WO 2015031595, A PROCESS FOR PREPARATION OF SAXAGLIPTIN AND ITS HYDROCHLORIDE SALT, AMNEAL

WO2015031595,  A PROCESS FOR PREPARATION OF SAXAGLIPTIN AND ITS HYDROCHLORIDE SALT 
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015031595

AMNEAL PHARMACEUTICALS LLC





KUMAR, Agarwal Virendra; (IN).
BADRULHUSAN, Siddiqui Arif; (IN).
KESHAV, Kataria Lalit; (IN).
SUBODHBHAI, Maheta Abhay; (IN).
CHANGANBHAI, Butani Pankaj; (IN).
PRABHAKARRAO, Patil Shashikant; (IN).
YASHWANT, Patil Tushar; (IN).
SURYAKANT, Deore Ganesh; (IN).
JAHYANTIBHAI, Pansuriya Ketan; (IN).
SURESHBHAI, Patel Hitesh; (IN).
BADHABHAI, Sondharava Lalit; (IN)

Described is an improved and industrially feasible process for the preparation of Saxagliptin or its hydrochloride salt. Also described are the novel intermediates and their use in the preparation of Saxagliptin or its hydrochloride salt.

Dipepeptidyl peptidase IV inhibitors (DPP-IV inhibitors) are a class of oral hypoglycemic agents that block the enzyme DPP-rV and have been used to treat diabetes mellitus type 2. Saxagliptin has the chemical names (l_lS',3_lS^,,5_lS^,)-2-[2(_lS^,)-2-amino-2-(3-hydroxy-adamantan- l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile or (lS,3S,5S)-2-[(2S)-2- 3 7

amino-2-(3-hydroxytricyclo[3.3.1.1 ' ]dec- l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile and the structural formula [I] . It is an orally active reversible DPP-IV inhibitor that is the active ingredient in the form of its hydrochloride salt in the ONGLYZA® tablet products originally developed by Bristol-Myers S uibb, and now marketed by AstraZeneca.

 

Saxagliptin and its hydrochloride and trifluoroacetic acid salts are disclosed in U.S. Patent 6,395,767. U.S. Patent 7,420,079 and U.S. Patent 8,278,462 disclose a process for the preparation of saxagliptin, its hydrochloride salt, trifluoroacetate, and benzoate salts, and saxagliptin monohydrate. U.S. Patent 7,705,033 discloses a process for the preparation of saxagliptin monohydrate. U.S. Patent 7,214,702 discloses a process for the preparation of saxagliptin or its hydrochloride salt.

The above documents disclose a process for the preparation of saxagliptin, which involves condensation of 2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid amide with adamantan-1-yl-tert-butoxycarbonylamino acetic acid.

U.S. Patent 7,186,846 discloses a process for the preparation of saxagliptin which involves reacting 2-aza-bicyclo[3.1.0]hexane-3-carbonitrile with trifhioroacetic acid 3-[carboxy-(2,2,2-trifluoroacetylamino)-methyl]adamantan-l-yl ester, followed by reductive cleavage of protected saxagliptin.

Hiroshi Fukushima et al., "Synthesis and Structure- Activity Relationships of Potent 1- (2-Substituted-aminoacetyl)-4-fluoro-2-cyanopyrrolidine Dipeptidyl Peptidase IV Inhibitors," Chemical and Pharmaceutical Bulletin, Vol. 56(8), pages 1110-1117 (2008), reports the instability of 2-cyanofluoropyrrolidine derivatives at pH 6-8, due to intramolecular cyclization of basic nitrogen to a cyano group, leading to the formation of cyclic amidine which further transforms to diketopiperazine derivatives. Saxagliptin, being a 2-cyanopyrrolidine derivative, may undergo intramolecular cyclization to form a cyclic amidine.

The above reported processes suffer from the drawback that the tert-butyloxy carbonyl ("BOC") group is too sensitive in acidic conditions, which exist during the condensation of 2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid amide with adamantan-l-yl-tert-butoxycarbonylamino acetic acid, which leads to formation of unwanted impurities. Further, deprotection of BOC requires harsh and more acidic conditions. Moreover, using BOC as a protecting group makes the reaction monitoring difficult using thin layer chromatography ("TLC" ) and tedious since it is less sensitive to ultraviolet ("UV"). BOC also is relatively expensive, making the process not viable industrially.

Indian Application 2065/CHE/2012 discloses a process for the preparation of saxagliptin which involves the use of the benzyloxy carbonyl group ("CBZ") for protection of the amino group. However, CBZ deprotection would eventually lead to saxagliptin, which by itself is unstable and prone to intramolecular cyclization. Moreover, CBZ is difficult to handle on an industrial scale because of its liquid state and lacrimating properties.

Scheme-I

 

In yet another aspect, the present invention provides a process for preparation of saxagliptin hydrochloride as depicted in the scheme-II below.

Scheme-II

 

Potassium Carbonate

 

The following examples are provided only for the purpose of illustrating certain specific aspects and embodiments of the present invention and should not be considered as limiting the scope or spirit of the invention in any manner.

Example 1

Preparation of (lS)-a-amino-3-hydroxyadamantane-acetic acid hydrochloride

A solution of (lS)-l-[[(l,l-Dimethylethoxy)carbonyl]amino]-3-hydroxyadamantane-l-acetic acid (1.0 g) in dichloromethane (10 ml) at 10-20°C was mixed with 20-25% isopropanol-HCl (2 ml) and stirred at 25-35°C for 8 hours. Solvent was evaporated from the reaction mixture to give the product (lS)-a-amino-3-hydroxyadamantane-acetic acid hydrochloride as a solid (0.72 g). (Yield: 90.0%)

Example 2

Preparation of (lS)-l-[triphenylmethyl amino]-3-hydroxyadamantane-l-acetic acid

A solution of (lS)-a-amino-3-hydroxyadamantane-acetic acid (1.0 g) in dichloromethane (10 ml) at 15-25°C was mixed with triethylamine (1.18 ml) and triphenylmethyl chloride (1.2 g). The reaction mixture was stirred at 25-35°C for 4 hours. Solvent was evaporated from the reaction mixture to give the product (lS)-l-[triphenylmethyl amino] -3-hydroxyadamantane-l-acetic acid (1.24 g). (Yield: 70.0%)

Example 3

Preparation of methanesulfonic acid salt of (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide

Tert-butyl (lS,3S,5S)-3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate (100 g, 0.442 mole) was combined with isopropyl alcohol (600 ml), with stirring at 25-30°C. The mixture was heated to 60-70°C and methanesulfonic acid (55.2 g, 0.575 mole) was added in small amounts over 60 minutes. The mixture was stirred for 4 hours at 60-70°C. Completion of the reaction was confirmed using TLC. The mixture was cooled to 5-15°C and stirred for 1 hour.

The mixture was filtered and the solid was washed with chilled isopropyl alcohol (2x50 ml). The filtrate was dried under vacuum to obtain the methanesulfonic acid salt of (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide. (Yield=96.7%; HPLC purity= 96%)

Mass: 434 [M+H]⁺

1H-NMR (CDCI₃) δ: 6.96 (1 H, s), 5.68 (1 H, s), 5.39-5.42 (1 H, d), 4.88-4.91 (1 H, dd), 4.52-4.54 (1 H, d), 3.67-3.70 (1 H, m), 2.50-2.53 (1 H, dd), 2.22 (2 H, s), 2.03 (1 H, s), 1.47-1.75 (15 H, m), 1.41 (9 H, s), 1.24 (1 H, s), 0.81-0.95 (2 H, m)

Example 4

Preparation of (lS,3S,5S)-2-[(2S)-2-triphenylmethylamino-2-(3-hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide

A solution of (lS)-l-[triphenylmethyl amino] -3-hydroxyadamantane-l -acetic acid (1.0 g), (1S,3S, 5S)-2-azabicyclo [3.1.0]-hexane-3-carboxamide methanesulphonate (0.47 g), 1-hydroxybenzotriazole monohydrate (HOBt^»H20) (0.08 g), dichloromethane (5 ml), and triethyl amine (0.4 ml) at 5-15°C was combined with triethylamine (0.65 ml) and l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HC1) (0.5 g) and stirred at ambient temperature (25-35°C) for 12 hours. Completion of the reaction was verified using TLC. The reaction mixture was successively washed with water (5 ml), IN HC1 (5 ml), 5% aqueous sodium bicarbonate solution (3x5 ml), and then with brine (5 ml). The solvent from the organic phase was evaporated to give a residue. To the residue was added toluene (5 ml) and water (5 ml) and the mixture was heated to 45-55°C and maintained for 1 hour. The mixture was cooled to 25°C, stirred for 2 hours and filtered. The solid was washed with toluene (2 ml) and dried at 50-60°C in an oven to give the title compound (0.984 g). (Yield: 80.0%)

Example 5

Preparation of (lS,3S,5S)-2-[(2S)-2-(tritylamino)-2-(3-hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide

l-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HC1) (1.2 eq., 12.3 g) was added in portions to a solution of 3-hydroxyadamantane-l-yl (lS)-tritylamino-acetic acid

(25.0 g) in tetrahydrofuran (175 ml) and stirred for 15 minutes. 1 -Hydroxybenzotriazole monohydrate (HOBt^»H20) (1.0 eq., 8.2 g) and (1S,3S, 5S)-2-azabicyclo [3.1.0]-hexane-3-carboxamide methanesulphonate (1.0 eq., 11.88 g) were added to the mixture in portions.

Triethyl amine (3.2 eq., 17.28 g) was added dropwise to the reaction mixture over 20 minutes. The reaction mixture was stirred at 25°C for 5 hours. Completion of the reaction was verified using TLC. The solvent was distilled from the reaction mixture to give a residue.

Dichloromethane (250 ml) and water (100 ml) were mixed with the residue and the organic

phase was separated. The organic phase was washed with aqueous dilute HC1 (100 ml), aqueous 10% sodium bicarbonate solution (100 ml), and then with brine (100 ml). The organic phase was dried over sodium sulfate and the solvent evaporated to give a residue, which was dried under high vacuum at 30-40°C for 2 hours to obtain (lS,3S,5S)-2-[(2S)-2-(tritylamino)-2-(3-hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide (18.0 g). (Yield: 59%)

Example 6

Preparation of (lS,3S,5S)-2-[(2S)-2-tritylamino-2-(3-hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide

Tert-butoxycarbonylamino-(3-hydroxy-adamantan-l-yl)-acetic acid (100 g; 0.307 mole) was added to dichloromethane (500 ml) with stirring. The methanesulfonic acid salt of (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide (64.8 g; 0.292 mole) was added, and the reaction mixture was stirred for 15 minutes at 25-35°C. In a separate flask, 1-hydroxybenzotriazole monohydrate (11.8 g; 0.077 mole) and triethylamine (34.2 g) were added to dichloromethane (500 ml) and stirred to form a solution. This solution was added to the reaction mixture gradually over 30 minutes at 25-30°C. The reaction mixture was then cooled to 5-15°C, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1) (70.6 g) was added, and the mixture was stirred for 15 minutes at 5-15°C. Triethylamine (65.2 g) was added to the reaction mixture and stirred for 30 minutes. Temperature of the reaction mixture was raised to 25-35°C and stirred continuously for 12 hours. Reaction completion was confirmed by HPLC. Water (500 ml) was added, the mixture was stirred, and the organic layer was separated. The organic layer was washed with dilute hydrochloric acid solution (500 ml, prepared by adding concentrated hydrochloric acid (60 ml) to water (440 ml)), and further washed with sodium bicarbonate solution (3 times), followed by washing with sodium chloride solution. Hydrogen chloride in isopropanol (14.2% w/w, 315.6 g) was added over 60 minutes, and the mixture was stirred for 4 hours. Completion of the reaction was confirmed by HPLC. The mixture was distilled under vacuum to remove dichloromethane. Toluene was added to the residue and distilled under vacuum. Acetonitrile (400 ml) was added to the residue followed by addition of triethylamine (79.2 g) over 15 minutes with stirring. The reaction mixture was cooled to 10-20°C, and trityl chloride (72.7 g) was added gradually, followed by stirring for 2 hours. Completion of the reaction was confirmed by HPLC. The mixture was distilled under vacuum to remove acetonitrile. Toluene was added to the residue and distilled under vacuum. Toluene (500 ml) followed by water (500 ml) were added to the residue, the mixture was heated at 45-55°C and filtered and dried to obtain the product. (Yield=60.3%; HPLC purity=94%)

Mass: 576 [M+H]⁺

1H-NMR (CD₃OD) δ: 7.43-7.45 (5 H, d), 7.06-7.17 (10 H, m), 4.50 (1 H, s), 3.84-3.87 (1 H, dd), 3.42 (1 H, s), 3.09-3.13 (1 H, m), 2.87-2.91 (1 H, m), 2.15-2.23 (1 H, m), 2.09 (1 H, s), 1.90-1.92 (1 H, d), 1.42-1.77 (13 H, m), 1.19-1.22 (1 H, t), 0.72-0.76 (1 H, m), 0.50-0.55 (1H, m)

Example 7

Preparation of (lS,3S,5S)-2-[(2S)-2-tritylamino-2-(3-hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile

A solution of (lS,3S,5S)-2-[(2S)-2-tritylamino-2-(3-hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide (15.0 g) in tetrahydrofuran (150 ml) was mixed with pyridine (12.3 g) and cooled to 0-10°C. Trifluoroacetic anhydride (19.1 g) was added to the reaction mixture slowly over 30 minutes. The reaction mixture was stirred at 0-10°C for 3 hours. Completion of the reaction was confirmed by HPLC. Aqueous potassium carbonate solution (20%, 240 ml) was added to the reaction mixture over 30 minutes to obtain pH 10-11. Methanol (50 ml) was added, and the reaction mixture was stirred at 25°C for 3 hours. Completion of the reaction was verified using TLC. The reaction mixture was cooled to 0°C and stirred for 30 minutes. The solid was filtered and washed with water (2x15 ml). The solid was dried under vacuum at 50-60°C for 8 hours to give the title compound (10.0 g). (Yield=79%; HPLC purity=99%)

Mass: 558 [M+H]⁺

1H-NMR (DMSO d₆) δ: 7.47-7.49 (6 H, d), 7.24-7.28 (6 H, t), 7.16-7.19 (3 H, t), 4.46 (1 H, s), 4.05-4.08 (1 H, dd), 3.10-3.13 (1 H, m), 2.95-2.98 (1 H, d), 2.20-2.26 (1 H, m), 2.12-2.18 (2 H, m), 1.88-1.95 (3 H, m), 1.38-1.75 (1 H, m), 0.75-0.80 (1 H, q), 0.42-0.46 (1 H, m)

Example 8

Preparation of saxagliptin hydrochloride

A mixture of aqueous hydrochloric acid (34.5% w/w) (2.3 g) and methanol (20 ml) was added to a mixture of (lS,3S,5S)-2-[(2S)-2-tritylamino-2-(3-hydroxyadamantan-l-yl)acetyl]-2-

azabicyclo[3.1.0]hexane-3-carbonitrile (10.0 g) in methanol (80 ml), and the mass was stirred at 25°C for 3 hours. Completion of the reaction was verified by HPLC. Solvent was distilled from the reaction mixture to give a residue. Ethyl acetate (100 ml) was mixed with the residue for 30 minutes at ambient temperature. The solid was filtered and washed with ethyl acetate (2x5 ml). The solid was dried under vacuum at 50-60°C for 8 hours to give the title product (6.0 g). (Yield=90 ; HPLC purity=99.5 )

Mass: 316 [M+H]⁺

1H-NMR (DMSO d₆) δ: 8.29 (3 H, s), 5.21-5.24 (1 H, dd), 4.63 (1 H, s), 4.23 (1 H, s), 4.09-4.12 (1 H, m), 2.54-2.57 (1 H, m), 2.23-2.27 (1 H, dd), 2.15 (1 H, s), 1.93-1.98 (1 H, m), 1.40-1.67 (12 H, m), 1.00-1.05 (1 H, m), 0.73-0.77 (1 H, m)

Amneal Pharmaceuticals' co-CEO Chirag Patel to be honored by the New Jersey City University Foundation - Community - The American Bazaar



Chirag Patel (c), president of Bridgewater, N.J.-based Amneal Pharmaceuticals.

///

WO 2016012927, ANAGLIPTIN HYDROCHLORIDE , NEW PATENT, LUPIN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016012927&redirectedID=true

WO 2016012927,  ANAGLIPTIN HYDROCHLORIDE , NEW PATENT, LUPIN

A PROCESS FOR PREPARATION OF ANAGLIPTIN HYDROCHLORIDE 



ANSARI, Shahid, Akhtar; (IN).
YADAV, Ashok, Keshavlal; (IN).
PATIL, Tushar, Yashwant; (IN).
PATHAK, Dharmendrakumar, Shripati; (IN).
BARIA, Reenaben, Ratansing; (IN).
PATIL, Shashikant, Prabhakar; (IN)


The present invention relates to process for preparing dipeptidyl peptidase IV inhibitor Anagliptin free base or its hydrochloride salt by using novel methane sulfonic acid salt of (2S)-1-{[(1-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile (formula IIa). Anagliptin is used for the treatment of diabetes.

The present invention relates to process for preparing dipeptidyl peptidase IV inhibitor Anagliptin free base or its hydrochloride salt by using novel methane sulfonic acid salt of (2S)-l-{ [(l-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile.

Anagliptin is used for the treatment of diabetes.

Background of the Invention:

Glucagon-like peptide- 1 (GLP-1), a thirty-amino acid peptide hormone, is secreted by intestinal L-cells in response to food ingestion and stimulates insulin secretion from b-cells in a glucose-dependent manner. GLP-1 is also known to have multiple actions such as suppression of glucagon secretion, inhibition of gastric emptying and induction of satiety. Based on these findings, GLP-1 has been considered to be an attractive target for the therapy of type 2 diabetes mellitus (T2DM). However, GLP-1 is rapidly degraded into inactive GLP-1 by a serine protease, dipeptidyl peptidase IV (DPP-IV), which fueled the development of biologically stable GLP-1 analogs. Therefore, inhibitors of DPP-IV capable of increasing the circulating concentration of active GLP- 1 have now emerged as promising treatments for T2DM. In addition, it was demonstrated in a clinical study of diabetic patients receiving active GLP- 1 infusion that a 24-h infusion of active GLP- 1 resulted in a more marked improvement in glycemic control than a 16-h infusion, and based on accumulating clinical studies, greater than 2-fold enhancement of circulating levels of active GLP-1 is known to result from inhibition of 80% or more of the plasma DPP-IV activity. Consequently, optimal glycemic control requires continuous high-level exposure to DPP-IV inhibitors.

US Patent 7,345, 180 B2 relates to one such DPP-IV inhibitor, Anagliptin Hydrochloride (Formula I). US Patent ' 180 also discloses process and intermediates for preparation of Anagliptin Hydrochloride.

Object of the invention

The object of the present invention is to provide a novel salt of methane sulfonic acid (Ila) of (2S)-l-{ [(l-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile (Formula II).

Another object of the present invention is to provide a process for preparation of novel salt (Ila) of (2S)-l-{ [(l-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile (Formula II).

Further object of the present invention is use of novel salt of methane sulfonic acid (Ila) of (2S)-l-{ [(l-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile (Formula II) in preparation of Anagliptin free base or its hydrochloride salt.

Example 1

(2S)-l-{[(l-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile methane sulfonate salt

Titled compound was prepared by adding t-butyl (S)-{2-[(2-cyanopyrrolidine-l-yl)-2-oxoethylamino]-2-methyl-l -propyl} carbamate (25. Og) to acetonitrile (150 ml) followed by drop-wise addition of methane sulfonic acid (10 g). The reaction mass was heated to 50-55 °C for 2 hours. Completion of reaction was monitored by TLC. After completion of reaction, the reaction mass was cooled to 0-5°C and stirred for 1 hour at same temperature. Obtained solid was filtered and washed with chilled acetonitrile (15ml). The obtained solid is less hydroscopic, crystalline as compared with hydrochloric salt , Wet-cake was dried under vacuum till a constant weight was obtained (22.6g, yield 91.58% purity 99.93%).

Example 2 (2S)-l-{[(l-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile methane sulfonate salt

Titled compound was prepared by adding t-butyl (S)-{2-[(2-cyanopyrrolidine-l-yl)-2-oxoethylamino]-2-methyl-l -propyl} carb-amate (lOg, 0.0277) to Toluene (60ml, 6 volumes) at 25-30°C, followed by drop-wise addition of methane sulfonic acid (4.0g, 0.0416 moles) at 25-30°C. The reaction mass was heated to50-55°C for 2 hours. Completion of reaction was monitored by TLC. After completion of reaction, the reaction mass was cooled to 0-5 °C and stirred for 1 hour at same temperature. The obtained solid was filtered and washed with chilled toluene (15ml). The obtained solid is less hydroscopic, crystalline as compared with hydrochloric salt. The Wet-cake was dried under vacuum till a constant weight.

Example 3 Anagliptin free base

2-methylpyrazolo [1, 5-a] pyrimidine-6-carboxylic acid was coupled with (2S)-1-{ [(1-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile methane sulfonate salt in presence of EDC.HC1, HOBT, TEA. The reaction was carried out in DCM (yield 69.3%, purity 99.73%).

Anagliptin free base could be converted to Anagliptin hydrochloride by processes as disclosed in the literature

WO 2016014324, New Patent, Omarigliptin, MERCK SHARP & DOHME CORP

Omarigliptin , MK-3102

WO2016014324, PROCESS FOR PREPARING CHIRAL DIPEPTIDYL PEPTIDASE-IV INHIBITORS

MERCK SHARP & DOHME CORP. [US/US]; 126 East Lincoln Avenue Rahway, New Jersey 07065-0907 (US).

CHUNG, John, Y. L.; (US).
PENG, Feng; (US).
CHEN, Yonggang; (US).
KASSIM, Amude Mahmoud; (US).
CHEN, Cheng-yi; (US).
MAUST, Mathew; (US).
MCLAUGHLIN, Mark; (US).
ZACUTO, Michael, J.; (US).
CHEN, Qinghao; (US).
TAN, Lushi; (US).
SONG, Zhiguo Jake; (US).
CAO, Yang; (US).
XU, Feng; (US)

A process for preparing a compound of structural Formula Ia: comprising Boc deprotection with TFA of, reductive amination of:.

The present invention is directed to a novel process for the preparation of omarigliptin, (2R,35^,,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3 -amine, a dipeptidyl peptidase-IV (DPP-4) inhibitor, for the treatment of Type 2 diabetes, and related intermediates.

BACKGROUND OF THE INVENTION

Syntheses of omarigliptin have previously been described in PCT international patent applications numbers WO 2010/056708 and WO2013/003250. The process described in WO 2010/056708 does not result in a favorable yield of the compound of structural Formula la, as it results in a racemic mixture. WO2013/003250 describes the following scheme to make the compound of structural Formula la, an intermediate for synthesizing omarigliptin:

In WO2013/003250, synthesis of the compound of structural Formula la involves using benzenesulfonic acid (BSA) to remove the Boc protecting group of the compound of structural Formula 1, by first forming a BSA salt of the compound of structural Formula la. The BSA salt is then isolated and undergoes reductive amination with Boc -ketone of the compound of structural Formula 7, to produce the compound of structural Formula la, as a 19: 1 diastereomeric mixture. The BSA mediated Boc deprotection requires up to 72 h to reach full conversion.

An alternative process which eliminates the need to isolate the BSA salt of the compound of Formula la and reduces the overall reaction time of the process is desired. The inventors have now discovered a process for making the compound of structural Formula la which eliminates the step of isolating a salt of the compound of structural Formula la and reduces the overall reaction time. The present process also produces an end-of reaction homogeneous solution via reductive amination, which facilitates crystallization of the compound of structural Formula la. The described process also improves the diastereoselectivity, overall yield, cost and cycle time over the process described in WO2013/003250.

WO2013/003250 also describes the Boc deprotection of the compound of Formula la to produce omarigliptin (Formula I) shown below. As described in WO2013/003250, the Boc deprotection of the compound of Formula la involves aging the substrate in aqueous sulfuric acid in DMAc at 30 °C for 15-20 h, then working up with ammonium hydroxide. This work up produces large amounts of poorly soluble ammonium sulfate which co-crystallizes with the desired product. As a result, isolation of the desired product requires a long cycle time for filtration, washing and drying.

Formula I (omarigliptin)

Because the processes described herein use trifluoroacetic acid with or without a co-solvent for the transformation of the compound of Formula la to omarigliptin, which offers good solubility for the compound of Formula la, omarigliptin is achieved with fast reaction kinetics and good purity profiles.

the compound of structural Formula 1 is prepared by the following processes:

reagents

and,

or alternatively

10 R = Ms

X=OAc

SCHEME 3: Synthesis of the Boc Ketone

16 17 18 19

IPA, H₂Q ,

¹⁾⁹⁵⁶

Step 1 : As

A round bottom flask was charged with ligand L (0.829 g), Cu(II) propionate

monohydrate (0.402 g) (or Cu(II) acetate (0.31 g) or CuCl or CuCl₂) and EtOH (350 ml) and agitated at room temperature for lh. 2,4-Difluorobenzaldehyde (100.0 g) was added followed by DABCO (2.368 g) (or 2,4-dimethylpiperizine) and the mixture was cooled to -5 - -15 °C. Cold (0°C) nitromethane (190 ml or 215 g) was added slowly to the cold solution and the solution was aged at -5 to -15 °C for 20-24 h and at 0 °C for 2-4h. 5 wt% EDTA^»2Na (500 ml) followed by

water (200 mL) and MTBE (1.0 L) was added to the cold solution, and the temperature was raised to 20°C. The layers were separated and the organic layer was washed with additional 5 wt% EDTA^»2Na (500 ml), followed by water (50 mL) and brine (250 mL). The organic layer, containing Compound 17, was concentrated to remove nitromethane, then the solvent was switched to THF.

Step 2: Michael-Lactolization - Nitro lactol

To Compound 17 in 2 volumes of THF (258 mL) from Step 1 under 2 and cooling at 0 °C, 1 equivalent of Hunig's base was added. 1.15 equivalents of acrolein was added over 1 h via syringe pump at 0-5 °C. The reaction was stirred at -10-0 °C overnight. The resulting mixture was used directly in the next step.

Alternatively, the mixture was concentrated at 0-5 °C to remove excess acrolein, then the residue was flushed with acetonitrile until Hunig's base and water are mostly removed. The residue was taken up in 8 volumes of acetonitrile and used directly in the next step.

Alternatively, at the end of the reaction the mixture was worked up by diluting with MTBE and washing with aqueous citric acid solution, and aqueous NaHCC solution, and the solvent was switched to acetonitrile. Alternatively, the end reaction mixture was taken forward directly to the next step.

Step 3: Dehydration - Nitro dihydropyrans

1.1 Equivalents of TEA was added to the acetonitrile solution of lactol 18 from Step 2 followed by 1.2 equivalents of mesyl chloride and 1.2 equivalents of S-collidine under < +10 °C . The reaction was aged at 10°C for 0.5-1 h. Alternatively, the end of the reaction mixture from Step 2 was cooled to between -20 °C to 0 °C. Two equivalents of S-collidine and 1.4 equivalents of mesyl chloride were then added. The mixture was heated to 36 °C and aged overnight. The mixture was cooled to room temperature. 15 volumes of MTBE was added and the solution was

washed with 3 volumes 10 wt% citric acid and 6 volumes water, 10 volumes water, then 3 volumes of 5% aHC03 solution and 6 volumes water. The organic was concentrated with 20 volumes of MTBE using 10 volumes MTBE. The organic solution was stirred with 20-30 wt% AQUAGUARD for 2 hours at room temperature. The mixture was filtered and washed with 2 volumes of MTBE.

Step 4: Dynamic Kinetic Resolution (DKR) crystallization - rraws-nitro-dihydropyran (19t)

The organic MTBE solution of Step 3 was solvent switched to 2 volumes of IPA and the final volume was -300 mL. 10 Mol% of TEA (or DAB CO or morpholine or DMAP) was added. Then water (1 15 mL) was slowly added over 3 hours. The slurry was filtered, washed with 80/20 IP A/water (2x100 mL) and vacuum dried under N₂.

Step 5: Hydroboration/oxidation - Trans-nitro-pyranol

To a vessel charged with /raws-nitro-dihydropyran (10 g), MTBE (100 mL) was added under nitrogen. The mixture was stirred at room temperature to give a clear orange solution. The solution was cooled to +2 °C and borane dimethyl sulfide complex (9.55 ml) was added. The clear solution was aged for 2-5h until >99% conversion by HPLC analysis. The reaction was slowly quenched with water (7.25 ml) keeping at < +9 °C. After the solution was aged at 5°C for 5 min, water (78 mL) was added at < +13 °C. Solid sodium percarbonate (13.26 g, 84 mmol) was added. The suspension was stirred at 5 °C for 15h. The mixture was transferred to a separatory funnel with the aid of 60 mL MTBE and 20 mL water. The mixture was allowed to warm to room temperature. The aqueous phase was back-extracted with 40 mL MTBE. The combined organic phase was washed once with 30 mL half saturated sodium chloride solution, once with 15 mL brine and 15 mL 0.2N HC1, and once with 30 mL half-saturated sodium chloride solution. The organic layer was dried over a2S04. The organic was filtered, washed with 10 mL MTBE and concentrated to an oil. The oil was diluted to 200 mL for a 0.191M solution.

Step 6: Nitro Reduction/Boc protection - Pyranol

A 3 -neck jacketed round bottom flask equipped with overhead stirrier was charged with 0.191M (5R,6S)-5-nitro-pyran-3-ol (119 ml) (Compound 20) in ethanol and ethanol (32 ml). The solution was cooled to 1 1-12 °C. Cold 6N HC1 (19.55 ml, 1 17 mmol) was added at <

+17°C. Zinc dust (12.93 g) was added in five portions (5x2.59g) at < +26 °C. The mixture was stirred at 12 °C for 22 h. 1M K₂C0₃ (76 mL) was added in one portion. MTBE (59 mL) was added then EDTA 2K 2H₂0 (22.55 g) was added over 10 min at < +14 °C. To the solution 45 wt% KOH (4.86 mL) solution was added. The solution was cooled to 5 °C, and 1.1 equivalents of B0C2O (5.46 g) was added. The solution was rinsed with MTBE (10 mL) and stirred at 5 °C for 2h, then at 12 °C for 16h, and then at 24 °C for lOh until >99.5% conversion. The solution was transferred to a separatory funnel with the aid of MTBE (30 mL) and water (5 mL). The organic layer was filtered and washed with MTBE (20 mL). The organic filtrate was concentrated. MTBE (60 mL), water (30 mL) and saturated sodium chloride solution (15 mL) were added. The mixture was warmed in a 30 °C bath to dissolve solid, and then concentrated. The concentrate was flushed with toluene in a 60 °C bath, then concentrated. Toluene (8.4 mL) was added and the mixture was heated to 80 °C. Heptane (70.8 mL) was added over lh at 80 °C, then cooled slowly to room temperature. The mixture was filtered and washed with 1 :2 toluene/heptane (23.55 mL), filterated and vacuum dried under nitrogen until a constant weight.

The purity could be further upgraded by the following procedure: a round bottom flask was charged with the product of Step 6 (7.069 g) from above. EtOH (21 mL) was added and the mixture was heated to 45 °C. Water (31.5 mL) was slowly added over 1 h at 45 °C. The mixture was aged for lh. Water (31.5 mL) was added in one portion, then cooled slowly to room temperature and aged overnight. The slurry was filtered and washed with 1 :3.5 EtOH/water (23.56 mL). Crystals were vacuum dried under nitrogen until a constant weight.

Alternatively, Compound 20 was reduced with 100 psi hydrogen in 20 volume wet THF in the presence of 10-30 wt% Raney nickel at 50 °C. Then the reaction mixture was basified with 2 equivalent of K2CO₃ and a slight execess B0C2O to afford crude Compound 21 after aqueous work up.

Compound 7 was obtained from 21via oxidation as described in WO2013/003250.

S

Boc-mesyl-pyrazole solid 1 was added to 2.5 volumes of TFA at 0-2 °C, over 2-3 minutes under nitrogen, followed by 0.5 volume of TFA rinse. Conversion to TFA salt was complete within 0.5-lh at 1-2 °C. DMAc (14 vol) followed by triethylamine (5 equivalents or 2.3 volumes) were slowly added to the TFA reaction mixture at 0 °C maintaining < +20 °C. Boc-ketone 7 (0.89 equivalent) was then added at -15 °C followed by solid NaBH(OAc)₃ (1.4 equivalents) which was added in three portions over lh. The reaction solution was aged at -15 °C overnight. The solution was then warmed to 22 °C, and after aging for 2-5 h. Diastereomeric ratio was > 96.5:3.5.

The solution was seeded with Boc amine 1 wt% at 22 °C and stirred at 22-40 °C for 2-4 h. 0.36 volume 28% ammonium hydroxide was added over 2-4 h, then, 3.64 volumes 28% ammonium hydroxide was added over 4-10h at 22-60 °C. After cooling to 22 °C, the batch was filtered, washed with 5: 1 DMAc/water, then water. The wet cake was vacuum dried under nitrogen at ambient affording the product. Diastereoselectivity was > 30: 1.

Boc Deprotection of Formula la

A reactor was charged with 2.5 X (by volume) of trifluoroacetic acid. The batch was cooled to 5-10 °C. The reactor was then charged with 0.4 X (by volume) water. The batch was cooled to 0-5 °C. The reactor was then charged with 1 equivalent (1 kg) of the compound of Formula la over 0.5-lh while maintaining the temperature between 0 -5°C. The reactor was then charged with 0.5 X (by volume) trifluoroacetic acid to reactor while maintaining the temperature between 0-5°C. The batch was then heated between 15-20°C and aged for 2-2.5 h. The batch was then cooled to between 5-10°C. A crystallizer was charged with water 5.0 X (by volume) and 0.1 X (by volume) of ammonia water and adjusted to between 3-13°C. To generate a seed bed, Compound I seed (lwt% vs la) was added and the temperature as adjusted to between 3-13°C. A solution of ammonia water 3.8 X (by volume) and of the compound of Formula la was added simultaneously to the seed bed over 2.5 - 3.5 hours while maintaining temperature at 3-13°C and pH -9-10. The batch was aged for at least 30 minutes and then filtered. The resulting crystals were washed with 3. OX (by volume) water at 3 - 13°C twice and vacuum dried at < 50°C to afford the compound of formula I.

//////WO 2016014324, New Patent, Omarigliptin, MERCK SHARP & DOHME CORP, MK-3102

Regorafenib, SHILPA MEDICARE LIMITED, New patent, WO 2016005874

WO2016005874, 

PROCESS FOR THE PREPARATION OF REGORAFENIB AND ITS CRYSTALLINE FORMS

SHILPA MEDICARE LIMITED [IN/IN]; 10/80,Second Floor,Rajendra Gunj, Raichur, ರಾಯಚೂರು , karnataka 584102 (IN)

RAMPALLI, Sriram; (IN).
UPALLA, Lav Kumar; (IN).
RAMACHANDRULA, Krishna Kumar; (IN).
PUROHIT, Prashant; (IN).
AKSHAY KANT, Chaturvedi; (IN)

The present invention relates to a process for the preparation of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2- carboxamide or Regorafenib (I): Formula (I). The present invention further relates to a process for the purification of 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2- carboxamide or Regorafenib (I) to provide highly pure material. The present invention further relates to a process for the preparation stable crystalline material of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]- N-methyl pyridine-2-carboxamide or Regorafenib (I) useful in the preparation of pharmaceutical compositions for the treatment of cancer.

4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide or Regorafenib is low molecular weight, orally available, inhibitor of multiple protein kinases, including kinases involved in tumour angiogenesis (VEGFR1, -2, -3, TIE2), oncogenesis (KIT, RET, RAF-1, BRAF, BRAFV600E), and the tumour microenvironment (PDGFR, FGFR). In preclinical studies regorafenib has demonstrated antitumour activity in a broad spectrum of tumour models including colorectal tumour models which is mediated both by its antiangiogenic and antiproliferative effects. Major human metabolites (M-2 and M-5) exhibited similar efficacies compared to Regorafenib both in vitro and in vivo models.

Regorafenib was approved by USFDA in 2012 and is marketed under the brand name Stivarga®, is an important chemotherapeutic agent useful for the treatment of adult patients with metastatic colorectal cancer (CRC) who have been previously treated with, or are not considered candidates for, available therapies. These include fluoropyrimidine-based chemotherapy, an anti-VEGF therapy and an anti-EGFR therapy.

Regorafenib is chemically known as 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide (I). Regorafenib is a white to slightly pink or slightly brownish solid substance with the empirical formula C2iHi5ClF4N403 and a molecular weight of 482.82. Regorafenib is practically insoluble in water, dilute alkaline solution, dilute acid solution, n-heptane, glycerine and toluene. It is slightly soluble in acetonitrile, dichloromethane, propylene glycol, methanol, 2-propanol, ethanol and ethyl acetate. It is sparingly soluble in acetone and soluble in PEG 400 (macrogol). Regorafenib is not hygroscopic.

Regorafenib is generically disclosed in US 7351834, and specifically disclosed in US 8637553. US ‘553 disclose a process for the preparation of Regorafenib starting from 3-fluoro-4-nitrophenol. The process is as demonstrated below:

The present inventors has repeated the above process and found the following disadvantages:

Unwanted reactions are observed during the formation of Regorafenib, due to the involvement of prolonged time in process.

> Incomplete reactions were observed with excessive impurity formations due to incomplete conversion.

Removal of impurities from final product

US 2010173953 disclose Regorafenib monohydrate and crystalline Form I of Regorafenib. This patent application further discloses that crystalline Form I of Regorafenib stated in this application is obtained as per the process disclosed in WO 2005009961 A2 (Equivalent to US ‘553). The compound obtained was having a melting point of 186-206° C.

This patent publication discloses a process for the preparation of Regorafenib monohydrate comprises dissolving Regorafenib Form I obtained as per WO ‘961 in acetone

and the solution is filtered, followed by addition of water until precipitation, which was filtered and dried at room temperature

US 2010/0113533 discloses crystalline Form II of Regorafenib, comprises dissolving Regorafenib Form I obtained as per WO ‘961 in ethyl acetate, the suspension was heated to 40-45°C, addition of isocyanate solution (isocyanate in ethyl acetate) and is cooled to room temperature to yield the crystals, which was filtered, washed with ethyl acetate and dried at room temperature.

US 2010/0063112 discloses Form III of Regorafenib, process comprises of heating

Regorafenib monohydrate at 100°C or 60 min, and further 15 min at 110°C, followed by cooling to room temperature.

As polymorphism has been given importance in the recent literatures owing to its relevance to the drugs having oral dosage forms due to its apparent relation to dose preparation/suitability in composition steps/ bioavailability and other pharmaceutical profiles, stable polymorphic form of a drug has often remained the clear choice in compositions due to various reasons of handling, mixing and further processing including bioavailability and stability.

Exploring new process for these stable polymorphic forms which are amenable to scale up for pharmaceutically active / useful compounds such as 4-[4-({[4-chloro-3-(trifluoro methyl)phenyl]carbamoyl } amino)-3 -fluorophenoxy] -N-methylpyridine-2 -carboxamide or Regorafenib may thus provide an opportunity to improve the drug performance characteristics of such products.

Hence, inventors of the present application report a process for the preparation of a stable and usable form of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluoi phenoxy]-N-methylpyridine-2-carboxamide or Regorafenib, which may be industrially amenable and usable for preparing the corresponding pharmaceutical compositions. The present invention provides an improved process for the preparation of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fiuorophenoxy]-N-methylpyridine-2-carboxamide or Regorafenib crystalline forms specifically for crystalline polymorphic forms Form I and Form III. Crystalline polymorphic forms of 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl } amino)-3 -fluorophenoxy] -N-methylpyridine-2 -carboxamide or Regorafenib obtained by the process of the present invention is non-hygroscopic and chemically stable and has good dissolution properties.

The process related impurities that appear in the impurity profile of the Regorafenib may be substantially removed by the process of the present invention resulting in the formation of highly pure material. The process of the present invention is as summarized below:

Example 1

Preparation of 4-(4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methyl amide

4-Amino-3-fiuorophenol (l lg, 0.08 moles) and of 4-Chloro-N-methyl-2-pyridinecarboxamide (8.85 g, 0.05 moles) was added to a reaction flask containing N, N-dimethylacetamide (55 ml) at 25-30°C and stirred for 15 minutes. The reaction mixture was heated to 110-115°C and then potassium tert-butoxide in tetrahydrofuran (60 ml, 0.06 moles) was added slowly over a period of 3 to 4hours. Distill off solvent at same temperature, cooled the reaction mass to 25-30°Cand water(110 ml) was added slowly over a period of 15min. and cooled the reaction mass to 0-5°C . Adjust the pH of the reaction mass in between 7 and 7.5 by using 10% aqueous hydrochloric acid (~7 ml). Stir the reaction mass for 30min at the same temperature. Filter the product, washed with water (22 mL) and Dried at 50-55 °C for 12hrs. The obtained crude material was added to the flask containing Ethyl acetate (55 mL).The reaction mass was heated to reflux to get a clear solution and stirred for 15min at reflux. Cooled to 0-5°C, stir for 2hrs at the same temperature. Filter the product, washed with Toluene (9 mL) and dried at 50-55°C for 3-5hrs.

Above recrystallized material was added to the reaction flask containing methylene dichloride (270 mL) at 25-30°C and stirred for 10-15 min. Activated carbon (1 g) and silica gel (4.4 g) was added to the reaction mass and stir for lh at the same temperature. Filter the reaction mass through hyflow bed and wash with methylene dichloride (18 mL).Distill off solvent still~l-2 volumes of methylene dichloride remains in the flask and then cooled to 25-30°C. Toluene (20 mL) was added and stirred for 30min at the same temperature. Filtered the product, washed with Toluene (9 mL) and dried at 50-55°C for 12h.

Yield: 9 gm

Chromatographic Purity (By HPLC): 98%

Example 2

Preparation of Regorafenib

4-(4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methyl amide (4g, 0.01 moles) was added in to a reaction flask containing acetone (20 ml) at 25-30°C and stirred for 15 minutes. 4-chloro-3-trifluoromethylisocyanate (6.1g, 0.02 moles) was added slowly over a period of 5 to 10 minutes and stirred the reaction mixture 3 to 4 hours. Toluene (20 n L) was added to the reaction mass and stirred for 30 min at 25-30°C.The obtained reaction mass was filtered and washed with toluene (8 mL). Dried the material still constant weight appears to yield title product a crystalline material.

Yield: 5.5 gm

Chromatographic Purity (By HPLC): 97%

Example 3

Purification of Regorafenib using acetone and toluene mixture

4- [4-( { [4-chloro-3 -(trifluoromethyl)phenyl] carbamoyl } amino)-3 -fluorophenoxy] -N-methylpyridine-2-carboxamide (I) or Regorafenib (1 g) was added slowly in to the reaction flask containing acetone (2 mL) and toluene (3 mL) at 25-30°C and stirred for 15 minutes.

The reaction mixture was heated to 50-55°C and stirred the reaction mixture for 30 minutes.

Cooled the reaction mass to 25-30°C and stirred for 1 hour. Filter the material, washed with toluene (2 mL) and suck dried for 15 min, followed by drying at 50-55°C for 10-12h to yield

Pure 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methyl pyridine-2-carboxamide (I) or Regorafenib.

Yield: 0.88gm

Chromatographic Purity (By HPLC): 99.3 %

Example 4

Purification of Regorafenib using acetone

4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3 -fluorophenoxy] -N-methylpyridine-2-carboxamide (I) or Regorafenib (1 g) was added slowly in to the reaction flask containing acetone (5 mL) at 25-30°C and stirred for 15 minutes. The reaction mixture was heated to 50-55°C and stirred the reaction mixture for 30 minutes. Cooled the reaction mass to 0-5°C and stirred for 1 hour. Filter the material, washed with acetone (1 mL) and suck dried for 15 min. The obtained wet cake was added in to the reaction flask containing acetone (5 mL) at 25-30°C and stirred for 15 minutes. The reaction mixture was heated to 50- 55°C and stirred the reaction mixture for 30 minutes. Cooled the reaction mass to 0-5°C and stirred for 1 hour. Filter the material, washed with acetone (1 mL) and dried at 60-65°C for 12 h to yield Pure 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methyl pyridine -2-carboxamide (I) or Regorafenib.

Yield: 0.7 gm

Chromatographic Purity (By HPLC): 99.77%

Example 5

Double – Purification of Regorafenib using acetone and toluene mixture

4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] Carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide (I) or Regorafenib (1 g) was added slowly in to the reaction flask containing acetone (2 mL) and toluene (3 mL) at 25-30°C and stirred for 15 minutes. The reaction mixture was heated to 50-55°C and stirred the reaction mixture for 30 minutes. Cooled the reaction mass to 25-30°C and stirred for 1 hour. Filter the material, washed with toluene (2 mL) and suck dried for 15 min. The obtained wet cake was added in to the reaction flask containing acetone (2 mL) and toluene (3 mL) mixture at 25-30°C and stirred for 15 minutes. The reaction mixture was heated to 50-55°C and stirred the reaction mixture for 30 minutes. Cooled the reaction mass to 25-30°C and stirred for 1 hour. Filter the material, washed with toluene (2 mL) and dry at 60-65°C for 12h.

Yield: 0.80gm

Chromatographic Purity (By HPLC): 99.79 %

Moisture content: 0.09%

Impurity-A: 0.03%

Impurity-B: Not detected

Impurity-C: 0.02%

Example 6

Preparation of Regorafenib Form I

4-(4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methyl amide (1.3 g, 0.004 moles) was added in to a reaction flask containing acetone (13 mL) at 25-30°C and stirred for 15 minutes.4-chloro-3-trifluoromethylisocyanate (6.6 g, 0.006 moles) wasadded slowly over a period of 15 to 20 minutes and stirred the reaction mixture 3 to 4 hours. The obtained reaction mass was filtered and washed with acetone. Dried the material still constant weight appears to yield title product a crystalline material.

Yield: 1.9 g

Chromatographic Purity (By HPLC): 98.4 %

XRPD was found to resemble similar to Fig-1.

Omprakash Inani – Chairman, Vishnukant C Bhutada – Managing Director, Namrata Bhutada – Non Executive Director, Ajeet Singh Karan – Independent Director, Carlton Felix Pereira – Independent Director, Pramod Kasat – Independent Director, Rajender Sunki Reddy – Independent Director, N P S Shinh – Independent Director,

Mr. Omprakash Inani		Mr. Omprakash Inani – CHAIRMAN Mr. Omprakash Inani has more than 30 years of Business experience. He monitors business and functional aspects of the Company along with the operations of all the plants. Additionally, he is member of Audit and Remuneration committee of Shilpa Medicare Group of Companies. Currently he is also a council Member in “Academy of Medical Education, Dental College & V.L. College of Pharmacy”, “Taranath Shikshana Samsthe, Raichur” and a trustee in “Akhil Bhartiya Maheshwari Education Trust, Pune”. Mr. Omprakash Inani is also Managing Committee Member of “Karnataka State Cotton Assn., Hubli”.
Mr. Vishnukant C. Bhutada		Mr. Vishnukant C. Bhutada – MANAGING DIRECTOR Mr. Vishnukant has vast and diverse Business experience of API and Intermediates and presently leads the core Business and functional teams which accelerate growth and performance by Innovating for Affordable solutions at Shilpa Medicare Group of Companies. He is the key decision maker with the teams for Shilpa Group for successful API and Generics formulation strategies. His untiring efforts have led the company to a leadership position in the Indian pharmaceutical domain and helped create a prominent presence for Oncology APIs globally. For his efforts on APIs Business, Mr. Vishnukant was awarded “Best Entrepreneur Award” by Late Dr Shankar Dayal Sharma – President of India in 1995. Subsequently, various state honours were conferred upon him -like -“Best Entrepreneur” from Karnataka State Govt. in 1996; “Excellence in Exports” from Vishweshwarayya Industrial Trade Centre, Bangalore 1996; and Export Excellence Award-2006” by FKCCI, Bangalore. Success has never stopped coming his way- as he was awarded “First runner up” at the Emerging India Awards London 2008 by CNBC TV18. Recently, his efforts in the Shilpa Group for environment sustainability, has led to “Best National Energy Conservation Award in Drugs & Pharmaceutical Sector for the year 2012” by Hon’ble President of India, Dr. Pranab Mukherjee.
Dr. Vimal Kumar Shrawat		Dr. Vimal Kumar Shrawat – CHIEF OPERATING OFFICER Dr. Shrawat by qualification holds degrees of M.Sc (Organic Chemistry), Ph.D. (from Delhi University) and joined Shilpa Medicare in 2009. He has vast experience of more than 25 years of working in large pharma industries like Ranbaxy/ Dabur Pharma- presently known as Fresenius Kabi Oncology Ltd., spanning across activities of R&D, Pilot and Plant Productions, QA/QC, Administration, CRAMS, Project management etc. Presently, Dr. Shrawat is spearheading the entire Operations/ Control of Shilpa Medicare. His vision of team work and time bound approach always guides and motivates teams at all operational sites. His keen interest and consistent efforts for R&D has led him to become one of key contributor in large number of Patent/applications of Shilpa Medicare.
Dr. Pramod Kumar		Dr. Pramod Kumar – MANAGING DIRECTOR(LOBA FEINCHEMIE GMBH AUSTRIA), SENIOR VICE-PRESIDENT (SHILPA MEDICARE LTD) Dr. Pramod Kumar, who by qualification holds degrees of M.Pharm, Ph.D (Pharmaceutical chemistry) and a PGDBA, joined Shilpa Medicare in 1989. Since 2009 he is Managing Director of Loba FeinchemieGmBH, Austria and driving all R&D driven commercial processes. Dr. Pramod Kumar has more than 25 years of experience in Pharmaceutical industry, spanning across activities of production, QA/QC, administration, import/export, CRAMS etc. His efforts in CRAMS have led to the formation of Joint venture company RAICHEM MEDICARE Pvt LTD with Italian companies ICE SPA / P.C.A SPA.
Mr. Prashant Purohit		Mr. Prashant Purohit – VICE-PRESIDENT-CRD Mr. Prashant Purohit by qualification holds degrees of, M.Sc.(Organic Chemistry) and Diploma in Business Management and joined Shilpa Medicare in 1996. He is presently heading Chemical R&D wings of Shilpa Medicare Group. He has vast experience of handling CRAMS and Generics APIs R&D. His vast experience of nearly 35 years in R & D and production in Pharmaceutical Industry has consistently enriched the portfolio of Shilpa Medicare Group of Companies. He is one of key contributor in large number of Patent/applications of Shilpa Medicare.
Dr. Akshay Kant Chaturvedi		Dr. Akshay Kant Chaturvedi – HEAD- CORPORATE IPM & LEGAL AFFAIRS Dr. Akshay Kant by qualification holds degrees of M.Sc, Organic Chemistry (Univ. Gold Medalist), Ph.D. (Medicinal Chem), LL.B., M.B.A. and joined Shilpa Medicare in Jun 2012. Besides above qualifications, he is a Registered Patent Agent (IN-PA-1641) at Indian patent Office. He has various certificates of Advanced Courses of IP from WIPO-Geneva, which include Patent Searching/ Drafting of Patents/ Arbitration and Mediation through WIPO/ Copyrights in Publishing Industries/ Patent Management/ Biotech IP etc. He has vast experience of about 21 years of working in large pharma industries like Jubilant Organosys Ltd./Dabur Pharma Ltd.- presently known as Fresenius Kabi Oncology Ltd./ DrReddys Labs, spanning across activities of R&D and IP-Patenting etc. Presently, Dr. Akshay is spearheading the entire IP portfolio management/ Legal Affairs of Contractual Business of Shilpa Medicare Group. His vision of innovative and creative thinking, team work and time bound approach always guide and motivate teams at all locations.His keen interest and consistent efforts for R&D has led him to become one of key contributor in large number of Patent/applications of Shilpa Medicare.
Dr. Seshachalam U.		Dr. Seshachalam U. -ASSOCIATE VICEPRESIDENT- QUALITY AND RA Dr. Seshachalam by qualification holds M.Sc (Chemistry) and Ph.D. (Chemistry) and joined Shilpa Medicare in 2008. He is presently heading Regulatory Affairs wings of Shilpa Medicare Group of Companies. He has vast experience of handling regulatory affairs related to Generics APIs. Being instrumental in Shilpa Medicare’s efforts to achieve recognition of different authorities, his key contribution in successful inspection and audit by various regulatory authorities is one of the core strength to the organization’s aims and objectives.
Mr. Sharath Reddy		Mr. Sharath Reddy – VICE-PRESIDENT PROJECTS & OPERATIONS Mr. Sharath Reddy by qualification holds M.Pharm from BITS Pilani and has overall experience of about 22 years predominately in the field of pharmaceuticals new projects and operations. His expertise of Oncology specialized equipment and Utilities designing has boosted organizations confidence to takeover new endeavors of upcoming projects with faster pace of time. His efforts have led to successfully executing Energy Saving projects of Shilpa Medicare Group of Companies and registration of the project under Clean Development Mechanism with UNFCC (Under Kyoto Protocol).
Mr. R K Somani		Mr. R K Somani – VICE-PRESIDENT FORMULATION -BUSINESS DEVELOPMENT Mr. R. K. Somani is a professional Chartered Accountant and holds a Diploma in Central Excise.He has overall business experience of more than 21 years predominately in the field of pharmaceuticals. Mr. Somani is one of the key drivers of Formulation business besides handling various key Contract Businesses of advanced oncology/ Non-Oncology APIs. He is known for successfully building formulations portfolio and spearheading the Generic sales operation.

Shilpa Medicare Limited
1st Floor, 10/80,
Rajendra Gunj,
RAICHUR ರಾಯಚೂರು – 584 102.
Karnataka, India.
Telephone: +91-8532-236494
Fax: +91-8532-235876
Email: info@vbshilpa.com

RAICHUR ರಾಯಚೂರು, Karnataka, India

Raichur

City in India

Raichur is a city municipality in the district of Raichur in the south indian state of Karnataka. Raichur, located between Krishna and Tungabhadra rivers, is the headquarters of Raichur district. Wikipedia

Historical Stone Elephants in Malayabad, Raichur Taluk ...

View of Raichur city and lake Aam Talab

///Regorafenib, SHILPA MEDICARE LIMITED, new patent, WO 2016005874, raichur, karnataka, india