing improved pharmacological profiles.

Opioid receptor modulators, agonists or antagonists are useful in the treatment and prevention of various mammalian disease states, for example pain and gastrointestinal disorders such as diarrheic syndromes, motility disorders including post-operative ileus and constipation, and visceral pain including post-operative pain, irritable bowel syndrome and inflammatory bowel disorders.

It is an object of the present invention to provide opioid receptor modulators. It is a further object of the invention to provide opioid receptor agonists and opioid receptor antagonists. It is an object of the present invention to provide opioid receptor ligands that are selective for each type of opioid receptor, mu, delta and kappa. It is a further object of the present invention to provide opioid receptor ligands that modulate two or three opioid receptor types, mu, delta and kappa, simultaneously.

It is an object of the invention to provide certain instant compounds that are also useful as intermediates in preparing new opioid receptor modulators. It is also an object of the invention to provide a method of treating or ameliorating a condition mediated by an opioid receptor. And, it is an object of the invention to provide a useful pharmaceutical composition comprising a compound of the present invention useful as an opioid receptor modulator.

5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1 h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid is an opoid receptor modulator (mu receptor agonist and delta receptor antagonist) and may be useful for treating irritable bowel syndrome, pain or other opioid receptor disorders.

5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid and methods of making this molecule are disclosed in

US application 2005/02033143. Example 9 of US application 2005/02033143 makes the hydrochloride salt of 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid.

Applicants have discovered a process of making the zwitterion of 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid and two novel crystals of this zwitterion. In Applicant’s hands, these novel crystals provide improved properties and can be purified at higher purity. Applicant’s new process results in improved and less costly process manufacturing conditions than the procedure disclosed in US application 2005/02033143.

FIG. 6 is the molecular structure of the zwitterion 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid.

US7994206

SYNTHESIS OF 5-formyl-2- methoxy-benzoic acid methyl ester

WO2002022612A1

Example 8: 2-Methoxy-5-formylbenzoic acid

Lithium hydroxide (1.04g, 0.043mol, 3eq) in water (lOmL) was added to a stirred solution of methyl 2-methoxy-5-formylbenzoate (2.8g, 0.014mol, leq) in a mixture of tetrahydrofuran (30mL) and methanol (20mL). The solution was stirred overnight, acidified to pH 1 with 10% HCl and the organic solvents removed in vacuo. The aqueous solution was extracted with ethyl acetate (lOOmL) and the organic solution washed with brine (lOOmL), then extracted with saturated aqueous sodium bicarbonate (3 x lOOmL). The basic solution was washed with ethyl acetate (lOOmL), then acidified to pH 1 with 10% HCl and back extracted with dichloromethane (3 x lOOmL). The organic solution was dried over sodium sulfate and evaporated in vacuo to give a cream coloured powder (2.01g, 77%). 1H NMR (CDC1₃) δ 9.99 (s, IH, O=C- H), 4.14 (s, 3H, CH₃).

ANALOGOUS METHOD TO PREPARE..2-methoxy-5-{[1 -(4-phenyl-1 H-imidazol-2-yl)- ethylamino]-methyl}-benzoic acid methyl ester

USE 5-formyl-2- methoxy-benzoic acid methyl ester  for 3,4- dimethoxybenzaldehyde, TO GET 2-methoxy-5-{[1 -(4-phenyl-1 H-imidazol-2-yl)- ethylamino]-methyl}-benzoic acid methyl ester 

Example 4

(3,4-Dimethoxy-benzyl)-[1-(4-phenyl-1 H-imidazol-2-yl)-ethyl]-amine

A solution of 1-(4-phenyl-1 W-imidazol-2-yl)-ethylamine (0.061 g, 0.33 mmol) of Example 3, and 0.55 g (0.33 mmol) of 3,4-dimethoxybenzaldehyde in 5 ml_ of anhydrous methanol was stirred at room temperature for 1 h and then cooled to about 0-10⁰C in an ice bath for 1 h. The reaction was treated carefully with 0.019 g (0.49 mmol) of sodium borohydride in one portion and maintained at about 0-10⁰C for 21 h. Cold 2M aqueous HCI was added dropwise (30 drops), the mixture was stirred for 5 min, and then partially concentrated in vacuo unheated. The residual material was taken up in EtOAc to yield a suspension that was treated with 5 ml_ of cold 3M aqueous NaOH and stirred vigorously until clear. The phases were separated and the aqueous layer was extracted three times additional with EtOAc. The combined extracts were dried over MgSO₄, filtered, and concentrated to yield (3,4-dimethoxy- benzyl)-[1-(4-phenyl-1 H-imidazol-2-yl)-ethyl]-amine as a light yellow oil (HPLC: 87% @ 254nm and 66% @ 214 nm).

MS (ES⁺) (relative intensity): 338.1 (100) (M+1)

This sample was of sufficient quality to use in the next reaction without further purification.

SYNTHESIS

WO2006099060A2

In an embodiment, the present invention is directed to processes for the preparation of the compound of formula (IV)

also known as, 5-({[2-amino-3-(4-carbamoyl-2,5-dimethyl-phenyl)- propionyl]-[1 -(4-phenyl-1 H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy- benzoic acid

Example 1

(S)-2-ferf-Butoxycarbonylamino-3-(4-carbamoyl-2.6-dimethyl-phenyl)- propionic acid

STEP A: Trifluoromethanesulfonic acid 4-bromo-3,5-dimethyl-phenyl ester

To a cooled (0°C) solution of 4-bromo-3,5-dimethylphenol (3.05 g, 15.2 mmol) in pyridine (8 ml_) was added trifluoromethanesulfonic anhydride (5.0 g, 17.7 mmol) dropwise. After completion of addition, the resulting mixture was stirred at 0°C for 15 min, and then at room temperature overnight. The reaction was quenched by addition of water, and then extracted with EtOAc. The organic extracts were washed sequentially with water, 2N HCI (2x ), brine, and then dried over MgSO₄. Filtration and evaporation to dryness yielded compound 1 b as a colorless oil.

¹H NMR (300 MHz, CDCI₃): δ 2.45 (6H, s), 7.00 (2H, s).

Step B: 4-Bromo-3,5-dimethylbenzoic acid

Into a solution of compound 1 b (6.57 g, 19.7 mmol) in DMF (65 ml_) were added K₂CO₃ (13.1 g, 94.7 mmol), Pd(OAc)₂ (0.44 g, 1.97 mmol) and 1 ,1′-bis(diphenylphosphino)ferrocene (2.29 g, 4.14 mmol). The resulting mixture was bubbled in gaseous CO for 10 min and was heated to 60°C for 7.5h with a CO(₉) balloon. The cooled mixture was partitioned between aqueous NaHCO₃ and EtOAc, and filtered. The aqueous phase was separated, acidified with aqueous 6N HCI, extracted with EtOAc, and then dried over Na₂SO₄. Filtration and concentration of the filtrate yielded crude compound 1c as a brown residue, which was used in the next step without further purification. STEP C: Method A: 4-Bromo-3,5-dimethyl-benzamide

Into a suspension of compound 1c in DCM (40 ml_) was added SOCI₂ (3.1 rnL, 42 mmol) and the mixture was heated at reflux for 2 h. Upon removal of the solvent by evaporation, the residue was dissolved in DCM (40 ml_) and then ammonium hydroxide (28% NH₃ in water, 2.8 ml_) was added. The reaction mixture was heated at 5O⁰C for 2 h and concentrated. The residue was diluted with H₂O, extracted with EtOAc, and the organic portion was dried over Na₂SO₄. After filtration and evaporation, the residue was purified by flash column chramotagraphy (eluent: EtOAc) to yield compound 1 d as an off-white solid.

¹H NMR (300 MHz, CD₃CN): δ 2.45 (6H, s), 5.94 (1 H, br s), 6.71 (1 H, br s), 7.57 (2H, s)

MS(ES⁺)(relative intensity): 228.0 (100%) (M+1).

Step C: Method B: 4-Bromo-3,5-dimethyl-benzamide

A mixture of compound 1 b (3.33 g, 10 mmol), PdCI₂ (0.053 g, 0.3 mmol), hexamethyldisilazane (HMDS, 8.4 ml_, 40 mmol), and DPPP (0.12 g, 0.3 mmol) was bubbled with a gaseous CO for 5 min and then stirred in a CO balloon at 80°C for 4 h. To the reaction mixture was added MeOH (5 ml_). The reaction mixture was stirred for 10 min, diluted with 2N H₂SO₄ (200 ml_), and then extracted with EtOAc. The EtOAc extract was washed with saturated aqueous NaHCO₃, brine, and then dried over Na₂SO₄. Filtration and evaporation of the resultant filtrate yielded a residue, which was purified by flash column chromatography (eluent: EtOAc) to yield compound 1d as a white solid.

Step D: 2-terf-Butoxycarbonylaminoacrylic acid methyl ester

To a suspension of /V-Boc-serine methyl ester (Compound 1e, 2.19 g, 10 mmol) and EDCI (2.01 g, 10.5 mmol) in DCM (70 ml_) was added CuCI (1.04 g, 10.5 mmol). The reaction mixture was stirred at room temperature for 72 h. Upon removal of the solvent, the residue was diluted with EtOAc, washed sequentially with water and brine and then dried over MgSO₄. The crude product was purified by flash column chromatography (eluent: EtOAc:hexane ~1 :4) to yield compound 1f as a colorless oil.

¹H NMR (300 MHz, CDCI₃): δ 1.49 (9H, s), 3.83 (3H, s), 5.73 (1 H, d, J = 1.5 Hz), 6.16 (1 H₁ S), 7.02 (1 H, s).

STEP E: (2)-2-fert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl- phenyl)acrylic acid methyl ester

A flask charged with compound 1d (0.46 g, 2.0 mmol), compound 1f (0.80 g, 4.0 mmol), tri-o-tolylphosphine (0.098 g, 0.32 mmol) and DMF (8 ml_) was purged with N₂(g) 3 times. After the addition of tris(dibenzylideneacetone)dipalladium (0) (0.074 g, 0.08 mmol) and TEA (0.31 ml_, 2.2 mol), the reaction mixture was heated at 110°C for 24 h. At that time, the reaction was quenched by addition of water, and then extracted with EtOAc. The organic phase was washed with 1 N HCI, saturated aqueous NaHCO₃, brine, and dried over MgSO₄. The mixture was concentrated to a residue, which was purified by flash column chromatography (eluent: EtOAc:hexane~1 :1 to EtOAc only) to yield compound 1g as a white solid.

¹H NMR (300 MHz, CD₃OD): δ 1.36 (9H, s), 2.26 (6H, s), 3.83 (3H, s), 7.10 (1 H, s), 7.56 (2H, s); ¹³C NMR (75 MHz, DMSO-d₆): δ 17.6, 25.7, 50.2, 78.7, 124.9, 126.4,

128.3, 131.2, 135.2, 135.5, 152.8, 164.3, 169.6;

MS (ES⁺) (relative intensity): 349.1 (38%)(M+1).

STEP F: (S)-2-ferf-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl- phenyl)propionic acid methyl ester

Into a reactor charged with a solution of compound 1g (0.56 g, 1.6 mmol) in degassed MeOH (80 mL) was added [Rh(COd)(H₁R-DIPAMP)J⁺BF₄ ^“ under a stream of argon. The reactor was sealed and flushed with H₂, stirred at 6O⁰C under 1000 psi of H₂ for 14 days. The crude product was purified by flash column chromatography (eluent: EtOAc:hexane ~1 :1) to yield compound 1 h as a white solid. ee: >99%; ¹H NMR (300 MHz, CDCI₃): δ 1.36 (9H, s), 2.39 (6H, s), 3.11 (2H, J = 7.2 Hz), 3.65 (3H, s), 4.53-4.56 (1 H, m), 5.12 (1 H, d, J = 8.7 Hz), 5.65 (1 H, br s), 6.09 (1 H, br s), 7.46 (2H, s);

MS(ES⁺) (relative intensity): 250.9 (100) (M-BoC)⁺.

STEP G: (S)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl- phenyl)propionic acid

Into an ice-cooled solution of compound “I h (0.22 g, 0.63 mmol) in THF (3.5 ml_) was added an aqueous LiOH solution (1 N, 3.5 ml_) and the reaction mixture stirred at 0°C. Upon completion of the reaction, the reaction mixture was concentrated and the aqueous phase was neutralized with cooled aqueous 1 N HCI at 0°C, and then extracted with EtOAc. The combined extracts were dried over Na₂SO₄ overnight. Filtration and evaporation of the filtrate to dryness yielded compound 1j as a white solid. ¹H NMR (300 MHz, DMSO-cfe): δ 1.30 (9H, s), 2.32 (6H, s), 2.95(1 H, dd,

J= 8.8, 13.9 Hz), 3.10 (1 H, dd, J= 6.2, 14.0 Hz), 4.02-4.12 (1 H, m), 7.18-7.23 (2H, m), 7.48 (2H₁ s), 7.80 (1 H, s);

MS(ES⁺) (relative intensity): 236.9 (6) (M-BoC)⁺.

Example 5

5-((r2-Amino-3-(4-carbamoyl-2.6-dimethyl-phenyl)-propionvn-n-(4-phenyl- 1 H-imidazol-2-yl)-ethvπ-aminol-methyl)-2-methoxy-benzoic acid

STEP A. 2-Methoxy-5-{[1-(4-phenyl-1 W-imidazol-2-yl)-ethylamino]-methyl}- benzoic acid methyl ester

Using the procedures described for Example 4, substituting 5-formyl-2- methoxy-benzoic acid methyl ester (WO 02/22612) for 3,4- dimethoxybenzaldehyde, 2-methoxy-5-{[1 -(4-phenyl-1 H-imidazol-2-yl)- ethylamino]-methyl}-benzoic acid methyl ester was prepared.

STEP B. 5-({[2-ferf-ButoxycarbonylmethyI-3-(4-carbamoyl-2,6-dimethyl- phenyl)-propionyl]-[1 -(4-phenyl-1 H-imidazoI-2-yl)-ethyl]-amino}-methyl)-2- methoxy-benzoic acid methyl ester

Using the procedure of Example 3 for the conversion of Cpd 3d to Cpd 3e, substituting 2-methoxy-5-{[1-(4-phenyl-1 /-/-imidazol-2-yl)-ethylamino]- methylj-benzoic acid methyl ester for Cpd 3d and substituting 2-tert- Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionic acid for 2- tø/t-Butoxycarbonylamino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionic acid, Cpd 5a was prepared.

STEP C. 5-({[2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl- phenyl)-propionyl]-[1 -(4-phenyl-1 W-imidazol-2-yl)-ethyl]-amino}-methyl)-2- methoxy-benzoic acid

5-({[2-tørf-Butoxycarbonylmethyl-3-(4-carbamoyl-2,6-dimethyl-phenyl)- propionyl]-[1-(4-phenyl-1 H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy- benzoic acid methyl ester was dissolved in an ice-chilled (0-10°C), mixed solvent system of THF (10 ml_) and MeOH (5 ml_). A LiOH H₂O/water suspension (2.48 M; 3.77 ml_) was added dropwise, then the reaction was allowed to warm to room temperature and stirred overnight. The resulting mixture was cooled in an ice bath and the basic solution was neutralized with 2N citric acid until slightly acidic. The mixture was concentrated under reduced pressure to remove the volatile materials, after which time the remaining aqueous phase was extracted with EtOAc (3 x 26 ml_). These combined organic phases were dried over MgSO₄, filtered, and concentrated under reduced pressure to yield a pale yellowish white solid. This crude material was dissolved in a 10% MeOH/CH₂CI₂ solution and adsorbed onto 30 g of silica. The adsorbed material was divided and chromatographed on an ISCO normal phase column over two runs, using a 40 g Redi-Sep column for both runs. The solvent system was a gradient MeOHZCH₂CI₂ system as follows: Initial 100% CH₂CI₂, 98%-92% over 40 min; 90% over 12 min, and then 88% over 13 min. The desired product eluted cleanly between 44-61 min. The desired fractions were combined and concentrated under reduced pressure to yield 5-({[2-terf- butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4- phenyl-1 /-/-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid, Cpd 5b, as a white solid.

STEP D. 5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1 – (4-phenyl-1 W-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid

A portion of Cpd 5b (0.27g, 0.41 mmol) was dissolved in EtOAc (39 ml_)/THF (5 ml_), filtered, and subsequently treated with gaseous HCI for 15 min. After completion of the HCI addition, the reaction was slowly warmed to room temperature and a solid precipitate formed. After 5 h the reaction appeared >97% complete by LC (@214nm; 2.56 min.). The stirring was continued over 3 d, then the solid was collected and rinsed with a small amount of EtOAc. The resulting solid was dried under high vacuum under refluxing toluene for 2.5 h to yield Cpd 5c as a white solid di-HCI salt.

Example 2

Racemic 2-terf-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethvl- phenvD-propionic acid

STEP A: Racemic 2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6- dimethyl-phenyl)propionic acid methyl ester

To a reactor charged with a solution of compound 1g (0.68 g, 1.95 mmol) in MeOH (80 mL) was added 10% Pd-C (0.5 g). The reactor was connected to a hydrogenator and shaken under 51 psi of H₂ overnight. The mixture was filtered through a pad of Celite and the filtrate was concentrated to dryness to yield compound 2a as a white solid.

The ¹H NMR spectrum was identical to that of (S)-2-tert- butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)propionic acid methyl ester, compound 1 h.

STEP B: Racemic 2-terf-butoxycarbonylamino-3-(4-carbamoyl-2,6- dimethyl-phenyl)propionic acid

Following the procedure described for Example 1 , STEP G (preparation of (S)-2-teAt-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl- phenyl)propionic acid), compound 2b – racemic 2-te/?-butoxycarbonylamino-3- (4-carbamoyl-2,6-dimethyl-phenyl)propionic acid – was prepared.

POLYMORPHS

US8609865

Example 1 Preparation of the zwitterion of 5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid

A 1 L three-necked round-bottomed flask equipped with a mechanical stirrer, addition funnel and a thermocouple was charged without agitation. 34.2 g of 5-({[2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid (see Example 9 of US 2005/0203143), 340 ml of acetone, and 17 ml of 204 mmolar concentrated HCl were combined in the flask. The stirring was started and the resulting slurry formed a clear solution. This solution was heated to 45° C. under vigorous stirring and aged at this temperature for a period of two hours. After the completion, the reaction mass was cooled to ambient temperature and the supernatant was removed by suction. The vessel along with the residue was rinsed with 20 ml of acetone and then removed as previously. 170 ml of water was added and the reaction mass and was aged under stirring until a homogeneus solution resulted. This solution was then added over a period of ˜½ hr to a solution of 90 ml of 1N NaOH and water. The pH was adjusted to 6.5-7.0 accordingly. The resulting slurry was aged for about 2 hrs at ambient temperature, cooled to 10-15° C., aged at that temperature for about 1 hr, and then filtered. The solid was washed with 10 ml water, air-dried for a period of 4 to 5 hrs, and then placed in a vacuum oven at 50-55° C. until the water content was less than 3%.

Example 2 Preparation of the Form α Crystal

The Form α crystal can be prepared by storing the zwitterion of 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid at 0-25% relative humidity for 3 days. Representative PXRD, TGA, and DSC data are shown in FIGS. 1-3 respectively.

Example 3 Preparation of the Form β crystal

The Form β crystal can be prepared by storing the zwitterion of 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid at greater than 60% relative humidity for 3 days. Representative PXRD, TGA, and DSC data are shown in FIGS. 1, 4, and 5 respectively.

SYNTHESIS

US20050203143

Example 9 5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid

A. 2-Methoxy-5{[1-(4-phenyl-1 H-imidazol-2-yl)-ethylamino]-methyl}-benzoic acid methyl ester.

Using the procedures described for Example 3, substituting 5-formyl-2-methoxy-benzoic acid methyl ester (WO 02/22612) for 3,4-dimethoxybenzaldehyde, 2-methoxy-5-{[1-(4-phenyl-1H-imidazol-2-yl)-ethylamino]-methyl}-benzoic acid methyl ester was prepared.

B. 5-({[2-tert-Butoxycarbonyl methyl-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid methyl ester.

Using the procedure of Example 1 for the conversion of Cpd 1d to Cpd 1e, substituting 2-methoxy-5-{[1-(4-phenyl-1H-imidazol-2-yl)-ethylamino]-methyl}-benzoic acid methyl ester for Cpd 1 d and substituting 2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl-propionic acid of Example 8 for 2-tert-Butoxycarbonylamino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionic acid, Cpd 9a was prepared.

C. 5-({[2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[11-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid.

5-({[2-tert-Butoxycarbonyl methyl-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid methyl ester was dissolved in an ice-chilled (0-10° C.), mixed solvent system of THF (10 mL) and MeOH (5 mL). A LiOH.H₂O/water suspension (2.48 M; 3.77 mL) was added dropwise, then the reaction was allowed to warm to room temperature and stirred overnight. The resulting mixture was cooled in an ice bath and the basic solution was neutralized with 2N citric acid until slightly acidic. The mixture was concentrated under reduced pressure to remove the volatile materials, after which time the remaining aqueous phase was extracted with EtOAc (3×26 mL). These combined organic phases were dried over MgSO₄, filtered, and concentrated under reduced pressure to give 2.26 g (146% of theory) of pale yellowish white solid. This crude material was dissolved in a 10% MeOH/CH₂Cl₂ solution and adsorbed onto 30 g of silica. The adsorbed material was divided and chromatographed on an ISCO normal phase column over two runs, using a 40 g Redi-Sep column for both runs. The solvent system was a gradient MeOH/CH₂Cl₂ system as follows: Initial 100% CH₂Cl₂, 98%-92% over 40 min; 90% over 12 min, and then 88% over 13 min. The desired product eluted cleanly between 44-61 min. The desired fractions were combined and concentrated under reduced pressure to yield 1.74 g (113% of theory) of 5-({[2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid, Cpd 9b, as a white solid.

D. 5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid.

A portion of Cpd 9b (0.27g, 0.41 mmol) was dissolved in EtOAc (39 mL)/THF (5 mL), filtered, and subsequently treated with gaseous HCl for 15 min. After completion of the HCl addition, the reaction was slowly warmed to room temperature and a solid precipitate formed. After 5 h the reaction appeared >97% complete by LC (@214 nm; 2.56 min.). The stirring was continued over 3 d, then the solid was collected and rinsed with a small amount of EtOAc. The resulting solid was dried under high vacuum under refluxing toluene for 2.5 h to yield 0.19 g (71%) of desired Cpd 9c as a white solid di-HCl salt.

Example 8 (S)-2-tert-Butoxycarbonylamino-3-(2,6-dimethyl-4-trifluoromethanesulfonylphenyl)-propionic acid methyl ester

A. (S)-2-tert-Butoxycarbonylamino-3-(2,6-dimethyl-4-trifluoromethanesulfonylphenyl)-propionic acid methyl ester. Into a cool solution of Boc-L-(2,6-diMe)Tyr-OMe (7.0 g, 21.6 mmol; Sources: Chiramer or RSP AminoAcidAnalogues) and N-phenyltrifluoromethanesulfonimide (7.9 g, 22.0 mmol) in dichloromethane (60 mL) was added triethylamine (3.25 mL, 23.3 mmol). The resulting solution was stirred at 0° C. for 1 h and slowly warmed to rt. Upon completion, the reaction was quenched by addition of water. The separated organic phase was washed with 1 N NaOH aqueous solution, water and dried over Na₂SO₄ overnight. After filtration and evaporation, the residue was purified by flash column chromatography (eluent: EtOAc-hexane: 3:7) to give the desired product (9.74 g, 99%) as a clear oil; ¹H NMR (300 MHz, CDCl₃): δ 1.36 (9H, s), 2.39 (6H, s), 3.06 (2H, d, J=7.7 Hz), 3.64 (3H, s), 4.51-4.59 (1H, m), 5.12 (1H, d, J=8.5 Hz), 6.92 (2H, s); MS (ES+) (relative intensity): 355.8 (100) (M−Boc)⁺.

B. (S)₄-(2-tert-Butoxycarbonylamino-2-methoxycarbonylethyl)-3,5-dimethylbenzoic acid. To a suspension of (S)-2-tert-butoxycarbonylamino-3-(2,6-dimethyl-4-trifluoromethanesulfonylphenyl)-propionic acid methyl ester (9.68 g, 21.3 mmol), K₂CO₃ (14.1 g, 0.102 mol), Pd(OAc)₂ (0.48 g, 2.13 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (2.56 g, 4.47 mmol) in DMF (48 mL) was bubbled in gaseous CO for 15 min. The mixture was heated to 60° C. for 8 h with a CO balloon. The cool mixture was partitioned between NaHCO₃ and EtOAc, and filtered. The aqueous layer was separated, acidified with 10% citric acid aqueous solution, extracted with EtOAc, and finally dried over Na₂SO₄. Filtration and concentration of the filtrate resulted in a residue. The residue was recrystallized from EtOAc-hexanes to afford the desired product (7.05 g, 94%); ¹H NMR (300 MHz, CDCl₃): δ 1.36 (9H, s), 2.42 (6H, s), 3.14 (2H, J=7.4 Hz), 3.65 (3H, s), 4.57-4.59 (1H, m), 5.14 (1H, d, J=8.6 Hz), 7.75 (2H, s); MS(ES+) (relative intensity): 251.9 (100) (M−Boc)⁺.

C. (S)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethylphenyl)propionic acid methyl ester. Into a stirring solution of (S)-4-(2-tert-butoxycarbonylamino-2-methoxycarbonylethyl)-3,5-dimethyl benzoic acid (3.00 g, 8.54 mmol), PyBOP (6.68 g, 12.8 mmol) and HOBt (1.74 g, 12.8 mmol) in DMF (36 mL) was added DIPEA (5.96 mL, 34.2 mmol) and NH₄Cl (0.92 g, 17.1 mmol). The resulting mixture was stirred at rt for 40 min before being partitioned between aqueous NH₄Cl solution and EtOAc. The separated organic phase was washed sequentially with 2N citric acid aqueous solution, saturated aqueous NaHCO₃ solution, and brine, then dried over Na₂SO₄ overnight. After filtration and concentration, the residue was purified by flash column chromatography (eluent: EtOAc) to give the product. (3.00 g, 100%); ¹H NMR (300 MHz, CDCl₃): δ 1.36 (9H, s), 2.39 (6H, s), 3.11 (2H, J=7.2 Hz), 3.65 (3H, s), 4.53-4.56 (1H, m), 5.12 (1H, d, J=8.7 Hz), 5.65 (1H, brs), 6.09 (1H, br s), 7.46 (2H, s); MS(ES+) (relative intensity): 250.9 (100) (M−Boc)⁺.

D. (S)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethylphenyl)propionic acid. Into an ice-cooled solution of methyl ester from Step C (2.99 g, 8.54 mmol) in THF (50 mL) was added an aqueous LiOH solution (1N, 50 mL) and stirred at 0° C. Upon consumption of the starting materials, the organic solvents were removed and the aqueous phase was neutralized with cooled 1N HCl at 0° C., and extracted with EtOAc, and dried over Na₂SO₄ overnight. Filtration and evaporation to dryness led to the title acid (S)-2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethylphenyl)propionic acid (2.51 g, 87%); ¹H NMR (300 MHz, DMSO-d₆): δ 1.30 (9H, s), 2.32 (6H, s), 2.95 (1H, dd, J=8.8, 13.9 Hz), 3.10 (1H, dd, J=6.2, 14.0 Hz), 4.02-4.12 (1H, m), 7.18-7.23 (2H, m), 7.48 (2H, s), 7.80 (1H, s); MS(ES+) (relative intensity): 236.9 (6) (M−Boc)⁺.

PAPER

Bioorg Med Chem Lett. 2012 Jul 15;22(14):4869-72.

PATENTS

1.WO 2005090315

2..WO 2006099060

3.WO 2009009480

4. WO 2010062590

5.US 2011263868 *

Patent

https://patentscope2.wipo.int/search/de/detail.jsf;jsessionid=17DB1184234A30C42C287EBFB95A7EF3?docId=WO2018198101&tab=PCTDESCRIPTION&office=&prevFilter=%26fq%3DOF%3AWO&sortOption=Ver%C3%83%C2%B6ffentlichungsdatum+ab&queryString=&recNum=9351&maxRec=3410922

Eluxadoline chemically is 5-[[[(25)-2-amino-3-[4-(aminocarbonyl)-2, 6-dimethylphenyl] – 1 -oxopropyl] [( 15)- 1 -(4-phenyl- lH-imidazol-2-yl)ethyl] amino] methyl] -2-methoxybenzoic acid, represented by Formula I.

Formula I

Eluxadoline is a mu-opioid receptor agonist, indicated in adults for the treatment of irritable bowel syndrome with diarrhea (IBS-D).

U.S. Patent No. 7,741 ,356 describes a process for the preparation of eluxadoline. U.S. Patent Nos. 7,629,488 and 8,710,256 describe processes for the preparation of intermediates of eluxadoline.

PCT Publication No. WO2009/009480 purportedly discloses forms alpha and beta crystals of eluxadoline and processes thereof. PCT Publication No. WO2009/009480 discloses that form alpha crystals can be prepared by storing the zwitterion of eluxadoline at 0-25% relative humidity (RH) for 3 days and form beta crystals can be prepared by storing the zwitterion of eluxadoline at greater than 60% RH for 3 days.

PCT Publication No. WO2017/015606 purportedly discloses amorphous form, crystalline forms I, II, III and IV, and processes for their preparation and a process for the preparation of form alpha crystal of eluxadoline

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018138274

Eluxadoline is the INN denomination assigned to the compound having lUPAC name 5-({[(2S)-2-amino-3-(4-carbamoyl-2,6-dimethylphenyl)propanoyl][(1 S)-1 -(4-phenyl-1 /-/-imidazol-2-yl)ethyl]amino}methyl)-2-methoxybenzoic acid and the formula reported below:

Eluxadoline is a μ- and κ-opioid receptor agonist and δ-opioid receptor antagonist that acts locally in the enteric nervous system. The drug, administered orally, is active locally in the intestine and is able to control gastrointestinal function (Gl) and at the same time to reduce the pain and mitigate the effect of constipation. Its use has been approved for the treatment of diarrhea and abdominal pain in individuals with diarrhea-predominant irritable bowel syndrome (IBS-D).

The family of compounds to which eluxadoline belongs is disclosed in patent application WO 2005/090315 A1 , while patent application WO 2006/099060 A2 is directed to processes for the preparation of these compounds.

As generally known, any active principle may exist under amorphous or different crystalline forms (polymorphs), either as pure compound or in forms in which, in the structure of the crystal, are present molecules of water (hydrates) or of another solvent (solvates); besides, in case of hydrates and solvates, the ratio between the number of molecules of active principle and molecules of water or solvent may vary, giving rise to different solid forms of the compound.

Different salts and solid-state forms of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid-state forms may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favourable direction, or improving stability (polymorphic and/or chemical) and shelf-life. These variations in the properties of different salts and solid-state forms may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts, solid-state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which, in turn, may provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.

While not intending to be bound by any theory, certain solid forms are characterized by physical properties, e.g., stability, solubility and dissolution rate, appropriate for pharmaceutical and therapeutic dosage forms. Moreover, while not wishing to be bound by any theory, certain solid forms are characterized by physical properties (e.g., density, compressibility, hardness, morphology, cleavage, stickiness, solubility, water uptake, electrical properties, thermal behaviour, solid-state reactivity, physical stability, and chemical stability) affecting particular processes (e.g., yield, filtration, washing, drying, milling, mixing, tableting, flowability, dissolution, formulation, and lyophilization) which make certain solid forms suitable for the manufacture of a solid dosage form. Such properties can be determined using analytical chemical techniques, including solid-state analytical techniques (e.g., X-ray diffraction, microscopy, spectroscopy and thermal analysis), as described herein and known in the art.

For these reasons, chemical compounds useful in the pharmaceutical field are systematically screened looking for the physical form(s) that present an improved set of production, storage and handling properties, and which result in an improved administration to the patients.

Patent application WO 2009/009480 A2 discloses two crystalline forms of eluxadoline, referred to in the document respectively as Form a and Form β. Form a is characterized by an X-ray powder diffraction pattern having the main peaks at about 10.2°, 1 1.3°, 1 1.8°, 14.0°, 14.3°, 14.7°, 16.1 ° and 18.3° 2Θ, while Form β is characterized by an X-ray powder diffraction pattern having the main peaks at about 1 1.0°, 12.4°, 14.9°, 15.2°, 22.1 °, 25.6°, 27.4°, and 30.4° 2Θ.

Patent application WO 2017/015606 A1 discloses several crystalline forms of eluxadoline, referred to therein as Form I, Form II, Form III, and Form IV. Form I is characterized by an X-ray powder diffraction pattern having peaks at about 6.4°, 7.5°, 9.1 °, 10.0°, and 13.0° 2Θ. Form II is characterized by an X-ray powder diffraction profile having peaks at about 7.2°, 1 1 .6°, 12.1 °, 12.7° and 16.9° 2Θ. Form III is characterized by an X-ray powder diffraction pattern having peaks at about 9.3°, 10.2°, 1 1 .5°, 13.3° and 21.8° 2Θ. Form IV is characterized by an X-ray powder diffraction profile having peaks at about 9.3°, 10.2°, 1 1.5°, 13.3° and 21 .8° 2Θ.

However, no information is provided in any of these documents about any useful

properties from the standpoint of the pharmaceutical industry, neither regarding ease of handling of the forms in the production of formulations nor regarding the storage stability (polymorphic and/or chemical) of eluxadoline when prepared in one of these crystalline forms.

An object of the present invention is the provision of a novel process for the preparation of a polymorphic form a’ of eluxadoline (as defined hereinbelow) which, surprisingly, is polymorphically and chemically stable. Since this polymorphic form represents a valuable product, it is an object that upscaling of this process, in order to meet the needs of industrial-scale production, should be easily accomplishable. It is a further object of the present invention that said novel process should produce high-purity products which must contain as low an amount of possibly harmful compounds as possible.

Surprisingly, it was found that new solvate forms ε of eluxadoline allow for the realization of this process and, thus, of the new polymorphically and chemically stable crystalline form α’. It was found that in terms of the starting material from which the solvate forms ε of eluxadoline can be produced, they are extremely flexible.

Further, it was found that the reaction conditions necessary to produce these solvate forms are highly advantageous in terms of energy consumption in combination with the chemical nature of the solvents used

High Performance Liquid Chromatography-Ultraviolet Detection (HPLC-UV):

Chemical stability tests were performed using the following HPLC method

Column: XBridge C8 150 X 4.6 mm, 3.5 μηι

Mobile Phase A: 0.1 % (V/V) phosphoric acid aqueous solution

Mobile Phase B: Acetonitrile

Diluent: 1 :1 (V/V) Mixture of Mobile Phases A and B

Flow Rate: 1.3 mL/min

Runtime: 35 min

Column Temperature 30 °C

Autosampler Temperature: Ambient

Injection Volume: 5 μΙ_

Detection: 210 nm

Sample concentration: 0.4 mg/mL

Gradient Program:

PATENT

WO 2018020450

https://patents.google.com/patent/WO2018020450A2/en

Example 1

Preparation of Eluxadoline

Step 1- Preparation of 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[l- (4-phenyl- lH-imidazol-2-yl)-ethyl]-amino} -methyl)-2-methoxy-benzoic acid

To a stirred solution of 1 -(4-phenyl- lH-imidazole-2-yl)-ethyl amine (20 gm) and 5-formyl-2-methoxy-benzoic acid methyl ester (20 gm) in methanol was added catalytic amount of acetic acid (3 ml). The reaction mixture was cooled at 5°C-10°C and sodium borohydride (4 gm) was added. The reaction mixture was further stirred for 2-3 hours at room temperature. The resultant mixture was diluted with water and then partially concentrated. To this mixture was added 2N HCl solution followed by addition of dichloromethane. The phases were separated and the pH (9-1 1) of aqueous layer was adjusted using 2N NaOH solution; which was further extracted with dichloromethane. The combined organic layers were concentrated under vacuum to afford titled compound as oil (yield: 40 gm).

Step 2- Preparation of 5-({[2-tert-butoxycarbonylmethyl-3-(4-carbamoyl-2,6-dimethyl- phenyl)-propionyl] – [ 1 -(4-phenyl- 1 H-imidazol-2-yl)-ethyl] -amino} -methyl)-2-methoxy- benzoic acid methyl ester

To a stirring mixture of 2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6- dimethyl-phenyl-propionic acid (100 gm), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (159.4 gm) and 1- hydroxybenzotriazole (45.4 gm) in dimethylformamide (80 ml) & dichloromethane (1920 ml) was added 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[l-(4- phenyl-lH-imidazol-2-yl)-ethyl] -amino }-methyl)-2-methoxy-benzoic acid (step 1 product, 146.6 gm). The resulting mixture was stirred at room temperature for overnight and further diluted with water. The separated organic phase was washed sequentially with aqueous Na2C03 solution, IN HCl solution, water and brine. After concentration, the residue was further dissolved in DCM. The resultant solution was washed sequentially with water & IN HCl solution and then concentrated under vacuum to afford titled compound (yield: 145 gm).

Step 3- Preparation of methyl 5-((2-amino-3-(4-carbamoyl-2,6-dimethylphenyl)-N-(l-(4- phenyl- 1 H-imidazol-2-yl)ethyl) enzoate

To a stirred solution of 5-({[2-tert-butoxycarbonylmethyl-3-(4-carbamoyl-2,6- dimethyl-phenyl)-propionyl] – [ 1 -(4-phenyl- 1 H-imidazol-2-yl)-ethyl] -amino } -methyl)-2- methoxy-benzoic acid methyl ester (step -2 product, 20 gm) in THF (80 ml) was added Cone. HCl solution (30 ml). The reaction mixture was heated at 40°C-45°C. After completion of reaction, the mixture was concentrated and resultant residue was diluted with water. The pH (9-10) was adjusted using 3N NaOH solution; and resultant stick mass was dissolved in methanol. The resultant solution was concentrated under vacuum to afford titled compound (yield: 18.1 gm).

Step 4- Preparation of Eluxadoline

Into an ice cooled solution of methyl 5-((2-amino-3-(4-carbamoyl-2,6- dimethylphenyl)-N-( 1 -(4-phenyl- 1 H-imidazol-2-yl)ethyl)propanamido)methyl)-2- methoxybenzoate (step 3 product, 15 gm) in methanol was added an aqueous lithium hydroxide (3.23 gm in 30 ml water) and resultant mixture was heated at 40°C-45°C. After completion of reaction, mixture was concentrated and further diluted with water. The pH (6-7) was adjusted using 2N citric acid and resultant residue was dissolved in methanol. The resultant solution was added slowly to the acetone and stirring was continued for overnight. The solid precipitated was filtered, washed with acetone and dried to obtain an amorphous form of titled compound (Yield: 3.50 gm).

Example 2

Preparation of Eluxadoline

Step 1 : Preparation of 5-( {[2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl- phenyl)-propionyl] – [ 1 -(4-phenyl- 1 W-imidazol-2-yl)-ethyl] -amino } -methyl)-2-methoxy- benzoic acid

Into an ice cooled solution of 5-({[2-tert-butoxycarbonylmethyl-3-(4-carbamoyl- 2,6-dimethyl-phenyl)-propionyl] – [ 1 -(4-phenyl- 1 H-imidazol-2-yl)-ethyl] -amino } -methyl)- 2-methoxy-benzoic acid methyl ester (160 gm) in methanol (800 ml) was added an aqueous solution of lithium hydroxide (29.46 gm in 350 ml water) and resultant mixture was stirred at room temperature for overnight. After completion of reaction, mixture was partially concentrated and further diluted with water. The pH (4-5) was adjusted using 2N citric acid and further stirred for 60 min. The solid precipitated was filtered, washed with water and dried to obtain titled compound (yield: 140 gm). Step 2: Preparation of Eluxadoline

To a stirred solution of 5-( {[2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6- dimethyl-phenyl)-propionyl] – [ 1 -(4-phenyl- 1 H-imidazol-2-yl)-ethyl] -amino } -methyl)-2- methoxy-benzoic acid (step-1 product, 100 gm) in acetone (1200 ml) was added Cone. HC1 solution (50 ml). The reaction mixture was heated at 40°C-45°C. After completion of reaction, the supernatant solution was decanted; resultant residue was rinsed with acetone and further dissolved in water. The pH (6-7) was adjusted using IN NaOH solution and the precipitated was filtered, washed with water and dried to obtain an amorphous form of eluxadoline (yield: 72 gm).

Example 3

Preparation of Eluxadoline

To a stirred solution of 5-( {[2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6- dimethyl-phenyl)-propionyl] – [ 1 -(4-phenyl- 1 -imidazol-2-yl)-ethyl] -amino } -methyl)-2- methoxy-benzoic acid (50 gm) in dichloromethane (250 ml) were added solution of Cone. HC1 (50 ml) and water (50 ml). The reaction mixture was heated at 35°C-40°C and further stirred for 10-20 minutes. Tetrahydrofuran (50 ml) & Cone. HC1 (20 ml) were added to the sticky mass and reaction mixture was heated at 40°C for 2 hours. After completion of reaction, the mixture was diluted with water. The pH (6-7) was adjusted using 4N NaOH solution and the obtained sticky mass was dissolved in methanol. The resultant solution was concentrated under vacuum to afford eluxadoline (yield: 16 gm).

Example 4

Preparation of amorphous form of eluxadoline Eluxadoline (1 gm) was dissolved in methanol (20 ml) at 25-30°C. Water (60 ml) was added to the resultant solution and stirred for 15-20 minutes. The resultant slurry was filtered, washed with water and further dried to obtain amorphous form of eluxadoline (Yield: 0.80 gm).

Example 5

Preparation of amorphous form of eluxadoline

Eluxadoline (1 gm) was dissolved in methanol (20 ml) at 25-30°C. Acetone (80 ml) was added to the resultant solution and stirred for 15-20 minutes. The resultant slurry was filtered, washed with acetone and further dried to obtain amorphous form of eluxadoline (Yield: 0.80 gm).

Example 6

Preparation of Form L of eluxadoline

Eluxadoline (1 gm) was charged into flask containing acetonitrile (60 ml) and slurried for 24 hours to 25 hours at 50°C. The resultant solid was filtered, and dried to obtain titled compound (Yield: 0.80 gm).

clip

Eluxadoline (Viberzi)

References

The active ingredient in VIBERZI is eluxadoline, a mu-opioid receptor agonist.

The full chemical name is 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1- oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid.

Eluxadoline has a molecular weight of 569.65 and a molecular formula of C₃₂H₃₅N₅O₅. The chemical structure of eluxadoline is:

VIBERZI is available as 75 mg and 100 mg tablets for oral administration. In addition to the active ingredient, eluxadoline, each tablet contains the following inactive ingredients: silicified microcrystalline cellulose, colloidal silica, crospovidone, mannitol, magnesium stearate, and Opadry II (partially hydrolyzed polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, iron oxide yellow, and iron oxide red).

Eluxadoline

Clinical data
Trade names	Viberzi (US), Truberzi (Europe)
Synonyms	JNJ-27018966
License data	EU EMA: by INN
Routes of administration	Oral
ATC code	A07DA06 (WHO)
Legal status
Legal status	US: Schedule IV
Pharmacokinetic data
Protein binding	81%
Elimination half-life	3.7–6 hours
Excretion	82.2% (feces), <1% (urine)[1]
Identifiers
IUPAC name[show]
CAS Number	864821-90-9
PubChem CID	11250029
IUPHAR/BPS	7691
ChemSpider	9425062
UNII	45TPJ4MBQ1
KEGG	D10403
Chemical and physical data
Formula	C32H35N5O5
Molar mass	569.6508 g/mol
3D model (JSmol)	Interactive image

//////////////////JNJ-27018966, iberzi, элуксадолин ,إيلوكسادولين ,艾沙多林 ,ELUXADOLINE, FDA 2015, エルクサドリン,

CC1=CC(=CC(=C1CC(C(=O)N(CC2=CC(=C(C=C2)OC)C(=O)O)C(C)C3=NC=C(N3)C4=CC=CC=C4)N)C)C(=O)N

Epitinib succinate; HMPL-813; Huposuan yipitini

1203902-67-3, 430.50, C₂₄ H₂₆ N₆ O₂

1-Piperazinecarboxamide, 4-ethyl-N-[4-[(3-ethynylphenyl)amino]-7-methoxy-6-quinazolinyl]-

4-Ethyl-N-[4-[(3-ethynylphenyl)amino]-7-methoxy-6-quinazolinyl]-1-piperazinecarboxamide

Cancer; Glioblastoma; Non-small-cell lung cancer

Epitinib is in phase I clinical trials by Hutchison MediPharma for the treatment of solid tumours.

Epitinib succinate is an oral EGFR tyrosine kinase inhibitor in early clinical development at Hutchison China MediTech (Chi-Med) for the treatment of solid tumors and the treatment of glioblastoma patients with EGFR gene amplification.

• Originator Hutchison MediPharma
• Class Antineoplastics; Small molecules
• Mechanism of Action Epidermal growth factor receptor antagonists

• Phase I/II Glioblastoma; Non-small cell lung cancer
• No development reported Oesophageal cancer; Solid tumours

• 28 May 2018 No recent reports of development identified for preclinical development in Oesophageal-cancer in China (PO)
• 06 Mar 2018 Hutchison Medipharma plans a phase III pivotal study for Non-small cell lung cancer (NSCLC) patients with brain metastasis in China in 2018
• 06 Mar 2018 Phase-I/II clinical trials in Glioblastoma (Second-line therapy or greater) in China (PO)

PATENT

WO2018210255

https://patentscope2.wipo.int/search/en/detail.jsf;jsessionid=42BB6AE0DA712D6A9C7C741E97BDE64C?docId=WO2018210255&tab=FULLTEXT&office=&prevFilter=&sortOption=Pub+Date+Desc&queryString=&recNum=889&maxRec=71731866

The compound 4-ethyl-N- (4- ( (3-ethynylphenyl) amino) -7-methoxyquinazolin-6-yl) piperazine-1-carboxamide as well as the preparation thereof was described in patent CN101619043A.

pon extensive explorations and researchs, we have found that compound 4-ethyl-N- (4- ( (3-ethynylphenyl) amino) -7-methoxyquinazolin-6-yl) piperazine-1-carboxamide can be prepared into succinate salts, the chemical structure of its semisuccinate and monosuccinate being shown by Formula A. Studies have shown that, compared with its free base, the solubility of compound of Formula A is significantly increased, which is beneficial for improving the pharmacokinetic characteristics and in vivo bioavailability of the compound. We have also found that compound of Formula A can exist in different crystalline forms, and can form solvates with certain solvents. We have made extensive studies on the polymorphic forms of compound of Formula A and have finally prepared and determined the polymorphic forms which meet the requirement of pharmaceutical use. Based on these studies, the present invention provides the compound 4-ethyl-N- (4- ( (3-ethynylphenyl) amino) -7-methoxyquinazolin -6-yl) piperazine-1-carboxamide succinate and the various crystalline forms thereof, solvates and the crystalline forms thereof, which are designated as Form I, Form IV and Form V respectively.

The compound 4-ethyl-N- (4- ( (3-ethynylphenyl) amino) -7-methoxyquinazolin-6-yl) piperazine-1-carboxamide raw material used in the examples were prepared according to CN101619043A.

Example 1 Preparation of Form I of compound of Formula A

The 4-ethyl-N- (4- ( (3-ethynylphenyl) amino) -7-methoxyquinazolin-6-yl) piperazine-1-carboxamide (60g, 0.139mol) was dissolved in 150 times (volume/weight ratio) of tetrahydrofuran (9L) under refluxing. Then the obtained solution was cooled to 50℃, and succinic acid (65.8g, 0.557mol, 4 equivalents) was added in one portion. Then the obtained mixed solution was cooled naturally under stirring. The white precipitate was appeared at about 28℃. After further stirring for 18 hours, the white solid was collected by filtration, and dried at 40℃ under vacuum. A powder sample of 56.7g was obtained (yield 83%) .

¹H NMR (400 MHz, cd3od) δ 8.52 (s, 1H) , 8.45 (s, 1H) , 7.93 –7.89 (m, 1H) , 7.77 –7.73 (m, 1H) , 7.35 (t, J = 7.9 Hz, 1H) , 7.24 (dd, J = 5.2, 3.8 Hz, 1H) , 7.19 (s, 1H) , 4.05 (s, 3H) , 3.69 –3.61 (m, 4H) , 3.49 (s, 1H) , 2.71 –2.64 (m, 4H) , 2.60 (q, J = 7.2 Hz, 2H) , 2.53 (s, 2H) , 1.18 (t, J = 7.2 Hz, 3H) .

The obtained powder sample is Form I of compound of Formula A, the X-ray powder diffractogram of which is shown in Figure 1. Peaks (2θ) chosen from the figure has the following values: 6.1, 7.9, 10.2, 11.6, 12.2, 13.6, 15.3, 15.9, 16.6, 17.8, 19.6, 20.4, 21.4, 21.7, 22.3, 23.5, 24.3, and 25.1 degrees, the measured 2θ values each having an error of about ± 0.2 degrees (2θ) , wherein characteristic peaks (2θ) are at 6.1, 7.9, 12.2, 15.3, 15.9, 16.6, and 20.4 degrees. DSC result is given in Figure 2, showing that the melting point range of Form I is about 193.4-197.3℃.

PATENT

https://patents.google.com/patent/CN101619043B/zh

PATENT

CN 108863951

PATENT

US 20100009958

PATENT

WO 2010002845

////////////Epitinib , PHASE 1, PHASE 2, Epitinib succinate, HMPL-813,  Huposuan yipitini, 1203902-67-3,

Savolitinib

CAS 1313725-88-0, Molecular Formula, C17-H15-N9, Molecular Weight, 345.3685

1H-1,2,3-Triazolo(4,5-b)pyrazine, 1-((1S)-1-imidazo(1,2-a)pyridin-6-ylethyl)-6-(1-methyl-1H-pyrazol-4-yl)-

• AZD-6094
• AZD6094
• HMPL-504
• HMPL504
• Savolitinib
• Savolitinib [INN]
• UNII-2A2DA6857R
• Volitinib
• HM 5016504

A c-Met kinase inhibitor with antineoplastic activity.

NCI: volitinib. An orally bioavailable inhibitor of the c-Met receptor tyrosine kinase with potential antineoplastic activity. Volitinib selectively binds to and inhibits the activation of c-Met in an ATP-competitive manner, and disrupts c-Met signal transduction pathways. This may result in cell growth inhibition in tumors that overexpress the c-Met protein. C-Met encodes the hepatocyte growth factor receptor tyrosine kinase and plays an important role in tumor cell proliferation, survival, invasion, and metastasis, and tumor angiogenesis; this protein is overexpressed or mutated in a variety of cancers.(NCI Thesaurus)

Savolitinib is an experimental small molecule inhibitor of c-Met. It is being investigated for the treatment of cancer by AstraZeneca.^[1] It is in phase II clinical trials for adenocarcinoma, non-small cell lung cancer, and renal cell carcinoma.^[2]

Savolitinib is a first-in-class inhibitor of c-Met in phase III clinical development at at Hutchison China MediTech (Chi-Med) and AstraZeneca for the treatment of patients with MET-driven, unresectable and locally advanced or metastatic papillary renal cell carcinoma. Phase II trials are also under way for the oral treatment of locally advanced or metastatic pulmonary sarcomatoid carcinoma. AstraZeneca is conducting phase II clinical trials for the treatment of non-small cell lung cancer. Phase I/II trials are ongoing at Samsung Medical Center for the second-line treatment of advanced gastric adenocarcinoma patients with MET amplification.

In 2011, the drug was licensed to AstraZeneca by at Hutchison China MediTech (Chi-Med) for worldwide codevelopment and marketing rights for the treatment of cancer.

SYNTHESIS

PAPER

Journal of Organic Chemistry (2018),

A multidisciplinary approach covering synthetic, physical, and analytical chemistry, high-throughput experimentation and experimental design, process engineering, and solid-state chemistry is used to develop a large-scale (kilomole) Suzuki–Miyaura process. Working against clear criteria and targets, a full process investigation and optimization package is described highlighting how and why key decisions are made in the development of large-scale pharmaceutical processes.

Process Design and Optimization in the Pharmaceutical Industry: A Suzuki–Miyaura Procedure for the Synthesis of Savolitinib

Neil K. Adlington, Lauren R. Agnew, Andrew D. Campbell, Robert J. Cox, Andrew Dobson, Cristina Fernandez Barrat, Malcolm A. Y. Gall, William Hicks, Gareth P. Howell* , Anna Jawor-Baczynska, Lucie Miller-Potucka, Michael Pilling, Katy Shepherd, Ross Tassone, Brian A. Taylor, and Aled Williams

AstraZeneca Pharmaceutical Technology and Development, Macclesfield SK10 2NA, United Kingdom

J. Org. Chem., Article ASAP

DOI: 10.1021/acs.joc.8b02351

Publication Date (Web): October 23, 2018

Copyright © 2018 American Chemical Society

*E-mail: gareth.howell@astrazeneca.com.

This article is part of the Excellence in Industrial Organic Synthesis 2019 special issue.

Savolitinib (1) were added, and the resulting suspension was cooled to 0 °C over 8 h. After stirring for a further 4 h at 0 °C, the solid was collected via filtration, washed twice with cold s-BuOH (150 kg, 186 L), and dried in vacuo at 40 °C to give Savolitinib (1) as a white crystalline solid (105 kg, 304 mol, 76%): mp 205.9–208.8 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 9.19 (s, 1H), 8.83 (s, 1H), 8.64 (s, 1H), 8.31 (s, 1H), 8.01 (s, 1H), 7.62–7.55 (m, 2H), 7.42 (dd, J = 1.7, 9.4 Hz, 1H), 6.45 (q, J= 7.1 Hz, 1H), 3.98 (s, 3H), 2.22 (d, J = 7.1 Hz, 3H); ¹³C {1H} NMR (DMSO-d₆, 101 MHz) δ 147.9, 147.2, 143.9, 141.9, 138.5, 137.4, 133.7, 131.6, 125.4, 124.3, 123.9, 119.4, 117.1, 113.8, 55.5, 40.1, 39.1, 19.6 ppm; HRMS (ESI/Q-ToF) m/z [M + H – N₂]⁺ calcd for C₁₇H₁₆N₇ 318.1462, found 318.1486.

NMR Summary S6 1H‐NMR

S7 13C‐NMR

S8 HSQC‐DEPT‐NMR

S9 COSY‐NMR

S10 HMBC‐13C/1H‐NMR

S11 NOESY‐NMR

S12 HRMS

PAPER

Journal of Medicinal Chemistry (2014), 57(18), 7577-7589

HGF/c-Met signaling has been implicated in human cancers. Herein we describe the invention of a series of novel triazolopyrazine c-Met inhibitors. The structure–activity relationship of these compounds was investigated, leading to the identification of compound 28, which demonstrated favorable pharmacokinetic properties in mice and good antitumor activities in the human glioma xenograft model in athymic nude mice.

Discovery of (S)-1-(1-(Imidazo[1,2-a]pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (Volitinib) as a Highly Potent and Selective Mesenchymal–Epithelial Transition Factor (c-Met) Inhibitor in Clinical Development for Treatment of Cancer

PATENT

WO 2018175251

WO 2018055029

WO 2018024608

WO 2016087680

WO 2016081773

PATENT

JP 2016069348

PATENT

CN 105503906

The present invention provides a triazolopyrazine derivatives, the chemical name (S) -1- (l_ (imidazo [l, 2_a] pyrazin-6-yl) ethane-yl) -6-α _ -1H- pyrazol-4-yl-methyl) -1Η- [1,2,3] triazolo [4,5-b] pyrazine, of formula (I), the

[0005] This compound is an inhibitor of the activity c -Me t, may be used for treatment or prevention of inhibition of c -Me t sensitive cancers. In the Chinese patent CN 102906092A (W02011 / 079804), discloses the synthesis and use triazolopyrazine derivatives. Prepared by repeating the above patent, the compound powder obtained by detecting an amorphous state. As those skilled in the art, although amorphous higher solubility and dissolution rate than polymorph in most cases, but it is unstable, hygroscopic, readily converted to stable crystalline form.Thus, without the presence of processing stability and poor storage stability shaped, and in the production process, the smaller the bulk density of the particles of amorphous, high surface free energy, are likely to cause aggregation, poor flowability, and a series of powerful elastic deformation of the formulation problem seriously affecting the clinical value of amorphous Drug triazolopyrazine derivatives.

PATENT

CN 105503905

PATENT

WO 2014174478

CN 102127096

PATENT

WO 2011079804

References

Savolitinib

Clinical data
Synonyms	Volitinib
Identifiers
IUPAC name[show]
CAS Number	1313725-88-0
ChemSpider	34501055
KEGG	D11139
Chemical and physical data
Formula	C17H15N9
Molar mass	345.37 g·mol−1
3D model (JSmol)	Interactive image
SMILES[hide] C[C@@H](C1=CN2C=CN=C2C=C1)N3C4=NC(=CN=C4N=N3)C5=CN(N=C5)C
InChI[hide] InChI=1S/C17H15N9/c1-11(12-3-4-15-18-5-6-25(15)10-12)26-17-16(22-23-26)19-8-14(21-17)13-7-20-24(2)9-13/h3-11H,1-2H3/t11-/m0/s1 Key:XYDNMOZJKOGZLS-NSHDSACASA-N

///////////////Savolitinib, Phase III, AZD-6094, AZD6094, HMPL-504, HMPL504, UNII-2A2DA6857R, Volitinib, HM 5016504

C[C@@H](c1ccc2nccn2c1)n3c4c(ncc(n4)c5cnn(c5)C)nn3

In some embodiments, the c-Met inhibitor is ARQ197 (Tivantinib). Tivantinib has the IUPAC name (3R,4R)-3-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-2,5-pyrrolidinedione and the following chemical structure:

[0058] In some embodiments, the c-Met inhibitor is EMD1214063 (MSC2156119J; Tepotinib).

Tepotinib has the IUPAC name 3-(1-(3-(5-((1-methylpiperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-1,6-dihydro-6-oxopyridazin-3-yl)benzonitrile and the following chemical structure:

[0059] In some embodiments, the c-Met inhibitor is GSK/1363089/XL880 (Foretinib). Foretinib has the IUPAC name N1’-[3-fluoro-4-[[6-methoxy-7-(3-morpholinopropoxy)-4-quinolyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide and the following chemical structure:

[0060] In some embodiments, the c-Met inhibitor is XL184 (Cabozantinib). Cabozantinib has the IUPAC name N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide and the following chemical structure:

[0061] In some embodiments, the c-Met inhibitor is HMPL-504/AZD6094/volitinib (Savolitinib). Volitinib has the IUPAC name (S)-1-(1-(imidazo[1,2-a]pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine and the following chemical structure:

[0062] In some embodiments, the c-Met inhibitor is MSC2156119J (EMD 1214063, Tepotinib).

Tepotinib has the IUPAC name Benzonitrile, 3-[1,6-dihydro-1-[[3-[5-[(1-methyl-4-piperidinyl)methoxy]-2-pyrimidinyl]phenyl]methyl]-6-oxo-3-pyridazinyl]- and the following chemical structure:

[0063] In some embodiments, the c-Met inhibitor is LY2801653 (Merestinib). Merestinib has the IUPAC name N-(3-fluoro-4-{[1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5 yl]oxy}phenyl)-1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide and the following chemical structure:

[0064] In some embodiments, the c-Met inhibitor is AMG 337. AMG 337 has the IUPAC name 7-methoxy-N-((6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine and the following chemical structure:

[0065] In some embodiments, the c-Met inhibitor is INCB28060 (Capmatinib). Capmatinib has the IUPAC name 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide and the following chemical structure:

[0066] In some embodiments, the c-Met inhibitor is AMG 458. AMG 458 has the IUPAC name 1-(2-hydroxy-2-methylpropyl)-N-(5-((7-methoxyquinolin-4-yl)oxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide and the following chemical structure:

[0067] In some embodiments, the c-Met inhibitor is PF-04217903. PF-04217903 has the IUPAC name 2-(4-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanol and the following chemical structure:

[0068] In some embodiments, the c-Met inhibitor is PF-02341066 (Crizotinib). Crizotinib has the IUPAC name (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine and the following chemical structure:

[0069] In some embodiments, the c-Met inhibitor is E7050 (Golvatinib). Golvatinib has the IUPAC name N-(2-fluoro-4-((2-(4-(4-methylpiperazin-1-yl)piperidine-1-carboxamido)pyridin-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide and the following chemical structure:

[0070] In some embodiments, the c-Met inhibitor is MK-2461. MK-2461 has the IUPAC name N-((2R)-1,4-Dioxan-2-ylmethyl)-N-methyl-N’-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide and the following chemical structure:

[0071] In some embodiments, the c-Met inhibitor is BMS-777607. BMS-777607 has the IUPAC name N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide and the following chemical structure:

[0072] In some embodiments, the c-Met inhibitor is JNJ-38877605. JNJ-38877605 has the IUPAC name 6-(difluoro(6-(1-methyl-1H-pyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline and the following chemical structure:

Golvatinib

E-7050, cas 928037-13-2

1-N’-[2-fluoro-4-[2-[[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino]pyridin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

• N’-[2-fluoro-4-[2-[[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino]pyridin-4-yl]oxyphenyl]-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
  UNII:516Z3YP58E
• Originator Eisai Co Ltd

• Class Amides; Antineoplastics; Cyclopropanes; Fluorobenzenes; Piperazines; Piperidines; Pyridines; Small molecules
• Mechanism of Action Angiogenesis inhibitors; Proto oncogene protein c met inhibitors; Vascular endothelial growth factor receptor-2 antagonists

• Discontinued Gastric cancer; Glioblastoma; Head and neck cancer; Liver cancer; Malignant melanoma; Solid tumours

• 15 Nov 2013Eisai completes enrolment in its phase Ib/II trial for Head and neck cancer (second-line combination therapy, late-stage disease) in USA, United Kingdom, South Korea & Ukraine (NCT01332266)
• 14 Nov 2013Phase-I/II clinical trials in liver cancer (first-line combination therapy, late-stage disease) in Italy & Ukraine (PO)
• 01 Jul 2013Eisai completes a phase I trial in Solid tumours in Japan (NCT01428141)

Method for producing a phenoxy pyridine derivative (3)

The present invention, hepatocyte growth factor receptor (Hepatocyte growth factor receptor; hereinafter, abbreviated as “HGFR”) inhibitory action, antitumor action, anti-tumor agents with such angiogenesis inhibitory activity and cancer metastasis inhibitory action, a cancer metastasis suppressing the method for producing a useful phenoxy pyridine derivatives as agents.

Patent Document 1 has a HGFR inhibitory activity, anti-tumor agents, useful phenoxy pyridine derivative as an angiogenesis inhibitor or cancer metastasis inhibitor has been disclosed.

(In the formula, ^{R 1,} .R ² and ^{R 3} means such as 3-10 membered non-aromatic heterocyclic ^{group, .R 4, R 5, R} 6 and ^{R 7} which represents a hydrogen atom, same or different, a hydrogen atom, a halogen atom, .R ⁸ to mean a C _1-6 alkyl group, .R ⁹ to mean a hydrogen atom or the like is and 3-10 membered non-aromatic heterocyclic group meaning .n is .X to mean 1 to 2 integer, it refers to a group or a nitrogen atom represented by the formula -CH =.)

As a method for producing the phenoxy pyridine derivative, to the Example 48 of Patent Document 1, N, N-dimethylformamide, triethylamine and benzotriazol-1-yloxytris (dimethylamino) or lower in the presence of a phosphonium hexafluorophosphate discloses that perform the reaction.

Patent Document 2, as a manufacturing method suitable for industrial mass synthesis of the phenoxy pyridine derivative in the presence a condensing agent, production method of reacting an aniline derivative with a carboxylic acid derivative.

(In the formula, ^{R 1,} is ^{.R 2, R 3,} R ⁴ and ^{R 5,} which means such good azetidin-1-yl group which may have a substituent, the same or different and each represents a hydrogen atom or fluorine It refers to an atom .R ⁶ means a hydrogen atom or a fluorine atom.)

Patent Document 3, another manufacturing method of the phenoxy pyridine derivative, there is disclosed the manufacturing method shown in the following scheme.

(In the formula, ^{R 1} means a 4- (4-methylpiperazin-1-yl) piperidin-1-yl group or a 3-hydroxy-1-yl group ^{.R 2, R 3,} R ⁴ and R ⁵ are the same or different, represents a hydrogen atom or a fluorine atom. ^However, among R ^2, R 3, ^{R 4} and ^{R 5,} 2 or 3 is a hydrogen atom .R ⁶ is a hydrogen atom or .R ⁷ to mean a fluorine atom, .Ar which means a protecting group for the amino group means a phenyl group.)

International Publication No. WO 2007/023768 International Publication No. WO 2008/026577 International Publication No. WO 2009/104520

Example A-5: Preparation of N- (2-fluoro-4 – {[2 – ({[4- (4-methylpiperazin- 1 –yl) piperidin- 1 – yl] carbonyl} amino) pyridin- oxy} phenyl) -N ‘- (4-fluorophenyl) cyclopropane-1,1 dicarboxamide
[Formula
17] 4- (4-methylpiperazin-1-yl) piperidine-1-carboxylic acid [4- ( To a solution of N, N-dimethylformamide (1 ml) of 4-amino-3-fluorophenoxy) pyridin-2-yl] amide (100 mg) and 1- (4-fluorophenylcarbamoyl) cyclopropanecarboxylic acid (78 mg) Triethylamine (71 mg) and O- (7-Azabenzotriazol-1-yl) -N, N, N ‘, N’- tetramethyluronium hexafluorophosphate (HATU) (222 mg) were added and stirred at room temperature for 21 hours. A 1 N sodium hydroxide aqueous solution (2 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 ml). After separation, the organic layer was washed with 5% brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a residue. The residue was dissolved in ethyl acetate (3 ml) and extracted with 2 N hydrochloric acid (3 ml × 1, 2 ml × 1). The aqueous layer was rendered alkaline with 5 N aqueous sodium hydroxide solution (5.5 ml). After extraction with ethyl acetate and drying over anhydrous magnesium sulfate, the solvent was distilled off to give the title compound (87 mg).
¹ H-NMR Spectrum (DMSO-d ₆) .Delta. (Ppm): 1.22-1.33 (2H, m), 1.54-1.63 (4H, m), 1.68-1.78 (2H, m), 2.12 (3H , S), 2.12-2.40 (5H, m), 2.40-2.60 (4H, m), 2.68-2.78 (2H, m), 4.06-4.14 (2H, t, J = 8 Hz), 7.22 (2H, m), 6.60 (1H, dd, J = 2.4 Hz, 5.6 Hz), 7.00 (1 H, dd, J = 2.4 Hz, 11.2 Hz), 7.40 (1 H, s), 7.61 (2 H, dd, J = 5.2 Hz, 8 Hz), 7.93 J = 8.8 Hz), 8.13 (1 H, d, J = 5.6 Hz), 9.21 (1 H, s), 9.90 (1 H, brs), 10.55 (1 H, brs).

///////////////Golvatinib, phase 2, ゴルバチニブ  ,

CN1CCN(CC1)C2CCN(CC2)C(=O)NC3=NC=CC(=C3)OC4=CC(=C(C=C4)NC(=O)C5(CC5)C(=O)NC6=CC=C(C=C6)F)F

Omadacycline tosylate

728.8521, C29H40N4O7. C7H8O3S

CAS: 1075240-43-5

389139-89-3 FREE FORM

FDA 2018/10/3, Nuzyra

オマダサイクリントシル酸塩;

UNII-5658Y89YCD

Omadacycline has been used in trials studying the treatment of Bacterial Pneumonia, Bacterial Infections, Community-Acquired Infections, and Skin Structures and Soft Tissue Infections. Omadacycline represents a significant advance over the well-known tetracycline family, and has been shown to be highly effective in animal models at treating increasingly problematic, clinically prevalent infections caused by gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), and by gram-negative, atypical and anaerobic bacteria, including those resistant to currently available classes of antibiotics and known to cause diseases such as pneumonias, urinary tract infections, skin diseases and blood-borne infections in both the hospital and community settings.

Omadacycline

Clinical data
Trade names	Nuzyra
Identifiers
CAS Number	389139-89-3
PubChem CID	54697325
ChemSpider	20131003
UNII	090IP5RV8F
KEGG	D09647
Chemical and physical data
Formula	C29H40N4O7
Molar mass	556.66 g·mol−1
3D model (JSmol)	Interactive image
SMILES[hide] CC(C)(C)CNCc1cc(c2c(c1O)C(=O)C3=C([C@]4([C@@H](C[C@@H]3C2)[C@@H](C(=C(C4=O)C(=O)N)O)N(C)C)O)O)N(C)C
InChI[hide] InChI=1S/C29H40N4O7/c1-28(2,3)12-31-11-14-10-17(32(4)5)15-8-13-9-16-21(33(6)7)24(36)20(27(30)39)26(38)29(16,40)25(37)18(13)23(35)19(15)22(14)34/h10,13,16,21,31,34,36-37,40H,8-9,11-12H2,1-7H3,(H2,30,39)/t13-,16-,21-,29-/m0/s1 Key:JEECQCWWSTZDCK-IQZGDKDPSA-N

/////////////FDA 2018, Nuzyra, Omadacycline tosylate, Omadacycline, オマダサイクリントシル酸塩 ,PTK-0796, PTK 0796

CC1=CC=C(C=C1)S(O)(=O)=O.[H][C@@]12CC3=C(C=C(CNCC(C)(C)C)C(O)=C3C(=O)C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@]1([H])C2)N(C)C

SELETALISIB

CAS 1362850-20-1

UCB-5857 , Plaque psoriasis,Sjoegren’s syndrome,Immunodeficiency disorders

PHASE 3 UCB

23H14ClF3N6O , 482.85

Phosphatidylinositol 3 kinase delta (PI3Kδ) inhibitors

3-{8-chloro-3-[(1R)-2,2,2-trifluoro-1-({pyrido[3,2-d]pyrimidin-4-yl}amino)ethyl]quinolin-2-yl}pyridin-1-ium-1-olate

Seletalisib has been used in trials studying the treatment and basic science of Primary Sjogren’s Syndrome.

• Originator UCB
• Class Anti-inflammatories; Small molecules
• Mechanism of Action Immunomodulators; Phosphatidylinositol 3 kinase delta inhibitors

• Phase III Immunodeficiency disorders

• Phase II Sjogren’s syndrome
• No development reported Plaque psoriasis

• 05 Dec 2017 UCB Celltech terminates a phase II trial in Sjogren’s syndrome in France, Spain, United Kingdom, Greece, Sweden, Italy, due to enrolment challenges (PO) (NCT02610543) (EudraCT2014-004523-51)
• 04 Nov 2017 No recent reports of development identified for phase-I development in Plaque-psoriasis in United Kingdom (PO, Capsule)
• 14 Jun 2017 Pharmacokinetics and pharmacodynamics data from Preclinical and Clinical studies in Immunodeficiency disorders presented at the 18^th Annual Congress of the European League Against Rheumatism (EULAR-2017)

SYN

US 9029392

https://patents.google.com/patent/US9029392B2/en

Example 27 N—{(R)-1-[8-Chloro-2-(pyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}N-(1-oxypyrido-[3,2-d]pyrimidin-4-yl)amine

A stirred solution of Example 1 (955 mg, 2.05 mmol) in DCM (40 mL) was cooled to 0° C. MCPBA (410 mg, 1.84 mmol) was added and the mixture was allowed to warm slowly to r.t. over 3 h. The reaction mixture was partitioned between DCM and saturated aqueous NaHCO₃ solution. The aqueous phase was extracted with further DCM and the combined organic fractions were washed with brine, dried Na₂SO₄) and evaporated in vacuo. The residue was purified by column chromatography (SiO₂, 3-60% MeOH in EtOAc) to give the title compound (39 mg, 4%) as a yellow solid. δ_H (DMSO-d₆) 9.64-9.52 (m, 1H), 9.30 (s, 1H), 9.06 (dd, J 4.2, 1.3 Hz, 1H), 8.78-8.71 (m, 2H), 8.67 (dd, J 4.9, 1.6 Hz, 1H), 8.64 (s, 1H), 8.16-8.01 (m, 4H), 7.75-7.69 (m, 1H), 7.52 (ddd, J 7.8, 4.9, 0.7 Hz, 1H), 6.65-6.52 (m, 1H). LCMS (ES+) 483 (M+H)⁺, RT 1.87 minutes.

AND

PATENT

WO 2012032334

PATENT

WO 2015181053

WO 2015181055

WO 2016170014

PATENT

WO 2017198590

A SPECIFIC TRIFLUOROETHYL QUINOLINE ANALOGUE FOR USE IN THE TREATMENT OF APDS

The present invention relates to the new therapeutic use of a known chemical compound. More particularly, the present invention concerns the use of a specific substituted quinoline derivative comprising a fluorinated ethyl side-chain in the treatment of activated phosphoinositide 3 -kinase delta syndrome (APDS).

N- {(R)- 1 -[8-Chloro-2-(l -oxypyridin-3-yl)quinolin-3-yl]-2,2,2-trifiuoroethyl} -pyrido[3,2-JJpyrimidin-4-ylamine is specifically disclosed in WO 2012/032334. The compounds described in that publication are stated to be of benefit as pharmaceutical agents, especially in the treatment of adverse inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive and ophthalmic conditions.

There is no specific disclosure or suggestion in WO 2012/032334, however, that the compounds described therein might be beneficial in the treatment of APDS.

Activated phosphoinositide 3-kinase delta syndrome (APDS), also known as

PASLI (pi ΙΟδ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency), is a serious medical condition that impairs the immune system.

APDS patients generally have reduced numbers of white blood cells (lymphopenia), especially B cells and T cells, compromising their propensity to recognise and attack invading microorganisms, such as viruses and bacteria, and thereby prevent infection. Individuals affected with APDS develop recurrent infections, particularly in the lungs, sinuses and ears. Recurrent respiratory tract infections may gradually lead to bronchiectasis, a condition which damages the passages leading from the windpipe to the lungs (bronchi) and can cause breathing problems. APDS patients may also suffer from chronic active viral infections, including Epstein-Barr virus infections and cytomegalovirus infections.

APDS has also been associated with abnormal clumping of white blood cells, which can lead to enlarged lymph nodes (lymphadenopathy). Alternatively, the white blood cells can build up to form solid masses (nodular lymphoid hyperplasia), usually in the moist lining of the airways or intestines. Whilst lymphadenopathy and nodular lymphoid hyperplasia are benign (noncancerous), APDS also increases the risk of developing a form of cancer called B cell lymphoma.

APDS is a disorder of childhood, typically arising soon after birth. However, the precise prevalence of APDS is currently unknown.

Phosphoinositide 3-kinase delta (ΡΒΚδ) is a lipid kinase which catalyses the generation of phosphatidylinositol 3,4,5-trisphosphate (PIP3) from phosphatidylinositol 4,5-bisphosphate (PIP2). PI3K5 activates signalling pathways within cells, and is specifically found in white blood cells, including B cells and T cells. PI3K5 signalling is involved in the growth and division (proliferation) of white blood cells, and it helps direct B cells and T cells to mature (differentiate) into different types, each of which has a distinct function in the immune system.

APDS is known to occur in two variants, categorised as APDSl and APDS2.

APDSl is associated with a heterozygous gain-of- function mutation in the PIK3CD gene encoding the PI3K5 protein; whereas APDS2 is associated with loss-of-function frameshift mutations in the regulatory PIK3R1 gene encoding the p85a regulatory subunit of class I phosphoinositide 3-kinase (PI3K) peptides. Both mutations lead to hyperactivated PI3K signalling. See I. Angulo et ah, Science, 2013, 342, 866-871; C.L. Lucas et ah, Nature Immunol, 2014, 15, 88-97; and M-C. Deau et al, J. Clin. Invest., 2014, 124, 3923-3928.

There is currently no effective treatment available for APDS. Because of the seriousness of the condition, and the fact that it arises in infancy, the provision of an effective treatment for APDS would plainly be a highly desirable objective.

It has now been found that N-{(R)-l-[8-chloro-2-(l-oxypyridin-3-yl)quinolin-3-yl]- 2,2,2-trifluoroethyl}pyrido[3,2-(i]pyrimidin-4-ylamine is capable of inhibiting the elevation of PI3K signalling in T cells (lymphocytes) from both APDSl and APDS2 patients in the presence or absence of T cell receptor activation.

The present invention accordingly provides N-{(R)-l-[8-chloro-2-(l-oxypyridin-3-yl)quinolinB-yl]-2,2,2-trifluoroethyl}pyrido[3,2-JJpyrimidin-4-ylamine of formula (A):

or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of APDS.

The present invention also provides a method for the treatment and/or prevention of APDS, which method comprises administering to a patient in need of such treatment an effective amount of N-{(R)-l-[8-chloro-2-(l-oxypyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoro-ethyl}pyrido[3,2-(i]pyrimidin-4-ylamine of formula (A) as depicted above, or a pharmaceutically acceptable salt thereof. The present invention also provides the use of N-{(R)-l-[8-chloro-2-(l-oxypyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}pyrido[3,2-JJpyrimidin-4-ylamine of formula (A) as depicted above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prevention of APDS.

PAPER

Journal of Pharmacology and Experimental Therapeutics (2017), 361(3), 429-440.

http://jpet.aspetjournals.org/content/361/3/429

///////////////SELETALISIB, PHASE 3, UCB, селеталисиб , سيلستاليسيب , 司来利塞 , 

[O-][N+]1=CC(=CC=C1)C1=NC2=C(Cl)C=CC=C2C=C1[C@@H](NC1=NC=NC2=CC=CN=C12)C(F)(F)F

Clotrimazole

• Molecular FormulaC₂₂H₁₇ClN₂
• Average mass344.837 Da

245-764-8 [EINECS]

2912

Bis-fenil-(2-clorofenil)-1-imidazolil-metano [Italian]

Bisphenyl-(2-chlorphenyl)-1-imidazolyl-methan [German]

Canesten [Trade name]

Canifug [Trade name]

Clotrimazole [BAN] [INN] [JAN] [USAN] [Wiki]

Clotrimazolum [Latin]

Empecid [Trade name]

Fungicip [Trade name]

G07GZ97H65

Gyne-Lotrimin [Trade name]

Imidazole, 1- (o-chloro-α,α-diphenylbenzyl)-

Lotrimin [Trade name]

Mono-baycuten [Trade name]

Mycelex [Trade name]

Mycelex G [Trade name]

Mycosporin [Trade name]

Pedisafe [Trade name]

Rimazole [Trade name]

Tibatin [Trade name]

Trimysten [Trade name]

UNII-G07GZ97H65

Clotrimaderm

Title: Clotrimazole CAS Registry Number: 23593-75-1 CAS Name: 1-[(2-Chlorophenyl)diphenylmethyl]-1H-imidazole Additional Names: 1-(o-chloro-a,a-diphenylbenzyl)imidazole; 1-[a-(2-chlorophenyl)benzhydryl]imidazole; 1-[(o-chlorophenyl)diphenylmethyl]imidazole; diphenyl-(2-chlorophenyl)-1-imidazolylmethane; 1-(o-chlorotrityl)imidazole Manufacturers’ Codes: FB-5097; Bay b 5097 Trademarks: Canesten (Bayer); Canifug (Wolff); Empecid (Bayer-Takeda); Gyne-Lotrimin (Schering-Plough); Lotrimin (Schering-Plough); Mono-Baycuten; Mycelex-G (Miles); Mycofug (Hermal); Mycosporin (Bayer); Pedisafe (Sagitta); Rimazole (Cheil Sugar); Tibatin (Dak); Trimysten Molecular Formula: C22H17ClN2 Molecular Weight: 344.84 Percent Composition: C 76.63%, H 4.97%, Cl 10.28%, N 8.12% Literature References: Prepn: K. H. Buechel et al., ZA 6805392; eidem, US 3705172 (1969, 1972 both to Bayer). Pharmacology: Plempel et al., Antimicrob. Agents Chemother. 1969, 271; eidem, Dtsch. Med. Wochenschr. 94, 1356 (1969). Clinical findings: Oberste-Lehn et al., ibid. 1365. Series of articles on prepn, toxicology, pharmacokinetics, clinical studies: Arzneim.-Forsch. 22,1260-1272, 1276-1299 (1972). Toxicity: D. Tettenborn, ibid. 1276. Comprehensive description: J. G. Hoogerheide, B. E. Wyka, Anal. Profiles Drug Subs. 11, 225-255 (1982). Properties: Crystals, mp 147-149°. A weak base, slightly sol in water, benzene, toluene; sol in acetone, chloroform, ethyl acetate, DMF. Hydrolyzes rapidly upon heating in aq acids. LD50 in male mice, rats (mg/kg): 923, 708 orally (Tettenborn). Melting point: mp 147-149° Toxicity data: LD50 in male mice, rats (mg/kg): 923, 708 orally (Tettenborn) Derivative Type: Hydrochloride Molecular Formula: C22H17ClN2.HCl Molecular Weight: 381.30 Percent Composition: C 69.30%, H 4.76%, Cl 18.60%, N 7.35% Properties: mp 159°. Melting point: mp 159° Therap-Cat: Antifungal. Therap-Cat-Vet: Antifungal. Keywords: Antifungal (Synthetic); Imidazoles.

Clotrimazole, sold under the brand name Canesten among others, is an antifungal medication.^[1] It is used to treat vaginal yeast infections, oral thrush, diaper rash, pityriasis versicolor, and types of ringworm including athlete’s foot and jock itch.^[1] It can be taken by mouth or applied as a cream to the skin or in the vagina.^[1]

Common side effects when taken by mouth include nausea and itchiness.^[1] When applied to the skin common side effects include redness and burning.^[1] In pregnancy, use on the skin or in the vagina is believed to be safe.^[1] There is no evidence of harm when used by mouth during pregnancy but this has been less well studied.^[1] When used by mouth, greater care should be taken in those with liver problems.^[1] It is in the azole class of medications and works by disrupting the cell membrane.^[1]

Clotrimazole was discovered in 1969.^[2] It is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system.^[3] It is available as a generic medication.^[1] The wholesale cost in the developing world as of 2014 is 0.20–0.86 USD per 20 gram tube of cream.^[4] In the United States a course of treatment typically costs less than 25 USD.^[5]

It is commonly available without a prescription in various dosage forms, such as a cream, vaginal tablet, or as a prescription troche or throat lozenge (prescription only). Topically, clotrimazole is used for vulvovaginal candidiasis (yeast infection) or yeast infections of the skin. For vulvovaginal candidiasis (yeast infection), clotrimazole tablets and creams are inserted into the vagina. Troche or throat lozenge preparations are used for oropharyngeal candidiasis (oral thrush) or prophylaxis against oral thrush in neutropenic patients.

Clotrimazole is usually used 5 times daily for 14 days for oral thrush, twice daily for 2 to 8 weeks for skin infections, and once daily for 3 or 7 days for vaginal infections.^[6]

Clotrimazole may be compounded with a glucocorticoid, such as betamethasone, in a topical cream for the treatment of tinea corporis (ringworm), tinea cruris (jock itch) and tinea pedis (athlete’s foot). Although FDA approved, clotrimazole-betamethasone combination cream is not the preferred treatment for dermatophyte infections due to increased side effects from the topical glucocorticoid. Although temporary relief and partial suppression of symptoms may be observed with the combination therapy, glucocorticoids can elicit an immunosuppressive response and rebound effect that results in more severe infection typically requiring systemic antifungal agents to treat the disease. Combination creams are best avoided in order to improve treatment outcome, reduce the possibility of skin atrophy associated with prolonged topical glucocorticoid use, and to limit the cost of treatment. It can be effective in treating chronic paronychia. The preferred treatment of tinea infections is therefore with clotrimazole monotherapy.^[7]

Topical and oral clotrimazole can be used in both adults and children.

Additionally, clotrimazole may be used to treat the sickling of cells (related to sickle cell anemia).^[8][9]

Pregnancy

Small amounts of clotrimazole may be absorbed systemically following topical and vaginal administration. However, this may still be used to treat yeast infections in pregnant women.^[10]

Side effects

Side effects of the oral formulation include itching, nausea, and vomiting. >10% of patients using the oral formulation may have abnormal liver function tests. Side effects include rash, hives, blisters, burning, itching, peeling, redness, swelling, pain or other signs of skin irritation.^[1] For this reason, liver function tests should be monitored periodically when taking the oral clotrimazole (troche). When used to treat vulvovaginal candidiasis (yeast infection), <10% of patient have vulvar or vaginal burning sensation. <1% of patients have the following side effects: Burning or itching of penis of sexual partner; polyuria; vulvar itching, soreness, edema, or discharge ^[6][11][12]

Clotrimazole creams and suppositories contain oil which may weaken latex condoms and diaphragms.^[10]

Drug interactions

There are no known significant drug interactions with topical clotrimazole. However, with oral (troche) clotrimazole, there are multiple interactions as the medication is a CYP450 enzyme inhibitor, primarily CYP3A4. Thus, any medication that is metabolized by the CYP3A4 enzyme will potentially have elevated levels when oral clotrimazole is used. The prescribing physician should be aware of any medication the patient is taking prior to starting oral clotrimazole. Certain medications should not be taken with oral clotrimazole.^[11]

Mechanism of action

Clotrimazole works by inhibiting the growth of individual Candida or fungal cells by altering the permeability of the fungal cell wall. It binds to phospholipids in the cell membrane and inhibits the biosynthesis of ergosterol and other sterols required for cell membrane production.^[12][11] Clotrimazole may be fungistatic (slow fungal growth) or fungicidal (result in fungal cell death).^[1]

Society and culture

It is available as a generic medication.^[1] The wholesale cost in the developing world as of 2014 is 0.20–0.86 USD per 20gm tube of cream.^[4]In the United States a course of treatment typically costs less than 25 USD.^[5] In 2016 Canesten was one of the biggest selling branded over-the-counter medications sold in Great Britain, with sales of £39.2 million.^[13]

syn

 

CLIP

Fig 4. Open Babel bond-line chemical structure with annotated hydrogens.
Click to toggle size.

Spectrum Plot

Fig 5. ¹H NMR spectrum of C₂₂H₁₇ClN₂ in CDCL3 at 400 MHz.

Figure 7. 2D 13 C13 C refocused INADEQUATE spectrum of clotrimazole showing intramolecular contacts among 13 C resonances as marked in the molecular structure on the right. The full spectrum is included in the Figure S4. The 2D spectrum was acquired in 17 hr at 106 K on 400 MHz, 384 scans per increment, 2 s recycle delay and 80 t 1 increments of a 27.7 ?s.

2D 13C-13C refocused INADEQUATE spectrum of clotrimazole showing intramolecular contacts among 13C resonances as marked in the molecular structure on the right. The 2D spectrum was acquired in 17 hr at 106 K on 400 MHz.

PATENT

https://patents.google.com/patent/CN105566156A/en

The object of the present invention is to provide a method for synthesizing a pharmaceutical Clotrimazole intermediate o-chlorobenzonitrile, comprising the steps of:

[0004] (i) in a reaction container equipped with a stirrer, a thermometer, a distillation apparatus, was added o-chlorobenzyl alcohol (2) 3. lmol, aniline (3) 3.6-3 · 9mol, nitromethane burning 310ml, chloro cuprous 1 · 56mol, hook are mixed, controlling the stirring speed 110-160rpm, the solution temperature increased to 110-115 ° C, 3-5h the reaction, the solution temperature increased to 130-135 ° C, the reaction 2-3h, solution temperature increased to 190-195 ° C, the reaction 90-120min, reducing the solution temperature to 15-20 ° C, was added 700 ml of saline solution, sodium bisulfite solution, 130ml, distilled under reduced pressure to collect 130-135 ° C fraction , washed with triethylamine in toluene and recrystallized to give crystals of o-chlorobenzonitrile (1).

[0005] wherein the mass fraction of nitromethane according to step (i) is 60-65%, of the salt solution in step (i) is ammonium nitrate, potassium iodide to any one of the steps of (i) mass fraction of sodium hydrogen sulfite solution was 40-45%, which pressure in the vacuum distillation of step (i) is 1.6-1.7kPa, triethylamine mass fraction of said step (i) is 70-75%, step (i) in toluene of the mass fraction of 90-95%. Throughout the reaction using the following reaction formula:

[0006

[0007 “not as good as Wu Ming 1 point Shi Bian: J Cheng less

A slave I anti Day “* 1, section A, J array low reaction temperature and reaction time, the reaction yield improved.

Detailed ways

[0008] The following examples with reference to specific embodiments of the present invention is further described:

Clotrimazole synthesis kinds drug intermediates of o-chlorobenzonitrile – [0009]

[0010] Example 1:

[0011] In a reaction vessel fitted with a stirrer, a thermometer, a distillation apparatus, was added o-chlorobenzyl alcohol (2) 3. Lmol, aniline (3) 3.6111〇1, mass fraction of 60% nitromethane 3,101,111 chloride cuprous 1.56111 〇1, mixing, stirring speed control lOrpm 1, the solution temperature increased to 110 ° C, the reaction 3h, the solution temperature increased to 130 ° C, the reaction 2h, the solution temperature is raised to 190 ° (:, reaction 9011 ^ 11, reducing the solution temperature to 15 ° (:, 7,001,111 ammonium nitrate solution was added, the mass fraction of 40% sodium bisulfite solution was 130ml, 1.6kPa vacuum distillation, collecting the fraction 130-135 ° C, mass fraction of 70 washed% triethylamine, 90% toluene to a mass fraction of recrystallized to give crystals of o-chlorobenzonitrile 308.02g, yield 72%.

[0012] Example 2:

[0013] In a reaction vessel fitted with a stirrer, a thermometer, a distillation apparatus, was added o-chlorobenzyl alcohol (2) 3. Lmol, aniline (3) 3.7111〇1, mass fraction of 62% nitromethane 31〇1111, 1.56111〇1 cuprous chloride, mixed, controlling the stirring speed of 130 rpm, the temperature was raised to 112 ° C, the reaction 4h, the solution temperature increased to 132 ° C, the reaction 2h, the solution temperature increased to 192 ° C, the reaction llOmin, reducing the solution temperature to 17 ° C, 700 ml of a solution of potassium iodide was added, the mass fraction of 42% sodium bisulfite solution 130ml, 1.65kPa vacuum distillation, collecting the fraction 130-135 ° C, mass fraction of 72% triethylamine washed, recrystallized from toluene to 92% mass fraction, to obtain crystals of o-chlorobenzonitrile 337.96g, yield 79%.

[0014] Example 3:

[0015] In a reaction vessel fitted with a stirrer, a thermometer, a distillation apparatus, was added o-chlorobenzyl alcohol (2) 3. Lmol, aniline (3) 3.9111〇1, mass fraction of 65% nitromethane 31〇1111, 1.56111 〇1 cuprous chloride, mixed, controlling stirring speed 160 rpm, temperature was raised to 115 ° C, the reaction 5h, the solution temperature increased to 135 ° C, the reaction 3h, the solution temperature increased to 195 ° C, the reaction 120min, reducing the solution temperature to 20 ° C, was added 700 ml of a solution of ammonium nitrate, 45% mass fraction of sodium bisulfite solution was 130ml, 1.7kPa vacuum distillation, collecting the fraction 130-135 ° C, mass fraction of 75% triacetyl amine scrubbing, 95%, recrystallized from toluene to a mass fraction to obtain crystals of o-chlorobenzonitrile 350.80g, yield 82%.

PATENT

https://patents.google.com/patent/US5091540A/en

Clotrimazole, i.e. 1-(o.Cl-α,α-diphenylbenzyl)imidazole, of formula: ##STR1## is a known antimycotic for human use, and a fungicide useful against plant pathogenic fungi.

Methods for its preparation are described in various patents. In particular, U.S. Pat. No. 3,929,820 describes a process starting from chlorophenyldiphenyl methylchloride and imidazole in the presence of a neutralizing agent, such as triethylamine, in a polar organic solvent. The process is strictly limited by the use, as the medium for the reaction in question, of a solvent falling within the given definition, i.e. having a dielectric constant of at least 4.5 and preferably between 15 and 50. In all the examples of the implementation of the process according to the patent in question, acetonitrile (D=37.5) is used as solvent.

EXAMPLE

900 g of benzene and 117.5 g of aluminium chloride are placed in a 2 liter flask fitted with a reflux condenser, stirrer and drying tube.

The mixture is cooled to 0° C. and a solution of 150 g of o.chlorobenzotrichloride in 150 g of benzene is added while maintaining a temperature not exceeding 15° C. The mixture is heated carefully under reflux for 4 hours. HCl is evolved.

The reaction mixture is then cooled to ambient temperature and slowly poured into 300 g of concentrated hydrochloric acid and 800 g of ice, so as not to exceed 25° C. The aqueous layer is then separated and discarded.

The benzene solution is washed with a solution of 230 g of sodium chloride in 800 g of water. The benzene phase is separated and dried over anhydrous sodium sulphate for 1 hour, and then filtered.

45 g of imidazole in 70 g of triethylamine are added to the filtrate and the mixture heated for 3 hours at 45°-50° C. It is then cooled to ambient temperature and 500 g of water are added while stirring. The aqueous layer is separated and discarded, and the benzene phase washed with 200 g of water. The benzene layer is separated and evaporated to dryness under vacuum.

The residue is dissolved in 250 g of ethyl acetate while stirring. 250 g of water are added and the solution titrated to calculate the exact quantity of nitric acid to add.

The solution is cooled to 15° C. and the calculated nitric acid quantity is quickly added. Stirring is halted when precipitation commences, and the system left until precipitation is complete.

The product is centrifuged and washed with 300 g of ethyl acetate and then with 300 g of water.

The moist product is placed into the reaction flask and 300 g of water, 450 g of methylene chloride, 5 g of triethylamine and 110 g of 30% sodium hydroxide are added. The mixture is stirred until a solution forms and the solution then left until the phases separate.

The aqueous phase is washed with 100 g of methylene chloride, and the pooled organic phases are washed twice with 200 g of water each time.

The solution in methylene chloride is treated with YMS decolorizing carbon and filtered, the filter then being washed with methylene chloride which si recovered by distillation. The residue is taken up in 100 g of acetone and redistilled to completely eliminate the methylene chloride.

The residue is taken up in 900 g of acetone and heated to 50° C. to obtain a complete solution. YMS decolorizing carbon and triethylamine are added, the mixture filtered and washed with acetone. Part of the acetone is then removed by distillation, reducing the volume to about 500 c.c. The mixture is cooled to 0° C. and, after five hours, the product is centrifuged and washed with 100 g of acetone. It is dried at 60° C., to obtain 150 g of final product.

References

1. ^ Jump up to:^{a b c d e f g h i j k l m} American Society of Health-System Pharmacists (8 February 2016). “Clotrimazole Monograph for Professionals”. http://www.drugs.com. Archived from the original on 28 October 2016. Retrieved 28 October 2016.
2. ^ Walker, S. R. (2012). Trends and Changes in Drug Research and Development. Springer Science & Business Media. p. 109. ISBN 9789400926592. Archived from the original on 2016-09-14.
3. ^ “WHO Model List of Essential Medicines (19th List)” (PDF). World Health Organization. April 2015. Archived (PDF) from the original on 13 December 2016. Retrieved 8 December 2016.
4. ^ Jump up to:^a b “Clotrimazole”. International Drug Price Indicator Guide. Archived from the original on 10 May 2017. Retrieved 28 October 2016.
5. ^ Jump up to:^a b Tarascon Pharmacopoeia 2016 Professional Desk Reference Edition. Jones & Bartlett Publishers. 2016. p. 176. ISBN 9781284095302. Archived from the original on 2016-10-28.
6. ^ Jump up to:^a b “Clotrimazole: MedlinePlus Drug Information”. The American Society of Health-System Pharmacists, Inc. Archived from the original on 18 April 2014. Retrieved 17 April2014.
7. ^ Moriarty, B; Hay, R; Morris-Jones, R (10 July 2012). “The diagnosis and management of tinea”. BMJ (Clinical research ed.). 345: e4380. doi:10.1136/bmj.e4380. PMID 22782730.
8. ^ Marieb & Hoehn, (2010). Human Anatomy and Physiology, p. 643. Toronto: Pearson
9. ^ Rodgers, Griffin. “Hydroxyurea and other disease-modifying therapies in sickle cell disease”. UpToDate. Archived from the original on 15 April 2014. Retrieved 14 April2014.
10. ^ Jump up to:^a b “Diseases Characterized by Vaginal Discharge”. CDC. Archived from the original on 28 April 2014. Retrieved 17 April 2014.
11. ^ Jump up to:^a b c “Clotrimazole”. DrugBank. Archived from the original on 17 April 2014. Retrieved 17 April 2014.
12. ^ Jump up to:^a b “Clotrimazole (Oral)”. Lexicomp Online. Archived from the original on 23 January 2015. Retrieved 17 April 2014.
13. ^ “A breakdown of the over-the-counter medicines market in Britain in 2016”. Pharmaceutical Journal. 28 April 2017. Retrieved 29 May 2017.

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Diclofenac Sodium

15307-79-6; Sodium diclofenac; Diclofenac sodium salt; Voltaren; Solaraze

Diclofenac, sold under the trade names Voltaren among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain and inflammatory diseases such as gout.^[3] It is taken by mouth or applied to the skin.^[3] Improvements in pain typically occur within half an hour and last for as much as eight hours.^[3] It is also available in combination with misoprostol in an effort to decrease stomach problems.^[4]

Common side effects include abdominal pain, gastrointestinal bleeding, nausea, dizziness, headache, and swelling.^[3] Serious side effects may include heart disease, stroke, kidney problems, and stomach ulceration.^[4][3] Use is not recommended in the third trimester of pregnancy.^[3] It is likely safe during breastfeeding.^[4] It is believed to work by decreasing the production of prostaglandin.^[5] It blocks both cycloxygenase-1 (COX-1) and cycloxygenase-2 (COX-2).^[3]

Diclofenac was patented in 1965 by Ciba-Geigy and came into medical use in the United States in 1988.^[3][6] It is available as a generic medication.^[3] In the United States the wholesale cost per dose is less than US$0.15 as of 2018.^[7] In 2016 it was the 78th most prescribed medication in the United States with more than 9 million prescriptions.^[8] It is available as both a sodium and a potassium salt.^[4]

Medical uses

Diclofenac is used to treat pain, inflammatory disorders, and dysmenorrhea.^[9]

Pain

Inflammatory disorders may include musculoskeletal complaints, especially arthritis, rheumatoid arthritis, polymyositis, dermatomyositis, osteoarthritis, dental pain, temporomandibular joint (TMJ) pain, spondylarthritis, ankylosing spondylitis, gout attacks,^[10] and pain management in cases of kidney stones and gallstones. An additional indication is the treatment of acute migraines.^[11] Diclofenac is used commonly to treat mild to moderate postoperative or post-traumatic pain, in particular when inflammation is also present,^[10] and is effective against menstrual pain and endometriosis.

Diclofenac is also available in topical forms and has been found to be useful for osteoarthritis but not other types of long-term musculoskeletal pain.^[12]

It may also help with actinic keratosis, and acute pain caused by minor strains, sprains, and contusions (bruises).^[13]

In many countries,^[14] eye drops are sold to treat acute and chronic nonbacterial inflammation of the anterior part of the eyes (e.g., postoperative states). Diclofenac eye drops have also been used to manage pain for traumatic corneal abrasion.^[15]

Diclofenac is often used to treat chronic pain associated with cancer, in particular if inflammation is also present (Step I of the World Health Organization (WHO) scheme for treatment of chronic pain).^[16] Diclofenac can be combined with opioids if needed such as a fixed combination of diclofenac and codeine.

• Voltaren (diclofenac) 50 mg enteric coatedtablets

• Arthrotec (diclofenac and misoprostol) 50 mg tablets

• Dyloject (diclofenac) 2 ml for IV and IMadministration

• Sintofarm (diclofenac) for suppositoryadministration

Contraindications

• Hypersensitivity against diclofenac
• History of allergic reactions (bronchospasm, shock, rhinitis, urticaria) following the use of other NSAIDs such as aspirin
• Third-trimester pregnancy
• Active stomach and/or duodenal ulceration or gastrointestinal bleeding
• Inflammatory bowel disease such as Crohn’s disease or ulcerative colitis
• Severe insufficiency of the heart (NYHA III/IV)
• Pain management in the setting of coronary artery bypass graft (CABG) surgery
• Severe liver insufficiency (Child-Pugh Class C)
• Severe renal insufficiency (creatinine clearance <30 ml/min)
• Caution in patients with pre-existing hepatic porphyria, as diclofenac may trigger attacks
• Caution in patients with severe, active bleeding such as cerebral hemorrhage
• NSAIDs in general should be avoided during dengue fever, as it induces (often severe) capillary leakage and subsequent heart failure.
• Caution in patients with fluid retention or heart failure
• Can lead to onset of new hypertension or worsening of pre-existing hypertension
• Can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal^[17]

Adverse effects

Diclofenac consumption has been associated with significantly increased vascular and coronary risk in a study including coxib, diclofenac, ibuprofen and naproxen.^[18] Upper gastrointestinal complications were also reported.^[18] Major adverse cardiovascular events (MACE) were increased by about a third by diclofenac, chiefly due to an increase in major coronary events.^[18] Compared with placebo, of 1000 patients allocated to diclofenac for a year, three more had major vascular events, one of which was fatal.^[18] Vascular death was increased significantly by diclofenac.^[18]

Heart

In 2013, a study found major vascular events were increased by about a third by diclofenac, chiefly due to an increase in major coronary events.^[18] Compared with placebo, of 1000 people allocated to diclofenac for a year, three more had major vascular events, one of which was fatal.^[18] Vascular death was increased by diclofenac (1·65).^[18]

Following the identification of increased risks of heart attacks with the selective COX-2 inhibitor rofecoxib in 2004, attention has focused on all the other members of the NSAIDs group, including diclofenac. Research results are mixed, with a meta-analysis of papers and reports up to April 2006 suggesting a relative increased rate of heart disease of 1.63 compared to nonusers.^[19] Professor Peter Weissberg, Medical Director of the British Heart Foundation said, “However, the increased risk is small, and many patients with chronic debilitating pain may well feel that this small risk is worth taking to relieve their symptoms”. Only aspirin was found not to increase the risk of heart disease; however, this is known to have a higher rate of gastric ulceration than diclofenac. In Britain the Medicines and Healthcare Products Regulatory Agency (MHRA) said in June 2013 that the drug should not be used by people with serious underlying heart conditions—people who had suffered heart failure, heart disease or a stroke were advised to stop using it completely.^[20] As of January 15, 2015 the MHRA announced that diclofenac will be reclassified as a prescription-only medicine (POM) due to the risk of cardiovascular adverse events.^[21]

A subsequent large study of 74,838 Danish users of NSAIDs or coxibs found no additional cardiovascular risk from diclofenac use.^[22] A very large study of 1,028,437 Danish users of various NSAIDs or coxibs found the “Use of the nonselective NSAID diclofenac and the selective cyclooxygenase-2 inhibitor rofecoxib was associated with an increased risk of cardiovascular death (odds ratio, 1.91; 95% confidence interval, 1.62 to 2.42; and odds ratio, 1.66; 95% confidence interval, 1.06 to 2.59, respectively), with a dose-dependent increase in risk.”^[23]

Diclofenac is similar in COX-2 selectivity to celecoxib.^[24]

Gastrointestinal

• Gastrointestinal complaints are most often noted. The development of ulceration and/or bleeding requires immediate termination of treatment with diclofenac. Most patients receive a gastro-protective drug as prophylaxis during long-term treatment (misoprostol, ranitidine 150 mg at bedtime or omeprazole 20 mg at bedtime).

Liver

• Liver damage occurs infrequently, and is usually reversible. Hepatitis may occur rarely without any warning symptoms and may be fatal. Patients with osteoarthritis more often develop symptomatic liver disease than patients with rheumatoid arthritis. Liver function should be monitored regularly during long-term treatment. If used for the short-term treatment of pain or fever, diclofenac has not been found more hepatotoxic than other NSAIDs.
• As of December 2009, Endo, Novartis, and the US FDA notified healthcare professionals to add new warnings and precautions about the potential for elevation in liver function tests during treatment with all products containing diclofenac sodium.^[25]
• Cases of drug-induced hepatotoxicity have been reported in the first month, but can occur at any time during treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation.
• Physicians should measure transaminases periodically in patients receiving long-term therapy with diclofenac. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 week after initiating treatment with diclofenac.

Kidney

• NSAIDs “are associated with adverse renal [kidney] effects caused by the reduction in synthesis of renal prostaglandins“^[26] in sensitive persons or animal species, and potentially during long-term use in nonsensitive persons if resistance to side effects decreases with age. However, this side effect cannot be avoided merely by using a COX-2 selective inhibitor because, “Both isoforms of COX, COX-1 and COX-2, are expressed in the kidney… Consequently, the same precautions regarding renal risk that are followed for nonselective NSAIDs should be used when selective COX-2 inhibitors are administered.”^[26] However, diclofenac appears to have a different mechanism of renal toxicity.^{[citation needed]}
• Studies in Pakistan showed diclofenac caused acute kidney failure in vultures when they ate the carcasses of animals that had recently been treated with it. Drug-sensitive species and individual humans are initially assumed to lack genes expressing specific drug detoxification enzymes.^[27]

Mental health

• Mental health side effects have been reported. These symptoms are rare, but exist in significant enough numbers to include as potential side effects. These include depression, anxiety, irritability, nightmares, and psychotic reactions.^[28]

Mechanism of action

The primary mechanism responsible for its anti-inflammatory, antipyretic, and analgesic action is thought to be inhibition of prostaglandin synthesis by inhibition of the transiently expressed prostaglandin-endoperoxide synthase-2 (PGES-2) also known as cycloxygenase-2 (COX-2). It also appears to exhibit bacteriostatic activity by inhibiting bacterial DNA synthesis.^[29]

Inhibition of prostaglandin synthesis occurs systemically resulting in undesirable symptoms such as irritation of the gastric epithelium.^{[citation needed]} This is the main side effect of diclofenac. Diclofenac inhibits COX-2 with 20 times greater potency than the constitutively expressed isoenzyme COX-1^[30] and has, therefore, a somewhat lower incidence of gastrointestinal complaints than noted with aspirin which inhibits COX-1 to a greater extent.

The action of one single dose is much longer (6 to 8 hr) than the very short 1.2–2 hr half-life of the drug would indicate. This could be partly because it persists for over 11 hours in synovial fluids.^[31]

Diclofenac may also be a unique member of the NSAIDs. Some evidence indicates it inhibits the lipoxygenase pathways, thus reducing formation of the leukotrienes(also pro-inflammatory autacoids). It also may inhibit phospholipase A2 as part of its mechanism of action. These additional actions may explain its high potency – it is the most potent NSAID on a broad basis.^[32]

Marked differences exist among NSAIDs in their selective inhibition of the two subtypes of cyclooxygenase, COX-1 and COX-2. Much pharmaceutical drug design has attempted to focus on selective COX-2 inhibition as a way to minimize the gastrointestinal side effects of NSAIDs such as aspirin. In practice, use of some COX-2 inhibitors with their adverse effects has led to massive numbers of patient family lawsuits alleging wrongful death by heart attack, yet other significantly COX-selective NSAIDs, such as diclofenac, have been well tolerated by most of the population.^\

Besides the COX-inhibition, a number of other molecular targets of diclofenac possibly contributing to its pain-relieving actions have recently been identified. These include:

• Blockage of voltage-dependent sodium channels (after activation of the channel, diclofenac inhibits its reactivation also known as phase inhibition)^{[citation needed]}
• Blockage of acid-sensing ion channels (ASICs)^[33]
• Positive allosteric modulation of KCNQ- and BK-potassium channels (diclofenac opens these channels, leading to hyperpolarization of the cell membrane)

Ecological effects

Use of diclofenac for animals is controversial due to toxicity when eaten by scavenging birds that eat dead animals; the drug has been banned for veterinary use in many countries.

Use of diclofenac in animals has been reported to have led to a sharp decline in the vulture population in the Indian subcontinent – a 95% decline by 2003^[34] and a 99.9% decline by 2008. The mechanism is presumed to be renal failure;^[35] however, toxicity may be due to direct inhibition of uric acid secretion in vultures.^[36] Vultures eat the carcasses of livestockthat have been administered veterinary diclofenac, and are poisoned by the accumulated chemical,^[37] as vultures do not have a particular enzyme to break down diclofenac. At a meeting of the National Wildlife Board in March 2005, the Government of India announced it intended to phase out the veterinary use of diclofenac.^[38] Meloxicam is a safer alternative to replace use of diclofenac.^[39] It is more expensive than diclofenac, but the price is coming down as more pharmaceutical companies begin to manufacture it.

Steppe eagles have the same vulnerability to diclofenac as vultures and may also fall victim to it.^[40] Diclofenac has been shown also to harm freshwater fish species such as rainbow trout.^{[41][42][43][44]} In contrast, New World vultures, such as the turkey vulture, can tolerate at least 100 times the level of diclofenac that is lethal to Gyps species.^[45]

“The loss of tens of millions of vultures over the last decade has had major ecological consequences across the Indian Subcontinent that pose a potential threat to human health. In many places, populations of feral dogs (Canis familiaris) have increased sharply from the disappearance of Gyps vultures as the main scavenger of wild and domestic ungulatecarcasses. Associated with the rise in dog numbers is an increased risk of rabies“^[39] and casualties of almost 50,000 people.^[46] The Government of India cites this as one of the major consequences of a vulture species extinction.^[38] A major shift in the transfer of corpse pathogens from vultures to feral dogs and rats could lead to a disease pandemic, causing millions of deaths in a crowded country like India, whereas vultures’ digestive systems safely destroy many species of such pathogens. Vultures are long-lived and slow to breed. They start breeding only at the age of six and only 50% of young survive. Even if the government ban is fully implemented, it will take several years to revive the vulture population.^[47]

The loss of vultures has had a social impact on the Indian Zoroastrian Parsi community, who traditionally use vultures to dispose of human corpses in Towers of Silence, but are now compelled to seek alternative methods of disposal.^[39]

Despite the vulture crisis, diclofenac remains available in other countries including many in Europe.^[48] It was controversially approved for veterinary use in Spain in 2013 and continues to be available, despite Spain being home to around 90% of the European vulture population and an independent simulation showing that the drug could reduce the population of vultures by 1-8% annually. Spain’s medicine agency presented simulations suggesting that the number of deaths would be quite small.^[49][50]

Formulations and trade names

The name “diclofenac” derives from its chemical name: 2-(2,6-dichloranilino) phenylacetic acid. Diclofenac was first synthesized by Alfred Sallmann and Rudolf Pfister and introduced as Voltaren by Ciba-Geigy (now Novartis) in 1973, now by Glaxo SmithKline.^[51]

In the United Kingdom, United States, India, and Brazil diclofenac may be supplied as either the sodium or potassium salt; in China, it is most often supplied as the sodium salt, while in some other countries it is only available as the potassium salt.

Pennsaid is a minimally systemic prescription topical lotion formulation of 1.5% w/w diclofenac sodium, which is approved in the US, Canada and other countries for osteoarthritis of the knee.

Flector Patch, a minimally systemic topical patch formulation of diclofenac, is indicated for acute pain due to minor sprains, strains, and contusions. The patch has been approved in many other countries outside the US under different brand names.

Voltaren and Voltarol contain the sodium salt of diclofenac. In the United Kingdom, Voltarol can be supplied with either the sodium salt or the potassium salt, while Cataflam, sold in some other countries, is the potassium salt only. However, Voltarol Emulgel contains diclofenac diethylammonium, in which a 1.16% concentration is equivalent to a 1% concentration of the sodium salt. In 2016 Voltarol was one of the biggest selling branded over-the-counter medications sold in Great Britain, with sales of £39.3 million.^[52]

Diclofenac is available in stomach acid-resistant formulations (25 and 50 mg), fast-disintegrating oral formulations (25 and 50 mg), powder for oral solution (50 mg), slow- and controlled-release forms (75, 100 or 150 mg), suppositories (50 and 100 mg), and injectable forms (50 and 75 mg).

Diclofenac is also available over-the-counter in some countries: 12.5 mg diclofenac as potassium salt in Switzerland (Voltaren dolo), the Netherlands (Voltaren K), and preparations containing 25 mg diclofenac as the potassium salt in Germany (various trade names), New Zealand, Australia, Japan, (Voltaren Rapid), and Sweden (Voltaren T and Diclofenac T). Diclofenac as potassium salt can be found throughout the Middle East in 25 mg and 50 mg doses (Cataflam).

Solaraze (3% diclofenac sodium gel) is topically applied, twice a day for three months, to manage the skin condition known as actinic or solar keratosis. Parazone-DP is a combination of diclofenac potassium and paracetamol, manufactured and supplied by Ozone Pharmaceuticals and Chemicals, Gujarat, India. It is sold in Uruguay alone or, in combination with orphenadrine to treat muscle spasms/pain due to injuries (Dicloflex Ion).

On 14 January 2015, diclofenac oral preparations were reclassified as prescription-only medicines in the UK. The topical preparations are still available without prescription.^[53]

Diclofenac formulations are available worldwide under many different trade names.^[1]

Title: Diclofenac CAS Registry Number: 15307-86-5 CAS Name: 2-[(2,6-Dichlorophenyl)amino]benzeneacetic acid Additional Names: [o-(2,6-dichloroanilino)phenyl]acetic acid Trademarks: Motifene (Sankyo) Molecular Formula: C14H11Cl2NO2 Molecular Weight: 296.15 Percent Composition: C 56.78%, H 3.74%, Cl 23.94%, N 4.73%, O 10.80% Literature References: Prepn: NL 6604752; A. Sallmann, R. Pfister, US 3558690 (1966, 1971 both to Geigy). Pharmacology: Renaud, Lecompte, Thromb. Diath. Haemorrh. 24, 577 (1970), C.A. 74, 86215m (1971); Krupp et al., Experientia 29, 450 (1973). HPLC determn in plasma and urine: J. Godbillon et al., J. Chromatogr. 338, 151 (1985). Symposium on pharmacology and clinical experience: Semin. Arthritis Rheum. 15, Suppl. 1, 57-110 (1985); on pharmacology, efficacy and safety: Am. J. Med. 80, Suppl. 4B, 1-87 (1986). Comprehensive description: C. M. Adeyeye, P-K. Li, Anal. Profiles Drug Subs. 19, 123-144 (1990). Review of clinical trials in actinic keratosis: D. C. Peters, R. H. Foster, Drugs Aging 14, 313-319 (1999). Properties: Crystals from ether-petr ether, mp 156-158°. Melting point: mp 156-158° Derivative Type: Diethylammonium salt CAS Registry Number: 78213-16-8 Trademarks: Voltarol (Novartis) Molecular Formula: C14H11Cl2NO2.C4H11N Molecular Weight: 369.29 Percent Composition: C 58.54%, H 6.00%, Cl 19.20%, N 7.59%, O 8.66% Derivative Type: Sodium salt CAS Registry Number: 15307-79-6 Manufacturers’ Codes: GP-45840 Trademarks: Allvoran (TAD); Benfofen (Sanofi-Synthelabo); Dealgic (Pharmacia); Deflamat (Sankyo); Delphinac (Riemser); Dicloflex (Dexcel); Diclomax (Provalis); Diclophlogont (Azupharma); Dicloreum (Alfa); Duravolten (Dura); Ecofenac (Ecosol); Effekton (Teofarma); Lexobene (Merckle); Neriodin (Nagase); Novapirina (Novartis); Primofenac (Streuli); Prophenatin (Nipro); Rewodina (AWD); Rhumalgan (Sandoz); Voldal (Novartis); Voltaren (Novartis); Xenid (RPG) Molecular Formula: C14H10Cl2NNaO2 Molecular Weight: 318.13 Percent Composition: C 52.86%, H 3.17%, Cl 22.29%, N 4.40%, Na 7.23%, O 10.06% Properties: Crystals from water, mp 283-285°. uv max (methanol) 283 nm (e 1.05 ´ 105); (phosphate buffer, pH 7.2) 276 nm (e1.01 ´ 105). Soly at 25°C (mg/ml): deionized water (pH 5.2) >9; methanol >24; acetone 6; acetonitrile <1; cyclohexane <1; HCl (pH 1.1) <1; phosphate buffer (pH 7.2) 6. pKa 4. Partition coefficient (N-octanol/aq. buffer): 13.4. LD50 in mice, rats (mg/kg): ~390, 150 orally (Krupp). Melting point: mp 283-285° pKa: pKa 4 Log P: Partition coefficient (N-octanol/aq. buffer): 13.4 Absorption maximum: uv max (methanol) 283 nm (e 1.05 ´ 105); (phosphate buffer, pH 7.2) 276 nm (e 1.01 ´ 105) Toxicity data: LD50 in mice, rats (mg/kg): ~390, 150 orally (Krupp) Derivative Type: Potassium salt CAS Registry Number: 15307-81-0 Manufacturers’ Codes: CGP-45840B Trademarks: Cataflam (Novartis) Molecular Formula: C14H10Cl2KNO2 Molecular Weight: 334.24 Percent Composition: C 50.31%, H 3.02%, Cl 21.21%, K 11.70%, N 4.19%, O 9.57% Therap-Cat: Anti-inflammatory. Keywords: Anti-inflammatory (Nonsteroidal); Arylacetic Acid Derivatives.

Synthesis

The mechanism begins with the condensation of hydrazine onto a ketone (details not shown) to give a hydrazone. Under basic conditions, this hydrazone is deprotonated at nitrogen to give an anionic intermediate. In this case, the negative charge can be delocalized onto oxygen, resulting in an enolate structure. Typically, the negative charge is only shared between a nitrogen and carbon, so this substrate gives a particularly stable intermediate. Protonation of the enolate at carbon gives the first C-H bond necessary to form the product. A second deprotonation at nitrogen gives a similar flow of electrons to form another enolate structure, this time with cleavage of the C-N bond and release of nitrogen gas. Another C-protonation gives the lactam precursor to diclofenac. Cleavage of the amide with hydroxide (details not shown) gives the target.

Manufacturing Process
2, 6-Dichlorophenol is reacted with MMCA, Aniline and Chloro Acetyl Chloride and AlCl3 to yield (2, 6 –
Dichlorophenol) Indolinone is hydrolyzed using isopropyl alcohol and sodium hydroxide to give crude Diclofenac
Sodium. This on purification using deminerlised water and isopropyl alcohol gives the pure Diclofenac Sodium

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