FORM 2
THE PATENT ACT, 1970
(39 OF 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"PROCESS FOR THE PREPARATION OF ANAGLIPTIN AND ITS INTERMEDIATES"
2. APPLICANT:
a. NAME: INDOCO REMEDIES LIMITED
b. NATIONALITY: INDIAN
c. ADDRESS: Indoco House,166 C.S.T. Road, Santacruz East,
Mumbai - 400 098, Maharashtra, India

TITLE: Process for the preparation of Anagliptin and its intermediates
FIELD OF INVENTION:
The present invention relates to a process for the preparation of anagliptin.
The present invention further relates to novel intermediates and process for the
preparation of the novel intermediates of anagliptin.
BACKGROUND OF THE INVENTION:
The compound N-[2-[[2-[(2S)-2-cyanopyrrolidin-l-yl]-2-oxoethyl]amino]-2-
methylpropyl]-2-methylpyrazolo[l,5-a]pyrimidine-6-carboxamide commonly known as anagliptin represented below as compound of Formula I, is a potent and selective DPP-IV inhibitor useful for the treatment of diabetes and particularly type 2 diabetes.

Anagliptin and its pharmaceutical acceptable salts, and process for their preparation are described in US 7,345,180 ("US'180 Patent). The process described in US'180 patent involves selective protection of 2-methylpropane-l,2-diamine by reacting with 2-(tert-Butoxycarbonyloxyimino)-2-phenylacetonitrile to get the compound tert-butyl (2-amino-2-methylpropyl)carbamate. The compound tert-butyl (2-amino-2-methylpropyl)carbamate on reaction with (S)-l-(2-chloroacetyl)pyrrolidine-2-carbonitrile yields compound tert-butyl (S)-{2-[(2-cyanopyrrolidine-l-yl)-2-oxoethylamino]-2-methyl-l-propyl} carbamate, which is purified by column chromatography with mixture of eluting solvent dichloromethane and methanol followed by reaction with hydrochloric acid in dioxane yields the compound (S)-l-[(2-amino-l,l-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitrile dihydrochloride. The dihydrochloride salt obtained is reacted with 2-methylpyrazolo[l,5-a]pyrimidine-6-carboxylic acid in tetrahydrofuran in presence of N,N'-carbonyldiimidazole and triethylamine results in crude anagliptin, which is purified by column chromatography

using mixture of eluting solvent dichloromethane and methanol to isolate pure anagliptin.
Another process disclosed in US'180 patent involves reaction of 2-methylpyrazolo[l,5-a]pyrimidine-6-carboxylic acid with oxalyl chloride in solvent dimethylformamide and dichloromethane to get 2-methylpyrazolo[l,5-a]pyrimidine-6-carbonyl chloride, which on reaction with 2-methylpropane-l,2-diamine in presence of base and solvent dichloromethane yields the compound N-(2-amino-2-methylpropyl)-2-methylpyrazolo[l,5-a]pyrimidine-6-carboxamide. The compound N-(2-amino-2-methylpropyl)-2-methylpyrazolo[l,5-a]pyrimidine-6-carboxamide obtained above is reacted in presence of solvent, base and sodium iodide with (S)-l-(2-chloroacetyl)pyrrolidine-2-carbonitrile to get crude anagliptin, which is purified by column chromatography using eluting solvent dichloromethane and methanol to isolate pure anagliptin.
The drawback of the process described in the US'180 patent is the use of costly reagent 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile for selective protection, the reaction generates hazardous by product N-hydroxybenzimidoyl cyanide, which necessitate disposal creating environmental hazard. Further the use of column chromatographic purification for intermediate and the final product makes the process tedious, time consuming and uneconomical to practice on industrial scale.
Further there are various processes disclosed for the preparation of anagliptin compound in WO 2011/075699, WO 2006/060122, WO 2009/047240, WO 2011/026241, and WO 2011/006074, JP 2010/064982, Freire Felix et. al., in Journal of the American Chemical Society, 131(23), 7970-7972 (2009) and Bioorganic and Medicinal Chemistry 19(23), 7221-7227(2011).
There is always a need to develop a safe and cost effective process for the preparation of anagliptin, the compound of Formula I by using economical reagents and by controlling the formation of impurities, which makes the process industrially viable and overcomes the problems associated with the processes known in the art. The present invention therefore seeks to address these issues.

The inventors of the present invention ameliorate the problems of the prior art processes by employing cost effective reagent and novel intermediate compounds as described herein that avoids the formation of impurities, thereby eliminating the use of column chromatography for the purification of the intermediates, and the final product anagliptin, the compound of Formula I.
OBJECTIVES OF THE INVENTION:
The objective of the present invention is to prepare anagliptin, the compound of Formula I with an industrially viable and cost effective process.
Another objective of the present invention is to provide a process for the preparation of anagliptin, the compound of Formula I with controlled formation of impurities.
Yet another objective of the present invention is to provide certain novel intermediate compounds and an efficient process for the preparation of the novel intermediate compounds useful for the preparation of anagliptin, the compound of Formula I.
SUMMARY OF THE INVENTION:
Accordingly, the present invention provides a process for preparing anagliptin, the compound of Formula I or its pharmaceutically acceptable salts using readily available, cost effective, and industrially safe starting materials.
According to primary object of the present invention, there is provided a novel, simple, cost effective and industrially safe process for the preparation of anagliptin, the compound of Formula I,

which comprises the steps of:
a) reacting the compound 2-methyl-l-nitropropane-2-amine of Formula II or its salt,


with an amine protecting group in presence of base to get the compound of Formula III,

(wherein Pr is an amine protecting group); b) reducing the compound of Formula III with reducing reagent in presence of solvent to get the compound of Formula IV or its salt,

(wherein Pr is an amine protecting group); c) coupling the compound of Formula IV or its salt with the compound 2-methylpyrazolo[l,5-a]pyrimidine-6-carboxylic acid of Formula V

in presence of coupling reagent and solvent to get the compound of Formula VI,

(wherein Pr is an amine protecting group); d) deprotecting the compound of Formula VI to isolate the compound of Formula VII or its salt;


e) reacting the compound of Formula VII or its salt with the compound (S)-l-(2-chloroacetyl)pyrrolidine-2-carbonitrile of Formula VIII

in presence of base and solvent to get crude anagliptin the compound of
Formula I; and f) purifying the crude compound obtained in step (e) to obtain pure compound
anagliptin of Formula I. Yet, in another aspect, the present invention provides a process for purification of anagliptin, the compound of Formula I comprising; i. suspending crude anagliptin in a solvent; ii. adding water and treating with an acid to get the corresponding acid addition
salt; iii. separating the aqueous layer and basifying to pH between 7 to 8; iv. extracting the aqueous layer with a solvent; and v. concentrating the solvent and isolating pure anagliptin compound of Formula I.
In another aspect, the present invention provides acid addition salt of the compound anagliptin with acetic acid.
(wherein Pr is an amine protecting group)
In another aspect, the present invention provides a novel compound of Formula III.



In another aspect, the present invention provides a novel compound of Formula VI.
(wherein Pr is an amine protecting group) Within the context of this embodiment, Pr is an amine protecting group. Suitable amine protecting group includes tert-butoxycarbonyl, allyloxycarbonyl, acetyl, benzoyl, pivaloyl, Formyl, 9-fluorenylmethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl, butyryl, phenoxycarbonyl, trichloroacetyl, trifluoroacetyl, propionyl, benzyl and benzyloxycarbonyl.
DETAILED DESCRITION OF THE INVENTION:
The present invention relates to a process for preparing anagliptin, the compound of Formula I or its pharmaceutical^ acceptable salt.

The present invention discloses novel synthetic route for the preparation of anagliptin. Within the context of the present disclosure, the novel intermediates that are formed, provide an improved and efficient method for the synthesis of anagliptin, the compound of Formula I.
In an aspect, the present invention provides a process for the preparation of anagliptin, the compound of Formula I, which comprises the steps of;
a) reacting the compound 2-methyl-l-nitropropane-2-amine of Formula II or its salt,


with an amine protecting group in presence of base to get the compound of Formula III,

(wherein Pr is an amine protecting group);
b) reducing the compound of Formula III with reducing reagent in presence of solvent to get the compound of Formula IV or its salt,

in presence of coupling reagent and solvent to get the compound of Formula VI,

(wherein Pr is an amine protecting group); c) coupling the compound of Formula IV or its salt with the compound 2-methylpyrazolo[l,5-a]pyrimidine-6-carboxylic acid of Formula V

(wherein Pr is an amine protecting group);
d) deprotecting the compound of Formula VI to isolate the compound of Formula VII or its salt;



e) reacting the compound of Formula VII or its salt with the compound (S)-l-(2-chloroacetyl)pyrrolidine-2-carbonitrile of Formula VIII
in presence of base and solvent to get crude anagliptin the compound of Formula I; and f) purifying the crude compound obtained in step (e) to obtain pure compound anagliptin of Formula I.
In an embodiment of the present invention, the suitable base used in step (a) of the process is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium acetate, N,N-diisopropylethylamine, diisopropylamine, 1,1,3,3-tetramethylguanidine, n-methylmorpholine, tributylamine, l,8-diazabicyclo[5.4.0]undec-7-ene, potassium tert-butoxide, triethylamine or a mixture thereof.
In an embodiment of the present invention, the preferred base used in step (a) of the process is selected from potassium carbonate, sodium carbonate, and triethyl amine, wherein the most preferred base used is triethyl amine.
In an embodiment of the present invention, the amine protecting group used in step (a) of the process is selected from the group consisting of tert-butoxycarbonyl, allyloxycarbonyl, acetyl, benzoyl, pivaloyl, formyl, 9-fluorenylmethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl, butyryl, phenoxycarbonyl, trichloroacetyl, trifluoroacetyl, propionyl, benzyl and benzyloxycarbonyl. The preferred amine protecting group used is tert-butoxycarbonyl, allyloxycarbonyl, acetyl, benzoyl, pivaloyl, wherein the most preferred protecting group used for the amine protection is tert-butoxycarbonyl.
In an embodiment of the present invention, the reaction of step (a) is carried out in presence of solvent selected from the group consisting of dichloromethane, tetrachloroethane, chlorobenzene, ethyl acetate, methyl acetate, isopropyl acetate,

toluene, cyclohexane, n-hexane, n-heptane, methyl tert-butyl ether and diisopropyl ether or mixture thereof. The preferred solvent used for the reaction is dichloromethane, tetrachloroethane, chlorobenzene, toluene, cyclohexane, n-hexane, n-heptane or mixture thereof, wherein the most preferred solvent used for the reaction is dichloromethane for the reaction and cyclohexane for the isolation of the compound of Formula III.
In an embodiment of the present invention, the solvent used in step (b) of the process is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, ethyl acetate, isopropyl acetate and methyl acetate or mixture thereof.
In an embodiment of the present invention, the preferred solvent used in step (b) is methanol, ethanol, n-propanol, isopropanol and n-butanol, wherein the most preferred solvent used for the reaction is methanol.
In an embodiment of the present invention, the reducing agent used in step (b) of the reaction is selected from the group consisting of palladium on carbon (Pd/C), palladium hydroxide on carbon (Pd(OH)2/C), palladium on alumina (Pd/Al2O3), platinum on carbon (Pt/C), palladium on barium sulfate (Pd/BaS04) and platinum oxide (Pd/C). The preferred reagent used is selected from palladium on carbon (Pd/C), palladium hydroxide on carbon (Pd(OH)2/C), wherein the most preferred reducing agent used is palladium on carbon (Pd/C).
In an embodiment of the present invention, the reduction reaction is carried out in presence of hydrogen gas at preferred temperature range of 20°C to 40°C.
In an embodiment of the present invention, the coupling reagent used in step (c) process is selected from the group consisting of N,N-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), N-tert-butyl-N'-methylcarbodiimide (TBMC), N-tert-butyl-N'-ethylcarbodiimide (TBEC) and l,l'-carbonyldiimidazole (CDI). The preferred coupling reagent used is l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC).

In an embodiment of the present invention, the coupling reaction of step (c) is
optionally carried out in presence of an additive selected from the group of N-
hydroxysuccinimide, N-hydroxy-5-norbornene-2,3-dicarboximide, 1-
hydroxybenzotriazole (HOBT), 6-chloro-l-hydroxybenzotriazole (6-C1-HOBT), 1-hydroxy-7-azabenzotriazole (HOAT) and 3-hydroxy-4-oxo-3,4-dihydro-l,2,3-benzotriazine or hydrates thereof.
In an embodiment of the present invention, the coupling reaction of step (c) is carried out in presence of a base selected from the group of N-methylmorpholine (NMM), diisopropylethylamine (DIPEA), triethylamine (TEA), tributylamine (TBA) and the like. The preferred base used for the reaction is N-methylmorpholine
(NMM).
In an embodiment of the present invention, the solvent used for coupling reaction of step (c) process is selected from the group consisting of ethyl acetate, isopropyl . acetate, 2-methoxyethyl acetate, acetonitrile, propionitrile, dichloromethane, tetrachloroethane, chlorobenzene, N,N-dimethylformamide, N,N-dimethylacetamide tetrahydrofuran dimethyl sulfoxide, N-methylpyrrolidone, toluene, cyclohexane, n-hexane, n-heptane, methyl tert-butyl ether, diisopropyl ether, ethyl tert-butyl ether, 1,4-dioxane or mixtures thereof. The preferred solvent used for the coupling reaction is dichloromethane, tetrachloroethane, chlorobenzene, wherein the most preferred solvent for the coupling reaction is dichloromethane.
In an embodiment of the present invention, the coupling reaction of step (c) is carried out at preferred temperature in the range of-15°C to 15°C.
In an embodiment of the present invention, the deprotection reaction in step (d) process is carried out using reagents based on the amine protecting group, and deprotection may be carried out by treatment with an acid or by catalytic hydrogenation.
In an embodiment of the present invention, the deprotection reaction is carried out using an acid as deprotecting agent selected from aqueous acid or anhydrous acidic solution. The preferred deprotecting agent used is aqueous hydrochloric acid,

isopropanol/hydrochloric acid and methanol/hydrochloric acid. The most preferred deprotecting agent used is isopropanol / hydrochloric acid solution.
In an embodiment of the present invention, the deprotection reaction in step (d) is carried out in presence of solvent selected from the group consisting of 1,4-dioxane, dichloromethane, tetrachloroethane, chlorobenzene, methanol, ethanol, n-propanol, isopropanol and n-butanol or mixture thereof. The preferred solvent used for the reaction is dichloromethane, methanol, n-propanol and isopropanol, wherein the most preferred solvent used is dichloromethane.
In an embodiment of the present invention, the compound Formula VII or its salt, is isolated using the solvent selected from the group consisting of dichloromethane, tetrachloroethane, chlorobenzene, methanol, ethanol, n-propanol, isopropanol, n-butanol, ethyl acetate, isopropyl acetate, 2-methoxyethyl acetate, methyl tert-butyl ether, diisopropyl ether, ethyl tert-butyl ether, acetone, methyl ethyl ketone and methyl isobutyl ketone or mixture thereof.
In an embodiment of the present invention, the deprotection reaction of step (d) is carried out at preferred temperature in the range of 30°C to 50°C.
In an embodiment of the present invention, the base used for the reaction in step (e) is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium acetate, N,N-diisopropylethylamine, diisopropylamine, 1,1,3,3-tetramethylguanidine, N-methylmorpholine, tributylamine, l,8-diazabicyclo[5.4.0]undec-7-ene, potassium tert-butoxide, sodium hydride, triethylamine and 2,6-lutidine. The preferred base used for the reaction are 1,1,3,3-tetramethylguanidine, N-methylmorpholine, tributylamine, l,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine and 2,6-lutidine, wherein the most preferred base used for the reaction is 1,1,3,3-tetramethylguanidine.
In an embodiment of the present invention, the solvent used for the reaction in step
(e) process is selected from the group consisting of ethyl acetate, methyl acetate,
isopropyl acetate, 2-methoxyethyl acetate, acetonitrile, dichloromethane,
tetrachloroethane, chlorobenzene, N,N-dimethylformamide, N,N-

dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetone, methyl ethyl ketone and methyl isobutyl ketone or mixture thereof.
In an embodiment of the present invention, the preferred solvent used is polar protic solvent selected from the group consisting of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, wherein the most preferred solvent used for the reaction is acetonitrile.
In an embodiment of the present invention, the salt of the compound N-(2-amino-2-methylpropyl)-2-methylpyrazolo[l,5-a]pyrimidine-6-carboxamide of Formula VII is used for the reaction with the compound (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile, wherein the preferred salt is hydrochloride salt.
In an embodiment of the present invention, the reaction in step (e) is optionally carried out in presence of a catalyst selected from the group consisting of sodium iodide or potassium iodide.
In another embodiment of the present invention, the process for obtaining pure anagliptin, the compound of Formula I, in step (f) as above, comprises the steps of;
i. suspending crude anagliptin in a solvent;
ii. adding water and treating with an acid to get the corresponding acid addition
salt; iii. separating the aqueous layer and basifying to pH between 7 to 8; iv. extracting the aqueous layer with a solvent; and v. concentrating the solvent and isolating pure anagliptin compound of Formula
I.
In an embodiment of the present invention, the solvent used in step (i) of the process is selected from the group consisting of acetonitrile, dichloromethane, toluene, ethyl acetate, isopropyl acetate, chlorobenzene, tetrachloroethane, methyl isobutyl ketone, methyl ethyl ketone, methyl tert-butyl ether and diisopropyl ether or a mixture thereof. The preferred solvent used for the reaction is dichloromethane, methyl isobutyl ketone, toluene and ethyl acetate, wherein the most preferred solvent used is dichloromethane.

In an embodiment of the present invention, the acid addition salt in step (ii) of the process is a pharmaceutically acceptable salt selected from suitable acids consisting of inorganic acids or organic acids.
In an embodiment of the present invention, the suitable inorganic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid.
In an embodiment of the present invention, the suitable organic acids include, for acetic acid, formic acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, lactic acid, succinic acid, glutamic acid, salicylic acid, methanesulphonic acid, para-toluenesulphonic acid and malonic acid.
In an embodiment of the present invention, the preferred acid addition salts in step (ii) of the process are hydrochloric acid salt, hydrobromic acid salt, acetic acid salt, maleic acid salt, tartaric acid salt and methanesulphonic acid, wherein the most preferred acid addition salt is hydrochloric acid salt and acetic acid salt.
In an embodiment of the present invention, the base used for the pH adjustment in step (iii) of the process is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and aqueous ammonia solution.
In an embodiment of the present invention, the solvent used for the extraction in step (iv) of the process is selected from the group consisting of dichloromethane, toluene, ethyl acetate, isopropyl acetate, chlorobenzene, tetrachloroethane, methyl isobutyl ketone, methyl ethyl ketone, methyl tert-butyl ether and diisopropyl ether or a mixture thereof. The preferred solvent used for the extraction is dichloromethane, methyl isobutyl ketone and ethyl acetate, wherein the most preferred solvent used is dichloromethane.
In an embodiment of the present invention, the isolation of pure anagliptin compound of Formula I in step (v) of the process is accomplished using solvent selected from the group consisting of methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, n-hexane, cyclohexane, n-heptane and methyl isobutyl ether or a mixture thereof.

In an additional embodiment, the present invention provides a novel compound of Formula III,

within the context of this embodiment, Pr is an amine protecting group. Suitable amine protecting group includes tert-butoxycarbonyl, allyloxycarbonyl, acetyl, benzoyl, pivaloyl, Formyl, 9-fluorenylmethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl, butyryl, phenoxycarbonyl, trichloroacetyl, trifluoroacetyl, propionyl, benzyl and benzyloxycarbonyl.
In an embodiment, the present invention provides the compound of formula III (as described above) for use in the process for the manufacture of anagliptin, the compound of formula I.
Still more preferably, the compounds of Formula III according to the invention are selected from the following;

In an additional embodiment, the present invention provides novel compound of Formula VI,


within the context of this embodiment, Pr is an amine protecting group. Suitable amine protecting group includes tert-butoxycarbonyl, allyloxycarbonyl, acetyl, benzoyl, pivaloyl, Formyl, 9-fluorenylmethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl, butyryl, phenoxycarbonyl, trichloroacetyl, trifluoroacetyl, propionyl, benzyl and benzyloxycarbonyl.
In an embodiment, the present invention provides the compound of formula VI (as described above) for use in the process for the manufacture of anagliptin, the compound of formula I.
Still more preferably, the compounds of Formula VI according to the invention are selected from the following;

The following examples, which fully illustrate the practice of the preferred embodiments of the present invention, are intended to be for illustrative purpose only, and should not be considered to be limiting to the scope of the present invention.

Examples:
Example 1: Preparation of 2-methyl-l-nitropropan-2-amine hydrochloride:
In a RB flask, ammonia gas purged into methanol (400 ml) at 10°C - 15°C for an hour. Nitromethane (100 gm) added slowly to the reaction mass and continued ammonia gas purging for additional two hours at 10°C - 15°C. After completion of the reaction, purging of ammonia gas stopped and acetone (95.14 gm) added into the reaction mass. Reaction mass temperature slowly raised to 20°C - 30°C and stirring continued for about 10-12 hours. Solvents distilled off under vacuum below 35°C and residual mass obtained. Isopropyl alcohol (200 ml) added to the above residual mass and cooled to 0°C - 5°C. 15% - 20% Hydrochloric acid solution in isopropyl alcohol (350 ml) added into above residual mass at 0°C - 5°C. Stirred further for two hours and filtered the precipitated solid mass, washed with chilled isopropyl alcohol (100 ml). Solid material dried at 45°C - 50°C to get 2-methyl-l-nitropropan-2-amine hydrochloride (130 gm, yield 51.3%).
Example 2: Preparation of tert-butyl (2-methyl-l-nitropropan-2-yl) carbamate:
In a RB flask, 2-methyl-1-nitropropan-2-amine hydrochloride (100 gm) in dichloromethane (700 ml) was stirred and cooled to 10°C - 15°C. Triethylamine (98.23 gm) added and stirred the reaction mass for 30 min at 10°C - 15°C. Added di-tert-butyl dicarbonate (211.87 gm) in to the reaction mass and slowly raised the temperature of the reaction mass to 35°C - 40°C. Monitored the completion of the reaction on TLC maintaining the reaction mass at 35°C - 40°C for about 2 hours. After completion of the reaction, cooled the reaction mass to 20°C - 30°C and water (500 ml) added in to the reaction mass. Separated the organic layer, washed the organic layer once with 10% citric acid solution (500 ml) and followed with 10% sodium bicarbonate solution (500 ml). Distilled off the solvent under vacuum to obtain the residual mass. Added cyclohexane (100 ml) to the above residual mass and raised the temperature of the reaction mass to 45°C to get the clear solution. Cooled the solution to 15°C - 20°C and stirred for about 1hour. Filtered the separated solid mass and washed with cyclohexane (30 ml). Solid material dried at 30°C - 35°C under vacuum to get tert-butyl (2-methyl-1-nitropropan-2-yl)carbamate (98.8 gm, yield 70%).

Example 3: Preparation of tert-butyl (l-amino-2-methylpropan-2-yl) carbamate:
In an autoclave, charged methanol (250 ml), tert-butyl (2-methyl-1-nitropropan-2-yl)carbamate (25 gm) and catalyst 5% palladium on carbon (2.5 gm, 50% wet). Started purging hydrogen gas in to the reaction mass at 25°C - 35°C maintaining hydrogen pressure about 3 kg/cm . Monitored the reaction completion on TLC. After completion of the reaction stopped purging of hydrogen gas and flushed the reaction mass with nitrogen gas. Filtered the catalyst and distilled off solvent under vacuum below 35°C to get thick colourless product tert-butyl (l-amino-2-methylpropan-2-yl) carbamate (21.0 gm, yield 97.30%).
Example 4: Preparation of tert-butyl (2-methyl-l-(2-methyIpyrazoIo[1,5-a]pyrimidine-6-carboxamido) propan-2-yI) carbamate:
In a RB flask, charged dichloromethane (80 ml), tert-butyl (l-amino-2-methylpropan-2-yl) carbamate (8.0 gm), 2-methylpyrazolo[l,5-a]pyrimidine-6-carboxylic acid (7.15 gm) and 1-hydroxybenzotriazole (0.789 gm) at 25°C to 30°C. Cooled the reaction mass to -10°C and added N-methylmorpholine (5.15 gm) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (9.77 gm) continued stirring the reaction mass for 2 hours at -10°C to 0°C. Monitored the reaction completion on TLC. After completion of the reaction water (40 ml) added in to the reaction mass. Stirred and separated the organic layer, extracted the aqueous layer with dichloromethane (40 ml). Combined organic layer was washed with 10% sodium hydroxide solution (40 ml), with 10% citric acid solution (40 ml) and followed with brine solution (40 ml). Distilled off solvent under vacuum below 35°C to get the residual mass. Added toluene (40 ml) to the above residual mass and raised the temperature of the reaction mass to 60°C. Cooled the solution gradually to 0°C - 5°C, maintained under stirring for about 1 hour. Filtered the solid mass, washed with cold toluene (10 ml) and dried the Solid at about 50°C to get tert-butyl(2-methyl-l-(2-methylpyrazolo[l,5-a]pyrimidine-6-carboxamido)- propan-2-yI)carbamate (8.1 gm, yield 55%).
Example 5: Preparation of N-(2-amino-2-methylpropyl)-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride:

In a RB flask, to a stirred solution of tert-butyl (2-methyl-l-(2-methylpyrazolo[l,5-a]pyrimidine-6-carboxamido)propan-2-yl)carbamate (12 gm) in dichloromethane (24 ml), a solution of 15% - 20% hydrochloric acid in isopropyl alcohol (60 ml) was added at 25°C - 30°C. Reaction mass temperature was slowly raised to 40°C and continued stirring for about 3 hours. Monitored the reaction completion on TLC. After completion of the reaction, distilled off solvent under vacuum below 40°C to obtain the residual mass. Dichloromethane (48 ml) was added to the above residual mass. The solid isolated by filtration and dried under vacuum to get N-(2-amino-2-methylpropyl)-2-methylpyrazolo[l,5-a]pyrimidine-6-carboxamide hydrochloride (8.8 gm, yield 89.8 %).
Example 6: Preparation of (S)-N-(2-((2-(2-cyanopyrrolidin-l-yl)-2-oxoethyl)amino)-2-methylpropyl)-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide (Anagliptin):
In a RB flask, to a stirred solution of N-(2-amino-2-methylpropyl)-2-methylpyrazolo[l,5-a]pyrimidine-6-carboxamide hydrochloride (10 gm) in acetonitrile (80 ml), added 1,1,3,3-tetramethylguanidine (8.1 gm) at 25°C - 30°C. Reaction mass temperature raised to 40°C - 45°C and added solution of (S)-l-(2-chloroacetyl)pyrrolidine-2-carbonitrile (6.53 gm) in acetonitrile ( 20 ml) in to the reaction mass. Reaction mass temperature was further raised to 60°C - 65°C and continued stirring for about 2 hours. Monitored the reaction completion on TLC. After completion of the reaction distilled off solvent under vacuum below 35°C to obtain the residual mass. Dichloromethane (50 ml) added to the above residual mass and under stirring added water (25 ml). Separated the organic layer, added water (25 ml) and adjusted the pH of the solution with acetic acid in the range of 3 - 4. Stirred the reaction mass and separated the aqueous layer. Adjusted pH of the aqueous layer using saturated sodium bicarbonate solution in the range of 7 - 8, added dichloromethane (50 ml) to the aqueous layer stirred and separated the organic layer. Solvent Distilled off under vacuum maintaining temperature below 40°C to isolate the product (S)-N-(2-((2-(2-cyanopyrrolidin-l-yl)-2-oxoethyl)amino)-2-methylpropyl)-2-methylpyrazolo[l,5-a]pyrimidine-6-carboxamide (Anagliptin) (7.9 gm, yield 58.4%).

Example 7: Purification of anagliptin:
In a RB flask, crude anagliptin (10 gm) and isopropyl alcohol (20 ml) was stirred and raised the temperature of the mixture to 50°C - 55°C. The clear solution obtained was cooled gradually to 25°C - 30°C and further cooled to 5°C - 10°C, stirred for about 1 hour. Filtered the solid mass, washed with chilled isopropyl alcohol (5 ml) and dried at 45°C - 50°C to get pure crystalline anagliptin (7.5 gm, yield 75.0%).
Example 8: Purification of anagliptin:
In a RB flask, crude anagliptin (10 gm) and methyl tert-butyl ether (20 ml) was stirred and raised the temperature of the mixture to 50°C - 55°C. The clear solution obtained was cooled gradually to 25°C - 30°C, stirred for about 1 hour. Filtered the solid mass, washed with chilled isopropyl alcohol (5 ml) and dried at 45°C - 50°C to get pure crystalline anagliptin (7.0 gm, yield 70.0%).
Example 9: Purification of anagliptin:
In a RB flask, crude anagliptin (10 gm) and isopropyl acetate (40 ml) was stirred and raised the temperature of the mixture to 50°C - 55°C. The clear solution obtained was cooled gradually to 10°C - 15°C, stirred for about 1 hour. Filtered the solid mass, washed with chilled isopropyl alcohol (5 ml) and dried at 45°C - 50°C to get pure crystalline anagliptin (6.7 gm, yield 67.0%).

We claim:
1. A process for preparation of anagliptin, the compound of Formula I,

which comprises the steps of:
a) reacting the compound 2-methyl-l-nitropropane-2-amine of Formula II or its salt,

with an amine protecting group in presence of base to get the compound of Formula III,

(wherein Pr is an amine protecting group); b) reducing the compound of Formula III with reducing reagent in presence of solvent to get the compound of Formula IV or its salt,
(wherein Pr is an amine protecting group); c) coupling the compound of Formula IV or its salt with the compound 2= methylpyrazolo[l,5-a]pyrimidine-6-carboxylic acid of Formula V


in presence of coupling reagent and solvent to get the compound of Formula VI,

(wherein Pr is an amine protecting group); d) deprotecting the compound of Formula VI to get the compound of Formula VII or its salt;

e) reacting the compound of Formula VII or its salt with the compound (S)-l-(2-chloroacetyl)pyrrolidine-2-carbonitrile of Formula VIII

in presence of base and solvent to get crude anagliptin the compound of Formula I; and f) purifying the crude compound obtained in step (e) to obtain pure compound anagliptin of Formula I.
2. The process according to claim 1, wherein the suitable base used in step (a) is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium acetate, triethylamine N,N-diisopropylethylamine, diisopropylamine, N-methylmorpholine, tributylamine, 1,1,3,3-tetramethylguanidine, 1,8-diazabicyclo[5.4.0]undec-7-ene, potassium tert-butoxide or a mixture thereof.

3. The process according to claim 1, wherein the amine protecting compound used in step (a) of the process is selected from the group consisting of acetyl, benzoyl, benzyl tert-butoxycarbonyl, allyloxycarbonyl, pivaloyl, formyl, butyryl, propionyl, methoxycarbonyl, trichloroacetyl, trifluoroacetyl, ethoxycarbonyl, isobutoxycarbonyl, 9-fluorenylmethoxycarbonyl, phenoxycarbonyl and benzyloxycarbonyl.
4. The process according to claim 1, wherein the reaction of step (a) is carried out in the presence of solvent selected from the group consisting of dichloromethane, tetrachloroethane, chlorobenzene, ethyl acetate, methyl acetate, isopropyl acetate, toluene, cyclohexane, n-hexane, n-heptane, methyl tert-butyl ether and diisopropyl ether or mixture thereof.
5. The process according to claim 1, wherein the solvent used in step (b) of the process is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, ethyl acetate, isopropyl acetate and methyl acetate or mixture thereof.
6. The process according to claim 1, wherein the reducing agent used in step
(b) of the reaction is selected from the group consisting of palladium on
carbon (Pd/C), palladium hydroxide on carbon (Pd(OH)2/C), palladium on
alumina (Pd/Al2O3), platinum on carbon (Pt/C), palladium on barium sulfate
(Pd/BaSO4) and platinum oxide (PtO2).
7. The process according to claim 1, wherein the coupling reagent used in step
(c) process is selected from the group consisting of N,N-
dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-
(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC), l-(3-
dimethylaminopropyl)-3-ethylcarbodiimide (EDC), N-tert-butyl-N'-
methylcarbodiimide (TBMC), N-tert-butyl-N'-ethylcarbodiimide (TBEC)
and l,1'-carbonyldiimidazole (CDI).

8. The process according to claim 1, wherein the coupling reaction of step (c) is optionally carried out in presence of an additive selected from the group consisting of N-hydroxysuccinimide, N-hydroxy-5-norbornene-2,3-dicarboximide, 1 -hydroxy-7-azabenzotriazole (HOAT), 1 -hydroxybenzotriazole (HOBT), 6-chloro-1-hydroxybenzotriazole (6-C1-HOBT) and 3-hydroxy-4-oxo-3,4-dihydro-l,2,3-benzotriazine or hydrates thereof.
9. The process according to claim 1, wherein the coupling reaction of step (c) is carried out in presence of a base selected from the group consisting of N-methylmorpholine (NMM), diisopropylethylamine (DIPEA), triethylamine (TEA), tributylamine (TBA) and the like.
10. The process according to claim 1, wherein solvent used for the coupling reaction of step (c) process is selected from the group consisting of ethyl acetate, isopropyl acetate, 2-methoxyethyl acetate, acetonitrile, propionitrile, dichloromethane, tetrachloroethane, chlorobenzene, N,N-dimethylformamide, N,N-dimethylacetamide tetrahydrofuran dimethyl sulfoxide, N-methylpyrrolidone, toluene, cyclohexane, n-hexane, n-heptane, methyl tert-butyl ether, diisopropyl ether, ethyl tert-butyl ether, 1,4-dioxane or mixtures thereof.
11. The process according to claim 1, wherein the deprotection of the compound of Formula VI in step (d) reaction is carried out using an acid selected from aqueous hydrochloric acid, isopropanol/hydrochloric acid and methanol/hydrochloric acid.
12. The process according to claim 1, wherein the deprotection of the compound of Formula VI in step (d) is carried out in presence of solvent selected from the group consisting of 1,4-dioxane, dichloromethane, tetrachloroethane, chlorobenzene, methanol, ethanol, n-propanol, isopropanol and n-butanol or mixture thereof.

13. The process according to claim 1, wherein the compound of Formula VII or its salt in step (d) is isolated using the solvent selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, ethyl acetate, isopropyl acetate, 2-methoxyethyl acetate, dichloromethane, tetrachloroethane, chlorobenzene, methyl tert-butyl ether, diisopropyl ether, ethyl tert-butyl ether, acetone, methyl ethyl ketone and methyl isobutyl ketone or mixture thereof.
14. The process according to claim 1, wherein the base used for the reaction in step (e) is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, N,N-diisopropylethylamine, diisopropylamine, 1,1,3,3-tetramethylguanidine, N-methylmorpholine, tributylamine, l,8-diazabicyclo[5.4.0]undec-7-ene, potassium tert-butoxide, sodium hydride, triethylamine and 2,6-lutidine.
15. The process according to claim 1, wherein the solvent used for the reaction in step (e) process is selected from the group consisting of ethyl acetate, methyl acetate, isopropyl acetate, 2-methoxyethyl acetate, acetonitrile, dichloromethane, tetrachloroethane, chlorobenzene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetone, methyl ethyl ketone and methyl isobutyl ketone or mixture thereof.
16. The process according to claim 1, wherein the reaction of step (e) is optionally carried out in presence of a catalyst selected from the group consisting of sodium iodide or potassium iodide.
17. The process according to claim 1, wherein the purification process of step (f) comprises the following steps;
i. suspending crude anagliptin in a solvent; ii. adding water and treating with an acid to get the corresponding acid addition salt; iii. separating the aqueous layer and basifying to pH between 7 to 8;

iv. extracting the aqueous layer with a solvent; and v. concentrating the solvent and isolating pure anagliptin compound of Formula I.
18. The process according to claim 18, wherein the solvent used in step (i) of the process is selected from the group consisting of acetonitrile, dichloromethane, toluene, ethyl acetate, isopropyl acetate, chlorobenzene, tetrachloroethane, methyl isobutyl ketone, methyl ethyl ketone, methyl tert-butyl ether and diisopropyl ether or a mixture thereof.
19. The process according to claim 18, wherein the acid addition salt in step (ii) of the process is a pharmaceutically acceptable salt selected from suitable acids consisting of inorganic acids hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or organic acids acetic acid, formic acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, lactic acid, succinic acid, glutamic acid, salicylic acid, methanesulphonic acid, para-toluenesulphonic acid and malonic acid.
20. The process according to claim 18, wherein the base used in step (iii) is of the process is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and aqueous ammonia solution.
21. The process according to claim 18, wherein the solvent used in step (iv) of the process is selected from the group consisting of dichloromethane, toluene, ethyl acetate, isopropyl acetate, chlorobenzene, tetrachloroethane, methyl isobutyl ketone, methyl ethyl ketone, methyl tert-butyl ether and diisopropyl ether or a mixture thereof.
22. The process according to claim 18, wherein the solvent used in step (v) for the isolation of pure anagliptin the compound of Formula I is selected from the group consisting of methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, n-

hexane, cyclohexane, n-heptane and methyl isobutyl ether or a mixture thereof.
23. A compound of Formula III,

wherein, Pr is an amine protecting group selected from tert-butoxycarbonyl,
allyloxycarbonyl, acetyl, benzoyl, pivaloyl, formyl, 9-
fluorenylmethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl,
isobutoxycarbonyl, butyryl, phenoxycarbonyl, trichloroacetyl,
trifluoroacetyl, propionyl, benzyl and benzyloxycarbonyl.

25. A compound of Formula VI,

24. The compound of Formula III as claimed in claim 23, are;

wherein, Pr is an amine protecting group selected from tert-butoxycarbonyl,
allyloxycarbonyl, acetyl, benzoyl, pivaloyl, formyl, 9-
fluorenylmethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl,
isobutoxycarbonyl, butyryl, phenoxycarbonyl, trichloroacetyl,
trifluoroacetyl, propionyl, benzyl and benzyloxycarbonyl.
26. The compound of Formula VI as claimed in claim 25, are;