WO 2016015596, Omarigliptin, Sunshine Lake Pharma Co Ltd, New patent

(WO2016015596) PROCESS FOR PREPARING 2, 3-DISUBSTITUTED-5-OXOPYRAN COMPOUND

SUNSHINE LAKE PHARMA CO., LTD. [CN/CN]; Northern Industrial Area, Songshan Lake Dongguan, Guangdong 523000 (CN)

SUN, Guodong; (CN).
LIU, Yongjun; (CN).
WEI, Mingjie; (CN).
LAI, Cailang; (CN).
LI, Dasheng; (CN).
ZHANG, Shouhua; (CN).
WANG, Zhongqing; (CN)

A 2, 3-disubstituted 5-oxopyran compound of formula (04) :

in which Ar is phenyl optionally substituted with R₄, R₄ is F, Cl, C1-C6 alkyl unsubstituted or substituted with fluorine, or C1-C6 alkoxy unsubstituted or substituted with fluorine； each of R₁ and R₂ is independently hydrogen, or an amino-protecting group； is useful in the synthesis of Omarigliptin or other compounds, is an important intermediate.

US Patent No. 7902376 and PCT Publication WO2007097931 disclose methods to prepare compounds of formula (04) , but both of the methods disclosed are complex to operate and need a special catalyst. So it is necess ary to explore an easy process.

Example 1:

tert-butyl ( (2R, 3S) -2- (2, 5-difluorophenyl) -5- (iodomethylene) tetrahydrofuran-3-yl) carbamate

To a mixture of methanol (42 mL) and tert-butyl ( (1R, 2S) -1- (2, 5-difluorophenyl) -1-hydroxypent-4-yn -2-yl) carbamate (7.0 g) cooled to-5℃ was added a solution of KOH (3.2 g) in methanol (28 mL) dropwise. After dropwise addition, the resulting mixture was stirred for 30 minutes, then iodine (5.7 g) was added to the mixture. The reaction mixture was stirred at 0 ℃ for 10 minutes, followed by 25 ℃ for 6 hours, and then quenched with water (140 mL) . Then the mixture was stirred at 25 ℃ for 2 hours. The precipitate was collected by filtration and washed sequentially with methanol/water (40 mL, v: v＝1: 1) . The resulting solid was dried at 45 ℃ in vacuo to give the title compound as awhite solid (8.8 g, purity: 95.0％)

The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z : 460.2, [M+Na] +；

1H NMR (600 MHz, CDCl₃) δ (ppm) : 7.09-6.90 (m, 3H) , 5.46 (s, 1H) , 4.92 (d, 1H) , 4.86 (d, 1H) , 4.36 (s, 1H) , 2.95 (ddd, 1H) , 2.62 (dd, 1H) , 1.43 (s, 9H) .

Example 2:

tert-butyl ( (2R, 3S) -5- (bromomethylene) -2- (2, 5-difluorophenyl) tetrahydrofuran- 3-yl) carbamate

To a mixture of methanol (150 mL) and sodium methoxide (13.0 g) cooled to -10 ℃ was added a solution of tert-butyl ( (1R, 2S) -1- (2, 5-difluorophenyl) -1-hydroxypent-4-yn-2-yl) carbamate (31.1 g) in methanol (200 mL) dropwise. After dropwise addition, N-bromosuccinimide (21.5 g) was added to the resulting mixture. The mixture was stirred at 0 ℃ for 10 minutes, followed by 25 ℃ for 6 hours, and then quenched with water (350 mL) and stirred for 30 minutes. The mixture was concentrated in vacuo until the precipitate appeared. After stirring at 25 ℃ for 30 minutes, the precipitate was collected by filtration and washed sequentially with methanol (80 mL) and water (80 mL) . The resulting solid was dried at 45 ℃ in vacuo to give the title compound as a white solid (35.4 g, purity: 92.8％) .

The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 414.0, [M+Na] ⁺；

¹H NMR (600 MHz, CDCl₃) δ (ppm) : 7.11 -6.87 (m, 3H) , 5.53-5.30 (m, 1H) , 5.13-5.06 (m, 1H) , 4.33 (s, 1H) , 2.95-2.86 (m, 1H) , 2.62-2.56 (m, 1H) , 1.43 (s, 9H) .

Example 3:

tert-butyl ( (2R, 3S) -5- (bromomethylene) -2- (2, 5-difluorophenyl) tetrahydrofuran-3-yl) carbamate

To a mixture of water (42 mL) , methanol (100 mL) and KOH (15.0 g) cooled to -10 ℃ was added a solution of tert-butyl ( (1R, 2S) -1- (2, 5-difluorophenyl) -1-hydroxypent-4-yn-2-yl) carbamate (41.6 g) in methanol (550 mL) dropwise. After dropwise addition, dibromohydantoin (23.1 g) was added to the resulting mixture. The reaction mixture was stirred at 0 ℃ for 30 minutes, followed with a temperature from 20 ℃ to 25 ℃ for 8 hours, and then quenched with water (650 mL) and stirred for 1.5 hours. The precipitate was collected by filtration and washed sequentially with methanol/water (400 mL, v: v＝1: 1) . The resulting solid was dried at 50 ℃ in vacuo to give the title compound as a white solid (46.5 g) .

The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 414.0, [M+Na] ⁺.

Example 4:

tert-butyl ( (1R, 2S) -1- (2, 5-difluorophenyl) -1-hydroxy-5-iodo-4-oxopentan-2-yl) carbamate

A solution of sodium hydrogen sulfate monohydrate (2.2 g) and tert-butyl ( (2R, 3S) -2- (2, 5-difluorophenyl) -5- (iodomethylene) tetrahydrofuran-3-yl) carbamate (7.2 g) in THF/water (35 mL/7 mL) was stirred at a temperature from 28 ℃ to 33 ℃ for 12 hours. Then the organic phase of the reaction mixture was separated and concentrated in vacuo at 40 ℃ to remove THF. Isopropyl acetate (35 mL) and water (28 mL) was added to the residue and the resulting mixture was stirred for 10 minutes. The seperated organic phase was concentrated in vacuo to give the title compound as brown oil (8.6 g) , which could be used for the next step without purification.

The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 477.8, [M+Na] ⁺, 381.8, [M-BuO] ⁺ .

Example 5:

tert-butyl ( (1R, 2S) -5-bromo-1- (2, 5-difluorophenyl) -1-hydroxy-4-oxopentan-2-yl) carbamate

A solution of sodium hydrogen sulfate monohydrate (6.9 g) and tert-butyl ( (2R, 3S) -5- (bromomethylene) -2- (2, 5-difluorophenyl) tetrahydrofuran-3-yl) carbamate (39.0 g) in THF/water (200 mL/40 mL) was stirred at 60 ℃ for 10 hours to complete the reaction. Then the organic phase of the reaction mixture was separated and concentrated in vacuo to remove THF. The residue was diluted with isopropyl acetate (200 mL) and water (120 mL) , and stirred to dissolve. The organic phase was seperated and concentrated in vacuo to give the title compound as brown oil (43.5 g) , which was used for the next step without purification.

The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 336.1, [M-BuO] ⁺.

Example 6:

tert-butyl ( (2R, 3S) -2- (2, 5-difluorophenyl) -5-oxotetrahydro-2H-pyran-3-yl) carbamate

To the brown oil (8.6 g) obtained from Example 4 were added THF (40 mL) and K₂CO₃ (2.6 g) . The reaction was stirred at 30 ℃ for 16 hours. Then the mixture was concentrated in vacuo to remove THF and the resulting residue was diluted with a mixture of ethyl acetate (40 mL) and water (20 mL) . The separated organic phase was concentrated in vacuo and the resulting residue was diluted with ethyl acetate (2.5 mL) , heated to 40 ℃ and stirred to dissolve. Then the mixture was cooled to 20 ℃ and n-heptane (7.5 mL) was added. After sitrring for 4 hours at 20 ℃, the precipitate was collected by filtration to give the title compound as a white solid (4.0 g) .

The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 350.0, [M+Na] ⁺, 368.0, [M+K] ⁺；

¹H NMR (600 MHz, CDCl₃) δ (ppm) : 7.24 (m, 1H) , 7.04 (m, 2H) , 4.85 (s, 1H) , 4.68 (s, 1H) , 4.31 (dd, 1H) , 4.16-4.11 (m, 1H) , 4.11-4.04 (m, 1H) , 3.10-3.02 (m, 1H) , 2.75 (s, 1H) , 1.64 (s, 1H) , 1.37-1.25 (s, 9H) .

Example 7:

tert-butyl ( (2R, 3S) -2- (2, 5-difluorophenyl) -5-oxotetrahydro-2H-pyran-3-yl) carbamate

To the brown oil (43.5 g) obtained from Example 5 were added THF (500 mL) and K₂CO₃ (15.2 g) . The reaction was stirred at 35 ℃ for 16 hours. Then the organic phase was separated and concentrated in vacuo at 40 ℃ to remove THF and the resulting residue was diluted with a mixture of ethyl acetate (500 mL) and water (100 mL) . Then the separated organic phase was concentrated in vacuo and the resulting residue was diluted with ethyl acetate (13 mL) , heated to 40 ℃ and stirred to dissolve. Then the mixture was cooled to 20 ℃ and n-heptane (39 mL) was added. After sitrring for 4 hours at 20 ℃, the precipitate was collected by filtration to give the title compound as a white solid (23.9 g) .

The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 350.0.

//////////WO 2016015596, Omarigliptin,  Sunshine Lake Pharma Co Ltd, NEW PATENT

WOCKHARDT, WO 2016016766, ISAVUCONAZONIUM SULPHATE, NEW PATENT

(WO2016016766) A PROCESS FOR THE PREPARATION OF ISAVUCONAZONIUM OR ITS SALT THEREOF

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

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

The present invention relates to a process for the preparation of stable Isavuconazonium or its salt thereof. In particular of the present invention relates to process for the preparing of isavuconazonium sulfate, Isavuconazonium iodide hydrochloride and Boc-protected isavuconazonium iodide has purity more than 90%. The process is directed to preparation of solid amorphous form of isavuconazonium sulfate, isavuconazonium iodide hydrochloride and Boc-protected isavuconazonium iodide. The present invention process of Isavuconazonium or its salt thereof is industrially feasible, simple and cost effective to manufacture of isavuconazonium sulfate with the higher purity and better yield.

Habil Khorakiwala, chairman of Indian generic drugmaker Wockhardt

Isavuconazonium sulfate is chemically known l-[[N-methyl-N-3-[(methylamino) acetoxymethyl]pyridin-2-yl] carbamoyloxy]ethyl-l-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazol-2-yl]butyl]-lH-[l,2,4]-triazo-4-ium Sulfate and is structurally represented by formula (I):

Formula I

Isavuconazonium sulfate (BAL8557) is indicated for the treatment of antifungal infection. Isavuconazonium sulfate is a prodrug of Isavuconazole (BAL4815), which is chemically known 4-{2-[(lR,2R)-(2,5-Difluorophenyl)-2-hydroxy-l-methyl-3-(lH-l ,2,4-triazol-l-yl)propyl]-l ,3-thiazol-4-yl}benzonitrile compound of Formula II

Formula II

US Ppatent No. 6,812,238 (referred to herein as '238); 7,189,858 (referred to herein as '858); 7,459,561 (referred to herein as '561) describe Isavuconazonium and its process for the preparation thereof.

The US Pat. '238 patent describes the process of preparation of Isavuconazonium chloride hydrochloride.

The US Pat. '238 described the process for the Isavuconazonium chloride hydrochloride, involves the condensation of Isavuconazole and [N-methyl-N-3((tert-butoxycarbonyl methylamino) acetoxymethyl) pyridine-2-yl]carbamic acid 1 -chloro-ethyl ester. The prior art reported process require almost 15-16 hours, whereas the present invention process requires only 8-10 hours. Inter alia prior art reported process requires too many step to prepare isavuconazonium sulfate, whereas the present invention process requires fewer steps.

Moreover, the US Pat. '238 describes the process for the preparation Isavuconazonium hydrochloride, which may be used as the key intermediate for the synthesis of isavuconazonium sulfate, compound of formula I. There are several drawbacks in the said process, which includes the use of anionic resin to prepare Isavuconazonium chloride hydrochloride, consequently it requires multiple time lyophilization, which makes the said prior art process industrially, not feasible.

The inventors of the present invention surprisingly found that Isavuconazonium or a pharmaceutically acceptable salt thereof in yield and purity could be prepared by using substantially pure intermediates in suitable solvent.

Thus, an object of the present invention is to provide simple, cost effective and industrially feasible processes for manufacture of isavuconazonium sulfate. Inventors of the present invention surprisingly found that isavuconazonium sulfate prepared from isavuconazonium iodide hydrochloride, provides enhanced yield as well as purity.

The process of the present invention is depicted in the following scheme:

Formula I

Formula-IA

The present invention is further illustrated by the following example, which does not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.

Examples

Example-1: Synthesis of l-[[N-methyl-N-3-[(t-butoxycarbonylmethylamino) acetoxymethyl]pyridin-2-yl]carbamoyloxy]ethyl-l-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3 - [4-(4-cyanophenyl)thiazol-2-yl]butyl] - 1 H-[ 1 ,2,4] -triazo-4-ium iodide

Isavuconazole (20 g) and [N-methyl-N-3((tert-butoxycarbonylmethylamino)acetoxy methyl)pyridine-2-yl]carbamic acid 1 -chloro-ethyl ester (24.7 g) were dissolved in acetonitrile (200ml). The reaction mixture was stirred to add potassium iodide (9.9 g). The reaction mixture was stirred at 47-50°C for 10-13 hour. The reaction mixture was cooled to room temperature. The reaction mass was filtered through celite bed and washed acetonitrile. Residue was concentrated under reduced pressure to give the crude solid product (47.7 g). The crude product was purified by column chromatography to get its pure iodide form (36.5 g).

Yield: 84.5 %

HPLC Purity: 87%

Mass: m/z 817.4 (M- 1)⁺

Example-2: Synthesis of l-[[N-methyl-N-3-[(methylamino)acetoxymethyl]pyridin-2-yl] carbamoyloxy]ethyl-l-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl) thiazol-2-yl]butyl]-lH-[l ,2,4]-triazo-4-ium iodide hydrochloride

l-[[N-methyl-N-3-[(t-butoxycarbonylmethylamino)acetoxymethyl]pyridin-2-yl] carbamoyloxy]ethyl-l-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl) thiazol-2-yl]butyl]-lH-[l ,2,4]-triazo-4-ium iodide (36.5 g) was dissolved in ethyl acetate (600 ml). The reaction mixture was cooled to -5 to 0 °C. The ethyl acetate hydrochloride (150 ml) solution was added to reaction mixture. The reaction mixture was stirred for 4-5 hours at room temperature. The reaction mixture was filtered and obtained solid residue washed with ethyl acetate. The solid dried under vacuum at room temperature for 20-24 hrs to give 32.0 gm solid.

Yield: 93 %

HPLC Purity: 86%

Mass: m/z 717.3 (M-HC1- 1)

Example-3: Preparation of Strong anion exchange resin (Sulfate).

Indion GS-300 was treated with aqueous sulfate anion solution and then washed with DM water. It is directly used for sulfate salt.

Example-4: Synthesis of l-[[N-methyl-N-3-[(methylamino)acetoxymethyl]pyridin-2-yl] carbamoyloxy]ethyl-l-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl) thiazol-2-yl]butyl]-lH-[l ,2,4]-triazo-4-ium Sulfate

Dissolved 10.0 g l-[[N-methyl-N-3-[(methylamino)acetoxymethyl]pyridin-2-yl] carbamoyloxy]ethyl-l-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl) thiazol-2-yl]butyl]-lH-[l ,2,4]-triazo-4-ium iodide hydrochloride in 200 ml deminerahzed water and 30 ml methanol. The solution was cooled to about 0 to 5°C. The strong anion exchange resin (sulfate) was added to the cooled solution. The reaction mixture was stirred to about 60-80 minutes. The reaction was filtered and washed with 50ml of demineralized water and methylene chloride. The aqueous layer was lyophilized to obtain

(8.0 g) white solid.

Yield: 93 %

HPLC Purity: > 90%

Mass: m/z 717.4 (M- HS0₄) ⁺

////////WOCKHARDT, WO 2016016766, ISAVUCONAZONIUM SULPHATE, NEW PATENT

LUPIN, SOFOSBUVIR, NEW PATENT, WO 2016016865

(WO2016016865) A PROCESS FOR THE PREPARATION OF NUCLEOSIDE PHOSPHORAMIDATE

LUPIN LIMITED [IN/IN]; 159 CST Road, Kalina, Santacruz (East), State of Maharashtra, Mumbai 400 098 (IN)

ROY, Bhairab, Nath; (IN).
SINGH, Girij, Pal; (IN).
SHRIVASTAVA, Dhananjai; (IN).
MEHARE, Kishor, Gulabrao; (IN).
MALIK, Vineet; (IN).
DEOKAR, Sharad, Chandrabhan; (IN).
DANGE, Abhijeet, Avinash; (IN)

The present invention pertains to process for preparing nucleoside phosphoramidates and their intermediates. Phosphoramidates are inhibitors of RNA-dependent RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals. One of the recently approved phosphoramidate by USFDA is Sofosbuvir [1190307-88-0]. Sofosbuvir is a component of the first all-oral, interferon-free regimen approved for treating chronic hepatitis C. The present invention provides novel intermediate, its process for preparation and use for the preparation of Sofosbuvir. The present invention also gives one pot process for preparation of Sofosbuvir.

Hepatitis C virus (HCV) infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals. There are limited treatment options for individuals infected with hepatitis C virus. The current approved therapeutic option is the use of immunotherapy with recombinant interferon- [alpha] alone or in combination with the nucleoside analog ribavirin.

US 7964580 ('580) is directed towards novel nucleoside phosphoramidate prodrug for the treatment of hepatitis C virus infection.

US'580 patent claims Sofosbuvir and rocess for preparation of Sofosbuvir of Formula 1.

Formula 1

Process for preparation of Sofosbuvir as per US '580 patent involve reaction of compound of Formula 4" with a nucleoside 5'

Compound 4" nucleoside 5'

Wherein X' is a leaving group, such as CI, Br, I, tosylate, mesylate, trifluoroacetate, trifluroslfonate, pentafluorophenoxide, p-nitro-phenoxide.

Objects of the invention

The object of the present invention is to provide a novel intermediate of Formula 2

Formula 2

wherein X' is a leaving group selected from 1-hydroxybenzotriazole, 5-(Difluoromethoxy)-lH-benzimidazole-2-thiol, 2-Mercapto-5-methoxybenzimidazole, cyanuric acid, 2-oxazolidinone, 2-Hydroxy Pyridine. The above leaving group can be optionally substituted with n-alkyl, branched alkyl, substituted alkyl; cycloalkyl; halogen; nitro; or aryl, which includes, but not limited to, phenyl or naphthyl, where phenyl or naphthyl are further optionally substituted with at least one of Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ci-C₆ alkoxy, F, CI, Br, I, nitro, cyano, Ci-C₆ haloalkyl, -N(R^r)2, Ci-C₆ acylamino, -NHS0₂Ci-C₆ alkyl, -S0₂N(R^r)₂, COR^1", and -S0₂Ci-C₆ alkyl; (R^r is independently hydrogen or alkyl, which includes, but is not limited to, Ci-C₂o alkyl, Ci-Cio alkyl, or Ci-C₆ alkyl, R¹" is -OR¹ or -N(R^r)₂).

Another object of the present invention is to provide a process to prepare the intermediate of Formula 2.

Another object of the present invention is use of the intermediate of Formula 2 in the preparation of Sofosbuvir of Formula 1.

Formula 1

Example 1:

Process for the preparation of S-oxazolidinone derivative of Formula 2

Step-1 Preparation of phosphorochloridate solution:

Dichloromethane (DCM 400ml) was charged in round bottom flask flushed with nitrogen. Phenyl phosphodichloridate (18.30ml) was added in one portion in the flask. The flask was cooled to -60°-70°C with a dry ice-acetone bath. Solution of L-alanine isopropyl ester hydrochloride (20.6gm)) in DCM (50ml) was added to the reaction flask. To this was added a solution of triethylamine (11.20ml) in MDC (100 ml) was added over a course of 60 minutes, while maintaining internal temperature below -70 °C throughout the addition. After completion of reaction, temperature of reaction mass was raised to room temperature.

100ml THF was charged in another round bottom flask flushed with nitrogen followed by the addition of S-4-phenyloxazolidnone (lOgm). Triethyl-amine (11.2ml) & LiCl (2.85gm) were added to the above flask. The reaction mass was stirred for 15-30 min at room temperature and was cooled to 0-5 °C. Phosphorochloridate solution from step-1 was added drop- wise to the reaction flask in 15-45 min maintaining reaction temperature at 0-5 °C. The reaction mass was stirred for 30-60min at 0°-5°C. The reaction progress was monitored on thin layer chromatography. After completion of the reaction, the reaction temperature was raised to room temperature. Agitation was resumed for an additional 30min. The reaction mass was filtered and concentrated under reduced pressure. To this was added diisopropyl ether (400ml) and aqueous saturated ammonium chloride solution and reaction mass was stirred for 10-15 minutes. Organic layer was separated and was washed with water (100ml) & dried over sodium sulfate and concentrated under vacuum. Cyclohexane (50ml) was charged to the obtained oily mass and reaction mass was stirred till solid precipitated out. Solid was filtered and washed with cyclohexane and dried under vacuum (8.80gm MP 56.5°-56.6°C). The obtained product was characterized by mass, NMR & IR. 1H NMR (DMSO-d₆) δ 1.142 -1.18

(m, 9H), 3.85-3.92 (m, 1H), 4.72-4.89(m, 2H), 5.31-5.32(d, 1H), 6.25-6.3 (m, 1H), 6.95-7.31 (m, 10H); MS, m/e 433 (M+l) ⁺

Example 2: Process for the preparation of 2-hydroxy pyridine derivatives of formula 2:

Anhydrous dichloromethane (DCM) 700ml was charged in round bottom flask flushed with nitrogen. The flask was cooled to -60° to -70°C in a dry ice acetone bath. Phenyl phosphodichloridate (76.04 gm) was added in one portion in the flask at -65°C. Solution of L-alanine isopropyl ester hydrochloride (60.56 gm) in DCM (50 ml) was added to the reaction mass. Solution of triethylamine (72.44gm) in DCM (50ml) was added to the reaction mass over a course of 60 minutes, while maintaining internal temperature below -70°C throughout the addition. The resulting white slurry was agitated for additional 60 minutes. Then the temperature of reaction mass was raised to room temperature. Reaction mass was stirred for 60 min & TLC was checked. Reaction mass was filtered and rinsed with anhydrous dichloromethane (2 XI 00 mL). The filtrate was concentrate under vacuum to 20 V and reaction mass was filtered, washed with DCM (15ml). The filtrate was transferred to RBF. The reaction mass was cooled to 0°-10°C. A solution of 2-hydroxy-3-nitro-5- (trifluoromethyl) pyridine (15.gm) in DCM (100ml) & triethyl amine (21.89gm) was added to the reaction mass. Temperature of reaction mass was raised to 20-30°C. Reaction mass was stirred overnight. Reaction was monitored using TLC. After completion, the reaction mass was filtered and washed with DCM (30ml). Filtrate was washed with water (150 ml x 2). Organic layer was concentrated under vacuum and degased. Diisopropyl ether (200ml) was charged to reaction mass and reaction mass was stirred for 15 minutes , filtered and washed with methyl ter-butyl ether (MTBE 30ml). Filtrate was concentrated under vacuum and dried. (8.68gm, MP-125.5°-131.5°C). Obtained compound was characterized by Mass, NMR & IR. 1H NMR (DMSO-d₆) δ 1.07 -1.27 (m, 9H), 4.04-4. l l(m, 1H), 4.73-4.79(m, 1H), 6.76-7.43 (m, 5H), 9.00-9.02 (d, 2H); MS, m/e 478 (M+l) ⁺; FTIR, 1203, 1409, 1580, 1732, 3217.

Other 2-hydroxy pyridine derivatives of Formula 2 were prepared by following the process disclosed in example 2-

2-Hydroxy-5-fluoropyridine derivative of Formula 2;-1H NMR (DMSO-d₆) δ 1.09 -1.23 (m, 9H), 3.02-3.06 (m, lH), 3.85-4.01 (m,lH), 4.79-4.87(m, 1H), 6.4-6.52 (m,lH), 7.10-7.89 (m,6H); MS, m/e 383 (M+l) ⁺,

2-Hydroxy-5-nitropyridine derivative of Formula 2:- 1H NMR (DMSO-d₆) δ 1.06 -1.22 (m, 9H),4.0-4.02 (m,lH), 4.7-4.8(m,lH), 6.5-6.6 (m,lH),7.12-7.42 (m,6H),8.66-8.68 (d, lH),9.07-9.13(d,lH); MS, m/e 410 (M+l) ⁺

2-Hydroxy-3, 5-dinitropyridine derivative of Formula 2:- 1H NMR (DMSO-d₆) δ 1.11 -1.24 (m, 9H), 3.04-3.09(m,lH), 4.8-4.86(m,lH), 7.09-7.39 (m,5H),8.97-9.06 (d,2H)

Example 3: Process for the preparation of Sofosbuvir by coupling of isopropyl(((3-nitro-5-(trifluromethyl)pyridin-2-yl)oxy)phenoxy)phosphoryl-L-alaninate with 1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione :

To a solution of l-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione (0.2gm) in THF (4 ml), tert- butylmagnesium chloride (0.80ml, 1.7 M solution in THF) was added dropwise at room temperature and reaction mass was stirred for 30 minutes. A solution of pyridine derivative from example 2 (0.36gm) in THF (4ml) was added dropwise to the reaction mass at room temperature. Completion of reaction was monitored using TLC. After completion of reaction, reaction mass was quenched by using saturated ammonium chloride solution (10ml). Reaction mass was extracted with ethyl acetate (50ml). Organic layer was separated, dried over magnesium sulfate and concentrated under vacuum. The resulting residue was purified by column chromatography on silica gel & obtained solid product was characterized. MS, m/e 530.2 (M+l) ⁺.

/////////LUPIN, SOFOSBUVIR, NEW PATENT, WO 2016016865

Canagliflozin , New patent, WO 2016016774, SUN PHARMACEUTICAL INDUSTRIES LIMITED

WO2016016774, CRYSTALLINE FORMS OF CANAGLIFLOZIN

SUN PHARMACEUTICAL INDUSTRIES LIMITED [IN/IN]; Sun House, Plot No. 201 B/1 Western Express Highway Goregaon (E) Mumbai, Maharashtra 400 063 (IN)

SANTRA, Ramkinkar; (IN).
NAGDA, Devendra, Prakash; (IN).
THAIMATTAM, Ram; (IN).
ARYAN, Satish, Kumar; (IN).
SINGH, Tarun, Kumar; (IN).
PRASAD, Mohan; (IN).
GANGULY, Somenath; (IN).
WADHWA, Deepika; (IN)

The present invention relates to crystalline forms of canagliflozin, processes for their preparation, and their use for the treatment of type 2 diabetes mellitus. A crystalline Form R1of canagliflozin emihydrate. The crystalline Form R1 of canagliflozin hemihydrate of claim 1, characterized by an X-ray powder diffraction peaks having d-spacing values at about 3.1, 3.7, 4.6, and 8.9 A

The present invention relates to crystalline forms of canagliflozin, processes for their preparation, and their use for the treatment of type 2 diabetes mellitus.

Canagliflozin hemihydrate, chemically designated as (l<S)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol hemihydrate, is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Its chemical structure is represented by Formula I.

Formula I

U.S. Patent Nos. 7,943,582 and 8,513,202 disclose crystalline forms of canagliflozin hemihydrate.

PCT Publication No. WO 2009/035969 discloses a crystalline form of

canagliflozin, designated as I-S.

PCT Publication No. WO 2013/064909 discloses crystalline complexes of canagliflozin with L-proline, D-proline, and L-phenylalanine, and the processes for their preparation.

PCT Publication No. WO 2014/180872 discloses crystalline non-stoichiometric hydrates of canagliflozin (HxA and HxB), and the process for their preparation.

PCT Publication No. WO 2015/071761 discloses crystalline Forms B, C, and D of canagliflozin.

Chinese Publication Nos. CN 103980262, CN 103936726, CN 103936725, CN 103980261, CN 103641822, CN 104230907, CN 104447722, CN 104447721, and CN 104130246 disclose different crystalline polymorphs of canagliflozin.

In the pharmaceutical industry, there is a constant need to identify critical physicochemical parameters of a drug substance such as novel salts, polymorphic forms, and co-crystals, that affect the drug's performance, solubility, and stability, and which may play a key role in determining the drug's market acceptance and success.

The discovery of new forms of a drug substance may improve desirable processing properties of the drug, such as ease of handling, storage stability, and ease of purification. Accordingly, the present invention provides novel crystalline forms of canagliflozin having enhanced stability over known crystalline forms of canagliflozin.

EXAMPLES

Example 1 : Preparation of a crystalline Form Rl of canagliflozin hemihydrate

Amorphous canagliflozin (5 g) was suspended in an aqueous solution of sodium formate (80 mL of a solution prepared by dissolving 137.7 g of sodium formate in 180 mL of de-ionized water). The suspension was stirred at room temperature for 20 hours to obtain a reaction mixture. De-ionized water (100 mL) was added to the reaction mixture, and then the reaction mixture was stirred for 1.5 hours. De-ionized water (50 mL) was added to the reaction mixture, and then the reaction mixture was stirred for 30 minutes. The reaction mixture was filtered, then washed with de-ionized water (300 mL), and then dried under vacuum for 12 hours to obtain a solid. The solid was further dried under vacuum at 60°C for 6 hours.

Yield: 4.71 g

Example 2: Preparation of a crystalline Form R2 of canagliflozin monohydrate

Amorphous canagliflozin (5 g) was suspended in an aqueous solution of sodium formate (80 mL of a solution prepared by dissolving 137.7 g of sodium formate in 180 mL of de-ionized water). The suspension was stirred at room temperature for 20 hours to obtain a reaction mixture. De-ionized water (100 mL) was added to the reaction mixture, and then the reaction mixture was stirred for 1.5 hours. De-ionized water (50 mL) was added to the reaction mixture, and then the reaction mixture was stirred for 30 minutes. The reaction mixture was filtered, then washed with de-ionized water (300 mL), and then dried under vacuum for 12 hours at room temperature.

Yield: 4.71 g

Example 3 : Preparation of a crystalline Form R2 of canagliflozin monohydrate

Canagliflozin hemihydrate (0.15 g; Form Rl obtained as per Example 1) was suspended in de-ionized water (3 mL). The suspension was stirred at room temperature for 24 hours. The reaction mixture was filtered, then dried at room temperature under vacuum for 5 hours.

Yield: 0.143 g

Example 4: Preparation of a crystalline Form R3 of canagliflozin hydrate

Amorphous canagliflozin (100 g) was suspended in an aqueous solution of sodium formate (1224 g of sodium formate in 1600 mL of de-ionized water). The suspension was stirred at room temperature for 20 hours to obtain a reaction mixture. De-ionized water

(2000 mL) was added to the reaction mixture, and then the reaction mixture was stirred for one hour. De-ionized water (1000 mL) was added to the reaction mixture, and then the reaction mixture was stirred for another one hour. The reaction mixture was filtered, then washed with de-ionized water (6000 mL), and then dried under vacuum for 30 minutes to obtain a solid. The solid was then dried under vacuum at 30°C to 35°C until a water content of 8% to 16% was attained.

Yield: 100 g

 

From top left: Abhay Gandhi (CEO-India Business-Sun Pharma), Kal Sundaram (CEO-TARO). Middle row (L-R): Israel Makov (chairman, Sun Pharma), Dilip Shanghvi (Founder and MD, Sun Pharma) Uday Baldota (CFO, Sun Pharma). Bottom: Kirti Ganorkar (Senior VP, Business development, Sun Pharma)

./////////////Canagliflozin , New patent, WO 2016016774, SUN PHARMACEUTICAL INDUSTRIES LIMITED

WO 2016012938, New patent, LINACLOTIDE, DR. REDDY’S LABORATORIES LIMITED,

WO2016012938,  IMPROVED PROCESS FOR PREPARATION OF AMORPHOUS LINACLOTIDE

DR. REDDY’S LABORATORIES LIMITED [IN/IN]; 8-2-337, Road No 3, Banjara Hills, Telangana, INDIA Hyderabad 500034 (IN)

KALITA, Dipak; (IN).
NIVRUTTI, Ramrao Jogdand; (IN).
BALAKUMARAN, Kesavan; (IN).
DESHMUKH, Shivshankar; (IN).
VUTUKURU, Naga Chandra Sekhar; (IN).
KASINA, Vara Prasad; (IN).
NALAMOTHU, Sivannarayana; (IN).
VILVA, Mohan Sundaram; (IN).
KHAN, Rashid Abdul Rehman; (IN).
TIRUMALAREDDY, Ramreddy; (IN).
MUSTOORI, Sairam; (IN)

The present application relates to an improved process for the formation of disulfide bonds in linaclotide. The present application also relates to an improved process for the purification of linaclotide.

The present application relates to an improved process for the preparation of amorphous linaclotide. Specifically, the present application relates to an improved process for the formation of disulfide bonds in linaclotide. The present application further relates to a purification process for the preparation of amorphous linaclotide.

INTRODUCTION

Linaclotide is a 14-residue peptide which is an agonist of the guanylate cyclase type-C receptor. Linaclotide may be used for the treatment of chronic constipation and irritable bowel syndrome. Structurally, linaclotide has three disulfide bonds and they are present between Cys¹-Cys⁶, Cys²-Cys-¹⁰ and Cys⁵-Cys¹³. The structure of linaclotide is shown below:

1 2 3 4 5 6 7 8- 9 10 11 12 13 14

Benitez et al. Peptide Science, 2010, Vol. 96, No. 1 , 69-80 discloses a process for the preparation of linaclotide. The process involves the use of 2-chlorotrityl (CTC) resin and 9-fluorenylmethoxycarbonyl (Fmoc) chemistry. The Cys residues are protected by Trt (trityl) group. The amino acids are coupled to one another using 3 equivalents of 1 -[bis(dimethylamino)methylene]-6-chloro-1 H-benzotriazolium hexafluorophosphate 3-oxide (HCTU) as coupling agent and 6 equivalents of diisoprpylethylamine (DIEA) as base in dimethylformamide (DMF). The Fmoc group is removed using piperidine-DMF (1 :4). The Cys residues are incorporated using 3 equivalents of Ν,Ν'-diisopropylcarbodiimide (DIPCDI) as coupling agent and 3 equivalents of 1 -hydroxybenzotriazole (HOBt) as an activating agent. After the elongation of the peptide chain, the peptide was cleaved from the solid support (CTC resin) by first treating with 1 % trifluoroacetic acid (TFA) and then with a mixture of TFA, triisoprpylsilane (TIS) and water in the ratio of 95:2.5:2.5. The disulfide bonds are prepared by subjecting the linear peptide to air oxidation in sodium dihydrogen phosphate (100 mM) and guanidine hydrochloride buffer (2 mM).

US2010/261877A1 discloses a process for purification of linaclotide. The process involves first purification of crude peptide by reverse-phase chromatographic purification followed by concentrating the purified pools and dissolving the purified linaclotide in aqueous-isopropanol or aqueous-ethanol and spray-drying the solution to afford pure Linaclotide.

The synthesis of a peptide containing disulfide bridges is difficult for two main reasons; one is potential risk of racemization during the formation of linear chain and the other is mis-folding of the disulfide bridges. Hence, there is a need in the art to a cost-effective process for the preparation of pure linaclotide.

EXAMPLES

Example 1 : Preparation of Crude Linaclotide using polyvinyl polymer bound complex of sulfur trioxide-pyridine

The linear chain of peptide of formula (I) (0.1 g) and polyvinyl polymer bound complex of sulfur trioxide-pyridine (0.062 g) was charged in water (100 mL). The pH of the reaction mass was adjusted to 8.5 to 9 by addition of ammonium hydroxide. The reaction mass was stirred at 25 °C for 15 hours and trifluoroacetic acid (2 mL) was added to the reaction mass to adjust the pH up to 2-2.5. The reaction mass was stirred for 3 hours at the same temperature to afford crude linaclotide.

HPLC Purity: 59.92%

Example 2: Preparation of Crude Linaclotide using DMSO in water

The pH of water (100 ml_) was adjusted to 9.1 by the addition of aqueous ammonia. DMSO (1 ml_) and linear chain of peptide of formula (I) (100 mg) were charged. The reaction mass was stirred for 17 hours at 25 °C and acidified with trifluoroacetic acid to pH 1 .9 and stirred for 8 hours at the same temperature to afford crude linaclotide.

HPLC Purity: 57%

Example 3: Preparation of Crude Linaclotide using DMSO in water

The pH of water (1500 ml_) was adjusted to 9 by the addition of aqueous ammonia. DMSO (15 ml_) and linear chain of peptide of formula (I) (15 g) were charged. The reaction mass was stirred for 17 hours at 25 °C and acidified with acetic acid to pH 1 .9 and stirred for 8 hours at the same temperature to obtain crude linaclotide.

HPLC Purity: 46.02%

Example 4: Preparation of Crude Linaclotide in water

To a mixture of water (1900 mL) and ammonium sulfate (26.4 g), ammonium hydroxide was added drop wise to adjust the pH up to 8.5. Linear chain of peptide of formula (I) (26.4 g) was added and the reaction mass was stirred for 8 hours at 25 °C. Trifluoroacetic acid (20 mL) was added drop wise and the reaction mixture was stirred for 15 hours at 25 °C to afford crude linaclotide.

HPLC Purity: 63.38%

Example 5: Preparation of Crude Linaclotide using a complex of pyridine-sulfur trioxide

Linear chain of peptide of formula (I) (0.2 g) was added to water (250 mL) and the pH of the reaction mass was adjusted to 8.91 by the drop wise addition of aqueous ammonia. A complex of pyridine-sulfur trioxide (0.124 g) was added to the reaction mass and stirred for 16 hours at 25 °C. Another lot of complex of pyridine-sulfur trioxide (0.124 g) was added to the reaction mass and stirred for 5 hours at 25 °C to afford crude linaclotide.

Example 6: Preparation of Crude Linaclotide using guanidine hydrochloride

To a solution of sodium bicarbonate (0.89 g) in water (100 mL), cysteine (0.363 g), cysteine (0.072 g) and guanidine hydrochloride (9.50 g) were charged. Acetonitrile (15 mL) and linear chain of peptide of formula (I) (0.1 g) was added to the reaction mass.

The reaction mass was stirred for 3 hours at 25 °C and trifluoroacetic acid (2 mL) was added. The reaction mass was stirred for 18 hours at the same temperature. Another lot of trifluoroacetic acid (2 mL) was added to the reaction mass and stirred for 18 hours at the same temperature to afford crude linaclotide.

Example 7: Preparation of Crude Linaclotide using Clear-OX™

Pre-conditioned Clear-Ox™ (0.5 g) was added to a solution of ammonium sulfate (1 .32 g) in water (100 mL) of pH 8.5, adjusted by addition of ammonium hydroxide. The linear chain of peptide of formula (I) (0.1 g) was added to the reaction mass and stirred for 3 hours at 25 °C. Another lot of Pre-conditioned Clear-Ox™ (0.5 g) was added to the reaction mass and stirred for 1 .30 hours. Trifluoroacetic acid (2 mL) was added to the reaction mass and stirred for 16 hours at the same temperature to afford crude linaclotide.

HPLC Purity: 67.5%

Example 8: Preparation of Crude Linaclotide using reduced Glutathione

To a mixture of ammonium sulphate (5.28 g) in water (400 mL) and isopropyl alcohol (400 mL), reduced glutathione (0.248 g) was added and the pH was adjusted to 8.5 by using aqueous ammonia. The linear chain of peptide of formula (I) (0.81 g) was added to the reaction mixture and stirred at ambient temperature for 17 hours. Isopropyl alcohol was evaporated under vacuum to afford crude linaclotide.

HPLC Purity: 69.56%%

Example 9: Preparation of Crude Linaclotide using DMSO and air bubbling

To a mixture of water (95 mL) and ammonium sulfate (1 .32 g), ammonium hydroxide was added drop wise to adjust the pH up to 8.5. Linear chain of peptide of formula (I) (0.1 g) and DMSO (5 mL) was added and the reaction mass was stirred for 20 hours at 25 °C with continuous air bubbling. Trifluoroacetic acid (2 mL) was added to the reaction mass and stirred for 19 hours with continuous air bubbling at the same temperature to afford the title product.

HPLC Purity: 59.1 1 %

Example 10: Preparation of Crude Linaclotide using solid supported TEMPO

To a mixture of water (100 mL) and silica bound TEMPO (0.01 g), linear chain of peptide of formula (I) (0.1 g) and sodium hypochlorite solution (1 mL) were added and the reaction mass was stirred 18 hours at 25 °C. Another lot of sodium hypochlorite solution (0.5 mL) was added to the reaction mass and stirred for further 7 hours at the same temperature to afford title product.

HPLC Purity: 42.70%..................see more in patent

Linaclotide

Systematic (IUPAC) name
L-Cysteinyl-L-cysteinyl-L-glutamyl-L-tyrosyl-L-cysteinyl-L-cysteinyl-L-asparaginyl-L-prolyl-L-alanyl-L-cysteinyl-L-threonylglycyl-L-cysteinyl-L-tyrosine cyclo(1-6),(2-10),(5-13)-tris(disulfide)
Clinical data
Trade names	Linzess
Licence data	US FDA:link
Pregnancy category	US: C (Risk not ruled out)
Legal status	US: ℞-only
Routes of administration	Oral
Identifiers
CAS Number	851199-59-2
ATC code	A06AX04
PubChem	CID 16158208
IUPHAR/BPS	5017
ChemSpider	17314504
UNII	N0TXR0XR5X
KEGG	D09355
Chemical data
Formula	C59H79N15O21S6
Molar mass	1526.74 g/mol

///////WO 2016012938, DR. REDDY’S LABORATORIES LIMITED , Telangana, INDIA , Hyderabad, LINACLOTIDE, new patent

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