CLIAMS:We claim,

1. A process for preparing Anagliptin (formula-1) comprising

Formula-I

(a) Reacting 2-amino-2-methylpropylamine with di-tert-butyl dicarbonate in presence of mixture of solvent and water to isolatet-butyl-2-amino-2-methyl-propylcarbamate;
(b) Reacting t-butyl-2-amino-2-methyl-propylcarbamate with S-1-(chloroacetyl)pyrrolidine-2-carbonitrile in presence of solvent, base and catalyst to obtain t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate;
(c) Reacting t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate with alcoholic hydrochloric acid and to isolate (S)-1-[2-Amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitriledihydrochloride and
(d) Reacting 2-methylpyrazolo [1,5-a]pyrimidine-6-carboxylicacid with 1,1-carbonyldiimidazole and (S)-1-[2-Amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitrile in presence of solvent to obtain anagliptin.
2. The process according to claim 1, wherein the solvent for step (a) is selected from the group consisting of isopropanol, methanol, ethanol, n-butanol, n-propanol.
3. The process according to claim 1, wherein the alcoholic hydrochloric acid is selected from the group consisting of methanolic hydrochloride, ethanolic hydrochloride, isopropanolic hydrochloride
4. The process according to claim 1, wherein,t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate is optionally purified by a process which comprises;
(a) Dissolving crude t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate in single or mixture of solvents at ambient temperature and stirring at -5 to 0°C and
(b) Isolating pure t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate.
5. The process according to claim 4, wherein the solvents are polar aprotic and polar protic solvents.
6. The process according to claim 5, wherein the polar aprotic solvent is selected from the group consisting of ethyl acetate, dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetrahydrofuran and acetonitrile.
7. The process according to claim 5, wherein the polar protic solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, formic acid, nitromethane, acetic acid, water and n-propanol.
8. The process according to claim 1, wherein t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate is optionally prepared insitu which comprises
(a) Reacting 2-amino-2-methylpropylamine with di-tert-butyl dicarbonate in alcohol solvent in presence of non-polar solvent, catalyst, base at 0-5?C;
(b) Adding S-1-(chloroacetyl)pyrrolidine-2-carbonitrile in ketone solvent at 35-40?C and
(c) Isolating t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate.
9. The process according to claim 8, wherein the alcohol solvent is selected from isopropanol, methanol, ethanol, n-butanol or n-propanol.
10. The process according to claim 8, wherein the non-polar solvent is selected from dichloromethane, diethylether, toluene or hexane.
11. The process according to claim 8, wherein the base is selected from diisopropylethylamine, triethyl amine, N-methyl morpholine or N-methyl pyrrolidine.
12. The process according to claim 8, wherein the catalyst is selected from potassium iodide and sodium iodide.
13. The process according to claim 1, wherein, the (S)-1-[2-Amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitriledihydrochloride is optionally purified by a process which comprises;
(a) Dissolving (S)-1-[2-Amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitriledihydrochloride in solvent or mixture of two or more solvents at heating temperature;
(b) Cooling at ambient temperature and
(c) Isolating pure (S)-1-[2-Amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitriledihydrochloride.
14. The process according to claim 13, wherein the solvents are selected from alcohol solvents and ether solvents.
15. The process according to claim 14, wherein the alcohol solvent is selected from isopropanol, methanol, ethanol and n-butanol.
16. The process according to claim 13, wherein the ether solvent is selected from isopropyl ether or methyl tert butyl ether.
17. The process according to claim 14, wherein the heating temperature is 40-50?C and cooling temperature is 25-30?C.
18. A process for preparing Anagliptin comprising;
(a) Reacting 2-methylpyrazolo [1,5-a]pyrimidine-6-carboxylicacid with cyanuric chloride and (S)-1-[2-Amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitrile in presence of solvent;
(b) Isolating Anagliptin and
(c) Crystallizing anagliptin from a solvent.
19. The process according to claim 18, wherein the solvent is ketone solvent selected from the group consisting of acetone, methyl ethyl ketone, diethylketone, methyl isobutyl ketone or isopropyl ketone.
20. A process for purification of Anagliptin comprising;
(a) Dissolving Anagliptin free base into solvent followed by treating with charcoal and acidifying with alcoholic hydrochloride to isolate anagliptin hydrochloride;
(b) Dissolving anagliptin hydrochloride into water and washing with solvent followed by basification with a base to adjust pH to 7 to isolate pure anagliptin.
21. The process according to claim 20, wherein the solvent for step (a) is selected from methanol, ethanol, isopropyl alcohol or n-propanol and for step(e) is selected from dichloromethane, hexane, toluene, 1,4-dioxane or diethyl ether.
22. The process according to claim 20, wherein the alcoholic hydrochloric acid is selected from the group consisting of methanolic hydrochloride, ethanolic hydrochloride or isopropanolic hydrochloride.
23. The process according to claim 20, wherein the base is selected from potassium carbonate, sodium carbonate, sodium bicarbonate or potassium bicarbonate.
24. A process for preparing crystalline form-H of Anagliptin comprising;
(a) Dissolving Anagliptin free base into a solvent followed by treating with charcoal and acidifying with alcoholic hydrochloride to isolate anagliptin hydrochloride and
(b) Dissolving anagliptin hydrochloride into water and washing with solvent followed by basification with a base to adjust pH to 7 to isolate pure anagliptin in crystalline form-H.
25. The process according to claim 24, wherein the solvent for step (a) is selected from methanol, ethanol, isopropyl alcohol, n-propanol and for step (e) is selected from dichloromethane, hexane, toluene, 1,4-dioxane or diethyl ether.
26. The process according to claim 24, wherein the alcoholic hydrochloric acid is selected from the group consisting of methanolic hydrochloride, ethanolic hydrochloride or isopropanolic hydrochloride
27. The process according to claim 24, wherein the base is selected from potassium carbonate, sodium carbonate, sodium bicarbonate or potassium bicarbonate.
28. A process for preparing dimer impurity of t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl} carbamate which comprises;
(a) Reacting t-butyl-2-amino-2 methyl-propylcarbamate with S-1-(chloroacetyl)pyrrolidine-2-carbonitrile in presence of solvent, base and catalyst at 40-45?C and
(b) Isolating dimer impurity of t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-
oxoethylamino}-2-propyl}carbamate.
29. The process according to claim 28, wherein the solvent is ketone solvent selected from acetone, methyl ethyl ketone, diethylketone, methyl isobutyl ketone, isopropyl ketone.
30. The process according to claim 28, wherein the base is selected from potassium carbonate, sodium carbonate, sodium bicarbonate or potassium bicarbonate.
31. The process according to claim 30, wherein the catalyst is selected from potassium iodide or sodium iodide.
32. A process for preparing an impurity (formula- XIII) of Anagliptin which comprises;

Formula-XIII
(a) suspending anagliptin free base in water followed by basifying with base;
(b) adding solvent and isolating impurity of anagliptin.
33. The process according to claim 32, wherein the base is selected from potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide.
34. The process according to claim 32, wherein the solvent is ketone solvent selected from acetone, methyl ethyl ketone, diethylketone, methyl isobutyl ketone, isopropyl ketone.
35. The process according to any of the preceding claims, wherein the purity of anagliptin is 99.9%.
36. Crystalline form H of anagliptin characterized by PXRD with at least one characteristic peak (expressed in 2?) at 8.32, 10.78, 11.72, 13.84, 14.38,16.10, 16.70, 18.74,19.86, 21.91.

Dated this 29th day of May, 2015

Dr. P. Aruna Sree
(Regn.No.: IN/PA 998)
Agent for the Applicant
Gopakumar Nair Associates ,TagSPECI:FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:

“AN ADVANTAGEOUS PROCESS FOR PREPARING ANAGLIPTIN AND ITS NOVEL CRYSTALLINE FORM-H”

2. APPLICANT:

(a) NAME: HARMAN FINOCHEM LIMITED

(b) NATIONALITY: Indian Company incorporated under the Indian
Companies Act, 1956

(c) ADDRESS: 107, Vinay Bhavya Complex, 159–A , C.S.T. Road, Kalina,
Mumbai - 400098, Maharashtra, India.

3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF INVENTION:
The present invention relates to an industrially feasible process for preparation of Anagliptin and its novel crystalline form-H

BACKGROUND OF INVENTION:
Anagliptin (Formula-I), DPP-IV inhibitor, is useful for treatment and prevention of type-2 diabetes and its related complications. Anagliptin is approved for use in Japan under the trade name Suiny.

Formula-I
US 7,345,180 (herein after US’180) discloses Anagliptin and its process for preparation. US’180 describes the process for preparing ofintermediate (S)-1-[(2-Amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitrile dihydrochloridewhich comprises the reaction of 2-Methylpropane-1,2-diamine with BOC-ON in presence of dichloromethane, chloroform to give t-butyl (2-amino-2-methyl-1-propyl)carbamate (Y.:74%) which further reacts with (S)-1-(2-Chloroacetyl)pyrrolidine-2-carbonitrile in presence of acetone, sodium iodide, potassium carbonate to obtain residue of t-butyl (S)-{2-[(2-cyanopyrrolidine-1-yl)-2-oxoethylamino]-2-methyl-1-propyl} carbamate which is purified on column chromatography to obtain pure t-butyl (S)-{2-[(2-cyanopyrrolidine-1-yl)-2-oxoethylamino]-2-methyl-1-propyl} carbamate (Y.:91%) which further reacts with HCl/1,4-dioxane in presence of dichloromethane to give (S)-1-[(2-Amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitrile dihydrochloride.

US’180 also discloses the process for preparing of (S)-2,7-Dimethylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid {2-[(2-cyanopyrrolidin-1-yl)-2-oxoethylamino]-2-methylpropy l}amide which is similar derivative of Anagliptin comprising reaction of N,N'-Carbonyldiimidazole with 2,7-dimethylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid in presence of tetrahydrofuran which further reacts with (S)-1-[(2-amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitrile dihydrochloride in presence of triethylamine to obtain residue of (S)-2,7-Dimethylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid {2-[(2-cyanopyrrolidin-1-yl)-2-oxoethylamino]-2-methylpropy l}amide which further purified by column chromatography to get pure (S)-2,7-Dimethylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid {2-[(2-cyanopyrrolidin-1-yl)-2-oxoethylamino]-2-methylpropy l}amide (Y. 33%). The general process is depicted in scheme-1.

Scheme-1
The above said process involves use of column chromatography for purification which is major drawback of the said process. Column chromatography is time consuming, tedious and industrially not feasible process. It also results in lower yield of the product. Moreover when practically the above said process followed, 42% dimer impurity of (t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate obtained. Further the said process involves use of 1,4-dioxane which is costly chemical and as per U.S.environmental protection agency it is classified as a probable human carcinogen. Thus the said process is not eco-friendly and commercially viable.

WO 2014034626 discloses crystal form of Anagliptin and its process for preparation.

WO 2014147640 discloses the process for preparing Anagliptin and its crystalline forms- I and II.

Thus in the view of scrutiny of prior art processes it is essential to develop an economical, ecofriendly,robustand time saving process for preparing Anagliptin.

Therefore, the objective of the present invention isto provide commercially feasible, advantageous process for preparing Anagliptin which involves purification process with simple solvents which makes the present invention cost-effective. Moreover it does not involve use of hazardous chemicals. Another objective of the present invention is to reduce the formation of the dimer impurity of (t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate. A further objective is to provide robustinsitu process for preparing (t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate which is time saving process as it reduces multiple step work ups, purification thus results in higher yield.

SUMMARY OF THE INVENTION:
In line with the above objectives, the present invention provides cost effective, industrially applicable process for preparing Anagliptin (Formula-I) and its novel crystalline form-H.

Formula-I
In one aspect, the present invention describes the process for preparation of t-butyl-2-amino-2methyl-propylcarbamate which comprises;
(a) Reacting 2-amino-2-methylpropylamine with di-tert-butyl dicarbonate in presence of mixture of solvent and water;
(b) Separating organic layer and
(c) Isolating t-butyl-2-amino-2-methyl-propylcarbamate.
In another aspect, the instant invention discloses the process for preparing t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate which comprises;
(a) Reacting t-butyl-2-amino-2-methyl-propylcarbamate with S-1-(chloroacetyl)pyrrolidine-2-carbonitrile in presence of solvent, base and catalyst and
(b) Isolating t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate.
In one another aspect the present invention discloses the process for purification of t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate which comprises;
(a) Dissolving crude t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate in single or mixture of solvents at ambient temperature and and stirring at 0-5°C and
(b) Isolating pure t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate.
In yet another aspect the present invention discloses the insitu process for preparing t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate which comprises;
(a) Reacting 2-amino-2-methylpropylamine with di-tert-butyl dicarbonate in alcohol solvent in presence of non-polar solvent, catalyst, base at 0-5?C;
(b) Adding S-1-(chloroacetyl)pyrrolidine-2-carbonitrile in ketone solvent at 35-40?C and
(c) Isolating t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate.
In one embodiment the present invention discloses the deprotection process for preparing (S)-1-[2-Amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitriledihydrochloride which comprises;
(a) Reacting t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate with alcoholic hydrochloric acid and
(b) Isolating (S)-1-[2-Amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitriledihydrochloride
In another aspect the instant invention discloses the process for purification of (S)-1-[2-Amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitriledihydrochloride which comprises;
(a) Dissolving (S)-1-[2-Amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitriledihydrochloride in solvent or mixture of two or more solvents at heating temperature;
(b) Cooling to ambient temperature and
(c) Isolating pure (S)-1-[2-Amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitriledihydrochloride.
In one aspect the present invention discloses the process for preparing anagliptin which comprises;
(a) Reacting 2-methylpyrazolo [1,5-a]pyrimidine-6-carboxylicacid with 1,1-carbonyldiimidazole and (S)-1-[2-Amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitrile in presence of solvent and
(b) Isolating anagliptin.
In another aspect the instant invention discloses the process for preparing Anagliptin which comprises;
(a) Reacting 2-methylpyrazolo [1,5-a]pyrimidine-6-carboxylicacid with cyanuric chloride and (S)-1-[2-Amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitrile in presence of solvent;
(b) Isolating Anagliptin and
(c) Crystallizing anagliptinfrom a solvent.
In one another aspect the present invention discloses the process for purification of Anagliptin which comprises;
(a) Dissolving Anagliptin free base into solvent;
(b) Treating with charcoal;
(c) Acidifying with alcoholic hydrochloride;
(d) Isolating anagliptin hydrochloride;
(e) Dissolving anagliptin hydrochloride into water and washing with solvent;
(f) Basifying with a base to adjust pH 7 and
(g) Isolating pure anagliptin.
In yet anonther aspect the present invention discloses the process for preparing crystalline form-H of Anagliptin which comprises;
(a) Dissolving Anagliptin free base into solvent;
(b) Treating with charcoal;
(c) Acidifying with alcoholic hydrochloride;
(d) Isolating anagliptin hydrochloride;
(e) Dissolving anagliptin hydrochloride into water and washing with solvent;
(f) Basifying with a base to adjust pH 7 and
(g) Isolating Anagliptin crystalline form-H.
In one more aspect the present invention also discloses the process for preparing dimer impurity of t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate which comprises;
(a) Reacting t-butyl-2-amino-2-methyl-propylcarbamate with S-1-(chloroacetyl)pyrrolidine-2-carbonitrile in presence of solvent, base and catalyst and
(b) Isolating dimer impurity of t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate.
In another embodiment the present invention discloses the process for preparing an impurity (formula- XIII) of Anagliptin which comprises;
(a) suspending anagliptin free base in water;
(b) Basifying with base;
(c) Adding solvent and
(d) Isolating impurity of anagliptin.

BRIEF DESCRIPTION OF FIGURES:
Fig.1 shows the XPRD pattern of crystalline Anagliptin form-H
Fig.2 shows the DSC of crystalline Anagliptin form-H

DETAILED DESCRIPTION OF THE INVENTION:
The instant invention provides an efficient, advantageous and economical process for preparing Anagliptin (Formula-I) and its novel crystalline form-H

Formula-I
In one embodiment, the present invention describes the process for preparation of t-butyl-2-amino-2methyl-propylcarbamate which comprises;
(a) Reacting 2-amino-2-methylpropylamine with di-tert-butyl dicarbonate in presence of mixture of solvent and water
(b) Separating organic layer and
(c) Isolating t-butyl-2-amino-2-methyl-propylcarbamate.
The process for t-butyl-2-amino-2-methyl-propylcarbamateisdepicted in the following reaction Scheme II

Scheme-II
In above said process the term solvent refers to alcohol solvent. The alcohol solvent is selected from the group consisting of isopropanol, methanol, ethanol, n-butanol.

According to above process, the reaction temperature is 0?C to 10?C.

In another embodiment, the instant invention discloses the process for preparingt-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate which comprises;
(a) Reacting t-butyl-2-amino-2-methyl-propylcarbamate with S-1-(chloroacetyl)pyrrolidine-2-carbonitrile in presence of solvent, base and catalyst and
(b) Isolating t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate.
The reaction scheme for preparingt-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate is given in Scheme III.

Scheme-III
In above said process the solvent is selected from halogenated hydrocarbon or a ketone solvent or an ester solvent. The ketone solvent is selected from the group consisting of acetone, methyl ethyl ketone, diethyl ketone, methyl iso butyl ketone, isopropyl ketone. The ester solvent is isopropylacetate. The term base refers to inorganic base selected from the group consisting of potassium carbonate, sodium carbonate, sodium bi carbonate, potassium bi carbonate. The catalyst is selected from potassium iodide, sodium iodide. The reaction is carried out at 35-40?C, so as to substantially reduce the dimer impurity.

The formation of dimer impurity of t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate can be minimized by maintainingthe reactiontemperature at 35-40?C; using appropriate amount of S-1-(chloroacetyl)pyrrolidine-2-carbonitrileand also conducting the reaction inappropriate solvents such as isopropylacetate, methylene dichloride.
In one another embodiment the present invention discloses the process for purification of t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamateof formula (VI) which comprises;
(a) Dissolving crude t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate in single or mixture of solvents at ambient temperature and stirring at 0-5°C and
(b) Isolating pure t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate.

The solvents are selected from polar aprotic and polar protic solvents. The polar aprotic solvent is selected from the group consisting of ethyl acetate, dimethylformamide, dimethylacetamide,dimethylsulfoxide, tetrahydrofuran, acetonitrile. The polar protic solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, formic acid, nitromethane, Acetic acid, Water. The ambient temperature is 20-30?C.

Practically when the prior art US’180 process followed, during reaction oft-butyl (2-amino-2-methyl-1-propyl)carbamate with (S)-1-(2-Chloroacetyl)pyrrolidine-2-carbonitrile in presence of acetone, sodium iodide, potassium carbonate42% dimer impurity of t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate(formula-XII)obtained. By following the process as per scheme III followed by purification process, the dimer impurity can be reduced by 12%.

In another aspect the present invention discloses the insitu process for preparing t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate which comprises;
(a) Reacting 2-amino-2-methylpropylamine with di-tert-butyl dicarbonate solution in alcohol solvent in presence of non-polar solvent, catalyst, base at 0-5?C;
(b) Adding S-1-(chloroacetyl)pyrrolidine-2-carbonitrile in ketone solvent at 35-40?C and
(c) Isolating t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate.
The alcohol solvent is selected from the group consisting of isopropanol, methanol, ethanol, n-butanol. The non-polar solvent is selected form the group consisting of Dichloromethane, Diethyl ether, Toluene, Benzene, Hexane. The base is organic base selected from diisopropylethylamine, triethyl amine, N-methyl morpholine, N-methyl pyrrolidine. The catalyst is selected from potassium iodide, sodium iodide. The ketone solvent is selected from the group consisting of acetone, methyl ethyl ketone, diethyl ketone, methyl iso butyl ketone, isopropyl ketone.
In one embodiment the present invention discloses the deprotectionprocess for preparing(S)-1-[2-Amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitriledihydrochloride of formula VII which comprises;
(a) Reacting t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate of formula VI with alcoholic hydrochloric acid and
(b) Isolating (S)-1-[2-Amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitriledihydrochloride.
The reaction scheme for preparing(S)-1-[2-Amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitriledihydrochloride is given in Scheme IV

Scheme-IV
The alcoholic hydrochloride for above said process is selected from the group consisting of methanolic hydrochloride, ethanolic hydrochloride, isopropanolic hydrochloride, propanolic hydrochloride. The temperature for the above said process is 40-50?C.

In another aspect the instant invention discloses the process for purification of (S)-1-[2-Amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitriledihydrochloride which comprises;
(a) Dissolving (S)-1-[2-Amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitriledihydrochloride in solvent or mixture of two or more solvents at heating temperature;
(b) Cooling at ambient temperature and
(c) Isolating pure (S)-1-[2-Amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitriledihydrochloride.

The solvents for above said process is alcohol solvent and ether solvent. The alcohol solvent is selected from methanol, ethanol, isopropyl alcohol, n-propanol, butanol. The ether solvent is selected from isopropyl ether, methyl tert-butyl ether. The heating temperature is 40-50?C and the ambient temperature is 25-30?C.

In one embodiment the present invention discloses the process for preparing anagliptin which comprises;
(a) Reacting 2-methylpyrazolo [1,5-a]pyrimidine-6-carboxylicacid of formula VIII with 1,1-carbonyldiimidazole of formula IX and (S)-1-[2-Amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitrile of formula X in presence of solvent and
(b) Isolating anagliptin.
The process for preparing Anagliptin is depicted in the following reaction Scheme V

Scheme-V

The solvent for above said process is selected from polar aprotic solvents, non-polar solvents. The polar aprotic solvent is selected from the group consisting of tetrahydrofuran,ethyl acetate, acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide. The non-polar solvent is selected from the group consisting of Hexane, Benzene, Toluene, 1,4-Dioxane, Chloroform, Diethyl ether, Dichloromethane.
In another embodiment the instant invention discloses the process for preparing Anagliptin which comprises;
(a) Reacting 2-methylpyrazolo [1,5-a]pyrimidine-6-carboxylicacid of formula VIII with cyanuric chloride of formula XI and (S)-1-[2-Amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitrile of formula X in presence of solvent;
(b) Isolating Anagliptin and
(c) Crystallizing anagliptin in solvent.

The process for preparing Anagliptin is depicted in the following reaction Scheme VI

Scheme-VI
The solvent for said above process is ketone solvent selected from the group consisting of acetone, methyl ethyl ketone,diethyl ketone, methyl iso butyl ketone, isopropyl ketone. For crystallization, the solvent is alcohol solvent selected from the group consisting of methanol, ethanol, isopropanol,n-butanol, n-propanol.

In one another embodiment the present invention discloses the process for purification of Anagliptin which comprises;
(a) Dissolving Anagliptin free base into solvent;
(b) Treating with charcoal;
(c) Acidifying with alcoholic hydrochloride;
(d) Isolating anagliptin hydrochloride;
(e) Dissolving anagliptin hydrochloride into water and washing with solvent;
(f) Basifying with a base to adjust pH 7 and
(g) Isolating pure anagliptin.

For above said process solvent for step (a) is alcohol solvent selected from methanol, ethanol,isopropyl alcohol, n-propanol. The alcoholic hydrochloride is selected from methanolic hydrochloride, ethanolic hydrochloride, isopropanolic hydrochloride. The solvent for step (e) is non-polar solvent. The non-polar solvent is selected from the group consisting of Dichloromethane, Hexane, Toluene, 1,4-Dioxane, Diethyl ether. The base is selected from the group consisting of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate.

The present invention also discloses a novel crystalline which is designated herein after form-H. In one aspect the present invention discloses the process for preparation ofofAnagliptinform H which comprises;
(a) Dissolving Anagliptin free base into solvent;
(b) Treating with charcoal;
(c) Acidifying with alcoholic hydrochloride;
(d) Isolating anagliptin hydrochloride;
(e) Dissolving anagliptin hydrochloride into water and washing with solvent;
(f) Basifying with a base to adjust pH 7 and
(g) Isolating Anagliptin crystalline form-H.

For above said process solvent for step (a) is alcohol solvent selected from methanol, ethanol,isopropyl alcohol,n-propanol, butanol. The alcoholic hydrochloride is selected from methanolic hydrochloride, ethanolic hydrochloride, isopropanolic hydrochloride, propanolic hydrochloride. The solvent for step (e) is non-polar solvent. The non-polar solvent is selected from the group consisting of Dichloromethane, Hexane, Toluene, 1,4-Dioxane, Diethyl ether. The base is selected from the group consisting of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate.

The novel crystalline form-H according to the present invention is characterised by PXRDwith peaks at 2? values by at least one characteristic peak (expressed in 2?) at 8.32, 10.78, 11.72, 13.84, 14.38,16.10, 16.70, 18.74,19.86, 21.91 . The novel crystalline form also characterised by DSC. A DSC Q 2000 V24.11 build 124 instrument was used to record DSC curves.
In one aspect the present invention also discloses the process for preparing dimer impurity (formula-XII) of t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate which comprises;
(a) Reacting t-butyl-2-amino-2methyl-propylcarbamate of formula IV with S-1-(chloroacetyl)pyrrolidine-2-carbonitrile of formula V in presence of solvent, base and catalyst and
(b) Isolating isolating dimer impurity of t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate of formula XII.
The reaction scheme for preparing dimer impurity oft-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate is given in Scheme VII.

Scheme-VII
In above said process the solvent is selected from ketone solvent. The ketone solvent is selected from the group consisting of acetone, methyl ethyl ketone, diethyl ketone, methyl iso butyl ketone, isopropyl ketone. The term base refers to inorganic base selected from the group consisting of potassium carbonate, sodium carbonate, sodium bi carbonate, potassium bi carbonate. The catalyst is selected from potassium iodide, sodium iodide. The reaction is carried out at 40-45 ?C.

In another embodiment the present invention discloses the process for preparing an amide impurity (formula-XIII) of Anagliptin which comprises;

Formula-XIII

(a) suspending anagliptin free base in water;
(b) Basifying with base;
(c) Adding solvent and
(d) Isolating impurity of anagliptin.

Scheme-VIII

The base for said above process is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate. The solvent is ketone solventselected from the group consisting of acetone, methyl ethyl ketone,diethyl ketone, methyl iso butyl ketone, isopropyl ketone. the reaction tempereature for said process is 0-5?C

The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

Examples:
Example-1: Preparation of t-butyl2-amino-2methyl-propylcarbamate
To the 40gm 2-amino-2-methylpropylamine added a mixture of 400ml isopropyl alcohol and 400 ml water and cooled to 0 ° C or less. Added a solution of 52.4g di-tert-butyl dicarbonate in isopropyl alcohol at 0~10 ° C and stirred for 3-5 hours. Added 500ml Methylene chloride to the reaction mixture and separated organic layer followed by washed successively with saturated potassium carbonate (3X50mL), 5% HCl (3X50mL) and saturated brine (3 X 50mL).Dried over anhydrous sodium sulfate the organic phase.The solvent was evaporated to dryness under reduced pressure to give 64% t-butyl2-amino-2methyl-propylcarbamate.
HPLC purity: 95%.

Example-2: Preparation of (t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate
To the solution of 50gm t-butyl2-amino-2methyl-propylcarbamate in 1000ml acetone added catalytic amount of potassiumiodide, 58.7gm potassiumcarbonate and cooled to 0-5°C. Added solution of 41.1 gm S-1-(chloroacetyl)pyrrolidine-2-carbonitrile in acetone and stirred at 38-40°C for 4 hours. Insolubles were removed by filtration and the filtrate was concentrated under reduced pressure to givet-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate.
HPLC purity: 95%

Example 3: Purification oft-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate
The 84gm crude residue of example-2 Cooled to ambient temperature and Added mixture of 175ml ethylacetate and 45ml methanol and stirred for 2hours -5 to 0°C. Filtered the mass and washed with chilled 30ml ethylacetate. Dried the material under vacuum pressure at 50°C to give 58% t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate.
HPLC purity:99%

Example-4: Preparation of (S)-1-[2-Amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitriledihydrochloride
To the 50gm t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate added 250ml isopropyl alcohol. Added 5NHCl in 250ml isopropyl alcohol undercooling condition and stirred for 2 hours at 40°C.The product was filtered and purified with using 125ml Isopropyl ether to give 96% the title compound as a white crystals.
HPLC purity: 93%

Example 5: Preparation of (S)-1-[2-Amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitriledihydrochloride
To the 50 gm t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate added 250ml isopropyl alcohol. Added 5NHCl 250ml in isopropyl alcohol undercooling condition and stirred for 2 hours at 40°C.The product was filtered and purified with using 150ml methanol to give 96% the title compound as a white crystals
HPLC purity: 93%

Example 6: Purification of (S)-1-[2-Amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitriledihydrochloride
To the 10gm (S)-1-[2-Amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitriledihydrochloride added 40times of Alcohol and heated to 50°C for 2hours. Cooled to room temperature and added isopropylether. Product was filtered and dried under vacuum at 50°C to get pure (S)-1-[2-Amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitriledihydrochloride.
HPLC purity: 99%

Example 7: Preparation of Anagliptin
To the solution of 24 gm 2-methylpyrazolo [1,5-a]pyrimidine-6-carboxylicacid in 240ml tetrahydrofuran added 44gm 1,1carbonyldiimidazole and stirred for about 3 hours at 25-30°C. Filtered the reaction mixture. To the solution of above wet cake material in THF added a solution of (S)-1-[2-Amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitrile in THF. The reaction mixture stirred for 15hours.Filtered and distilled completely.Added 400ml Dichloromethane and saturated sodium chloride solution to the residue and stirred for 30min. Separated Dichloromethane layer and distilled completely.Charged water and pH adjusted to 1 with Con HCl.
To this aqueous layer Charged 200ml MDC and stirred for 10min.Separated aqueous layer. pH adjusted to 7-8 with potassium bicarbonate and stirred 2 hours at room temperature.Precipitated crystals were collected by filtration. Dried this material under vacuum at 55°C to give 62% Anagliptin.
HPLC Purity: 95%

Example 8: Synthesis of t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate (Insitu)
To the 40gm 2-amino-2-methylpropylamine added 400ml dichloromethane and a solution of 52.4g di-tert-butyl dicarbonate in isopropyl alcohol at 0~10 ° C and stirred for 3-5 hours.The reaction mixture washed with 10%sodium hydroxide solution and followed by 5%HCl solution. To the organic layer added catalytic amount of potassiumiodide, 41gm diisopropylethylamine and cooled to 0-5°C. A solution of 41.1gm S-1-(chloroacetyl)pyrrolidine-2-carbonitrile in acetone was added the reaction mixture and stirred at 38-40°C for 4 hours. From the resulting mixture, insoluble’s removed by filtration and the filtrate concentrated under reduced pressure and purified with 100ml ethylacetate to give 47% t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate.
HPLC Purity:98%

Example 9: Preparation of anagliptin
To the 5.0gm 2-methylpyrazolo [1,5-a]pyrimidine-6-carboxylicacid and 1.7gm cyanuric chloride added 50ml Acetone and cooled at 0°C.The mixture stirred for 2 hours and filtered to remove insolubles.A solution of 8.9gm (S)-1-[2-Amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitrile in 20ml acetone added slowly and warmed to roomtemparature and stirred for 2hours. Themixture was concentrated under pressure and added ethylacetate to the residue. Insolublematter removed by filtration. And the filtrate concentrated under reduced pressure and crystallized the material in Ethanol to get 40% anagliptin.
HPLC Purity: 90 %

Example 10: Preparation of anagliptin
To the solution of 24gm 2-methylpyrazolo [1,5-a]pyrimidine-6-carboxylicacid in 240ml methelenechloride added 44gm 1,1carbonyldiimidazole and stirred for about 3 hours at 25-30°C. The reaction mixture filtered. To the filtrate added a solution of 40gm (S)-1-[2-Amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitrile 400ml in MDC and stirred for 15hours. Filtered and distilled completely. Added 400ml ethylacetate and saturated sodium chloride solution to the residue and stirred for 30min. Separated ethylacetate layer and distilled completely. Charged water and pH adjusted to 1 with Con HCl. To this aqueous layer Charged 200ml MDC and stirred for 10min.Separated aqueous layer. To this aqueous layer PH adjusted to 7 with potassium bicarbonate and stirred for 2 hours at room temperature.The precipitated crystals were collected by filtration. Dried this material under vacuum at 55°C to give 40%Anagliptin.
HPLC Purity:99%

Example 11: Preparation of anagliptin
To the solution of 24gm 2-methylpyrazolo [1,5-a]pyrimidine-6-carboxylicacid in 250ml methelenedichloride added 44gm 1,1carbonyldiimidazole and stirred for about 3 hours at 25-30°C. Filtered the reaction mixture. To the filtrate added a solution of 40gm (S)-1-[2-Amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitrile in MDC and stirred for 15hours.Filtered and distilled completely. Added 250ml ethylacetate and 100ml saturated sodium chloride solution to the residue and stirred for 30min. Separated ethylacetate layer and distilled completely.Chargedwater and stirred for 1 hour at room temperature. The solution was seeded and allowed to crystallize and cooled overnight to 20-25°C.The precipitate was collected and the cake was washed twice with water. The product was dried in vacuum at 40°C to give 60% Anagliptin.
HPLC Purity: 95%

Example-12: Purification of Anagliptin free Base
To the 32gm Anagliptin freebase added 220ml isopropyl alcohol and stirred. Treated with 3gm activated charcoal for 1hour followed by filtration over filter paper. The filter cake was washed with isopropyl alcohol.To the filtrate added 60ml IPA-HCl and stirred for 2hours at ambient temperature.Filtered the solid and the filtered cake was dissolved in 40 time methanol.Stirred for 30min.Added 40 times diisopropylether and stirred for another 2 hours.Filtered the mixture and washed filter cake with pre-cooled methanol at 0-5°C. Dried for 4 hours to give off-white to whiteAnagliptin hydrochloride salt. 30gm Anagliptin hydrochloride salt dissolved in 320ml water and washed with 50ml methylene dichloride twice. pH of aqueous layer adjusted to 7 with potassiumbicarbonate solution and stirred for 2 hours at ambient temperature.Precipitated crystals collected. Dried under vacuum at 55°C to give pure anagliptin.
HPLC purity: 99.9%

Example 13: Preparation of Anagliptin novel crystalline form-H
To the 32gm Anagliptin freebase added 220ml isopropyl alcohol and stirred. Treated with activated charcoal for 1hour followed by filtration over filter paper. The filter cake was washed with 100ml isopropyl alcohol.To the filtrate added 64ml IPA-HCl and stirred for 2hours at ambient temperature. Filtered the solid and the filtered cake was dissolved in 40 time methanol. Stirred for 30min.Added diisopropyl ether and stirred for another 2 hours. Filtered the mixture and washed the filtered cake with pre-cooled methanol at 0-5°C and dried for 4 hours to give off-white to whiteAnagliptin hydrochloride salt. Anagliptin hydrochloride salt dissolved in 300ml water and washed with 50ml methylenedichloride twice. pH of aqueous layer was adjusted to 7 with potassium bicarbonate solution and stirred for 2 hours at ambient temperature. Precipitated crystals collected and dried under vacuum at 55°C to give Anagliptin novel crystalline form-H.
HPLC purity: 99.9%
DSC: 103.76°C (endotherm)

Example-14: Preparation of dimer impurity of t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate
10gm (1.0eq) t-butyl2-amino-2methyl-propylcarbamate and 18.3 (2.029 eq) gm S-1-(chloroacetyl) pyrrolidine-2-carbonitrilec were suspended in 200ml acetone and heated upto 40-45°C. Added 12gm (1.6 eq) potassium carbonate, 10gm (1.2 eq) potassium iodide and maintained for 2-4 hours. After completion of the reaction, filtered the mass and distilled under vacuum pressure. Recrystallized the material with ethyl acetate and dried at 45°C for 5 hoursto give dimer impurity of t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate.
HPLC purity: 90-95%

Example-15: Preparation of impurity of Anagliptin(formula- XIII)
5gm Anagliptin free base was suspended in 25ml water and the solution was cooled to approximately 5°C in ice bath. Added a solution of 0.6gm sodium hydroxide in water dropwise over 5 minutes and stirred for 5 hours. Distilled the reaction mass completely. Added acetone and stirred overnight. Solid filtered and dried at 50°C to give impurity of Anagliptin.
HPLC purity: 98%

Example-16: Preparation of (t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate
To the solution of 50gm t-butyl2-amino-2methyl-propylcarbamate in 1000ml isopropylacetate added catalytic amount of potassium iodide, 58.7gm potassium carbonate and cooled to 0-5°C. Added solution of41.1gm (1.0 eq) S-1-(chloroacetyl) pyrrolidine-2-carbonitrile in acetone and stirred at 38-40°C for 4 hours. Insolubles were removed by filtration and the filtrate was concentrated under reduced pressure to give t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate.
HPLC purity: 95%
Dimer impurity: 25-30%

Example-17: Purification oft-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate
The 84gm of crude residue of example-2 was cooled to ambient temperature. Added 170ml ethylacetate and stirred for 2 hours at -5 to 0°C. Filtered the mass and washed with chilled 15ml ethylacetate. Dried the material under vacuum pressure at 50°C to give 58% t-butyl-(S)-{2-[2-cyanopyrrolidine-1-yl)-2-oxoethylamino}-2-propyl}carbamate.
HPLC purity: 99%