CLIAMS:1. A process for preparing crystalline form 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 monohydrate (Formula-II) comprising

Formula-II
(a) Dissolving 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 anhydrous in mixture of ketone solvent and water underheating;
(b) Cooling the reaction mixture and
(c) Isolating crystalline form 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 monohydrate.
2. The process according to claim 1, wherein the ketone solvent is selected from the group consisting of methyl ethyl ketone, acetone, diethyl ketone, methyl iso butyl ketone, isopropyl ketone,cyclic ketones such as cyclohexanone, cyclobutanone, cyclopentanone, cycloheptanone.
3. The process according to claim 1, wherein the heating temperature is 60-70?C.
4. The process according to claim 1, wherein the cooling temperature is 10-15?C.
5. The process according to any of the preceding claims, wherein purity of crystalline form 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 monohydrate is 99-99.9%
6. A novel crystalline form-H 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 monohydrate.
7. The crystalline form-H according to claim 6, characterized by XPRD pattern with at least one characteristic peak (expressed in 2?) at 18.54, 19.19,19.60, 21.20, 24.08, 24.41, 25.02.
8. The crystalline form-H according to claim 6, characterized by DSC having sharp endotherm at 209.82°C
,TagSPECI:FIELD OF INVENTION:
The present invention relates to an industrially feasible process for 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 monohydrate and its novel crystalline form H.

BACKGROUND OF INVENTION:
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 (Formula-I) is an oral antihyperglycemic agent of the dipeptidyl peptidase-4 (DPP-4) inhibitor class and is used for the treatment of diabetes mellitus type-2. 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 is widely used as a therapeutic agent for diabetes mellitus because it has lesser side effects.

Formula-I Formula-II

US 6,699,871(herein after US’871)discloses class of beta-amino tetra hydrotriazolo [4,3-a] pyrazines, DPP-IV inhibitors and its preparation process. Other pharmaceutically acceptable salts arealso described in US’ 871.

US7,326,708 discloses dihydrogen phosphate salt 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;its crystalline form anditspreparation process.

PCT application WO 2010000469 describes crystalline forms 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 monobasic, dibasic and tribasic acid addition salts like hydrochloric acid (Form I and Form II), sulfuric acid (Form I and Form II), methane sulfonic acid (Form I and Form II), fumaric acid (Form I and Form II), malonic acid, malic acid, succinic acid (Form I, Form II and Form III), lactic acid, glycolic acid, maleic acid (Form I and Form II), citric acid (crystalline and amorphous Form), aspartic acid and mandelic acid and process for the preparation thereof.

PCT applications WO 2005020920 and WO 2005030127 disclose crystalline polymorphs 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 dihydrogen phosphate anhydrate as Form I, Form II, Form III and Form IV.

SUMMARY OF THE INVENTION:
The present invention provides aprocess for 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 free base (Formula-I), 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 monohydrate (Formula-II) and novel crystalline form H 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 monohydrate.

Formula-I Formula-II
In one embodiment, the present invention provides an insitu process for preparing 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 free base (Formula-I) which comprises;
(a) Reacting (3R)-3-[(1,1-dimethyl ethoxy carbonyl)amino]-4-(2,4,5-trifluorophenyl butanoic acid with 3-trifluromentyl 5,6,7,8-tetrahydro ( 1 ,2,4) triazolo[4,3-a] pyrazineHCl in presence of coupling reagent, base, condensing agent and solvent;
(b) Basifying with sodium bicarbonate;
(c) Adding alcoholic HCl and separating layers;
(d) Adjusting pH to 10-11% to aqueous layer;
(e) Crystallized by IPA and heptanes; and
(f) Isolating crystallized 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 base.
In another embodiment the instant invention provides the process for preparing 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 anhydrous which comprises
(a) Dissolving 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 base in alcohol solvent underheating;
(b) Adding phosphoric acid;
(c) Cooling reaction mixture and
(d) Isolating 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 anhydrous.

In another embodiment the present invention provides novel crystalline form H 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 monohydrate from 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 anhydrous.

In another embodiment, the invention provides process for preparing novel crystalline form H 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 monohydrate from 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 anhydrous which comprises;
(a) Dissolving 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 anhydrous in mixture of ketone solvent and water underheating;
(b) Cooling the reaction mixture and
Isolating novel crystalline form 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 monohydrate.

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

DETAILED DESCRIPTION OF THE INVENTION:
The instant invention provides an efficient, advantageous and economical process for preparing 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 free base (Formula-I), 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 monohydrate (Formula-II)and crystalline form 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 monohydrate.

Formula-I Formula-II

In one embodiment, the present invention provides aninsitu process for preparing 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 free base (Formula-I) which comprises;
(a) Reacting (3R)-3-[(1,1-dimethyl ethoxy carbonyl)amino]-4-(2,4,5-trifluorophenyl butanoic acid with 3-trifluromentyl 5,6,7,8-tetrahydro ( 1 ,2,4) triazolo[4,3-a] pyrazineHCl in presence of coupling reagent, base, condensing agent and solvent ;
(b) Basifying with sodium bicarbonate;
(c) Adding alcoholic HCl and separating layers;
(d) Adjusting pH to 10-11% to aqueous layer;
(e) Crystallizing by IPA and heptanes; and
(f) Isolating crystallized 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 base.

The process for preparing 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 base according to the present invention is described by following reaction Scheme-I

Scheme-I
According to the above process, the term coupling reagent refers to N,N’-dicyclohexylcarbodiimide. The condensing agent is 1-hydroxybenzotriazole. The base is selected from organic base is selected from triethyl amine, diisopropyl ethyl amine, N-methyl morpholine, N-methyl pyrrolidine. The solvent for above said process is Dichloromethane.The alcoholic HCl is selected from the group consisting of methanolicHCl, ethanolicHCland IPAHCl.

The reaction temperature for said process is 25-30?C.

In another embodiment the instant invention provides a process for preparing 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 anhydrous which comprises
(a) Dissolving 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 base in alcohol solvent underheating;
(b) Adding phosphoric acid;
(c) Cooling reaction mixture; and
(d) Isolating 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 anhydrous.
The process for preparing 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 anhydrous is depicted in the following reaction Scheme II.

Scheme II
The alcohol solvent is selected from the group consisting of methanol, ethanol, isopropanol, butanol. The heating temperature ranges at 40-50?C. The cooling temperature ranges at 20-25?C.

In another embodiment the present invention provides novel crystalline form-H.

According to yet another embodiment, the invention provides a process for preparing novel crystalline form H 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 monohydrate from 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 anhydrous which comprises
(a) Dissolving 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 anhydrous in mixture of ketone solvent and water underheating;
(b) Cooling the reaction mixture and
(c) Isolating novel crystalline form H 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 monohydrate.

The novel crystalline form-H according to the present invention is characterised by PXRD data with peaks at 2? values by at least one characteristic peak (expressed in 2?) at18.54, 19.19,19.60, 21.20, 24.08, 24.41, 25.02. The novel crystalline form also characterised by DSC. ADSC Q 2000 V24.11 build 124 instrument was used to record DSC curves.
The process for preparing 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 monohydrate is given in Scheme-III

Scheme-III

The ketone solvent is selected from the group consisting of methyl ethyl ketone, acetone, diethyl ketone, methyl iso butyl ketone, isopropyl ketone, cyclic ketones such as cyclohexanone, cyclobutanone, cyclopentanone, cycloheptanone. The heating temperature for above said process is 60-70?C and the cooling temperature is10-15?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 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 free base (Insitu)
To the 100gm(3R)-3-[(1,1-dimethyl ethoxy carbonyl)amino]-4-(2,4,5-trifluorophenyl butanoic acid charged 700ml methylenedichloride and 67gm triethylamineandstirred for 10 minutes.Added 68gmNN'-Dicyclohexylcarbodiimide, 44.6 gm of anhydrous 1 -hydroxylbenzotriazole and maintained for about 10-20 minutes.Added75.5gm 3-trifluromentyl 5,6,7,8-tetrahydro ( 1 ,2,4) triazolo[4,3-a] pyrazineHCl and heated to 25-30°C and maintained for 4 hours. After completion of reaction,filtered the reaction mass and filtrate was washed with 2x350ml 2.5%sodium bicarbonate solutionandwashed with 2x500ml of water.MDC layer was taken without purification and Cooled to 0-10°C. 400ml 16%Methanolic HCl added and raised the temperature to 25-30°C and Stirred for 4 hours.After completion of the reaction added 1000ml water and separatedlayers.ExtractedtheMDClayer with 2x300ml DM water.Aqueous layer was washed with 300ml MDC and pH of the aqueous layer was adjusted to 10-11%with 10%sodium hydroxide solution.1000ml MDC charged and Stirred for 10min. The organic layer separated and the Aq layer was extracted twice with 300 ml MDC. The organic layer was separated and washed with 300 ml of water followed by 300ml 5% NaCl; and driedthe organic layer with anhydrous sodium sulfate. The organic layer separated and the solvent was distilled out under vacuum.100mlIPA was added to residue and again distilled under vacuum followed by addition of 800ml heptane. Filtered the crystallized Material and dried under vacuum at 50°C for 12-15 hours to get 96.5% titled compound.
HPLC purity:99-99.9%
Chiral purity : 99.9%

Example-2: 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 anhydrous
To the 100 g 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 base was charged 400 ml of Methanol and heatedupto at 40-50 °C under stirring to get a clear solution.Addedsolution of 29 gm phosphoric acid dissolved in 100 ml Methanol over a period of 30 minutesand stirred for 5 minutes and heated at 50-55°C for 2 hours. The reaction mixture was cooled gradually to 20-25 °C.Stirred for 2hours and filtered the product. Washed the product with Methanol and dried in oven under vacuum at 25°C to get titled compound.
HPLC purity:99-99.9%
Chiral purity : 99.9%

Example 3: Preparation of crystalline form H 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 Monohydrate.
To the 100gm 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 anhydrous charged mixture of 100 ml methyl ethyl ketone and 100ml water and heated at 60-70°C andstirred to get a clear solution.Cooledthe solution to room temperature and stirred for 2hours.Added 400ml methyl ethyl ketone and further stirred for 5 hours and cooled to 10-15°C.Filtered the Crystalline material and dried at 40-45°C for 5 hours to get 90% title compound.
DSC :sharp endotherm at 209.82°C
HPLC purity:99-99.9%
Chiral purity : 99.9%