WO2019186260A1

WO2019186260A1 - An improved process for the preparation of sitagliptin and pharmaceutically acceptable salts thereof

Info

Publication number: WO2019186260A1
Application number: PCT/IB2018/059746
Authority: WO
Inventors: Goverdhan Gilla; Swapnil Surendra Mohile; Sandeep TAPKIR; Sachin Ambadas Dawange; Abhijit Omprakash Bajaj; Shekhar Yashawant Gujar; Sudhir Nambiar; Amit Kumar Tiwari; Mukesh Vyankatkrishnamurti Samal
Original assignee: Hikal Ltd
Current assignee: Hikal Ltd
Priority date: 2018-03-28
Filing date: 2018-12-07
Publication date: 2019-10-03
Anticipated expiration: 2020-09-28

Abstract

The present invention relates to provide an improved process for the preparation of sitagliptin (I) and its pharmaceutical acceptable salts thereof, which is simple, economical, efficient, user and environment friendly, moreover commercially viable.

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF SITAGLIPTIN AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF

FIELD OF THE INVENTION

The present invention relates to an improved and commercially viable process for preparation ofsitagliptin and pharmaceutically acceptable salts thereof in high yield with high chemical and chiral purity.

BACKGROUND OF THE INVENTION

Sitagliptin is chemically known as (A ) - 3 - a m i n o - 1 - [ 3 - (t ri fl u o ro m c t h y 1 ) - 5 , 6 , dihydro [1,2,4] triazolo[4,3-a] pyrazin-7(8H)-yl]-4-(2,4,5-trifluorophenyl) butan-l-one and useful as a potent second-generation inhibitor of dipeptidyl -peptidase (DPP) IV for the treatment of Type-2 diabetes. The structure of sitagliptin(I) is represented below.

Sitagliptin is first disclosed in US Patent 6,699,871 and can be synthesized by different synthetic approaches as mentioned below. The first synthesis of sitagliptin appears to be set out in PCT patent publication WO 2003/004498 (henceforth '498). The said PCT'498 discloses a method of introducing a chiral-amine group using a chiral pyrazine derivative and to prepare sitagliptin by Arndt-Eistert homologation using t-butoxylcarbonylamino-4-(2,4,5- trifluorophenyl)-butyric acid as a sitagliptin intermediate. The said process is represented in scheme (I), which involves the use of unusual dihydropyarazine chiral promoters, diazomethane and silver salt which are not preferred reagents for industrial synthesis. Scheme-I:

Another synthetic process is described in the said PCT'498 and Tetrahedron Asymmetry2006,17, 205 discloses the use of expensive metal catalyst such as rhodium. A similar synthesis is subsequently reported in another PCT publication W02009/064476, which involves the enantio selective hydrogenation of b-enamino derivatives and the use of expensive precious ruthenium metal catalyst, ligands such as ferrocenyldiphospine ligands - JOSIPHOS catalyst which is disclosed in several PCT publication and articles for instance such as W02004/085378 (henceforth '378), W02005/097733 (henceforth 733), W02006/08l l5l(henceforth Ί51) and J. Am. Chem. Soc., 2004,725 (32), 9918-9919. The preparation of this compound is also described in J. Am. Chem. Soc., 2009, 131(25), 8798-8804. The reference further discloses that the compounds once obtained may be purified according to the methods standard in the field, obtaining sitagliptin and pharmaceutically acceptable salts thereof in pure form, well suitable for pharmaceutical applications. The said process is described in scheme (II).

Scheme-II:

The PCT Publication W02004/085661 described the process which involves the preparation of sitagliptin using (S)-phenyl glycine amide as a chiral auxiliary. The said process is described in scheme (III).

Scheme-Ill:

The PCT Publication W02004/087650 discloses the preparation of sitagliptin using the chiral benzyloxylazetidinone as an intermediate. The said PCT‘378,‘733 and‘l5l discloses the preparation of sitagliptin, which involves an enantioselective reduction of the intermediate chiral enamine in the presence of specific catalysts and the PCT Publication W02009/085990 discloses the preparation of sitagliptin using various chiral auxiliaries, as a chiral resolving agent. The methods disclosed in above PCT Publicationsare useful for preparing sitagliptin, an alternative method of the preparation, particularly for manufacturing scale production are desirable.

The PCT Publication WO 2015120111 (henceforth ‘111) discloses the preparation of sitagliptin and its pharmaceutically acceptable salt by preparing enamide compound of formula (II), reacting with Michael donar compound of formula (III). In one of the scheme (Scheme5) discloses the use ofl-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)-4(2,4,5trifluorophenyl)butane-l,3-dione for the preparation of enamide compound (formula II) on reacting with Michael donor compound formula (III) [(R)-phenyl ethyl amine, (lR)-l- carboxamidophenylmethanamine] to produce the compound of formula (VUIb) which on deprotection produces sitagliptin and its pharmaceutically acceptable salt. The said PCT ‘111 is silent on yield, chemical and chiral purity of the intermediate compound of formula (VUIb) and on sitagliptin and its pharmaceutically acceptable salt. Also, the Michael donor compound used in the process are bit expensive. The said process is described in scheme (IV).

Scheme-IV :

Thus, there is a need for a process which involved economical, user-friendly key raw materials which lead to high yield, high chemical and chiral purity.

In another research publication IP.com Journal, Vol.9, Iss.5B, Page 36, 2009 discloses the novel process for the preparation of sitagliptin by reacting l-(3-(trifluoromethyl)-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-l,3-dione with optically pure(S)-phenylethylamine (which may be substituted with an alkyl or alkoxy group on phenyl ring) in the presence of a drying agent to obtain (Z)-3-(l-phenylethylamino)-l-(3- (trifluoromethyl)-5,6-dihydro-[l,2,4] triazolo[4,3-a] pyrazin-7(8H)-yl)-4-(2,4,5- trifluorophenyl)but-2-en-l-one which on stereoselective reduction in presence of catecholborane or a derivative of catecholborane and further hydrogenolysis in the presence of Pd/C and hydrogen source provides sitagliptin. The process involves expensive reagents and involve CombiFlash chromatography technique for purification of compound. The said process is substantially described in scheme (V).

Scheme- V :

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) sitagliptin or its pharmaceutically acceptable salt thereof. To address mainly the drawbacks associated with the prior arts, which may be defined as a process that involve use of less hazardous, economical and environment friendly reagents and finally lead to highly pure material in a cost-effective manner.

OBJECTIVES OF THE INVENTION

The main objective of the present invention is to provide an improved process for the preparation of a compound of formula (I), which is simple, economical, user-friendly and commercially viable.

Another objective of the present invention is to provide a process for the preparation of a compound of formula (I) and its pharmaceutically acceptable salts with a greater yield and higher chiral and chemical purity, which would be easy to implement on commercial scale and makes the present invention eco-friendly as well.

Another objective of the present invention is to provide a process for the preparation of a compound of formula (I) and its pharmaceutically acceptable salts by exploring the use of substituted (S)-phcnyl glycine ester or its salts or its derivatives as a chiral auxiliary.

Yet another objective of the present invention is to provide a process for the preparation of a compound of formula (I), and its pharmaceutically acceptable salts in a high yield, with high chiral and chemical purity using economical, inexpensive chiral auxiliary substituted ( S )- phenyl glycine ester or its salts or its derivatives and keto amide as a key starting material.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides an improved process for the preparation of sitagliptin of formula (I) and pharmaceutically acceptable salts thereof;

which comprises the steps of:

a) obtaining a compound of formula (IV) by reacting a compound of formula (II) with compound of formula (III) in the presence of a suitable acid in a suitable solvent or mixture of solvents thereof at a suitable temperature;

b) obtaining a compound of formula (V) by reducing a compound of formula (IV) with a suitable reducing agent in presence of a suitable acid, suitable solvent or mixture of solvents thereof at a suitable temperature; and

c) obtaining a compound of formula (I) by reacting a compound of formula (V) in a suitable hydrogenating catalyst in a suitable solvent or mixture of solvents thereof, optionally in presence of suitable acid or base, at a suitable temperature. The above process is illustrated in the following general synthetic scheme;

DETAILED DESCRIPTION OF THE INVENTION

The present invention now will be described more fully hereinafter. The invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. As used in the specification, and in the appended claims, the singular forms“a”,“an”,“the”, include plural referents unless the context clearly indicates otherwise.

In accordance with the objectives, wherein the present invention provides an improved process for the preparation of sitagliptin of formula (I) and salt thereof via novel synthetic approach.

Accordingly, in an embodiment of the present invention, wherein the present process for the preparation of sitagliptin of formula (I), comprises reacting of compound of formula (II) with compound of formula (III) to obtain compound of formula (IV) followed by reduction in presence of suitable reducing reagent to obtain compound of formula (V) and further hydrogenation in presence of suitable catalyst to obtain compound of formula (I). In another embodiment of the present invention, wherein the compound of formula (IV) of step (a) is obtained by reacting compound of formula (II) with chiral compound of formula (III) such as substituted (S)-phcnylglycinc esters or its salts or its derivatives.

wherein the substituent“X” is Ci-C₆ alkyl chain, branched, substituted and unsubstituted aliphatic or aromatic ring or any halide substituent’s (halide may be of any noi. e. 1 to 5) and “R” is selected from the group consisting of C i -C₆ alkyl chain, branched, substituted and unsubstituted aromatic ring in presence of suitable acid in a suitable solvent at a suitable temperature.

In an another embodiment of the present invention, wherein the said solvent used in step (a), step (b) and step (c) is selected from group consisting of water, alcoholic solvents, ketonic solvents, esters, halogenating solvents, ethereal solvents, hydrocarbon solvent and the like or mixture of solvents.

In an another embodiment of the present invention, wherein the said solvent used in step (b) and step (c) is selected from group consisting, aprotic solvent and the like or mixture of solvents.

In an another embodiment of the present invention, wherein the said solvent used in step (a), step (b) and step (c) are alcoholic solvents such as methanol, ethanol, isopropanol, n- propanol, «-butanol and the like; or mixture of solvents.

In an another embodiment of the present invention, wherein the said solvent used in step (a), step (b) and step (c) the ketonic solvents such as acetone, methyl isobutyl ketone, ethyl methyl ketone and «-butanone and the like; or mixture of solvents. In an another embodiment of the present invention, wherein the said solvent used in step (a), step (b) and step (c) the halogenating solvents such as ethylene dichloride, chloroform, dichloromethane and the like; or mixture of solvents; more preferably dichloromethane.

In an another embodiment of the present invention, wherein the said solvent used in step (a), step (b) and step (c) esters used such as ethyl acetate, «- propyl acetate and isopropyl acetate and the like; or mixture of solvents.

In an another embodiment of the present invention, wherein the said solvent used in step (a), step (b) and step (c) ethereal solvents such as methyl tert-butyl ether, l,4-dioxane, tetrahydrofuran, l,2-dimethoxy ethane and the like or mixture of solvents, more preferably l,2-dimethoxy ethane.

In an another embodiment of the present invention, wherein the said solvent used in step (a), step (b) and step (c) hydrocarbon solvents such as cyclohexane, «-hexane, «-heptane, toluene, xylene and the like or mixture of solvents, more preferably toluene.

In an another embodiment of the present invention, wherein the said aprotic solvent used in step (b) and step (c) is preferably selected from N,N-dimethylformamide, dimethylsulfoxide and dimethyl acetamide and the like or mixture of solvents.

In an another embodiment of the present invention wherein the said acid of step (a) is preferably selected from group consisting of organic acid, inorganic acid and the like or mixture of acids, more preferably inorganic acids.

In another embodiment of the present invention wherein the said acid of step (a) is organic acid such as acetic acid and propionic acid, the inorganic acid such as cone hydrochloric acid, cone sulfuric acid, nitric acid, phosphoric acid, and the like or mixture of acids, more preferably cone sulfuric acid.

In an another embodiment of the present invention, wherein the suitable temperature may be preferably carried out at low to ambient temperature or to reflux temperature; more preferably at ambient to reflux temperature and the reaction is performed under atmospheric distillation or reduced pressure distillation of solvent.

In an another embodiment of the present invention, wherein the said reducing agent of step (b) is preferably selected from group consisting of suitable metal catalyst, such as sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, aluminium hydrides, sodium cyanoborohydride, sodium triacetoxyborohydride, platinum oxide, palladium on carbon and the like mixture of catalyst, more preferably sodium borohydride.

In an another embodiment of the present invention, wherein the said acid of step (b) is preferably selected from group consisting of methane sulphonic acid, trifluroacetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, pyridine sulfonic acid, camphor sulfonic acid, concentrated hydrochloric acid, zinc chloride or in combination of these mixture of acids, more preferably methanesulfonic acid.

In an another embodiment of the present invention, wherein the said temperature used in step (b) may be preferably carried out at low temperature to ambient temperature.

In an another embodiment of the present invention, wherein all the crude involved in step (a) and step (b) is used as such or is purified by distillation or crystallization or by different purification techniques well understood by those skilled in the art.

In an another embodiment of the present invention, wherein the hydrogenating catalyst used in step (c) is preferably selected from palladium on carbon, palladium hydroxide on carbon, nickel on carbon and the like or mixture of catalysts, more preferably palladium on carbon.

In an another embodiment of the present invention, wherein the acid used in step (c) is selected from organic or inorganic acids.

In an another embodiment of the present invention, wherein the base used in step (c) is selected from organic or inorganic or aromatic bases. In an another embodiment of the present invention, wherein the said temperature used in step (c) may be preferably carried out at low to ambient temperature or to reflux temperature; more preferably at ambient to reflux temperature.

A compound of formula (I) may be further converted into its pharmaceutically acceptable salts formula (VI) by treating with a suitable acid, more preferably hydrochloric acid.

In an another embodiment of the present invention, wherein one or all the steps may be performed in in-situ manner.

The term“pharmaceutically acceptable salts” compound of formula (VI) refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure and may also be in the form of hydrates. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'- dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine.

When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric and tartaric acids.

The key compounds involved in the above process are depicted below:

Advantages of current process:

1) The application of compound (III) or its salts or its derivatives was successfully explored as achiral auxiliary.

2) The use of inexpensive chiral auxiliary compound (III) or its saltsor its derivatives for the synthesis of sitagliptin successfully executed with better yield and higher chemical and chiral purity.

3) The purification of compound (I) provides the surprising results with the enhancement in chiral purity from 81% to more than 99.66%.

4) The current process is short, economical and less hazardous to the environment as compared to prior art processes which involves expensive reagents, catalysts and side products or impurities.

5) The process has effectively less number of steps that result in shortening of reaction time and lowering of labor.

6) The process of the present invention avoids excess usages of reagent(s) and organic solvent(s), thereby promoting green chemistry and ensuring a cleaner surrounding by putting less load on environment. 7) The process of the present invention involves the solvents, which can be recycled and reused thereby makes the process more economical, industrially and commercially viable.

The following non-limiting examples are given by way of illustration of the present invention and therefore should not be construed as limitation of the invention scope.

Example 1: Preparation of compound of formula (IV).

To a stirred solution of compound II (50. Og, 0.123 moles) and compound III (34.4g, 0.172 moles), toluene (750mL, 15V), cone sulfuric acid (l.l76g, 0.0123 moles) was added and heated the reaction mixture to 70°C to 80°C for lh. The solvent was removed by distillation from reaction mixture under reduced pressure till minimum stirrable volume. To above reaction mixture fresh toluene (750mL, 15V) was charged and continued distillation of solvent below 80°C. After completion of reaction, the reaction mixture was allowed to cool to 25°C to 30°C. The reaction mixture was quenched by water (300mL), stirred for 30 min. and the aqueous and organic layer were separated. The organic layer was washed with 2N hydrochloric acid (300mL), saturated sodium bicarbonate solution (300mL) and evaporated under reduced pressure to yield crude compound IV as a yellow to brown solid (72g, 99%) with chiral HPLC purity 97.77%, MS: 588 [M+H]⁺, 1H NMR: (DMSO, 400 MHz): 3.55-3.60 (3H, s); 3.55-3.60 (2H, s); 3.85-3.98 (2H, bt); 4.12-4.18 (2H, bt); 4.90 (2H, s); 5.13 (1H, s); 5.60-5.62 (1H, d), 7.14-7.54 (6 H, m); 10.42-10.44 (1H, s).

Example 2: Preparation of compound of formula (V).

To a stirred precooled solution of toluene (l25mL), l,2-Dimethoxy ethane (l25mL) and sodium borohydride (l.76g, 0.0467 moles) at -55°C to -65°C, methanesulphonic acid (11.3g, 0.1190 moles) was added slowly at -55°C to -65°C and reaction mixture was stirred and maintained for 2h. To above reaction mixture isopropyl alcohol (25mL, IV) was added and a solution of compound IV (25g, 0.0425 moles) in toluene (250mL, 10V) was charged over a period of 2h. The reaction was stirred at -55°C to -65°C for 2h and after completion of reaction, the reaction mixture was quenched using water, aq. ammonia solution. The organic layer was separated and washed with brine solution and evaporated under reduced pressure to yield compound V as a yellow to brown oil (24.5g, 97%) with chiral HPLC purity 83.99%, MS: 590 [M+H]⁺, 1H NMR(DMSO, 400 MHz): 2.43-2.80 (4H, 3), 3.17-3.26 (1H, m), 3.55 (3H, s), 3.89-4.22 (4H, m), 4.76-5.11 (3H, m), 6.79-6.95 (2H, m). 7.07-7.36 (4H, m).

Example 3: Preparation of compound of formula (I).

To a solution of compound V (25g, 0.0423 moles) in methanol (500mL) in a 2.0Lhydrogenator20% palladium on carbon (2.5g, 10 % w/w) was added and stirred under lOKg of hydrogen pressure. The reaction mixture was heated at60°C to 65°C for l2h. After completion of reaction the reaction mixture was allowed to cool to 20°C to 30°C, filtered on celite bed and bed was washed with methanol. The solvent was evaporated under reduced pressure and the crude compound (I)was isolated by acid-base purification technique using aq. hydrochloric acid to obtain crude sitagliptin free base (I) with HPLC chemical purity 96.21% and chiral purity 82.41%. The crude compound (I) (l.Oeq)was added into isopropyl alcohol (13.0V), stirred for 5 min. and cone hydrochloric acid (0.4V) was added. To above solution crystals of sitagliptin hydrochloric acid (l%w/w) with chiral purity more than 99.85% was added and cooled to 0°C to 5°C. The reaction mixture was heated to 75°C to 85°C till clear solution observed. The reaction mixture was allowed to cool to 20°C to 25°C gradually and stirred for lh. The solid compound was filtered, washed with isopropyl alcohol (2V) and further dissolved into water (5V) and pH of solution was maintained more than 9.0 using 1N sodium hydroxide solution. The aqueous layer was extracted with dichloromethane (5V X 3), separated the organic layer. The combined organic layer washed with water and evaporated under reduced pressure get yield pure Sitagliptin free base (I) (51% over three stages). HPLC chiral purity of 99.96% and chemical purity 99.70%, MS:408 [M-H] , 'H NMR (DMSO, 400 MHz): 1.53 (2H, s), 2.474 -2.72 (4H, m), (1H, m), 3.27-3.32 (1H, m), 3.93-4.24 (4H, m), 4.83-4.99 (2H, dd), 7.40-7.48 (2 H, m).

Example 4: Preparation of compound of formula (I).

Stage- 1 A: To a stirred solution of dichloromethane (2.8L), compound II (200g, 2.03moles) and compound III (137. lOg, 0.687moles) added cone sulfuric acid (4.8g, 0.0489 moles) and heated the reaction mixture to reflux at 39 °C for 3 h. The solvent was removed by distillation from reaction mixture under reduced pressure till minimum stirrable volume. After completion of reaction, the reaction mixture was allowed to cool to 25°C to 30°C. The reaction mixture was quenched by water, stirred for 30 min. and the aqueous and organic layer were separated. The organic layer was washed with aq. citric acid, saturated sodium bicarbonate solution and evaporated under reduced pressure to get dichloromethane layer containing compound IV as a yellow to brown solution (275.0g on dry basis, 95% yield) with a chiral HPLC purity of 98.14% and chemical purity of 97.55%. Stage-lB: To a stirred precooled solution of dichloromethane (0.7L), l,2-dimethoxy ethane (0.7L) and sodium borohydride (l9.46g, 0.5144 moles) at -55°C to -75°C, methanesulphonic acid (85mL, 1.309 moles) was added slowly at -55°C to -75°C and reaction mixture was stirred and maintained for 2h. To above reaction mixture isopropyl alcohol (280mL, 1.4V) was added and followed by addition of compound IV solution (275. Og, 0.468 moles) obtained in stage-lA over a period of 2h. The reaction was stirred at -55°C to -75°C for lh followed by warming to -5°C to +5°C. After completion of reaction, the reaction mixture was quenched using water, aq. ammonia solution. The organic layer was separated and washed with brine solution and evaporated under reduced pressure till minimum stirrable volumes remain in reaction mass. The methanol stripping is given to dichloromethane layer to get read of dichloromethane to get methanol layer containing compound V as a yellow to brown solution (275. Og on dry basis, 99%yield) with a chemical purity of 90.37 %.

Stage- 1C: To a methanolic solution of compound V (275.0 g on dry basis, 0.466 moles) and methanol (1.0 L) in a 2.0 L hydrogenator, 10% palladium on carbon (14.0 g) was added and stirred under 10 to 14 Kg of hydrogen pressure. The reaction mixture was heated at 60°C to 65°C for 8h. After completion of reaction the reaction mixture was allowed to cool to 20°C to 30°C, filtered on celite bed and bed was washed with methanol. The solvent was evaporated under reduced pressure till minimum stirrable volume remains in reaction mass. To the above reaction mass, charged fresh isopropyl alcohol (2.2L) and cone. HC1 (82mL, 0.1V) and heated reaction mass to 80°C to 90°C and maintain for 2h. Cool reaction mass to RT and then to 0°C to 5°C and maintained for 2h. Filtered the reaction mass and washed with isopropyl alcohol. Suck dried the solid and dried at 50°C for 6h, unloaded the hydrochloride salt of compound (I) as a white solid, (112 g,54 % yield) with a chiral HPLC purity of 99.67% and Chemical purity of 99.66%.

Claims

WE CLAIM:

1) An improved process for the preparation of sitagliptin of formula (I) and pharmaceutically acceptable salts thereof,

which comprising the steps of:

c) obtaining a compound of formula (I) by reacting a compound of formula (V) in a suitable hydrogenating catalyst, in a suitable solvent or mixture of solvents, optionally in presence of suitable acid or base, at a suitable temperature.

2) The process as claimed in step (a) of claim 1, the compound of formula (IV) is obtained by reacting compound of formula (II) with chiral compound of formula (III) wherein, substituent“X” is Ci-C₆ alkyl chain, branched, substituted and unsubstituted aliphatic or aromatic ring or any halide substituent’s ranging from 1 to 5 and“R” is selected from the group consisting of Ci-C₆ alkyl chain, branched, substituted and unsubstituted aromatic ring in presence of suitable acid in a suitable solvent at a suitable temperature.

3) The process as claimed in claim 1 and 2 wherein, the said chiral compound formula (III) is a substituted (S)-phcnyl glycine ester or its salts or its derivatives.

4) The process as claimed in claim 1, wherein the said acid used in step (a) is preferably selected from group consisting of organic acid, inorganic acid or mixture of acids.

5) The process as claimed in claim 1 and 4, wherein the said organic acid used in step (a) is preferably selected from propionic acid, the inorganic acid such as cone hydrochloric acid, cone sulfuric acid, nitric acid, phosphoric acid; more preferably sulfuric acid.

6) The process as claimed in claim 1, wherein the said solvent used in step (a), step (b) and step (c) is selected from group consisting of water, alcoholic solvents, ketonic solvents, esters, halogenating solvents, ethereal solvents, hydrocarbon solvent or mixture of solvents.

7) The process as claimed in claim 1, wherein the said aprotic solvent used in step (b) and step (c) is preferably selected from N, N-dimethylformamide, dimethylsulfoxide and dimethyl acetamide or mixture of solvents.

8) The process as claimed in claim 1, wherein the said solvent used in step (a), step (b) and step (c) is preferably selected from alcoholic solvents such as methanol, ethanol, isopropanol, «-propanol, «-butanol or mixture of solvents.

9) The process as claimed in claim 1, wherein the said solvent used in step (a), step (b) and step (c) is preferably selected from ketonic solvents such as acetone, methyl isobutyl ketone, ethyl methyl ketone and «-butanone or mixture of solvents.

10) The process as claimed in claim 1, wherein the said solvent used in step (a), step (b) and step (c) is preferably selected from halogenating solvents such as ethylene dichloride, chloroform, dichloromethane or mixture of solvents; more preferably dichloromethane. 11) The process as claimed in claim 1, wherein the said solvent used in step (a), step (b) and step (c) is preferably selected from esters used such as ethyl acetate, «-propyl acetate and isopropyl acetate or mixture of solvents.

12) The process as claimed in claim 1, wherein the said solvent used in step (a), step (b) and step (c) is preferably selected from ethereal solvents such as methyl tert-butyl ether, 1,4- dioxane, tetrahydrofuran, l,2-dimethoxy ethane or mixture of solvents; more preferably l,2-dimethoxy ethane.

13) The process as claimed in claim 1, wherein the said solvent used in step (a), step (b) and step (c) is preferably selected from hydrocarbon solvents such as cyclohexane, «-hexane, «-heptane, toluene, xylene or mixture of solvents more preferably toluene.

14) The process as claimed in claim 1, wherein the said suitable temperature used in step (a) and step (c) is preferably carried out at low to ambient temperature or to reflux temperature; more preferably at ambient to reflux temperature.

15) The process as claimed in claim 1, wherein the said reducing agent of step (b) is preferably selected from group consisting of suitable metal catalyst, such as sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, aluminium hydrides, sodium cyanoborohydride, sodium triacetoxyborohydride, platinum oxide, palladium on carbon or mixture of catalysts; more preferably sodium borohydride.

16) The process as claimed in claim 1, wherein the said acid of step (b) is preferably selected from group consisting of methanesulfonic acid, trifluoro acetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, pyridine sulfonic acid, camphor sulfonic acid, concentrated hydrochloric acid, zinc chloride or in combination of these mixture of acids; more preferably methanesulfonic acid.

17) The process as claimed in claim 1, wherein the said temperature used in step (b) may be preferably carried out at low temperature to ambient temperature.

18) The process as claimed in claim 1, wherein the crude involved in step (a) and step (b) is used as such or is purified by distillation or crystallization or by different purification techniques. 19) The process as claimed in claim 1, wherein the hydrogenating catalyst used in step (c) is preferably selected from palladium on carbon, palladium hydroxide on carbon, nickel on carbon or mixture of catalysts; more preferably palladium on carbon.

20) The process as claimed in claim 1, wherein the said acid used in step (c) is selected from organic or inorganic acids.

21) The process as claimed in claim 1, wherein the said base used in step (c) is selected from organic or inorganic or aromatic bases.

22) The process as claimed in claim 1, wherein the compound of formula (I) is further converted to pharmaceutically acceptable salts.

23) The process as claimed in claim 22, wherein the said pharmaceutically acceptable salt is hydrochloride salt.

24) The process as claimed in claim 1, wherein one or all the steps are performed in in- situ manner.