DESC:Field of the Invention
The present invention relates to a novel and commercially viable process for preparation of sitagliptin in high yield with high chemical and chiral purity.

Background of the Invention
Sitagliptin is chemically known as (R)-3-amino-1-[3-(trifluoromethyl)-5,6,dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-4-(2,4,5-trifluorophenyl)butan-1-oneand useful as a potent second generation inhibitor of dipeptidyl-peptidase (DPP) IV for the treatment of Type-2 diabetes. The structure of sitagliptin(I) and pharmaceutically acceptable salts is represented below.

(I)

Sitagliptin was 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 WO 2003/004498 (henceforth '498). This '498 PCT patent publication 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 as represented in scheme (I), which involves the use of unusual dihydropyarazine chiral promoters, diazomethane and silver salt which are not preferred reagent for industrial synthesis.

Scheme I

Another synthetic process is described in '498 PCTpatent publication and Tetrahedron Asymmetry2006,17, 205 involves the use of expensive metal catalyst such as rhodium. A similar synthesis is subsequently reported in another PCT publication WO2009/064476, that involves the enantioselective hydrogenation of ?-enamino derivatives and the use of expensive precious ruthenium metal catalyst and expensive ligands such as ferrocenyl diphospine ligands - JOSIPHOS catalyst which is disclosed in several PCT publication and articles for instance such as WO2004/085378, WO2005/097733, WO2006/081151 andJ. Am. Chem. Soc., 2004,126 (32), 9918-9919. The preparation of this compound is also described in J. Am. Chem. Soc., 2009, 131(25), 8798-8804; which discloses that compounds once obtained may be purified according to methods standard in the field, obtaining sitagliptin of purity suitable for pharmaceutical applications. The said process is described in scheme (II).

Scheme II:

According to PCT publication WO2004/085661 the described process involves the hydrogenation with cheaper achiral catalyst and chiral derivatization of enamines derived from phenylglycinamide but the enantiomeric excess (ee) values of the compounds obtained for determining the purity of chiral substance were not sufficient for the pharmaceutical use. The said process is described in scheme (III).

Scheme III

PCT publication WO2004/087650 discloses the introduction of chiral center by stereoselective reduction of ?-keto acid derivatives with precious metal catalyst. But this process involves the use of (S)-BINAP-RuCI2 catalyst in the presence of hydrochloric acid. Similar process is disclosed in another article published in year 2005 by Hansen KB et al in Organic Process Research and Development (OPRD). Use of BINAP-RuCI2 is not preferred for industrial synthesis.

Another PCT publication WO2009/045507 discloses the bio catalytic method for the synthesis of sitagliptin involving the stereoselective enzymatic reduction of methyl 4-(2,4,5- trifluorophenyl)-3-oxobutyrate using an enzyme. The reaction proceeds via the formation of azetidinone intermediates. But the major drawback associated with this process is the use of high pressure (250psi), very expensive chiral catalyst metal (rhodium or ruthenium), low stereoselectivity of rhodium, contamination of the product and difficulty in final purification. The said process is described in scheme (IV), where R is methyl group.

Scheme IV

Hence, there is no suitable process for synthesis of sitagliptin in the prior art that involve use of less hazardous, economical and environment friendly reagents that will give highly pure material and cost effective process. Therefore, there is a need for economically viable synthesis of highly pure (both chemical and chiral) sitagliptin or its pharmaceutically acceptable salt thereof.

Object of the Invention
The object 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 object 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 chemical purity, which would be easy to implement on commercial scale and makes the present invention eco-friendly as well.

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

comprising the steps of:
a) obtaining a compound of formula (III) by reacting a compound of formula (II) with nitromethane in presence of a suitable base in a suitable solvent or mixture of solvent thereof, followed by dehydration in presence of a suitable dehydrating agent;
b) obtaining a compound of formula (IV) by reacting a compound of formula (III) with a suitable reducing reagent in presence of a suitable solvent or mixture of solvent thereof;
c) obtaining a compound of formula (V) by reacting a compound of formula (IV) with alkylglyoxalate solution in presence of suitable base in a suitable solvent followed by dehydration with a suitable dehydrating reagent in a suitable solvent or mixture of solvent thereof;
d) obtaining a compound of formula (VI) by reacting a compound of formula (V) with a suitable reducing reagent in a suitable solvent or mixture of solvent thereof;
e) obtaining a compound of formula (VII) by resolving a compound of formula (VI) by enzymatic enantioselective hydrolysis to form (S) acid of formula (VIII) leaving behind (R)-ester compound of formula (VII) in an aqueous buffer or an organic solvent or mixture of solvent thereof;
f) obtaining optionally a compound of formula (IX) by racemizing unwanted compound of formula (VIII)in presence of a base in a suitable solvent;
g) converting optionally a compound of formula (IX)to a racemic compound of formula (VI) with alcohol and anacidic catalyst in a suitable solvent or mixture of solvent thereof;
h) converting a compound of formula (VII) to a compound of formula (X) by treating with a reducing reagent in presence of an acid with a suitable solvent or mixture of solvent thereof;
i) protecting a compound of formula (X) to form a compound of formula (XI) by treating with a protecting group in an aqueous or an organic solvent or a mixture thereof;
j) hydrolyzing a compound of formula (XI) to a compound of formula (XII) with a suitable alkali or an alkaline earth metal base in an aqueous or an organic solvent ora mixture thereof;
k) alternatively, converting a compound of formula (X) to a compound of formula (XII) by hydrolyzing ester group with a suitable alkali or an alkaline earth metal base in an aqueous or an organic solvent or a mixture thereof; subsequent coupling of the same with 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine to obtain a compound of formula (XIII) in presence of a suitable coupling reagent in aqueous or an organic solvent or a mixture thereof;
l) converting a compound of formula (XII)to a compound of formula (XIII) by treating with 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine in presence of a suitable coupling reagent in aqueous or an organic solvent or a mixture thereof;
m) alternatively, converting a compound of formula (XI)to a compound of formula (XIII) by treatment with 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine in presence of a suitable coupling reagent in an aqueous or an organic solvent or a mixture thereof;
n) alternatively, converting a compound of formula (X) to a compound of formula (XIII) by treatment with 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine in presence of a suitable coupling reagent in an aqueous or an organic solvent or a mixture thereof;
o) converting a compound of formula (XIII) to sitagliptin of formula (I) by deprotection of amine in presence of an acid in an aqueous or an organic solvent or a mixture thereof;
p) converting a compound of formula (I) to pharmaceutically acceptable salt of sitagliptin by treating with a suitable acid in water or an organic solvent or a mixture thereof.

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.

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

comprising the steps of:
q) obtaining a compound of formula (III) by reacting a compound of formula (II) with nitromethane in presence of a suitable base in a suitable solvent or mixture of solvent thereof, followed by dehydration in presence of a suitable dehydrating agent;
r) obtaining a compound of formula (IV) by reacting a compound of formula (III) with a suitable reducing reagent in presence of a suitable solvent or mixture of solvent thereof;
s) obtaining a compound of formula (V) by reacting a compound of formula (IV) with alkylglyoxalate solution in presence of suitable base in a suitable solvent followed by dehydration with a suitable dehydrating reagent in a suitable solvent or mixture of solvent thereof;
t) obtaining a compound of formula (VI) by reacting a compound of formula (V) with a suitable reducing reagent in a suitable solvent or mixture of solvent thereof;
u) obtaining a compound of formula (VII) by resolving a compound of formula (VI) by enzymatic enantioselective hydrolysis to form (S) acid of formula (VIII) leaving behind (R)-ester compound of formula (VII) in an aqueous buffer or an organic solvent or mixture of solvent thereof;
v) obtaining optionally a compound of formula (IX) by racemizing unwanted compound of formula (VIII)in presence of a base in a suitable solvent;
w) converting optionally a compound of formula (IX)to a racemic compound of formula (VI) with alcohol and anacidic catalyst in a suitable solvent or mixture of solvent thereof;
x) converting a compound of formula (VII) to a compound of formula (X) by treating with a reducing reagent in presence of an acid with a suitable solvent or mixture of solvent thereof;
y) protecting a compound of formula (X) to form a compound of formula (XI) by treating with a protecting group in an aqueous or an organic solvent or a mixture thereof;
z) hydrolyzing a compound of formula (XI) to a compound of formula (XII) with a suitable alkali or an alkaline earth metal base in an aqueous or an organic solvent or a mixture thereof;
aa) alternatively, converting a compound of formula (X) to a compound of formula (XII) by hydrolyzing ester group with a suitable alkali or an alkaline earth metal base in an aqueous or an organic solvent or a mixture thereof; subsequent coupling of the same with 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine to obtain a compound of formula (XIII) in presence of a suitable coupling reagent in aqueous or an organic solvent or a mixture thereof;
bb) converting a compound of formula (XII)to a compound of formula (XIII) by treating with 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine in presence of a suitable coupling reagent in aqueous or an organic solvent or a mixture thereof;
cc) alternatively, converting a compound of formula (XI)to a compound of formula (XIII) by treatment with 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine in presence of a suitable coupling reagent in an aqueous or an organic solvent or a mixture thereof;
dd) alternatively, converting a compound of formula (X) to a compound of formula (XIII) by treatment with 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine in presence of a suitable coupling reagent in an aqueous or an organic solvent or a mixture thereof;
ee) converting a compound of formula (XIII) to sitagliptin of formula (I) by deprotection of amine in presence of an acid in an aqueous or an organic solvent or a mixture thereof;
ff) converting a compound of formula (I) to pharmaceutically acceptable salt of sitagliptin by treating with a suitable acid in water or an organic solvent or a mixture thereof.

The above process is illustrated in the following general synthetic scheme

The substituent R appeared in compounds (V), (VI), (VII), (X) and (XI) is considered to constitute C1-C6alkyl chain, substituted and non-substituted aromatic, preferably R is ethyl. The substituent R1 appeared in compounds (VIII), (IX) and (XII) is defined as C1-C6 alkyl chain, substituted and non-substituted aromatic, H, Na, K, ammonium, other metals and salts thereof, preferably R1 is H.

Accordingly, in an embodiment of the present invention, the present process for the preparation of sitagliptin of formula (I), comprises in-situ coupling of compound of Formula (II) with nitromethane followed by dehydration in presence of suitable bases in solvent in step (a). The said solvent used in step (a) is selected from the group consisting of water, methanol, ethanol, isopropanol, n-propanol, n-butanol, ethyl acetate, 1,4-dioxane,ethylene dichloride, chloroform, methyl tert-butyl ether, cyclohexane, toluene, tetrahydrofuran, dichloromethane or mixture of solvent thereof; more preferably methanol, water, toluene, 1,4-dioxane, chloroform, methyl tert-butyl ether, tetrahydrofuran, dichloromethane or mixture of solvent thereof; most preferably toluene.

In another embodiment of the present invention, wherein the said base of step (a) is preferably selected from group consisting of mono, di and tri alkyl amine, pyridine, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide; more preferably sodium hydroxide or mono, di and tri alkyl amine; most preferably triethylamine.

In an another embodiment of the present invention, wherein the said dehydrating agent in step (a) and step (c)is preferably selected from the group consisting of methanesulfonyl chloride, phosphorus pentoxide, phosphoryl chloride, thionyl chloride, zinc chloride oxalyl chloride, cyanuric chloride, trifluoroacetic acid,N,N-dicyclohexylcarbodiimide, acetic anhydride, trifluoroacetic anhydride, polyphosphoric acid, propylphosphonic anhydride and the like; more preferably methanesulfonyl chloride, phosphoryl chloride, oxalyl chloride, cyanuric chloride, trifluoroacetic anhydride; most preferably methanesulfonyl chloride.

In an another embodiment of the present invention, wherein the said dehydrating agent in step (a) and step (c) is optionally used in combination with additives selected preferably from the group consisting of pyridine, triethylamine, N,N-diisopropylethylamine (DIPEA), 1,8-Diazabicyclo[5.4.0]undec-7-ene, 1,5-Diazabicyclo[4.3.0]non-5-ene, 1,5-Diazabicyclo [4.3.0]non-5-ene imidazole, dimethyl sulfoxide, 4-dimethylaminopyridine, acetic acid, pyridine trifluoroacetate, trifluoroacetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, pyridine sulfonic acid, camphor sulfonic acid, concentrated hydrochloric acid, zinc chloride or mixture of additives thereof; more preferably pyridine, triethylamine, pyridine trifluoroacetate, trifluoroacetic acid, pyridine sulfonic acid, camphor sulfonic acid, concentrated hydrochloric acid, zinc chlorideor mixture thereof; most preferably trimethylamine.

In another embodiment of the present invention, wherein all the reaction steps of step (a), step (b), step (c), step (d), step (i) and step (j)ispreferably carried out at 0°C to ambient temperature or to reflux temperature, more preferably at 0°C to ambient temperature.

In another embodiment of the present invention, wherein all the crude is used as such or is purified by distillation or crystallization or by different techniques well understood by those skilled in the art.

In another embodiment of the present invention, wherein the said reducing agent of step (b) and step (d) is preferably selected from group consisting of suitable metal catalyst, sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, aluminium hydrides; more preferably sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride; most preferably sodium borohydride.

In an another embodiment of the present invention, wherein the said solvent in step (b) is preferably selected from the group consisting of methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, dimethyl sulfoxide, acetic acid, dichloromethane, chloroform, tetrahydrofuran, 1,4 dioxane, methyl tert-butyl ether, cyclohexane or mixture of solvent thereof; more preferably methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, dimethyl sulfoxide, acetic acid, 1,4 dioxane or mixture thereof; most preferably 1,4 dioxane, acetic acid or mixture thereof.

In another embodiment of the present invention, wherein thestep (c) comprises in-situ coupling using alkyl glyoxalate, preferably ethylglyoxalate followed by dehydration.

In another embodiment of the present invention wherein the base used in step (c) and step (f) is preferably selected from the group consisting of mono, di and tri alkyl amine, 1,4-Diazabicyclo[2.2.2]octane (DABCO), 1,8-Diazabicycloundec-7-ene (DBU), pyridine, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, alkali or alkaline earth metal C1-C6 alkoxide or hydroxides such as sodium hydroxide, potassium hydroxide; more preferably sodium bicarbonate, potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine; most preferably sodium bicarbonate.

In another embodiment of the present invention, wherein the said solvent used in step (c) is preferably selected from the group consisting of methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, water, tetrahydrofuran, 1,4 dioxane, toluene, dichloromethane, chloroform, methyl tert-butyl ether, cyclohexane or the mixture of solvent thereof; more preferably toluene, water, methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, tetrahydrofuran, dichloromethane or mixture thereof; and most preferably water, tetrahydrofuran, dichloromethane, methanol or mixture thereof.

In another embodiment of the present invention, wherein the said solvent used in step (d) is preferably selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, dimethyl sulfoxide, toluene, tetrahydrofuran, 1,4-dioxane, acetic acid, dichloromethane, chloroform, methyl tert-butyl ether, cyclohexane or mixture of solvent thereof; more preferably water, methanol, ethanol, isopropyl alcohol, dimethyl sulfoxide, 1,4-dioxane, acetic acid or mixture thereof; most preferably dimethyl sulfoxide, acetic acid or mixture thereof.

In another embodiment of the present invention, wherein the crude compound of formula (VI)is used as such or is purified by crystallization in solvents such as hexane, heptane, cyclohexane, ethyl acetate, acetone, dimethyl sulfoxide,1,4-dioxane, alcohols, water or mixture thereof.

In another embodiment of the present invention, wherein the said hydrolysis enzyme of step (e)is preferably selected from the group consisting of Candida antarctica A, Candida antarctica B1, Candida antarctica BY2, Novozyme 435, Rhizomucor meihei, Thermomyces lanhginosa, Pseudomonas cepecia, Resinase HT, Lipex 100L, Bascillus subtillis, lipase 3.101, lipase 3.102, lipase 3.104, lipase 3.105, lipase 3.106, lipase 3.107, lipase 3.108, lipase 3.109, lipase 3.111, lipase 3.115, lipase 3.113, lipase 3.117, lipase 3.136, AYS Amino, AS Amano, PS Amano SD, AK Amano and the like; most preferably Novozyme 435.

In another embodiment of the present invention, wherein the racemic compound formula (VI)is converted to substantially enantiopure (R)-ester compound of formula (VII).

In another embodiment of the present invention, wherein the said aqueous buffer of step (e) ispreferably selected from the group consisting of sodium bicarbonate, potassium bicarbonate, disodium hydrogen phosphate, potassium dihydrogen phosphate and the like; more preferably sodium bicarbonate.

In another embodiment of the present invention, wherein the said solvent of step (e)is preferably selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, tert-butyl alcohol, acetone, methyl isobutyl ketone, acetonitrile, methyl tert-butyl ether, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, isobutanol, n-pentanol, isoamyl alcohol, hexanol, cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol, allyl alcohol, propargyl alcohol, dichloromethane, chloroform, toluene, cyclohexane, ionic liquids and the like or mixture thereof; more preferably water, methanol, ethanol, isopropyl alcohol, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, methyl tert-butyl ether, cyclopentyl methyl ether or mixture of solvent thereof; most preferably water, methyl tert-butyl ether, cyclopentyl methyl ether or mixture thereof.

In another embodiment of the present invention, wherein the pH of the reaction mixture of step (e) is maintained in the range of 6 to 11, more preferably the pH is maintained in the range 6.5 to 9 and most preferably in the pH range of 7.0 to 8.5. The pH of the reaction mixture is adjusted to the required pH by using a suitable buffer system.

In another embodiment of the present invention, wherein the reaction of step (e) is carried at temperature in the range of 0oC to 50oC.

In another embodiment of the present invention, wherein the solvent used in step (f) ispreferably selected from the group consisting of methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, isobutanol, tert-butyl alcohol, cyclohehanol, toluene, monochlorobenzene, dichlorobenzene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, sulfolane, water and the likeormixture thereof; more preferably water.

In another embodiment of the present invention, wherein the reaction of step (f) is carried out in the temperature range of 0 to 200oC for 1 to 80 hours.

In another embodiment of the present invention, wherein the pH of the reaction mixture of step (g) is adjusted to the required pH by using a suitable buffer system.

In another embodiment of the present invention, wherein the said alcohol in step (g) ispreferably selected from the group consisting of methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, isobutanol, tert-butyl alcohol, n-pentanol, isoamyl alcohol, hexanol, cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol, allyl alcohol, propargyl alcohol and the like or mixture thereof; more preferably ethanol.

In another embodiment of the present invention wherein the said solvent in step (g) ispreferably selected from the methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, isobutanol, tert-butyl alcohol, n-pentanol, isoamyl alcohol, hexanol, cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol, allyl alcohol, propargyl alcohol, toluene, ethyl acetate, acetone, methyl tertiary butyl ether and the like or mixture thereof; more preferably ethanol.

In another embodiment of the present invention, wherein the said acid catalyst in step (g) ispreferably selected from hydrochloric acid (HCl), sulfuric acid (H2SO4), thionyl chloride, trimethylsilyl chloride, methanesulfonic acid, p-toluenesulfonic acid (PTSA), benzene sulfonic acid, trifluoromethanesulfonic acid, Lewis acid or strongly acidic sulfonated resins well known in the art; more preferably thionyl chloride.

In another embodiment of the present invention, wherein the said reducing agent of step (h) ispreferably selected from the group consisting ofsodium borohydride, metals catalyst preferably nickel, palladium, ruthenium, rhodium, iridium, gold, platinum, zinc or tin; cation in low oxidation stage selected from Fe(II), Sn(II), Cr(II); hydrogen sulfide, metal sulfide and polysulfide and the like; more preferably zinc, palladium on carbon, sodium borohydride, nickel chloride hexahydrate (NiCl2.6H2O); most preferably zinc, nickel chloride hexahydrate.
In another embodiment of the present invention wherein, the said acid of step (h) is preferably selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, methane sulfonic acid, acetic acid, benzoic acid, oxalic acid, succinic acid, mandelic acid, fumaric acid, di-p-tolyl-L-tartaric acid, lactic acid, salicylic acid, tartaric acid, formic acid, glutamic acid, p-toluenesulfonic acid, 10-caphor sulfonic acid, galactaric acid, malic acid, gluconic acid, succinic acid, hydrobromic acid, thiocyanic acid, aspartic acid, ethanedisulfonic acid, pyroglutamic acid, glutaric acid; more preferably acetic acid.
In another embodiment of the present invention, wherein the said solvent used in step (h) is preferably selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, dichloromethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetic acid or mixture thereof; more preferably water, methanol, ethanol, isopropyl alcohol, tetrahydrofuran, 1,4-dioxane, acetic acid or mixture thereof; most preferably methanol.

In another embodiment of the present invention, wherein the said reaction of step (h), step (l) and step (o)is carried out at temperature in the range of -20oC to 100oC.

In another embodiment of the present invention, wherein the said reaction of step (h) the compound of formula (VII) undergoes catalytic hydrogenation wherein the hydrogen pressure is in the range of 0.5-25 kg/cm2 or equivalent unit; more preferably the range is 2-20 kg /cm2 or equivalent units and most preferably the range is 3-15 kg/cm2.

In another embodiment of the present invention, wherein the said reagent for N-protection used in step (i)is preferably selected from the group consisting of methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, carbobenzoxy chloride, di-tert-butyl dicarbonate, 2,2,2-trifluoroethyl chloroformate, aryl sulfonyl chloride and the like; more preferably di-tert-butyl dicarbonate, under the standard reaction condition followed by hydrolysis.

In another embodiment of the present invention, wherein the solvent of step (i) is selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, dichloromethane, chloroform acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane or mixture thereof; more preferably water, tetrahydrofuran, methanol, ethanol, dichloromethane or mixture thereof; most preferably tetrahydrofuran, ethanol.

In another embodiment of the present invention, wherein the base is used in step (i) selected preferably from the group consisting of triethylamine, diisopropylethylamine, 1,4-Diazabicyclo[2.2.2]octane (DABCO), 1,8-Diazabicycloundec-7-ene (DBU), potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, alkali and alkaline earth metal C1-C6 alkoxide and the like.

In another embodiment of the present invention, wherein the said base for hydrolysis of step (j) and (k) is preferably selected from the group consisting of alkali or alkaline earth metal hydroxides not limiting to lithium hydroxide (LiOH), sodium hydroxide, potassium hydroxide, calcium hydroxide(Ca(OH)2), magnesium hydroxide (Mg(OH)2), barium hydroxide (Ba(OH)2), C1-C5 quaternary ammonium hydroxide, lithium hydroxide (LiOH), sodium hydroxide, potassium hydroxide; most preferably sodium hydroxide.

In another embodiment of the present invention, wherein the base strength for hydrolysis of step (j) and (k) is selected from 0.1 to 5N; more preferably from 0.3 to 3N and most preferably from 0.5 to 2N.

In another embodiment of the present invention, wherein the said solvent in the step (j) and step (k) ispreferably selected from the group consisting of water, alcohols, acetone, ethyl acetate, isopropyl acetate, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-dioxane, dimethylformamide, toluene, cyclohexane, chlorobenzene, dichlorobenzene and the like or mixture thereof; more preferably water, methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, acetone; most preferably methanol, ethanol, acetone.

In another embodiment of the present invention, wherein the said coupling reagent of step (k) and step (l) ispreferably selected from the group consisting of propylphosphonic anhydride (T3P), hydroxybenzotriazole (HOBt), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (HATU), (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (Py-Bop), (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (Bop), N,N'-dicyclohexylcarbodiimide (DCC), mix anhydrides, O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), 3-[Bis(dimethylamino)methyliumyl]-3H-benzotriazol-1-oxide hexa?uorophosphate (HBTU), thionyl chloride (SOCl2), oxalyl chloride or self-condensation of ester or acid and amine; more preferably propylphosphonic anhydride solution (T3P).

In another embodiment of the present invention wherein, the said solvent of step (l) is selected from the group consisting of water, alcohols, acetone, ethyl acetate, isopropyl acetate, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile,1,4-dioxane,dimethylformamide, toluene, cyclohexane, chlorobenzene, dichlorobenzene and the like or mixture thereof; more preferably methanol, ethanol, dichloromethane, acetone, tetrahydrofuran or mixture thereof; most preferably acetone.

In another embodiment of the present invention wherein the base used in the coupling stage, in step (l) is selected from the group consisting of mono, di and tri alkyl amine, diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide; more preferably mono, di and tri alkyl amine, diisopropylethylamine; most preferably diisopropylethylamine, triethylamine.

In another embodiment of the present invention wherein the said step (m) and (n) are carried out by procedure described for step (l).

In another embodiment of the present invention wherein the said solvent of step (o) is selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, butanol, isobutanol, t-butyl alcohol, acetone, ethyl acetate, isopropyl acetate, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile,1,4-dioxane,toluene, cyclohexane, chlorobenzene, dichlorobenzene and the like or mixture thereof; more preferably water, methanol, ethanol, isopropyl alcohol or mixture thereof; most preferably methanol.

In another embodiment of the present invention, wherein the deprotection reagent used in step (o) is preferably selected from the group consisting of organic acids and inorganic acids; more preferably inorganic acids; most preferably concentrated hydrochloric acid and the like.

In another embodiment of the present invention, wherein the solvent of step (p) is preferably selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, butanol, isobutanol, t-butyl alcohol, acetone, ethyl acetate, isopropyl acetate, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-dioxane,toluene, cyclohexane the like or mixture thereof; more preferably water, methanol, ethanol, isopropyl alcohol or mixture thereof; most preferably mixture of water and isopropyl alcohol.

The term “pharmaceutically acceptable salts” 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, and the like.

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, mucic, 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:

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 1,2,4-trifluoro-5-(2-nitro-vinyl)-benzene

The reaction set up consist of 2L four neck RBF, mechanical stirrer and thermometer pocket in an ice bath was arranged. The toluene (900mL) and triethylamine (97.68g) was charged and cooled to 5°C, after cooling stir the reaction mass for 10 min. In above reaction mass, the solution of 2,4,5-trifluorobenzaldehyde (100g) and nitromethane (46.0g) in toluene (100mL) was added drop wise over 30 to 60 min. Internal temperature of reaction was maintained between 10 to 15°C. The reaction mass was agitated at 25 to 30°C for 2h, the reaction progress was monitored on Thin Layer Chromatography (TLC). After the complete consumption of starting materials, the reaction mass was cooled to 0 to 5°C and drop wise methanesulfonyl chloride (80.25g) was added followed by further drop wise addition of triethylamine (44.18g) in reaction mass and maintained the internal temp at 0 to 5°C with vigorous agitation for around 1 to 2h. The reaction progress on TLC was monitored, after complete consumption of starting materials; the reaction was quenched by adding water (500 mL) and warmed up to 25°C. The organic layer was separated. The aqueous layer was extracted in toluene (300mL X 2), combine all organic extract and washed by saturated NaHCO¬3(500mL) solution. The organic layer was evaporated to provide 106.6g [84% yield; purity 94.89% by High Performance Liquid Chromatography (HPLC)] of a compound of formula (III).1H-NMR (CDCl3, 400 MHz): 7.077 (1H, m), 7.366 (1H, m), 7.675 (1H, d), 7.978 (1H, d).

Example 2: Preparation of 1,2,4-trifluoro-5-(2-nitro-ethyl)-benzene

The reaction set up consist of 1L four neck RBF, mechanical stirrer and thermometer pocket in an ice bath was arranged. 36.0g compound of formula (III)and acetic acid:1,4-dioxane mix (432mL 2:10V respectively) was charged and the reaction mass was cooled to 10 to15°C.Sodium borohydride (17.0g, 2.5eq) was added lot wise in the reaction mass at 10 to 15°C. The internal temperature of this reaction was maintained between 5 to 12°C for 3h. The reaction progress was monitored by TLC. After complete consumption of starting materials, the reaction was quenched by adding water (250mL) and warmed to room temp. The reaction mass was extracted with methyl tert-butyl ether (108mL X 3). All organic extracts were combined and washed with water (36mL X 2), optionally dry over sodium sulphate. The organic layer was evaporated to give 29.6g (82% yield; purity 99.17% by HPLC) of a compound of formula (IV).1H-NMR (CDCl3, 400 MHz): 3.300 (2H, t), 4.615 (2H, t), 6.924 (1H, m), 7.066 (1H, m).

Example 3: Preparation of 2-hydroxy-3-nitro-4-(2, 4, 5-trifluoro-phenyl)-butyric acid ethylester

The reaction set up consist of 1L four neck RBF, mechanical stirrer and thermometer pocket in an ice bath was arranged. 29.6g compound of formula (IV) and mixture of tetrahydrofuran:methanol:water 10V (1:1:1 respectively) were charged, 12.11g of sodium bicarbonate in reaction mass was added and stirred at 25°C for 30 min. followed by the addition of ethyl glyoxalate solution (17.67g; 50% in toluene). The reaction mixture was stirred for 4h at 25 to 30°C and the reaction progress was monitored by TLC. After complete consumption of starting materials water (150mL) was added and the reaction mass was extracted with methyl tert-butyl ether (150mL X 2). Combined all organic extracts and evaporated under vacuum to obtain 43.0g (97% yield; purity 92.26% by LC) of a compound of formula (IV-A). 1H-NMR (CDCl3, 400 MHz): 1.242-1.347 (3H, t), 3.137-3.317 (1H, dd), 3.410-3.603(1H, m), 3.185-3.300 (2H, m), 4.243-4.399 (2H, q), 5.034-5.094 (1H, m), 6.920-7.213 (2H, m).

Example 4: Preparation of (z)-3-nitro-4-(2,4,5-trifluoro-phenyl)-but-2-enoic acid ethyl ester

The reaction set up consist of 25.0mL two neck RBF in an ice bath was arranged. To a solution of a compound of formula(IV-A) (42.0g, 1eq.) in dichloromethane (420mL; 10V), slowly addedthe methanesulfonyl chloride (47.0g, 3eq) over a period of 30 min at 0 to 5°C followed by slow addition of triethylamine (28.0g, 2eq) over a period of 30 min. The reaction mass was warmed and stirred at 10 to 15°C for 2 h. The water (400mL) was added to the reaction mass and warmed to room temp. The product was extracted using dichloromethane (120mL X 3) and the combined organic layer was treated with saturated sodium bicarbonate solution (400mL) and stirred for 1h. The organic layer was separated and the solvent was removed completely to get 26.0g (66% yield) of a compound of formula (V). 1H-NMR (CDCl3, 400 MHz): 1.339-1.375 (3H, t), 4.310-4.363 (2H, q), 4.437 (2H, s), 6.892-6.956 (1H, m), 7.052-7.118 (1H,m).7.221(1H,s).

Example 5: Preparation of 3-nitro-4(2,4,5-trifluoro-phenyl)-butyric acid ethyl ester

The reaction set up consist of 500mL four neck RBF, mechanical stirrer and thermometer pocket in an ice bath was arranged. 26.0g of a compound of formula (V) and acetic acid:dimethyl sulfoxide mixture (125mL, 4.8V, 0.8:4 ratio respectively) were charged. The reaction mixture was cool down to 0 to 5°C. 3.4g of sodium borohydride was added lot wise in the reaction mass over a period of 2h at 0 to 5°C. The reaction mixture stirred for an additional 30 min at 0 to 5°C. The reaction mass was quenched by adding ice water (150mL), filtered the solid, washed the solid with 50mL water and suck dried to crude compound of formula (VI). The said crude is crystallized using n-hexane (7V) at 60°C to obtain 18.0g (69.47% yield; purity 97.49% by HPLC) of a compound of formula(VI).1H-NMR (CDCl3, 400 MHz):1.242-1.287 (3H, t), 2.707-2.762 (1H, dd), 3.079-3.145 (1H, m), 3.180-3.296 (2H, m),4.142-4.195 (2H, q), 5.069-5.138(1H, m), 6.938-6.7.021 (2H, m).

Example 6: Preparation of (R)-3-Nitro-4-(2,4,5-trifluoro-phenyl)-butyric acid ethyl ester

Example 6.1: The reaction set up consist of 50mL two neck RBF equip with magnetic needle was arranged.10.0g of a compound of formula (VI), sodium bicarbonate buffer solution (200mL, 20V, pH 7.0 to 7.1) and co-solvent methyl tert-butyl ether (60mL; 6V) were charged, followed by the addition of enzyme (1.0mg, 10% loading), the heterogeneous mixture was stirred at 25 to 30°C for 14h. The reaction mixture was filtered, separated the layers and the aqueous layer was extracted with methyl tert-butyl ether (30mL X 3).Combined the organic extract and washed with sodium bicarbonate solution (30mL) followed by optional drying over anhydrous sodium sulphate and further concentrated the solvent to provide 3.6g (36% R-ester, >98% ee) of a compound of formula (VII).1H-NMR (CDCl3, 400 MHz):1.242-1.287 (3H, t), 2.707-2.762 (1H, dd), 3.079-3.145 (1H, m), 3.180-3.296 (1H, m),4.142-4.195 (2H, q), 5.069-5.138 (1H, m), 6.938-6.7.021 (2H, m).

Example 6.2: The reaction set up consists of 100mL four neck RBF, mechanical stirrer and thermometer pocket was arranged. 0.5g of a compound of formula (VI), 7% sodium bicarbonate buffer solution (5mL, 10V, pH 7.0 to 7.1) and co-solvent cyclopentyl methyl ether (1.5mL; 3V) were charged, followed by addition of enzyme (50.0mg, 10% loading), stirred the heterogeneous reaction mixture at 25 to 30°C for 22h, reaction was monitored by using chiral HPLC. The reaction mixture was filtered, methyl tert-butyl ether (3mL) was added, stirred and separated the layers. The aqueous layer was extracted with methyl tert-butyl ether (3mL X 3). Combined all organic extract and washed with sodium bicarbonate solution (5mL) followed by optional drying over anhydrous sodium sulphate and finally concentrated the solvent to provide 0.20g (40% R-ester, ~98.48 % ee) of a compound of formula(VII).

Example 6.3: The reaction set up consist of 25 mL two neck RBF equip with reflux condenser, magnetic needle was arranged. The compound of formula VIII (0.2 g,), NaHCO3 (0.127 g, 2.0 eq) and water (2 mL) were charged and the reaction mass was stirred for 10 min. The mixture was heated upto 50 °C for 5h. The reaction mixture was cooled to room temperature. Aqueous layer was washed with methyl tert-butyl ether (30 mL X 3), the layers were separated and the pH of aqueous layer was adjusted to acidic (pH~2) using concentrated hydrochloric acid. The product was extracted with ethyl acetate (30 mL X 3). The organic extract was combined, then dried over anhydrous sodium sulphate and further concentrated to obtain 0.15 g (Isomer –I- 49.41 % and isomer II- 50.59 %) of a compound of formula (IX). 1H-NMR (CDCl3, 400 MHz): 2.767-2.823 (1H, dd), 3.157-3.282 (3H, m), 5.051-5.120 (1H, m), 6.967-6.7.018 (2H, m).

Example 6.4: The reaction set up consist of 50 mL two neck RBF equip with magnetic needle was arranged. The compound of formula IX (0.435 g, 1.0 eq) and ethanol (4.3 ml) were charged, the reaction mass was stirred for 10 min and cooled to 0-5 °C. Thionyl chloride (0.236 g, 1.2 eq) was slowly added in reaction mass at 0-5 °C. After addition of thionyl chloride reaction mass was stirred to 30 min at same temperature, then gradually warmed to room temperature and stirred for 5 h. Reaction progress was monitored on TLC. Reaction mass was concentrated under vacuum and concentrated mass dissolved in ethyl acetate. Ethyl acetate layer was washed with saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulphate and further concentrated to obtain 0.420 g (Isomer –I- 53.66 % and isomer II- 46.34 %) of a compound of formula (VI). 1H-NMR (CDCl3, 400 MHz):1.234-1.278 (3H, t), 2.684-2.761 (1H, dd), 3.079-3.308 (2H, m), 4.128-4.195 (2H, q), 5.069-5.138 (1H, m), 6.937-7.019 (2H, m).

Example 7: Preparation of (R)-3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid ethyl ester

Example 7.1: The reaction set up consists of 100mL four neck RBF, mechanical stirrer and thermometer pocket was arranged. 1.0g of a compound of formula (VII), 10mL methanol and 0.81g of NiCl2.6H2O was charged. Portion wise sodium borohydride (0.130g) was added to the reaction mass at 0 to 5°C. The reaction mixture was warmed till 25°C and stirred for next 1h. The solvent was removed completely and water was added to the residue followed by addition of 1N hydrochloric acid, stirred for next 1h at 25°C and filtered the reaction mass on celite bed, filtrate was washed with ethyl acetate (5mL X 2) to remove impurities. Basify the aqueous layer with aqueous ammonia till pH 9 to10, followed by extraction using ethyl acetate (20mL X 2) and concentrate the extract to get a compound of formula (X). Tetrahydrofuran (2.0mL) was added to the said isolated compound (X) followed by addition of 0.408g of di-tert-butyl dicarbonate (BOC anhydride) over a period of 0.5h and stirred for 4h at 25°C. The reaction mixture was concentrated to get product. Isolated quantity was 0.6g (50% yield) of a compound formula (XI).1H-NMR (CDCl3, 400 MHz): 1.258-1.294 (3H, t), 1.378 (9H, s),2.505-2.592 (2H, m), 2.834-2.870 (2H, m)4.129-4.192 (3H, m), 5.127-5.141 (1H, d), 6.866-6.930 (1H, m), 7.038-7.058 (1H, m).

Example 7.2: The reaction set up consists of 100mL two necks RBF, equipped with magnetic needle and thermometer pocket in an ice bath was arranged. 3.9g of a compound of formula (VII), acetic acid (40mL; 10V) was charged. Portion wise zinc (8.70g, 10eq) was added to the reaction mass at 0 to 5°C. The reaction mixture was warmed till 25°C and stirred for next 3h. Water was added to the reaction mass followed by addition of 1N hydrochloric acid, stirred for next 1h at 25°C and filtered the reaction mass on celite bed. The celite bed was washed with ethyl acetate (20mL X 2). Stirred and separated the aqueous layer. Basify the aqueous layer with aqueous ammonia till pH 9 to10, followed by extraction using ethyl acetate (20mL X 2) and concentrate the extract to get a compound of formula (X). Tetrahydrofuran (30mL) is added to the said isolated compound (X) followed by addition of 2.50g of di-tert-butyl dicarbonate (BOC anhydride) over a period of 0.5h and stirred for 4h at 25°C. The reaction mixture was concentrated to get product. Isolated quantity is 3.9g (81% yield; purity 96.79% by HPLC) of a compound formula (XI). 3.9g of a compound of formula (XI) in methanol (39.0mL), was allowed to form solution and 2.5 N NaOH solution was slowly added (3.0mL) at 0 to 5°C. The reaction mixture was stirred at 10 to 15°C for 3h. The solvent was removed completely and water was added to the residue followed by washing with ethyl acetate (3.0mL X 2) to remove impurities. The aqueous layer was acidified using aqueous citric acid solution to pH 3 to 4 and the said layer was further extracted using ethyl acetate (3.0mL X 3). The organic layer washed with water and treated with brine and was further concentrated to get 3.24g (72.6% yield) of a compound of formula (XII).

Example 8: Preparation of (R)-3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid

Example 8.1:The reaction set up consist of 50mL two neck RBF equipped with magnetic stirrer and thermometer pocket in an ice bath was arranged. 0.1g of a compound of formula (XI) in methanol (1.0mL), was allowed to form solution and 2.5 N NaOH solution was slowly added(0.2mL) at 0 to 5°C. The reaction mixture was stirred at 10 to15°C for 3h. The solvent was removed completely and water was added to the residue followed by washing with methyl tert-butyl ether (3.0mL X 2) to remove impurities. The aqueous layer was acidified using aqueous citric acid solution to pH 3 to 4 and the said layer was further extracted using methyl tert-butyl ether (3.0mL X 3). The organic layer washed with water and treated with brine and was further concentrated to get 0.07g (76% yield) of a compound of formula (XII).1H-NMR (CDCl3, 400 MHz):1.208-1.262 (9H, s), 2.393-2.409 (2H, d), 2.554-2.578 (1H, dd), 2.810-2.854- (1H, dd), 3.993-4.005 (1H, m), 6.772-6.795 (1H, d), 7.264-7.307 (1H,m),7.444-7.487 (1H,m), 12.196 (1H, s).

Example 8.2: To a clean 100mL autoclave, 0.5g of a compound of formula (VII) in ethanol (5.0mL) in presence of catalyst Pd/C (0.1g, 10% w/w with respect to compound VII) was hydrogenated under hydrogen pressure of 15kg/cm2 at 28 to 30°C with 400 RPM for 12h. Filtered the catalyst through celite, washed twice with ethanol. 0.411g of di-tert-butyl dicarbonate (BOC anhydride) was slowly added in the filtrate and maintained the reaction temperature between 25 to 30°C. The reaction mass was stirred for additional 1h and ethanol layer wasconcentrated completely to obtain the crude product, which was dissolved in 10mL ethyl acetate and washed with water (5.0mL X 2) followed by brine solution (5.0mL), dried and concentrated to get 0.43g (70% yield) of a compound of formula (XI). 0.43g of a compound of formula (XI) in methanol (4.3mL), was allowed to form solution and 2.5N NaOH solution was slowly added (2.15mL) at 0 to 5°C. The reaction mixture was stirred at 25 to 30°C for 2h. The solvent was removed completely and water was added to the residue followed by washing with ethyl acetate (15mL X 2) to remove impurities. The aqueous layer was acidified using aqueous citric acid solution to pH 3 to 4 and the said layer was further extracted using ethyl acetate (15mL X 3). The organic layer washed with water and treated with brine and was further concentrated to get 0.367g (64.6% yield) of a compound of formula (XII).

Example 9: Preparation of7-[(3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine

The reaction set up consist of 25mL two neck RBF equipped with magnetic stirrer and thermometer pocket in an ice bath was arranged. 3.0g of a compound of formula (XI) in methanol (30.0mL), was allowed to form solution and 2.5N NaOH solution was slowly added (15.0mL) at 0 to 5°C. The reaction mixture was stirred at 10 to 15°C for 3h. The solvent was removed completely and water was added to the residue followed by washing with methyl tert-butyl ether (15mL X 2) to remove impurities. The aqueous layer was acidified using aqueous citric acid solution to pH 3 to 4 and the said layer was further extracted using methyl tert-butyl ether (15mL X 3). The organic layer washed with water and treated with brine and was further concentrated to get 2.4g of compound of formula (XII).The isolated compound of formula (XII)and 4.1g of 3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine was addedin acetone (30.0mL) andN,N-diisopropylethylamine (3.2g,) was added slowly at 0 to5°C followed by the addition ofpropylphosphonic anhydride (T3P) (50% solution in toluene, 7.9g). The reaction mixture was warmed and stirred at 10 to15°C for 3h. The water (30mL) was added to the reaction mixture and extracted using ethyl acetate (10mL X 3). The ethyl acetate layer was washed with water, concentrated to get3.5g of a compound of formula (XIII)(83% over two stages).1H-NMR (CDCl3, 400 MHz):1.357(9H, s), 2.644-2.967(4H, m), 3.969 (1H, m), 4.085-4.245 (4H, m), 4.929(1H,s), 5.068(1H, q), 6.833-6.911(1H,m),7.040-7.104(1H,m).

Example 10: Preparation of (R)-3-amino-1-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4] triazolo[4,3-a]pyrazin-7-yl)-4-(2,4,5-trifluoro-phenyl)-butan-1-one

The reaction set up consist of 25mL two neck RBF equipped with magnetic stirrer and thermometer pocket in an ice bath was arranged. 0.1g of a compound of formula (XII) and 0.063g of 3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine was added in acetone (1.0mL) and N,N-diisopropylethylamine (0.077g, 2eq.) was added slowly at 0 to5°C followed by the addition of propylphosphonic anhydride (T3P) (50% solution in toluene, 0.4mL, 2eq.). The reaction mixture was warmed and stirred at 10 to 15°C for 3h. The water (1.0mL) was added to the reaction mixture and extracted using ethyl acetate (5.0mL X 3). The ethyl acetate layer was washed with water, concentrated to get a compound of formula (XIII). The said compound (XIII) was dissolved in methanol (1.0mL), conc. hydrochloric acid (0.5mL) was added slowly at 0 to 5°C and stirred at 10 to 15°C for 3h. The acidic reaction mixture was washed with ethyl acetate (5.0mL X 3) to remove impurities. The aqueous layer was basify using aqueous ammonia solution and extracted the compound having formula (I) using ethyl acetate (5.0mL X 3) and the organic layer was washed with water and concentrated to get a compound of a formula (I) 0.04g (33% over two stages).1H-NMR (CDCl3, 400 MHz): 1.541(2H, bs), 2.471(2H, d), 2.616 (1H, m), 2.691 (1H, m), 3.281(1H, m), 3.976(2H, m), 4.104 (1H, m), 4.220 (1H, m), 4.883(1H, d), 4.990(1H, s), 7.464 (2H, m).

Example 11: Preparation of 7-[(3R)-3-amino-1-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine phosphate (1:1) monohydrate

The reaction set up consist of 25mL two neck RBF equipped with magnetic stirrer and thermometer pocket in an ice bath and oil bath was arranged. 2.0g of said compound (XIII) was dissolved in methanol (10mL), conc. hydrochloric acid (2.0mL) was added slowly at 0 to 5°C and stirred at 10 to 15°C for 3h. The solvent was removed completely and water was added to the residue. The aqueous layer was basify using aqueous ammonia solution and extracted the compound having formula (I) using ethyl acetate (5.0mL X 3) and the organic layer was washed with water and concentrated to get a compound of a formula (I) 1.2g.The isolated compound of formula (I) 1.0g was added in isopropyl alcohol (9.3mL) and water (0.9mL) and 0.30g aqueous phosphoric acid (85%) was further added under stirring over 10 min to get the slurry. The reaction mixture was heated and maintained to 75°C for 2h. The reaction mass was cool down to 21°C, over a period of 12h and then hold overnight at 21°C and the obtained solid was filtered, washed with 2mL of isopropyl alcohol, and dried the solid under vacuum to get 0.1g of sitagliptin phosphate monohydrate (99.79% purity by HPLC). 1H-NMR (D¬2O, 400 MHz): 2.716-2.760 (1H, m), 2.935-3.023 (2H, m), 3.574 (2H, s), 3.875-3.887(3H, m), 4.138-4.201(2H, m), 4.580-4.888 (4H, m), 6.995-7.062(1H, m), 7.175-7.189 (1H, m).

Example 12: Preparation of 7-[(3R)-3-amino-1-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine phosphate (1:1) monohydrate

The reaction set up consist of 25.0mL two neck RBF equipped with magnetic stirrer and thermometer pocket was arranged. 0.5g of a compound of formula (I) is added in isopropyl alcohol (1.0mL) and water (0.45mL) and 0.141g aqueous phosphoric acid (85%) was further added under stirring over 10 min to get the slurry. The reaction mixture was heated and maintained to 75°C for 2h. The reaction mass was cool down to 21°C, over a period of 12h and then holds overnight at 21°C and isopropyl alcohol (3.5mL) was added. The reaction mass was stirred for 1 to 2h and the obtained solid was filtered, washed with 1.5mL of isopropyl alcohol, and dried the solid under vacuum to get 0.62g of sitagliptin phosphate monohydrate(99.7% purity by HPLC). 1H-NMR (D¬2O, 400 MHz): 2.716-2.760 (1H, m), 2.935-3.023 (2H, m), 3.574 (2H, s), 3.875-3.887(3H, m), 4.138-4.201(2H, m), 4.580-4.888 (4H, m), 6.995-7.062(1H, m), 7.175-7.189 (1H, m). ,CLAIMS:1. An improved process for the preparation of sitagliptin of formula (I) and pharmaceutically acceptable salts thereof;

comprising the steps of;
a) obtaining a compound of formula (III) by reacting a compound of formula (II) with nitromethane in presence of a suitable base in a suitable solvent or mixture of solvent thereof, followed by dehydration in presence of a suitable dehydrating agent;

b) obtaining a compound of formula (IV) by reacting a compound of formula (III) with a suitable reducing reagent in presence of a suitable solvent or mixture of solvent thereof;

c) obtaining a compound of formula (V) by reacting a compound of formula (IV) with alkylglyoxalate solution in presence of suitable base in a suitable solvent followed by dehydration with a suitable dehydrating reagent in a suitable solvent or mixture of solvent thereof;

wherein substituent R is C1-C6 alkyl chain, substituted and non-substituted aromatic, preferably R is ethyl.
d) obtaining a compound of formula (VI) by reacting a compound of formula (V) with a suitable reducing reagent in a suitable solvent or mixture of solvent thereof;

e) obtaining a compound of formula (VII) by resolving a compound of formula (VI) by enzymatic enantioselective hydrolysis to form (S) acid of formula (VIII) leaving behind (R)-ester compound of formula (VII) in aqueous buffer or an organic solvent or mixture of solvent thereof;

wherein substituent R is C1-C6 alkyl chain, substituted and non-substituted aromatic, preferably ethyl; and the substituent R1 is C1-C6 alkyl chain, substituted and non-substituted aromatic, H, Na, K, ammonium, other metals and salts thereof; preferably R1 is H.
f) obtaining optionally a compound of formula (IX) by racemizing unwanted compound of formula (VIII) in presence of a base in a suitable solvent;

wherein the substituent R1 is C1-C6 alkyl chain, substituted and non-substituted aromatic, H, Na, K, ammonium, other metals and salts thereof; preferably R1 is H.
g) converting optionally a compound of formula (IX) to a racemic compound of formula (VI) with alcohol and an acidic catalyst in a suitable solvent or mixture of solvent thereof;
h) converting a compound of formula (VII) to a compound of formula (X) by treating with a reducing reagent in presence of an acid with a suitable solvent or mixture of solvent thereof;

wherein the substituent R is C1-C6 alkyl chain, substituted and non-substituted aromatic, preferably ethyl.
i) protecting a compound of formula (X) to form a compound of formula (XI) by treating with a protecting group in an aqueous or an organic solvent or a mixture thereof;

wherein P is Protecting group.
j) hydrolyzing a compound of formula (XI) to a compound of formula (XII) with a suitable alkali or an alkaline earth metal base in an aqueous or an organic solvent or a mixture thereof;

k) alternatively, converting a compound of formula (X) to a compound of formula (XII) by hydrolyzing ester group with a suitable alkali or an alkaline earth metal base in an aqueous or an organic solvent or a mixture thereof; subsequent coupling of the same with 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine to obtain a compound of formula (XIII) in presence of a suitable coupling reagent in an aqueous or an organic solvent or a mixture thereof;

l) converting a compound of formula (XII) to a compound of formula (XIII) by treating with 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine in presence of a suitable coupling reagent in an aqueous or an organic solvent or a mixture thereof;
m) alternatively, converting a compound of formula (XI) to a compound of formula (XIII) by treatment with 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine in presence of a suitable coupling reagent in an aqueous or an organic solvent or a mixture thereof;
n) alternatively, converting a compound of formula (X) to a compound of formula (XIII) by treatment with 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine in presence of a suitable coupling reagent in an aqueous or an organic solvent or a mixture thereof;
o) converting a compound of formula (XIII) to sitagliptin of formula (I) by deprotection of amine in presence of an acid in an aqueous or an organic solvent or a mixture thereof;
p) converting a compound of formula (I) to pharmaceutically acceptable salt of sitagliptin by treating with a suitable acid in water or an organic solvent or a mixture thereof.

2. The process as claimed in claim 1, wherein the said solvent used in step (a) ispreferablyselected from the group consisting of water, methanol, ethanol, isopropanol, n-propanol, n-butanol, ethyl acetate, 1,4-dioxane, ethylene dichloride, chloroform, methyl tert-butyl ether, cyclohexane, toluene, tetrahydrofuran, dichloromethane or mixture of solvent thereof; more preferably methanol, water, toluene, 1,4-dioxane, chloroform, methyl tert-butyl ether, tetrahydrofuran, dichloromethane or mixture of solvent thereof; most preferably toluene.

3. The process as claimed in claim 1, wherein the said base of step (a) is preferably selected from group consisting of mono, di and tri alkyl amine, pyridine, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide; more preferably sodium hydroxide or mono, di and tri alkyl amine; most preferably triethylamine.

4. The process as claimed in claim 1, wherein the said dehydrating agent in step (a) and step (c) is preferably selected from the group consisting of methanesulfonyl chloride, phosphorus pentoxide, phosphoryl chloride, thionyl chloride, zinc chloride oxalyl chloride, cyanuric chloride, trifluoroacetic acid, N,N-dicyclohexylcarbodiimide, acetic anhydride, trifluoroacetic anhydride, polyphosphoric acid, propylphosphonic anhydride; more preferably methanesulfonyl chloride, phosphoryl chloride, oxalyl chloride, cyanuric chloride, trifluoroacetic anhydride; most preferably methanesulfonyl chloride.

5. The process as claimed in claim 1, wherein the said dehydrating agent in step (a) and step (c) is optionally used in combination with additives selected preferably from the group consisting of pyridine, triethylamine, N,N-diisopropylethylamine, 1,8-Diazabicyclo[5.4.0]undec-7-ene, 1,5-Diazabicyclo[4.3.0]non-5-ene, 1,5-Diazabicyclo [4.3.0]non-5-ene imidazole, dimethyl sulfoxide, 4-dimethylaminopyridine, acetic acid, pyridine trifluoroacetate, trifluoroacetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, pyridine sulfonic acid, camphor sulfonic acid, concentrated hydrochloric acid, zinc chloride or mixture thereof; more preferably pyridine, triethylamine, pyridine trifluoroacetate, trifluoroacetic acid, pyridine sulfonic acid, camphor sulfonic acid, concentrated hydrochloric acid, zinc chloride or mixture thereof; most preferably triethylamine.

6. The process as claimed in claim 1 wherein, the said reducing agent of step (b) and step (d) is preferably selected from group consisting of sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, aluminium hydrides or suitable metal catalyst; more preferably sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride; most preferably sodium borohydride.

7. The process as claimed in claim 1 wherein, the said solvent in step (b) is preferably selected from the group consisting of methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, dimethyl sulfoxide, acetic acid, dichloromethane, chloroform, tetrahydrofuran, 1,4 dioxane, methyl tert-butyl ether, cyclohexane or mixture thereof; more preferably methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, dimethyl sulfoxide, acetic acid, 1,4 dioxane or mixture thereof; most preferably 1,4 dioxane, acetic acid or mixture thereof.

8. The process as claimed in claim 1, wherein the said alkyl glyoxalatein the step (c) is preferably ethylglyoxalate.

9. The process as claimed in claim 1, wherein the base used in step (c) and step (f) is preferably selected from the group consisting of mono, di and tri alkyl amine, 1,4-Diazabicyclo[2.2.2]octane, 1,8-Diazabicycloundec-7-ene, pyridine, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, alkali or alkaline earth metal C1-C6 alkoxide or hydroxides such as sodium hydroxide, potassium hydroxide; more preferably sodium bicarbonate, potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine; most preferably sodium bicarbonate.

10. The process as claimed in claim 1, wherein the said solvent used in step (c) is preferably selected from the group consisting of methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, water, tetrahydrofuran, 1,4 dioxane, toluene, dichloromethane, chloroform, methyl tert-butyl ether, cyclohexane or the mixture of solvent thereof; more preferably toluene, water, methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, tetrahydrofuran, dichloromethane or mixture thereof; most preferably water, tetrahydrofuran, dichloromethane, methanol or mixture thereof.

11. The process as claimed in claim 1, wherein the said solvent used in step (d) is preferably selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, dimethyl sulfoxide, toluene, tetrahydrofuran, 1,4-dioxane, acetic acid, dichloromethane, chloroform, methyl tert-butyl ether, cyclohexane or the mixture of solvent thereof; more preferably water, methanol, ethanol, isopropyl alcohol, dimethyl sulfoxide, 1,4-dioxane, acetic acid or mixture thereof; most preferably dimethyl sulfoxide, acetic acidor mixture thereof.

12. The process as claimed in claim 1, wherein the said hydrolysis enzyme of step (e) is preferably selected from the group consisting of Candida antarctica A, Candida antarctica B1, Candida antarctica BY2, Novozyme 435, Rhizomucor meihei, Thermomyces lanhginosa, Pseudomonas cepecia, Resinase HT, Lipex 100L, Bascillus subtillis, lipase 3.101, lipase 3.102, lipase 3.104, lipase 3.105, lipase 3.106, lipase 3.107, lipase 3.108, lipase 3.109, lipase 3.111, lipase 3.115, lipase 3.113, lipase 3.117, lipase 3.136, AYS Amino, AS Amano, PS Amano SD, AK Amano; most preferably Novozyme 435.

13. The process as claimed in claim 1, wherein the said aqueous buffer of step (e) is preferably selected from the group consisting of sodium bicarbonate, potassium bicarbonate, disodium hydrogen phosphate, potassium dihydrogen phosphate; more preferably sodium bicarbonate.

14. The process as claimed in claim 1, wherein the said solvent of step (e) is preferably selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, tert-butyl alcohol, acetone, methyl isobutyl ketone, acetonitrile, methyl tert-butyl ether, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, isobutanol, n-pentanol, isoamyl alcohol, hexanol, cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol, allyl alcohol, propargyl alcohol, dichloromethane, chloroform, toluene, cyclohexane, ionic liquids or mixture thereof; more preferably water, methanol, ethanol, isopropyl alcohol, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, methyl tert-butyl ether, cyclopentyl methyl ether or mixture thereof; most preferably water, methyl tert-butyl ether, cyclopentyl methyl ether or mixture thereof.

15. The process as claimed in claim 1, wherein the solvent used in step (f) is preferably selected from the group consisting of methanol, ethanol,isopropyl alcohol, n-propanol, n-butanol, isobutanol, tert-butyl alcohol, cyclohehanol, toluene, monochlorobenzene, dichlorobenzene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, sulfolane, water ormixture thereof; more preferably water.

16. The process as claimed in claim 1, wherein said alcohol in step (g) is preferablyselected from the group consisting of methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, isobutanol, tert-butyl alcohol, n-pentanol, isoamyl alcohol, hexanol, cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol, allyl alcohol, propargyl alcohol or mixture thereof; more preferably ethanol.

17. The process as claimed in claim 1, wherein the said solvent in step (g) is preferably selected from the methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, isobutanol, tert-butyl alcohol, n-pentanol, isoamyl alcohol, hexanol, cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol, allyl alcohol, propargyl alcohol, toluene, ethyl acetate, acetone, methyl tertiary butyl ether or mixture thereof; more preferably ethanol.

18. The process as claimed in claim 1, wherein the said acid catalyst in step (g) is preferably selected from hydrochloric acid, sulfuric acid, thionyl chloride, trimethylsilyl chloride, methanesulfonic acid, p-toluenesulfonic acid, benzene sulfonic acid, trifluoromethanesulfonic acid, Lewis acid or strongly acidic sulfonated resins; more preferably thionyl chloride.
19. The process as claimed in claim 1 wherein,the said reducing agent of step (h) is preferably selected from the group consisting of sodium borohydride, metals catalyst preferably nickel, palladium, ruthenium, rhodium, iridium, gold, platinum, zinc or tin; cation in low oxidation stage selected from Fe(II), Sn(II), Cr(II); hydrogen sulfide, metal sulfide and polysulfide; more preferably zinc, palladium on carbon, sodium borohydride, nickel chloride hexahydrate; most preferably zinc, nickel chloride hexahydrate.

20. The process as claimed in claim 1, wherein the said acid of step (h) is preferably selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, methane sulfonic acid, acetic acid, benzoic acid, oxalic acid, succinic acid, mandelic acid, fumaric acid, di-p-tolyl-L-tartaric acid, lactic acid, salicylic acid, tartaric acid, formic acid, glutamic acid, p-toluenesulfonic acid, 10-caphor sulfonic acid, galactaric acid, malic acid, gluconic acid, succinic acid, hydrobromic acid, thiocyanic acid, aspartic acid, ethanedisulfonic acid, pyroglutamic acid, glutaric acid; more preferably acetic acid.

21. The process as claimed in claim 1 wherein, thesaid solvent used in step (h) is preferably selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, dichloromethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetic acid or mixture thereof; more preferably water, methanol, ethanol, isopropyl alcohol, tetrahydrofuran, 1,4-dioxane, acetic acid or mixture thereof; most preferably methanol.

22. The process as claimed in claim 1 wherein, the said reagent for N-protection used in step (i) is preferably selected from the group consisting of methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, carbobenzoxy chloride, di-tert-butyl dicarbonate, 2,2,2-trifluoroethyl chloroformate, aryl sulfonyl chloride; more preferably di-tert-butyl dicarbonate.

23. The process as claimed in claim 1, wherein the said solvent of step (i) is preferably selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, dichloromethane, chloroform acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane or mixture thereof; more preferably water, tetrahydrofuran,methanol, ethanol, dichloromethane or mixture thereof; most preferably tetrahydrofuran, ethanol.
24. The process as claimed in claim 1, wherein the said base for hydrolysis of step (j) and (k) is preferably selected from the group consisting of alkali or alkaline earth metal hydroxides, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, C1-C5 quaternary ammonium hydroxide, lithium hydroxide, sodium hydroxide, potassium hydroxide; most preferably sodium hydroxide.

25. The process as claimed in claim 1, wherein the said solvent in the step (j) and step (k) is preferably selected from the group consisting of water, alcohols, acetone, ethyl acetate, isopropyl acetate, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-dioxane, dimethylformamide, toluene, cyclohexane, chlorobenzene, dichlorobenzene or mixture thereof; more preferably water, methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, acetone; most preferably methanol, ethanol, acetone.

26. The process as claimed in claim 1, wherein the said coupling reagent of step (k) and step (l) is preferably selected from the group consisting of propylphosphonic anhydride, hydroxybenzotriazole,N,N'-dicyclohexylcarbodiimide, thionyl chloride, oxalyl chloride, 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide, (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxid hexafluorophosphate), (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate, (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, 3-[Bis(dimethylamino)methyliumyl]-3H-benzotriazol-1-oxide hexa?uorophosphate,mix anhydrides; more preferably propylphosphonic anhydride.

27. The process as claimed in claim 1, wherein the said solvent of step (l) is preferably selected from the group consisting of water, alcohols, acetone, ethyl acetate, isopropyl acetate, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-dioxane, dimethylformamide, toluene, cyclohexane, chlorobenzene, dichlorobenzene or mixture thereof; more preferably methanol, ethanol, dichloromethane, acetone, tetrahydrofuran, or mixture thereof; most preferably acetone.

28. The process as claimed in claim 1, wherein the said step (m) and (n) are carried out by procedure described for step (l).

29. The process as claimed in claim 1, wherein the said solvent of step (o) is preferably selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, butanol, isobutanol, t-butyl alcohol, acetone, ethyl acetate, isopropyl acetate, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-dioxane,toluene, cyclohexane, chlorobenzene, dichlorobenzene or mixture thereof; more preferably water, methanol, ethanol, isopropyl alcohol or mixture thereof; most preferably methanol.

30. The process as claimed in claim 1, wherein an acid used in step (o) is preferably selected from the group consisting of organic acids and inorganic acids; more preferably inorganic acids most preferably concentrated hydrochloric acid.

31. The process as claimed in claim 1. Wherein the said solvent of step (p) is preferably selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, butanol, isobutanol, t-butyl alcohol, acetone, ethyl acetate, isopropyl acetate, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-dioxane,toluene, cyclohexane or mixture thereof; more preferably water, methanol, ethanol, isopropyl alcohol or mixture thereof; most preferably mixture of water and isopropyl alcohol.