Monday, 7 September 2015

NEW PATENT, WO 2015128718, HIKAL LIMITED NOVEL ECONOMIC PROCESS FOR VILDAGLIPTIN


WO2015128718, NOVEL ECONOMIC PROCESS FOR VILDAGLIPTIN
HIKAL LIMITED [IN/IN]; 3A, International Biotech Park Hinjewadi 411057 Pune (IN)
The present invention relates to a commercially viable novel process for manufacturing Vildagliptin in high yield with high chemical and chiral purity.
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Vildagliptin is chemically known as l-[{(3-hydroxy-l-adamantyl)amino}acetyl]-2-cyano(s)-pyrrolidine, which is a dipeptidylpeptidase IV (DPP-IV) inhibitor and found usefulness in the treatment of diabetes mellitus. Vilda liptin is represented below:

(Formula I)
Vildagliptin (I) and the process for its preparation was first disclosed in US Patent US 6,166,063. The said process is described in scheme (1) and involves purification by flash chromatography and therefore it can not be manufactured industrially.
Scheme 1:

Formula (1 )
A similar synthesis is subsequently reported in J Med. Chem. 2003, 46, 2774-2789. An improved process is described in PCT Patent Publication WO 2004/092127A1 , which is an improvement over the process in scheme (1) that involves the use of N-chloroacetyl
proline amide (III) in situ, use of Vilsmeier reagent for dehydration of amide to nitrile and replacement of column chromatography with crystallization making the process scalable. Another very similar synthesis of Vildagliptin is described in US Patent Publication US 2008/0167479A1 that involves the modification of dehydration of N-chloroacetyl proline amide (III) in scheme (1) to corresponding nitrile (IV) by using cheaper reagent cyanuric chloride. The related key intermediates 1 -(haloacetyl)-2-cyano pyrroloine are described in several patents although not targeting the synthesis of Vildagliptin. In International PCT Patent Publication WO 98/19998A2 proline amide is treated with bromoacetyl bromide followed by dehydration with TFAA. In another PCT Patent Publication WO 01/96295A2 the method described involve chloroacetylation in THF followed by dehydration with TFAA. In PCT Patent Publication WO 2006/10.0181, a process for the synthesis of l-(haloacetyl)-2-cyano pyrroloine is described wherein the proline amide was coupled with chloroacetyl chloride followed by dehydration of amide using Vilsmeier reagent and its variants e.g., POCl3-DMF, SOCl2-DMF, cyanuric chloride-DMF etc).
According to PCT Patent Publication WO 2004/092127A1 the process described involve coupling of (I) with chloroacetyl chloride in DMF-isopropylacetate followed by dehydration with Vilsmeier reagent to obtain (IV) that was converted to Vildagliptin by reaction with (V) in 2-butanone in presence of KI. Although the chiral purity of the final compound is very good (>99.99%) however there is no indication about yield and chemical purity.
Scheme 2

Formula (1)
The method disclosed in PCT Patent Publication WO 2008/084383A2 is described in scheme (3) that involves in situ preparation of compound (IV) in 66% yield by reaction of- (I) with (II) in DMF-isopropyl acetate followed by the addition of cyanuric chloride and final coupling was carried out in THF to minimize the formation of dialkyl product (VI).

Although the chiral purity is very good the chemical yield is moderate that too after repeated crystallizations thus making the process not feasible commercially. According to PCT Patent Publication WO2010/022690A2 the reaction of chloroacetyl chloride with prolinamide in ether type (THF) solvent resulting triethylamine hydrochloride contaminated amide (III) followed by dehydration with TFAA gave (IV) in 77% yield. The final step to Vildagliptin is carried out in a mixture of DMF, isopropyl acetate and ethyl methyl ketone and the product with 99.9% purity is obtained through a number of crystallization step of different fractions using methyl ethyl ketone. The yield is not reported for final step. It does not appear to be attractive for commercial purpose.
Scheme 4

Formula (1)
An altogether different method for the process of Vildagliptin is described in PCT Patent Publication WO201 1/101861 Al and summarized in scheme (4). The method involves preparation of acid (XI) by two different approaches consisting of coupling bromoacetyl ester (VII) with (V) followed by hydrolysis or formation of imine (X) by the reaction of (V) with 2-oxo acetic acid followed by reduction using NaBH4. All these steps are high yielding. Subsequently Vildagliptin is prepared by coupling of acid (XI) with (XII) using DCC-DMAP. The major drawback of the synthesis appears to be the significantly lower yield of final product after purification moreover the chiral integrity is not disclosed.
Another new approach (scheme 5) is described in PCT Patent Publication WO2012/00421 OA 1 that involves n-formyl protected acid (XIII) formed by the reaction of 3-hydroxy adamentyl amine with 50% aq. glyoxalic acid followed by the coupling of prolinamide with T3P or CDI followed by dehydration using TFAA. The hydrolysis of formyl group with acidic or basic condition produced Vildagliptin. Poor yield in the first step that involved costly 3-hydroxy adamantyl amine might be disadvantageous. Moreover the Yield of Vilgagliptin after final purification is very low and the chemical as well as chiral purity is not disclosed. Therefore this process does not look scalable.
Scheme 5

In yet another PCT Patent Publication WO 2013/083326A1 describes a process that involves the salt formation of prolinamide with chloro or bromo acetic acid followed by coupling with DCC to produce haloacetyl prolinamide which in situ reacted with 2.2 equivalent of 3-hydroxy adamentyl amine to compound (XXI) in 76.5% yield. The Vildagliptin is prepared by dehydration of compound (XXI) by POCI3 or isocyanuric acid in around 75% yields without any mention of chemical or chiral purity. The process does not offer any superiority over prior art except the use of inexpensive dehydrating agent. The use of high excess of 3-hydroxy adamantly amine however makes the process less attractive.

XXI
Accordingly therefore, based on the drawbacks mentioned in all the prior arts, there is an urgent need for economically viable synthesis of highly pure (both chemical and chiral) Vildagliptin to address mainly the drawbacks associated with the prior arts that can be defined as a process that involve use of less hazardous less costly and environment friendly reagents that will give highly pure material with fewer number of steps and finally cost effective.

Summary of the Invention
Accordingly, the present invention provides an improved process for the preparation of Vildagliptin of formula (I),

(Formula I)
which comprises the steps of:
(a) obtaining compound of formula (4) by reacting compound of formula (2) with compound of formula (3) under alkaline condition with or without a catalyst using a suitable solvent;
(b) obtaining a compound of formula (5) by hydrolyzing compound of formula (4) in acidic or basic condition with or without solvent;
(c) obtaining compound of formula (9) by reacting compound of formula (5) with (S)- pyrrolidine-2-carboxylic acid methyl ester and its salts of formula (6) in presence of a suitable acid-amine coupling agents in a suitable solvent or a combination of solvents;
(d) obtaining compound of formula (10) by reacting compound of formula (9) wherein R2 is H with compound of formula (7) in alkaline condition in a suitable solvent or a combination of solvents thereof;
(e) obtaining compound of formula (1 1) by reacting compound of formula (9) with ammonia optionally in a suitable organic solvent;
(f) optionally obtaining compound of formula (1 1) by reacting compound of formula (5) with L-prolinamide of formula (8) in presence of a suitable acid-amine coupling agents in a suitable solvent or a combination of solvents;
(g) obtaining compound of formula (12) by reacting compound of formula (10) with ammonia optionally in a suitable organic solvent;
(h) obtaining compound of formula (13) by dehydrating compound of formula (1 1) using a dehydrating agent in a suitable solvent;
(i) obtaining compound of formula (14) by dehydrating compound of formula (12) by a compatible dehydrating agent in a suitable solvent;
(j) obtaining Vildagliptin of formula (1) by dehydrating compound of formula (11),
The above process is illustrated in the followin general synthetic scheme 6):

(3)

Example 16.1: (S)-l-[2-(3-hydroxy-adamantan-l-ylamino)-acetyl]-pyrrolidine-2-carbonitrile (Vildagliptin)
Dissolved (S)- 1 -[2 -(3 -hydroxy-adamantan- 1 -ylamino)-acetyl] -pyrrolidine-2-carboxylic acid amide (50 g, 1 eq.) by adding 2-Me-THF (250 mL, 10V) under stirring in a clean and dry 1 L 4 neck RBF equipped with magnetic stirrer, thermometer pocket, reflux condenser and an addition funnel. Meanwhile a mixture of trifluoroacetic acid (23.8 mL, 2 eq.) and trifluoroacetic anhydride (43.90 mL, 2.0 eq.) was prepared and added slowly under stirring to the reaction mass over 5-6 h. The stirring continued at 20-25°C for 1 h. The reaction mixture was cooled to 5-10 °C and a solution of K2C03 (214.1 g, 10 eq.) in water (300 mL, 6V) was added slowly over 30 min and stirred for 5-6 h. After complete conversion checked by HPLC, water (200 mL, 2 V) was added and stirred for 10 min. separated organic and aqueous layers. The aqueous layer was extracted using DCM (1 χ 200 mL) (DCM-1). The 2-Me-THF layer was concentrated to isolate crude product. Added aqueous citric acid solution (citric acid - 98 g, 3.0 eq; water - 6V) to crude product and washed the combined aqueous layer with DCM extract obtained above (DCM-1) and then followed by DCM (3 χ 100 mL). Adjusted pH of aqueous layer to 9-10 after DCM wash using aq. ammonia and extracted aqueous layer using DCM (4 x 100 mL). Washed combined DCM layer with water (50 mL, IV). Concentrate DCM layer followed by stripping of ethyl acetate to isolate crude product; yield range: 75-85%. HPLC purity: > 99%. The crude was further purified by crystallization by dissolving under reflux with ethyl acetate (255 mL, 6V w.r.t to crude wt.) and IPA (85 mL, 2V) and crude compound (42.4 g) under stirring It was allowed to cool to 20-25°C and then to 0-5°C and stirred for 1 h at 0-5°C. Filtered the solid formed and washed with chilled ethyl acetate (42.5 mL, 1 V). Suck dried the solid for 3-4 h to get pure Vildagliptin 34.50 g (60-75 %); Ή NMR (CDC13, 400 MHz) δ: 1.52-1.69 (m, 12H); 1.78 (brs, 2H); 2.04-2.38 (m, 6H); 3.37-3.69 (m, 4H); 4.76-4.78 (m, 0.8H); 4.85-4.87 (m, 0.2H).

claim:
(1) An improved process for the synthesis of a compound of formula (I),

(I)
which comprises the steps of:
a) reacting a compound of formula (2) with a compound of formula (3) under alkaline condition with or without a catalyst using a suitable solvent to get a compound of formula (4);

(2) (3) (4)
wherein R2 = H, C2-C6 alkyl group containing a double bond optionally substituted with halogen (such as CI, Br, I etc), S, O, Si etc. or a group containing C7-C10 alkyl aryl optionally substituted by atoms selected from N, O, S, halogen Si etc. or the hetero atom can be a part of the chain.
b) hydrolyzing a compound of formula (4) in acidic or basic condition with or without solvent to get a compound of formula (5);

(5)
Wherein R2 = H.
c) reacting a compound of formula (5) with L-proline alkyl ester and its salts of formula (6) in presence of a suitable acid-amine coupling agents in a suitable solvent or a combination of solvents to get a compound of formula (9);

(9) (6)
Wherein R\ = C1-C3 linear, cyclic or branched chain or C7-C10 alkyl aryl group and R2 = H, C2-C6 alkyl group containing a double bond optionally substituted with halogen (such as CI, Br, I etc), S, O, Si etc. or a group containing C7-C10 alkyl aryl optionally substituted by atoms selected from N, O, S, halogen Si etc. or the hetero atom can be a part of the chain.
d) reacting a compound of formula (9) with a compound of formula (7) in alkaline condition in a suitable solvent or a combination of solvents thereof to get a compound of formula (10);

(10) (7)
Wherein RP = R3O-CO- or R4SO2- and Ri = Q-C3 linear, cyclic or branched chain or C7-C[0 alkyl aryl group.
e) obtaining compound of formula (1 1) by reacting compound of formula (9) with ammonia optionally in a suitable or anic solvent;

(")
Wherein R2 = H, C2-C6 alkyl group containing a double bond optionally substituted with halogen (such as CI, Br, I etc), S, O, Si etc. or a group containing C7-C10 alkyl aryl optionally substituted by atoms selected from N, O, S, halogen Si etc. or the hetero atom can be a part of the chain.
f) optionally obtaining a compound of formula (1 1) by reacting a compound of formula (5) with L-prolinamide of formula (8) in presence of a suitable acid-amine coupling agents in a suitable solvent or a combination of solvents;

(8)
g) reacting a compound of formula (10) with ammonia optionally in a suitable organic solvent to get compound of formula (12);

(12)
Wherein RP = R3O-CO- or R4SO2- h) obtaining a compound of formula (13) by dehydrating a compound of formula ( 1 1) by using a dehydrating agent in a suitable solvent;

(13)
Wherein R2 = H, C2-C6 alkyl group containing a double bond optionally substituted with halogen (such as CI, Br, I etc), S, O, Si etc. or a group containing C7-Ci0 alkyl aryl optionally substituted by atoms selected from N, O, S, halogen Si etc. or the hetero atom can be a part of the chain
i) obtaining a compound of formula ( 14) by dehydrating compound of formula (12) by a dehydrating agent in a suitable solvent;

(14)
Wherein RP = R3O-CO- or R4S02-j) dehydrating compound of formula (1 1) using a suitable dehydrating agent in a suitable solvent to get Vildagliptin of formula (I); CLIPPED HERE        SEE MORE IN PATENT

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..................ceremony by Mr. Jai Hiremath, Vice-Chairman and Managing Director, Hikal and his wife

(From Left)
Dr. Peter Pollak, Kannan Unni, Prakash Mehta, Sugandha Hiremath, Baba Kalyani, Jai Hiremath, Shivkumar Kheny,Sameer Hiremath.

Jai Hiremath, Chairman and Managing Director
Jai Hiremath is the Chairman and Managing Director of Hikal Ltd. A Chartered Accountant from England and Wales, he has completed the Advanced Management Program for professionals and entrepreneurs from Harvard University, USA in 2004. He has more than 35 years of experience in the chemical and pharmaceutical industry. Mr. Hiremath established the company in 1988 and under his leadership; Hikal has grown to become one of leading life sciences companies globally.
Mr. Hiremath is the Past President of the Indian Chemical Council (ICC) and the former Chairman of the Chemical Committee of the Federation of Indian Chamber of Commerce and Industry (FICCI). Mr. Hiremath is also a board member of Novartis (India) Ltd and National Safety Council (NSC) of India. Most recently he has been elected to serve as a board member of DCAT (Drug, Chemical and Associated Technology Association) headquartered in New Jersey, U.S.A.
Sameer Hiremath, President and Joint Managing Director
Sameer Hiremath is the President & Joint Managing Director of Hikal Ltd. His responsibilities include overseeing the day to day operations of the company. Mr. Hiremath did his Chemical Engineering from MIT (Maharashtra Institute of Technology), Pune and an MBA cum M.S. degree in Information Technology from Boston University, USA. Over the years, he has held various positions at Hikal including that of Executive Director. He has over 16 years of experience in plant operations and manufacturing at Hikal.

Hikal is headquartered in Mumbai, India.
Hikal Ltd.
Great Eastern Chambers
Sector 11, CBD-Belapur
Navi Mumbai
India - 400 614
Tel: +91-22-3097 3100
Fax: +91-22-2757 4277
//////WO2015128718, HIKAL LIMITED,  NOVEL ECONOMIC PROCESS FOR VILDAGLIPTIN

1 comment:

  1. Glyptins are class of oral anti-hyperglycemic agents that inhibit dipeptidyl peptidase 4 (DPP-4), which can act as a serine exopeptidase. ASide from there use in type 2 diabetes, gliptins have positive cardiovascular and anti-inflammtatory effects. Antidiabetic. Vildagliptin

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