WO2011060213A2

WO2011060213A2 - Preparation of sitagliptin and salts thereof

Info

Publication number: WO2011060213A2
Application number: PCT/US2010/056443
Authority: WO
Inventors: Srinivas Reddy Gade; Bindu Srivastava; Venkateswarlu Muvva
Original assignee: Dr. Reddy's Laboratories Ltd.; Dr. Reddy's Laboratories, Inc.
Priority date: 2009-11-12
Filing date: 2010-11-12
Publication date: 2011-05-19
Also published as: WO2011060213A3

Abstract

Processes for preparing sitagliptin and its pharmaceutically acceptable salts, and process intermediates.

Description

PREPARATION OF SITAGLIPTIN AND SALTS THEREOF

INTRODUCTION

Aspects of the present application relate to processes for the preparation of sitagliptin and pharmaceutically acceptable salts thereof. Aspects further relate to various salts of sitagliptin and processes for their preparation. Further aspects relate to processes for preparing crystalline sitagliptin polymorphic phosphate Form A.

The drug compound having the adopted name "sitagliptin phosphate" has chemical names: 7-[(3/?)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8- tetrahydro-3-(trifluoromethyl)-1 ,2,4-triazolo[4,3-a] pyrazine phosphate (1 :1); or (2ft)-4-oxo-4-[3-(trifluoromethyl) -5,6-dihydro[1 ,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]- 1-(2,4,5-thfluorophenyl)butan-2-amine phosphate; and is represented by structural Formula I.

H3PO4 Formula I

Sitagliptin is a glucagon-like peptide 1 metabolism modulator,

hypoglycemic agent, and dipeptidyl peptidase IV inhibitor, which is believed to exert its action in patients with type 2 diabetes by slowing the inactivation of incretin hormones. A product containing sitagliptin phosphate in its monohydrate form is marketed in the United States by Merck & Co., Inc. using the brand

JANUVIA™. JANUVIA™ is indicated to improve glycemic control in patients with type 2 diabetes mellitus.

Sitagliptin phosphate (1 :1) monohydrate, in combination with metformin hydrochloride, is sold by Merck & Co., Inc. using the brand JANUMET™ in the form of tablets for oral administration for combination therapy in the treatment of type 2 diabetes. U.S. Patent No. 6,699,871 describes various DPP-IV inhibitors including sitagliptin and their pharmaceutically acceptable salts, a pharmaceutical composition and method of treatment and a process for the preparation of sitagliptin hydrochloride. U.S. Patent No. 7,326,708 discloses a dihydrogen phosphate salt of (2f?)-4-oxo-4-[3- (trifluoromethyl)-5,6-dihydro[1 ,2,4]triazolo[4,3- a]pyrazin-7 (8H)-yl]- -(2,4,5- trifluorophenyl)butan-2-amine, and a process for the preparation thereof.

International Application Publication No. WO 2004/085661A2 discloses a process for the preparation of sitagliptin in which (S)-phenylglycine amide is used as a chiral auxiliary to form an intermediate, which subsequently provides the required enantiomer (sitagliptin). The application discloses the use of Adam's catalyst, i.e., platinum oxide, to promote the diastereoselective hydrogenation of the enamine carbon-carbon double bond in the chiral substrate.

International Application Publication No. WO 2005/072530 A1 , WO2010012781 A2, and WO2010092090A2 describe various crystalline salts of sitagliptin or hydrate. Also, a process for preparation of sitagliptin crystalline Form I is described in International Application Publication No. WO 2009/070314 A2. Further, WO2009084024A2 also disclosed crystalline form of sitagliptin free base. International Application Publication Nos. WO 2005/020920 A2, WO2005030127A2, WO 2009/120746 A2, WO2010000469A2, WO2010032264A2, WO2009085990A2 disclose crystalline forms of sitagliptin phosphate such as solvated Form II, desolvated Form II, Form I, Form III, Form IV, Form A and Form V and process for their preparation. Further, US20090247532A1 is directed to crystalline Form V of sitagliptin phosphate.

It is well known that the crystalline polymorph form of a particular drug is often an important determinant of the drug's ease of preparation, stability, solubility, storage stability, ease of formulation and in vivo pharmacology. Polymorphic forms occur where the same composition of matter crystallizes in a different lattice arrangement resulting in different thermodynamic properties and stabilities specific to the particular polymorphic form. In cases where two or more polymorph substances can be produced, it is desirable to have a method to make polymorphs in pure form. In deciding which polymorph is preferable, the numerous properties of the polymorphs must be compared and the preferred polymorph chosen based on the many physical property variables. It is entirely possible that one polymorphic form can be preferable in some circumstances where certain aspects such as ease of preparation, stability, etc. are deemed to be critical. In other situations, a different polymorph may be preferred for greater solubility and/or superior pharmacokinetics.

International PCT application publication No. WO2009085990A2 disclose anhydrous crystalline Form A of sitagliptin phosphate. The present invention describes the methods for preparation of said polymorphic Form A of sitagliptin phosphate.

Although several crystalline forms and their processes have been reported in the prior art for the preparation of sitagliptin phosphate, they suffer from disadvantages such as use of ethanol as solvent in scale-up or longer time-cycles. Hence, there remains a need for simple, cost effective, and industrially viable processes with shorter time-cycles for the production of crystalline form of sitagliptin phosphate.

Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods, and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

SUMMARY

In an aspect, there are provided stereoselective processes for the preparation of a phosphate salt of sitagliptin of Formula I, as a single enantiomer or in an enantiomerically enriched form, embodiments comprising:

Η₃Ρ0₄

Formula I

(i) reacting 7-(1 ,3-dioxo-4-(2,4,5-trifluorophenyl)butyl)-3-trifluoromethyl- 5,6,7,8-tetrahydro-1 ,2,4-triazolo [4,3-a]pyrazine of Formula III:

with a compound

Formula IV

wherein R is d-C₄alkyl and Ph is phenyl, to afford a compound of Formula V, or a tautomer thereof;

Formula V (ii) converting a compound of Formula V, or a tautomer thereof, to a compound of Formula VI or a salt thereof, by reduction in the presence of a borohydride and a sulfonic acid;

Formula VI

(iii) converting a compound of Formula VI or its salt to an

enantiomerically pure acid addition salt of sitagliptin of Formula VII:

Formula VII

wherein HY is an acid moiety such as hydrochloric acid, phosphoric acid, oxalic acid, hydrobromic acid, acetic acid, formic acid, succinic acid, mandelic acid, fumaric acid, benzoic acid, or the like; and

(iv) converting acid addition salt of sitagliptin obtained in step (iii) to an enantiomerically pure or enriched phosphate salt of sitagliptin of Formula I, by treating with a source of phosphate ion.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is an illustration of a powder X-ray diffraction ("PXRD") pattern of a crystalline formate salt of sitagliptin, prepared according to Example 7.

Fig. 2 is an illustration of a PXRD pattern of a crystalline acetate salt of sitagliptin, prepared according to Example 19.

Fig. 3 is an illustration of a PXRD pattern of a crystalline dihydrogen phosphate salt of sitagliptin, prepared according to Example 26. DETAILED DESCRIPTION

H₃P0₄

Formula I

(i) reacting 7-(1 ,3-dioxo-4-(2,4,5-trifluorophenyl)butyl)-3-trifluoromethyl- 5,6,7, 8-tetrahydro-1 ,2,4-triazolo [4,3-a]pyrazine of Formula III:

Formula

with a compound of Formula IV;

Formula IV

Formula V

(ii) converting a compound of Formula V, or a tautomer thereof, to a compound of Formula VI or a salt thereof, by reduction in the presence of a borohydride and a

₃

Formula VI

(iii) converting a compound of Formula VI or its salt to an

enantiomerically pure acid addition salt of sitagliptin of Formula VII:

Formula VII

wherein HY is an acid moiety such as hydrochloric acid, phosphoric acid, oxalic acid, hydrobromic acid, acetic acid, formic acid, succinic acid, mandelic acid, fumaric acid, benzoic acid, or the like; and (iv) converting acid addition salt of sitagliptin obtained in step (iii) to an enantiomerically pure or enriched phosphate salt of sitagliptin of Formula I, by treating with a source of phosphate ion.

Step (i) involves preparation of an enamide of structural Formula V, or a tautomer thereof, containing a (R)-phenylalkylamine, such as (R)-a-phenylethyl amine, as a chiral auxiliary. For the reaction of step (i), the quantity of (R)-cc- phenylalkylamine may range from about 1 to about 2 molar equivalents, per mole of the compound of Formula III.

Suitable solvents that may be used include, but are not limited to: alcohols such as methanol, ethanol, isopropyl alcohol, or n-butanol; halogenated hydrocarbons such as dichloromethane, ethylene dichloride, or chloroform; esters such as ethyl acetate, n-propyl acetate, or isopropyl acetate; hydrocarbons such as toluene, xylene, hexane, heptane, or cyclohexane; ethers such as 1 ,4-dioxane or tetrahydrofuran; organic acids such as acetic acid, propionic acid, or the like; or any mixtures thereof. Optionally, the reaction may be carried out in the absence of a solvent. Suitable temperatures for the reaction of step (i) may be less than about 150°C, less than about 120°C, less than about 80°C, less than about 60°C, or any other suitable temperatures. Suitable times for the reaction of step (i) may be from about 30 minutes to about 10 hours, or longer.

Step (ii) involves converting a compound of Formula V, or a tautomer thereof, to a compound of Formula VI or its salt. Step (ii) of the present application includes a diastereoselective reduction of the enamine carbon-carbon double bond in the chiral substrate of Formula V, or a tautomer thereof, to afford a protected chiral amine of Formula VI. The diastereoselective reduction may be carried out in the presence of a borohydride such as sodium borohydride, sodium cyanoborohydride, lithium borohydride, or the like, and a sulfonic acid such as methanesulfonic acid, p-toluenesulfonic acid, or the like. The quantities of sodium borohydride may range from about 1 to about 10 molar equivalents, per mole of the compound of Formula V. The quantities of sulfonic acid may range from about 1 to about 10 molar equivalents, per mole of the compound of Formula V.

Solvents that may be used in step (ii) include, but are not limited to: alcohols, such as methanol, ethanol, isopropyl alcohol, hexafluoroisopropyl alcohol, phenol, 2,2,2-trifluoroethanol (TFE), or the like; halogenated hydrocarbons such as dichloromethane, ethylene dichloride, or chloroform; hydrocarbons such as toluene, xylene, hexane, heptane, or cyclohexane; ethers such as 1 ,4-dioxane, tetrahydrofuran, diisopropyl ether, or methyl t-butyl ether; aprotic polar solvents such as Ν,Ν-dimethylformamide (DMF), dimethylsulfoxide (DMSO), or dimethylacetamide (DMA); or any mixtures thereof. Optionally, the reaction may be carried out without a solvent.

Suitable temperatures for the reaction may be less than about 150°C, less than about 100°C, less than about 60°C, less than about 25°C, less than about 0°C, less than about -25°C, less than about -50°C, or any other suitable temperatures. The reaction may be carried out for time periods ranging from about 30 minutes to about 10 hours, or longer.

Aspects of the present application provide processes for the preparation of enantiomerically enriched sitagliptin dihydrogen phosphate of Formula I. Each step of the processes disclosed herein are contemplated both in the context of the multi-step sequences described, and individually.

Optionally, the compound of Formula VI or its salt can further be purified by a process involving acidifying and basifying steps, in any order, crystallization, and combinations thereof, to enhance the diastereomeric ratio. The suitable crystallization techniques include, but are not limited to: concentrating, cooling, stirring, or shaking a solution containing the compound, combining a solution with an anti-solvent, adding seed crystals, evaporation, flash evaporation, or the like, including any combinations thereof. The solvents that can be employed for crystallization include, but are not limited to: alcohols, such as methanol, ethanol, isopropyl alcohol, hexafluoroisopropyl alcohol, phenol, or 2,2,2-trifluoroethanol (TFE); esters such as ethyl acetate, n-propyl acetate, or isopropyl acetate; ketones such as acetone or methyl isobutyl ketone; hydrocarbons such as toluene or xylene; halogenated hydrocarbons such as dichloromethane or chloroform; ethers such as 1 ,4-dioxane or tetrahydrofuran; nitriles such as acetonitrile; water; or any mixtures thereof. An anti-solvent as used herein refers to a solvent in which a compound of Formula VI is insoluble, less soluble, or poorly soluble.

Acids that can be employed for purification include, but are not limited to: inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, or the like; and organic acids such as acetic acid, methanesulfonic acid, oxalic acid, formic acid, or the like.

Bases that can be employed for purification include, but are not limited to: inorganic bases such as alkali metal hydroxides and carbonates; and organic bases such as triethylamine, dicyclohexylamine, diisopropylethylamine, morpholine, ammonium hydroxide, or the like.

Typically, the compound of Formula VI or its salt has a diastereomeric ratio of at least 80:20, or at least 95:5, or about 100:0.

Step (iii) in the process of the present application entails N-dealkylation under hydrogenolytic conditions to afford sitagliptin free base of Formula II or its salt, as a single enantiomer or in an enantiomerically enriched form, which, if desired, can further be converted to an acid addition salt of sitagliptin of Formula VII by reacting sitagliptin of Formula II with a suitable acid.

The N-dealkylation may be achieved by techniques known in the art. For example, it may be achieved by catalytic hydrogenation in the presence of a catalyst such as, for example, palladium on carbon, Raney® nickel, or palladium hydroxide on carbon, or by transfer hydrogenation using ammonium formate, hydrazine, formic acid, or the like as a source of hydrogen.

Solvents that may be used for hydrogenation include, but are not limited to: alcohols such as methanol, ethanol, isopropyl alcohol, or n-butanol; halogenated hydrocarbons such as dichloromethane, ethylene dichloride, or chloroform; esters such as ethyl acetate, n-propyl acetate, or isopropyl acetate; hydrocarbons such as toluene, xylene, hexane, heptane, or cyclohexane; ethers such as 1 ,4-dioxane or tetrahydrofuran; aprotic polar solvents such as Ν,Ν-dimethylformamide (DMF), dimethylsulfoxide (DMSO), or Ν,Ν-dimethylacetamide (DMA); water; or any mixtures thereof. Optionally, the reaction may be conducted without a solvent.

Suitable temperatures for the reaction may be less than about 150°C, less than about 100°C, less than about 80°C, less than about 60°C, or any other suitable temperatures. Suitable times for the hydrogenation step may be from about 30 minutes to about 10 hours, or longer.

Optionally, an enantiomerically pure acid addition salt of sitagliptin obtained in the above step is neutralized using a suitable base, for example, an ammonia solution. Optionally, enantiomerically pure sitagliptin free base of Formula II may be isolated, purified (if desired), and then subsequently converted to an acid addition salt of sitagliptin of Formula VII, by reacting with a suitable acid. Suitable acids for preparation of an acid addition salt of sitagliptin of Formula VII include, but are not limited to, hydrochloric acid, phosphoric acid, oxalic acid, hydrobromic acid, acetic acid, formic acid, succinic acid, mandelic acid, fumaric acid, benzoic acid, or the like.

Solvents that may be used for the conversion of enantiomerically pure sitagliptin free base to an acid addition salt of sitagliptin of Formula VII include, but are not limited to: alcohols such as methanol, ethanol, isopropyl alcohol, or n- butanol; halogenated hydrocarbons such as dichloromethane, ethylene dichloride, and chloroform; esters such as ethyl acetate, n-propyl acetate, and isopropyl acetate; hydrocarbons such as toluene, xylene, hexane, heptane, and cyclohexane; ethers such as 1 ,4-dioxane and tetrahydrofuran; aprotic polar solvents such as Ν,Ν-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA); water; and any mixtures thereof. Optionally, the reaction may be carried without a solvent. Suitable temperatures for the reaction may be less than about 100°C, less than about 80°C, less than about 60°C, or any other suitable temperatures. Suitable times for the reaction may be from about 30 minutes to about 10 hours, or longer.

Optionally, an acid addition salt of sitagliptin may be purified by processes known in the art. For example an acid addition salt of sitagliptin may be purified by precipitation or slurrying in a suitable solvent. The precipitation may be achieved by crystallization, by combining a solution with an anti-solvent, or any other suitable methods known in the art. An anti-solvent as used herein refers to a liquid in which a salt of sitagliptin is insoluble or poorly soluble.

Acid addition salts of sitagliptin prepared in accordance with the processes described in the present application are substantially free of process or structure related impurities. "Substantially free" as used herein refers to sitagliptin free base or a pharmaceutically acceptable salt having less than about 0.5%, or less than about 0.3%, or less than about 0.2%, or less than about 0.1 %, or less than about 0.05%, by weight of a corresponding process or structural related impurity. Conversion of an acid addition salt of sitagliptin of Formula VII back into sitagliptin free base is also contemplated.

Step (iv) in a process of the present application involves conversion of an acid addition salt of sitagliptin of Formula VII obtained from step (iii) to an enantiomerically pure or enriched phosphate salt of sitagliptin of Formula I, by treating with a source of phosphate ion. The mixture comprising acid addition salt of sitagliptin of formula VII in step iv) may be a suspension or a solution.

If it is intended to obtain a clear solution of acid addition salt of sitagliptin of Formula VII, the reaction mixture can be heated to dissolution temperature that can be any temperature as long as the stability of the sitagliptin salt is not compromised and a substantially clear solution is obtained. For example, the dissolution temperature may range from about 20°C to about the reflux temperature of the solvent.

Suitable source of phosphate ion for use in step (iv) include, but are not limited to, phosphoric acid, polyphosphoric acid, phosphorous pentoxide, dipotassium hydrogen phosphate, ammonium dihydrogen orthophosphate, sodium dihydrogen orthophosphate, or the like. Suitable temperatures for the reaction may be room temperature or ambient temperature, near about 60 °C, near about 80°C, or about the reflux temperature of solvent employed or any other suitable temperature. Suitable times for the reaction may be from about 30 minutes to about 10 hours, or longer. The phosphate salt of sitagliptin of Formula I thus obtained may be separated and dried.

In an aspect, there are provided stereoselective processes for the preparation of sitagliptin of Formula II, or a salt thereof, as a single enantiomer, or in an enantiomerically enriched form, embodiments comprising:

Formula II

(i) reacting 7-(1 ,3-dioxo-4(2,4,5-trifluorophenyl)butyl)-3-trifluoromethyl- 5,6,7, 8-tetrahydro-1 ,2,4-triazolo [4,3-a]pyrazine of Formula III:

Formula

with a compound of Formula IV;

Ph

H₂N^R

Formula IV

wherein R is C₁-C₄ alkyl and Ph is phenyl, to afford a compound of Formula V, a tautomer thereof;

Formula V

(ii) converting a compound of Formula V, or a tautomer thereof, to a compound of Formula VI or a salt thereof, by reduction in the presence of a borohydride and sulfonic

₃

Formula VI

(iii) converting a compound of Formula VI or its salt to an

enantiomerically pure acid addition salt of sitagliptin of Formula VII:

Formula VII wherein HY is an acid moiety such as hydrochloric acid, phosphoric acid, oxalic acid, hydrobromic acid, acetic acid, formic acid, succinic acid, mandelic acid, fumaric acid, benzoic acid, or the like; and

Formula I

In another aspect, there are provided processes for the preparation of crystalline sitagliptin phosphate Form A, embodiments comprising:

(i) providing a mixture of an acid addition salt of sitagliptin in a suitable solvent;

(ii) adding a source of phosphate ion to the mixture of (i); and

(iii) isolating crystalline sitagliptin phosphate Form A.

Step (i) involves providing a mixture of an acid addition salt of sitagliptin in a suitable solvent. Acid addition salts of sitagliptin may be prepared using hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid, formic acid, oxalic acid, succinic acid, mandelic acid, fumaric acid, benzoic acid, or any other acids that form addition salts with sitagliptin. Acid addition salts of sitagliptin may be obtained by any processes, including processes disclosed in India Patent Application Nos. 1453/CHE/2009 and 2786/CHE/2009, respectively filed on August 28, 2009 and November 12, 2009 and which are incorporated herein by reference in their entireties, as well as by other processes known in the art.

The mixture comprising acid addition salt of sitagliptin of Formula VII in step i) may be a suspension or a solution. A mixture of an acid addition salt of sitagliptin and a solvent may require heating to form a solution of desired concentrations, and the temperatures can be as high as the reflux temperature of the solvent, as long as stability of the compound is not affected. A suitable solution also can be provided from a process step that synthesizes the acid addition salt compound, without isolating the salt.

Solvents that may be used in step (i) include, but are not limited to: esters such as ethyl acetate, n-propyl acetate, or isopropyl acetate; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone, diethyl ketone, or the like; ethers such as 1 ,2-dimethoxyethane, 1 ,4-dioxane, tetrahydrofuran, or methyl t- butyl ether; or any mixtures thereof.

Step (ii) involves addition of a phosphate ion source to the mixture of (i). Suitable sources of phosphate ion include, but are not limited to, phosphoric acid, polyphosphoric acid, phosphorous pentoxide, dipotassium hydrogen phosphate, ammonium dihydrogen orthophosphate, sodium dihydrogen orthophosphate, or the like.

The reaction can be efficiently completed at room temperature or ambient temperature or if required reaction mass can be heated to elevated temperatures or up to about the reflux temperatures, and maintained for about 10 minutes to about 5 hours or longer. Suitable temperatures for crystallization are about 0 to about 50°C, about 10 to about 30°C, or any other temperatures may be used. Suitable times for crystallization will vary, and can be from about 10 minutes to about 10 hours, or longer. Once obtained, crystals of sitagliptin phosphate Form A may be used as the nucleating agent or "seed" crystals for subsequent crystallizations of Form A of sitagliptin phosphate from the crystallization solvent.

Step (iii) involves isolation of crystalline sitagliptin phosphate Form A. The crystalline sitagliptin phosphate Form A may be isolated using conventional techniques known in the art. For example, useful techniques include but are not limited to, decantation, centrifugation, gravity filtration, suction filtration, concentrating, cooling, stirring, shaking, combining with an anti-solvent, adding seed crystals, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying, freeze-drying, or the like. The isolation may be optionally carried out at atmospheric pressure or under reduced pressure. The solid that is obtained may carry a small proportion of occluded mother liquor containing a higher percentage of impurities and, if desired, the solid may be washed with a solvent to wash out the mother liquor. The resulting solid may be optionally further dried. Drying may be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve a desired purity of the product, such as, for example, about 1 to about 15 hours, or longer.

The compounds at any stage of the process of the present invention may be recovered from a suspension/solution using any of techniques such as decantation, filtration by gravity or by suction, centrifugation, slow evaporation, or the like, or any other suitable techniques. The crystals so isolated may carry a small proportion of occluded mother liquor containing a higher percentage of impurities. If desired, the crystals may be washed with a solvent to wash out the mother liquor and/or impurities and the resulting wet crystals may optionally be suction dried. Evaporation as used herein refers to distilling of solvent almost completely at atmospheric pressure or under reduced pressure. Flash evaporation as used herein refers to distilling of solvent by using a technique includes but is not limited to tray drying, spray drying, fluidized bed drying, thin film drying under reduced pressure, or thin film drying at atmospheric pressure.

A wet cake obtained at any stage of the process may be optionally further dried. Drying may be carried out using a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 200°C, or about 20°C to about 80°C, or about 30°C to about 60°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure. The drying may be carried out for any desired times until the desired quality of product is achieved, such as about 30 minutes to about 20 hours, or about 1 to about 10 hours. Shorter or longer times also are useful.

An aspect of the present disclosure includes crystalline sitagliptin acetate designated herein as "Form X," that can be characterized by PXRD. One embodiment of the present disclosure is sitagliptin or its salts of Formula I, substantially free from alkene impurity of Formula VIII having RRT of -1.40.

Sitagliptin and its impurities can be analyzed by HPLC using an XTerra®

RP-18 (250 mm x 4.6mm, δ.Ομητι) or equivalent column, with the following parameters:

Column temperature: 45°C.

Detector. UV detector.

Injection volume: 10 μΙ_.

Flow rate: 1.0 mL/minute.

Buffer: Dissolve 2.72g of (0.02M) of potassium dihydrogen phosphate in lOOOmL HPLC grade water and adjust the pH to 7.0 with dilute potassium hydroxide solution and degas.

Eluent A: Mixture of Buffer and Acetonitrile in the volume ratio of 950:50 (v/v)

Eluent B: Mixture of Acetonitrile and HPLC grade water in the ratio of 800:200 v/v. Gradient elution program (values in volume %):

In embodiments, there are provided pharmaceutical compositions that include crystalline sitagliptin phosphate Form A, together with at least one pharmaceutically acceptable excipient. In embodiments, there are provided pharmaceutical compositions comprising a therapeutically effective amount of sitagliptin or a pharmaceutically acceptable salt thereof that contains less than about 0.1% of any individual impurity, together with one or more pharmaceutically acceptable excipients.

Pharmaceutical compositions that include sitagliptin or a salt thereof with one or more pharmaceutically acceptable excipient may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions. Formulations may be in the form of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir systems or combinations of matrix and reservoir systems. The compositions may be prepared by direct blending, dry granulation, and wet granulation or by extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated. Compositions of the present invention may further comprise one or more pharmaceutically acceptable excipients.

Pharmaceutically acceptable excipients that are useful for preparing formulations include, but are not limited to: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methyl celluloses, pregelatinized starch, or the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidones, croscarmellose sodium, colloidal silicon dioxide, or the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, or the like; glidants such as colloidal silicon dioxide or the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methyl celluloses, ethyl celluloses, methyl celluloses, various grades of methyl methacrylates, waxes, or the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants or the like.

The processes of present invention are simple, cost-effective, ecologically friendly, reproducible, scalable, and robust, to produce salts of sitagliptin with high chemical and optical purity.

The processes of the present invention may be used to make anhydrous crystalline sitagliptin dihydrogen phosphate of Formula I. Crystalline forms obtained by the present application, unless stated otherwise, were characterized by their XRPD patterns. PXRD data reported herein are obtained using copper Ka radiation.

Crystalline forms are characterized by scattering techniques, e.g., x-ray diffraction powder pattern, by spectroscopic methods, e.g., infra-red, ¹³C nuclear magnetic resonance spectroscopy, and by thermal techniques, e.g., differential scanning calorimetry or differential thermal analysis. The compound of this invention is best characterized by the X-ray powder diffraction pattern determined in accordance with procedures that are known in the art. For a discussion of these techniques see J. Haleblian, J. Pharm. Sci. 1975 64:1269-1288, and J. Haleblian and W. McCrone, J. Pharm. Sci. 1969 58:911-929. Crystal forms of the invention can be further processed to modulate particle size. For example, the crystal forms of the invention can be milled to reduce average crystal size and/or to prepare a sample suitable for manipulation and formulation.

A polymorphic form may be described by reference to patterns, spectra, or other graphical data as "substantially" shown or depicted in a figure, or by one or more data points. It will be appreciated that patterns, spectra, and other graphical data can be shifted in their positions, relative intensities, or other values due to a number of factors known to those of skill in the art. For example, in the crystallographic and powder X-ray diffraction arts, shifts in peak positions or the relative intensities of one or more peaks of a pattern can occur because of, without limitation, the equipment used, the sample preparation protocol, preferred packing and orientations, the radiation source, operator error, method and length o,f data collection, and the like.

Generally, a diffraction angle (2Θ) in powder X-ray diffractometry may have an error in the range of ± 0.2°. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ± 0.2°. Accordingly, the present disclosure includes not only crystals whose peak diffraction angles in powder X-ray diffractometry completely coincide with each other, but also crystals whose peak diffraction angles coincide with each other with an error of about ± 0.2°. Therefore, in the present specification, the phrase "having a diffraction peak at a diffraction angle (2Θ ± 0.2°) of 7.9°" means "having a diffraction peak at a diffraction angle (2Θ) of 7.7° to 8.1 °. Although the intensities of peaks in the X-ray powder diffraction patterns of different batches of a compound may vary somewhat, the peaks and the peak locations are characteristic for a specific polymorphic form. Alternatively, the term "about" means within an acceptable standard error of the mean, when considered by one of ordinary skill in the art. The relative intensities of the PXRD peaks can vary depending on the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed. Moreover, instrument variation and other factors can affect the 2-theta values. Therefore, the term "substantially" in the context of PXRD is meant to encompass that peak assignments can vary by plus or minus about 0.2. degrees. Moreover, new peaks may be observed or existing peaks may disappear, depending on the type of the machine or the settings (for example, whether a Ni filter is used or not), and sample preparation techniques.

All percentages and ratios used herein are by weight of the total composition and all measurements made are at 25°C and atmospheric pressure unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. The present invention can comprise (open ended) the components of the present invention as well as other ingredients or elements described herein. All ranges recited herein include the endpoints, including those that recite a range "between" two values.

When a molecule or other material is identified herein as "pure," it generally means, unless specified otherwise, that the material has 99% purity or higher, as determined by methods conventional in the art such as high performance liquid chromatography (HPLC) or spectroscopic methods. In general, this refers to purity with regard to unwanted residual solvents, reaction by-products, impurities, and unreacted starting materials. In the case of stereoisomers, "pure" also means 99% of one enantiomer or diastereomer, as appropriate. "Substantially pure" refers to the same as "pure except that the lower limit is about 98% purity or greater and, likewise, "essentially pure" means the same as "pure" except that the lower limit is about 99% purity.

The processes of the present invention provide a compound of structural Formula I with high optical purity, typically in excess of 80% e.e... In embodiments, a compound of Formula I is obtained with an optical purity in excess of 90% e.e. In embodiments, a compound of Formula I is obtained with an optical purity in excess of 95% e.e. In embodiments, a compound of Formula I is obtained with an optical purity in excess of 97% e.e.

DEFINITIONS

The following definitions are used in connection with the present invention unless the context indicates otherwise. In general, the number of carbon atoms present in a given group is designated "C_x-C_y", where x and y are the lower and upper limits, respectively. For example, a group designated as "Ci-C₆" contains from 1 to 6 carbon atoms. A borohydride is a compound containing the tetrahydridoborate(lll) ion, BH₄ ^". "Borohydrides" include, but are not limited to, LiBH₄, NaBH₄, NaBH₃CN, KBH₄, or the like. Hyflow is flux-calcined diatomaceous earth treated with sodium carbonate. Hyflo Super Cel® is a registered trademark of the Manville Corp. Meldrum's acid is 2,2-dimethyl-1 ,3-dioxane-4,6-dione. Polymorphs are different solids sharing the same molecular formula, yet having distinct physical properties when compared to other polymorphs of the same formula. Raney® nickel is a sponge-metal catalyst produced when a block of nickel-aluminum alloy is treated with concentrated sodium hydroxide. Raney® is a registered trademark of W. R. Grace and Company. A sulfonic acid is a compound of the formula RS(0)₂-OH, where R is usually an alkyl or aryl radical. "Sulfonic acids" include, but are not limited to, methanesulfonic acid, benzenesulfonic acid, camphor sulfonic acid, perfluorooctanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, nafion, or the like. As used herein, "comprising" means the elements recited, or their equivalent in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise.

Terms such as "about," "generally," "substantially," or the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.

The term "% enantiomeric excess" (abbreviated "e.e.") shall mean the percentage of major enantiomer less the percentage of minor enantiomer. Thus, a 70% enantiomeric excess corresponds to 85% of one enantiomer and 15% of the other. The term "enantiomeric excess" is synonymous with the term "optical purity."

The term "enantioselective" means a reaction in which one enantiomer is produced (or destroyed) more rapidly than the other, resulting in the predominance of the favored enantiomer in the mixture of products.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner.

EXAMPLES

EXAMPLE 1 : Preparation of (Z)-7-(1 -oxo-3(R)-1 -phenylethylamino)-4- (2,4,5-trifluorophenyl)-but-2-enyl)-3 rifluoromethyl-5,6,7,8-tetrahydro-1 ,2,4- triazolo [4,3-a]pyrazine (Formula V). A round bottom flask is charged with 2,4,5-trifluorophenylacetic acid (25 g), Meldrum's acid (20.5 g), N,N- dimethylaminopyridine (1.28 g) and acetonitrile (75 mL). To this mixture, diisopropylethylamine (47.28 mL) is added dropwise while maintaining the temperature below 50°C. The mixture is then heated to 50°C followed by dropwise addition of pivaloyl chloride (17.8 mL) over about 45 minutes. The mixture is maintained at the same temperature under stirring for 3 hours, followed by addition of triazole hydrochloride (30 g) in one portion. Subsequently, trifluoroacetic acid (2.95 mL) is added and the mixture is maintained at 55°C for another 6 hours. The mixture is then cooled to room temperature, followed by evaporation to remove acetonitrile and afford a residue. Water (100 mL) and ethyl acetate (500 mL) are added to the residue, followed by separation of the organic layer. The organic layer is washed with 5% sodium bicarbonate, then brine solution (50 mL), and is dried over sodium sulfate, followed by distillation at 40°C to form a ketoamide, i.e., 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1 ,2,4]triazolo [4,3a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-one. Isopropyl alcohol (75 mL) and (R)-phenylethylamine (18.64 mL) are added, the mixture is heated to 45- 50°C for 4 hours. The isopropyl alcohol is evaporated completely below 40°C to result in a residue. Dichloromethane (200 mL) and water (100 mL) are added, followed by separation of the organic layer. The aqueous layer is extracted with dichloromethane (200 mL). The organic layers are combined, washed with brine, dried over sodium sulfate, and evaporated to afford residue which on purification results in the title compound (28.7g, 42.8% yield).

EXAMPLE 2: Preparation of 7-[1-oxo-(3 ?)-(R-1-phenylethylamino)- 4(2,4,54rifluorophenyl)-butyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1 ,2,4- triazolo[4,3-a] pyrazine (Formula VI). Dimethoxyethane (35 mL) is charged into a round bottom flask and is cooled to -40°C, followed by addition of sodium borohydride (1.12 g) in one portion. Methanesulfonic acid (4.7 mL) is slowly added with constant stirring at -40°C.

In a separate flask, dimethoxyethane (50 mL) and (Z)-7-(1-oxo-3(R)-1- phenylethylamino)-4-(2,4,5-trifluorophenyl)-but-2-enyl)-3-trifluoromethyl-5,6,7,8- tetrahydro-1 ,2,4-triazolo[4,3a]pyrazine are combined and stirred for 30 minutes at -40°C. This solution is added to the solution of sodium borohydride and methanesulfonic acid over 30 minutes, while maintaining a temperature of -40°C. The mixture is stirred at the same temperature for 3-4 hours, followed by addition of ethyl acetate (200 mL) and water (50 mL). The organic layer is separated, dried over sodium sulfate, and evaporated under vacuum at 40°C to afford the title compound (4.92 g, 98% yield).

EXAMPLE 3: Preparation of 7-[1-oxo-(3R)-(R-1-phenylethylamino)- 4(2,4,5-trifluorophenyl)-butyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4- triazolo[4,3-a] pyrazine (Formula VI). Dimethoxyethane (171 mL) is charged in a flask and cooled to -40°C followed by addition of sodium borohydride (7.3 g) in one lot to the same flask. To this mixture, methanesulfonic acid (31.02 mL) is slowly added with constant stirring at -40°C over 45-60 minutes.

In a separate flask, dimethoxy ethane (495 mL), isopropyl alcohol (34.3 mL) and (Z)-7-(1-oxo-3(R)-1-phenylethylamino)-4-(2,4,5-trifluorophenyl)-but-2- enyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1 ,2,4-triazolo[4,3a]pyrazine (33 g), are combined and stirred at 28°C followed by cooling to -50°C. This solution is slowly added to previously prepared solution of sodium borohydride and methanesulfonic acid, over 4 hours while maintaining a temperature of -50°C. The mixture is stirred at this temperature for 16 hours. The mixture is brought to 0°C followed by addition of ethyl acetate (600 mL). Water (330 mL) is added, stirred for 15 minutes and the organic layer is separated. The aqueous layer is extracted with ethyl acetate (720 mL). The two organic layers are combined and washed with brine solution (250 mL). The organic layer is separated, dried over sodium sulfate, and then evaporated under reduced pressure at 40°C until 0-15% solvent remains in the flask, at which point solid begins to precipitate. The solid is collected by filtration, washed with chilled ethyl acetate (200 mL) and suction dried for 1 hour. The compound is dried under reduced pressure at 50°C for 6 hours to afford the title compound (22.0 g) as a single diastereomer in 83% yield.

EXAMPLE 4: Preparation of 7-[(3/?)-3-amino-1-oxo-4-(2,4,5- trifluorophenyl)-butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1 ,2,4- triazolo[4,3-a]pyrazine (sitagliptin, Formula II). 7-[1-Oxo-(3R)-(R-1- phenylethylamino)-4(2,4,5-trifluorophenyl)-butyl)-3-trifluoromethyl-5,6,7,8- tetrahydro-1 ,2,4-triazolo[4,3-a]pyrazine of Formula VI (5 g), tetrahydrofuran (20 mL), methanol (20 mL), water (5 mL), formic acid (5 mL), and 20% palladium hydroxide on carbon (1.5 g) are charged into a round-bottom flask and heated at reflux for about 8-10 hours. The mass is then cooled to about 30°C and the catalyst is removed by filtration. The filtrate is evaporated completely under reduced pressure below 50°C. Water (100 mL) and chloroform (200 mL) are added to the residue, followed by separation of the organic layer. The organic layer is evaporated below 40°C under reduced pressure to afford the title compound (3.7 g, 93% yield). EXAMPLE 5: Preparation of 7-[(3 ?)-3-amino-1-oxo-4-(2,4,5-trifluoro phenyl)butyl] -5,6,7,8-tetrahydro-3-(trifluoromethyl)-1 ,2,4-triazolo[4,3-a] pyrazine phosphate (Formula I). 7-[(3R)-3-Amino-1-oxo-4-(2,4,5-trifluoro phenyl)butyl]-5,6J,8-tetrahydro-3-(trifluoromethyl)-1 ,2,4-triazolo[4,3-a] pyrazine (10 g) and isopropyl alcohol (100 ml.) are charged into a round bottom flask, heated to 80°C and stirred for 20 minutes. Formic acid (1.13 g) was added to the solution at 80°C and stirred for 40 minutes. The reaction solution is slowly cooled to 26°C and stirred for about 1 ½ hours. The precipitated solid is collected by filtration, washed with isopropyl alcohol (10 ml_), and dried under reduced pressure at 41 °C to obtain 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]- 5,6,7, 8-tetrahydro-3-(trifluoromethyl)-1 ,2,4-triazolo[4,3-a] pyrazine formate (10.5 g, 94.3% yield).

7-[(3f?)-3-Amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3- (trifluoromethyl)-1 ,2,4-triazolo[4,3-a] pyrazine formate (8.0 g) and isopropyl alcohol (120 ml_) are charged into a round bottom flask, heated to 80°C ,and stirred for 75 minutes. To this solution, 85% phosphoric acid (1.73 g) is added and the slurry is heated to 80°C for complete dissolution. The mixture is cooled to 26°C and stirred for about 5½ hours. The precipitated solid is collected by filtration, washed with isopropyl alcohol (16 ml_), and dried under reduced pressure at 40°C to afford the title compound (8.3 g, 93.2% yield).

EXAMPLE 6: Preparation of 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluoro phenyl) butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a] pyrazine phosphate (Formula I). 7-[(3R)-3-Amino-1-oxo-4-(2,4,5- trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1 ,2,4-triazolo[4,3-a] pyrazine (10 g) and isopropyl alcohol (100 mL) are charged into a round bottom flask, heated to 80°C and stirred for 20 minutes. Acetic acid (1.5 g) was added to the solution at 80°C and stirred for 30 minutes. The solution is slowly cooled to 26°C and stirred for about 2 hours. The precipitated solid is collected by filtration, washed with isopropyl alcohol (10 mL) and dried under reduced pressure at 41 °C to obtain 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro- 3-(trifluoromethyl)-1 ,2,4-triazolo[4,3-a] pyrazine acetate (10.7 g, 93.3% yield)

7-[(3R)-3-Amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3- (trifluoromethyl)-1 ,2,4-triazolo[4,3-a] pyrazine acetate (8.0 g) and isopropyl alcohol (120 mL) are charged into a round bottom flask, heated to 80°C ,and stirred for 75 minutes. To this solution, 85% phosphoric acid (1.68 g) is added and the slurry is heated to 80°C for complete dissolution. The mixture is cooled to 26°C and stirred for about 5½ hours. The precipitated solid is collected by filtration, washed with isopropyl alcohol (16 mL), and dried under reduced pressure at 40°C to afford the title compound (7.9 g, 91.3% yield).

EXAMPLE 7: Preparation of 7-[(3R)-3-amino-1-oxo-4-(2,4,5- trifluorophenyl) butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1 ,2,4- triazolo[4,3-a]pyrazine formate. 7-[1-Oxo-(3R)-(R-1-phenylethylamino)-4(2,4,5- trifluorophenyl)-butyl)-3-trifluoro methyl-5,6,7,8-tetrahydro-1 ,2,4-triazoleo[4,3- a]pyrazine hydrochloride of Formula VI (17 g), isopropyl alcohol (85 mL), 10% palladium on carbon (4.25 g) in water (68 mL), methanol (85 mL), and ammonium formate (16.8 g) are charged into a round-bottom flask and heated at reflux for about 2 hours. The mass is then cooled to 26°C, filtered, and washed with methanol (34 mL). The solvent is evaporated off under reduced pressure below 50°C. Isopropyl alcohol (255 mL) is added to the obtained oily residue and heated at reflux for about 1 hour. Formic acid (1.6 mL) is added to the solution and heated at reflux for about 1 hour. The reaction mass is slowly cooled to 8°C over about 2 hours. The precipitated solid is collected by filtration, washed with isopropyl alcohol (34 mL), and dried under reduced pressure at about 45°C, to afford the title compound (9.5 g, 63.3% yield).

EXAMPLE 8: Preparation of 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluoro phenyl) butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a] pyrazine phosphate (Formula I). 7-[(3R)-3-Amino-1-oxo-4-(2,4,5- trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1 ,2,4-triazolo[4,3-a] pyrazine formate (8.0 g) and isopropyl alcohol (16 mL) are charged into a round bottom flask, heated at reflux, and stirred for about 1 hour. 85% Phosphoric acid (2 g) is added to the reaction mass and heated at reflux for about 1 hour.

Isopropyl alcohol (64 mL) is added to the reaction mixture. The reaction mixture is cooled to 26°C and stirred for about 22½ hours. The precipitated solid is collected by filtration, washed with isopropyl alcohol (16 mL), and dried under reduced pressure at 45°C for about 5 hours, to afford the title compound (7.6 g, 85.2% yield; Purity by HPLC: 99.30%). EXAMPLE 9: Preparation of 7-[(3ft)-3-amino-1-oxo-4-(2,4,5-trifluoro phenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1 ,2,4-triazolo[4,3-a] pyrazine phosphate (Formula I). 7-[(3R)-3-Amino-1-oxo-4-(2,4,5- trifluorophenyl)butyl]-5,6J,8-tetrahydro-3-(trifluoromethyl)-1 ,2^-triazolo[4,3-a] pyrazine formate (5.0 g) and isopropyl alcohol (65 mL) are charged into a round bottom flask, heated at reflux, and stirred for about 1 hour. A solution of ammonium dihydrogen phosphate (1.3 g) in water (3 mL) is added to the reaction mass at reflux and stirred for about 30 minutes. The reaction mixture is cooled to 26°C and stirred for about 6 hours. The precipitated solid is collected by filtration, washed with isopropyl alcohol (8 mL), and dried under reduced pressure at 45°C for about 4 hours, to afford the title compound (3.6 g).

EXAMPLE 10: Preparation of 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluoro phenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a] pyrazine acetate. 7-[1-Oxo-(3R)-(R-1-phenylethylamino)-4(2,4,5-trifluorophenyl)- butyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1 ,2,4-triazolo[4,3-a]pyrazine (10.0 g), methanol (50 mL), 10% palladium on carbon (50% wet; 0.5 g), and acetic acid (1.4 mL) are charged into autoclave vessel at 28°C. The mass is heated to 55°C, and a hydrogen gas pressure of 10-15 kg/cm² is applied and maintained for 85 minutes. The mass is cooled to room temperature, filtered through a Hyflow (flux calcined diatomaceous earth) bed, and the solvent is evaporated at 50°C. Water (100 mL) and dichloromethane (100 mL) are added to the residue and stirred for 50 minutes. The mass is filtered and washed with dichloromethane (10 mL). The organic and aqueous layers are separated. The aqueous layer is extracted with dichloromethane (2x50 mL). Organic layers are combined, dried over sodium sulfate ( 0 g), and evaporated at 42°C. Isopropyl alcohol (120 mL) is added to the residue at 26°C and the mass is heated at reflux and stirred for 1 hour. Acetic acid (1.4 mL) is added and the mass is further maintained for 1 hour under reflux. The mass is allowed to cool to room temperature and stirred for 2 hours. The solid is collected by filtration, washed with isopropyl alcohol (20 mL), and dried at 46°C under reduced pressure for 5 hours to obtain the title compound. Yield: 5.6 g; Purity by HPLC: 99.35%.

EXAMPLE 11 : Preparation of 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluoro phenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a] pyrazine acetate. 7-[1 -Oxo-(3f?)-(R-1 -phenylethylamino)-4(2,4,5-trifluorophenyl)- butyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1 ,2,4-triazolo[4,3-a]pyrazine

hydrochloride (10.0 g), 10% palladium on carbon (50% wet; 0.5 g), methanol (30 mL), and water (30 mL) are charged into an autoclave vessel followed by addition of acetic acid (1.2 mL) at 28°C. The mass is heated to 60°C and hydrogen gas pressure of about 10-15 kg/cm² is applied and maintained for 5 hours. The mass is allowed to cool to room temperature and is filtered through a Hyflow bed. Water (200 mL) and dichloromethane (200 mL) are added to the filtrate and the mass is stirred for 25 minutes. The pH of the mass is adjusted to about 9.5 by adding ammonia solution (5 mL) and the mass is stirred for 50 minutes. The mass is filtered through a Hyflow bed. The organic and aqueous layers are separated. The aqueous layer is extracted with dichloromethane (100 mL). Organic layers are combined and evaporated at 40°C. Isopropyl alcohol (120 mL) is added to the residue at 26°C and the mass is heated at reflux and stirred for 1 hour. Acetic acid (1.4 mL) is added to the mass and it is maintained for 75 minutes under reflux. The mass is allowed to cool to room temperature and maintained for 90 minutes. Seed crystals (0.1 g) are added and further stirred for 3 hours. The solid is collected by filtration, washed with isopropyl alcohol (20 mL), and dried at 45°C under reduced pressure for 2½ hours to obtain the title compound. Yield: 5.3 g; Purity by HPLC: 99.49%.

EXAMPLE 12: Preparation of 7-[(3 ?)-3-amino-1-oxo-4-(2,4,5-trifluoro phenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a] pyrazine acetate. 7-[1 -Oxo-(3R)-(R-1 -phenylethylamino)-4(2,4,5-trifluorophenyl)- butyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1 ,2,4-triazolo[4,3-a]pyrazine (10.0 g), 10% palladium on carbon (50% wet; 0.5 g), methanol (40 mL), and water (10 mL) are charged into an autoclave vessel at 28°C. The mass is heated to 55°C and hydrogen gas pressure of 10-15 kg/cm² is applied and maintained for 30 minutes. The mass is allowed to cool to room temperature, and then is filtered through a Hyflow bed. Water (190 mL) and dichloromethane (200 mL) are added to the filtrate and the mass is stirred for 90 minutes. The pH of the mass is adjusted to about 9.5 by adding ammonia solution (5 mL) and it is stirred for 90 minutes. The mass is filtered through a Hyflow bed. The organic and aqueous layers are separated. The aqueous layer is extracted with dichloromethane (100 mL). Organic layers are combined, dried over sodium sulfate (10 g), and evaporated at 40°C. Isopropyl alcohol (120 mL) is added to the residue at 26°C. The mass is heated at reflux and stirred for 40 minutes. Acetic acid (1.2 mL) is added and the mass is maintained for 50 minutes under reflux. The mass is allowed to cool to room temperature and maintained for 3 hours. Seed crystals (0.1 g) are added and the mass is stirred for 4 hours. The solid is collected by filtration, washed with isopropyl alcohol (20 mL), and dried at 45°C for 19 hours to obtain the title compound. Yield: 5.7 g; Purity by HPLC: 99.58%.

EXAMPLE 13: Preparation of sitagliptin phosphate Form A. Sitagliptin formate (3.0 g) and ethyl acetate (30 mL) are charged into a round bottom flask and heated at reflux for 20 minutes. Ethyl acetate (2x30 mL) is added and the mass is further heated at reflux to obtain a clear solution. Phosphoric acid (0.8 g) is added to the solution and the mass is maintained at reflux temperature for 35 minutes. The mass is cooled to room temperature and maintained for 2 hours, 15 minutes. The solid is collected by filtration, washed with ethyl acetate (6 mL), and dried at 45°C for 8½ hours under reduced pressure to obtain the title compound. Yield: 3.1 g.

EXAMPLE 14: Preparation of sitagliptin phosphate Form A. Sitagliptin formate (3.0 g) and 1 ,2-dimethoxyethane (60 mL) are charged into a round bottom flask and heated at reflux to obtain a clear solution. Phosphoric acid (0.8 g) is added to the solution and the mass is maintained at reflux temperature for 30 minutes. The mass is cooled to room temperature and maintained for 75 minutes. The solid is collected by filtration, washed with 1 ,2-dimethoxyethane (6 mL), and dried at 49 ± 1 °C for 9 hours under reduced pressure to obtain the title compound. Yield: 2.7 g.

EXAMPLE 15: Preparation of sitagliptin phosphate Form A. Sitagliptin formate (3.0 g) and acetone (12 mL) are charged into a round bottom flask and heated at reflux to obtain a clear solution. Phosphoric acid (0.8 g) is added to the solution and the mass is maintained at reflux temperature for 30 minutes. The mass is cooled to room temperature and maintained for 2 hours, 45 minutes. The solid is collected by filtration, washed with acetone (6 mL), and dried at 49 ± 1°C for 7 hours under reduced pressure to obtain the title compound. Yield: 3.0 g. EXAMPLE 16: Preparation of sitagliptin phosphate Form A. Sitagliptin acetate (4.0 g) and acetone (16 mL) are charged into a round bottom flask and heated at reflux to obtain a clear solution. Phosphoric acid (0.9 g) is added to the solution followed by addition of acetone (16 mL) and the mass is maintained at reflux temperature for 1 hour. The mass is cooled to room temperature and maintained for 1 hour, 40 minutes. The solid is collected by filtration, washed with acetone (8 mL), and dried at 50°C for 7 hours under reduced pressure to obtain the title compound. Yield: 3.0 g.

EXAMPLE 17: Preparation of sitagliptin phosphate Form A. Sitagliptin acetate (4.0 g) and 1 ,2-dimethoxyethane (80 mL) are charged into a round bottom flask and heated at reflux to obtain a clear solution. Phosphoric acid (0.9 g) is added to the solution and the mass is maintained at reflux temperature for 1 hour. The mass is cooled to room temperature and maintained for 4 hours 45 minutes. The solid is collected by filtration, washed with 1 , 2-dimethoxyethane (8 mL), and dried at 50°C for 4½ hours under reduced pressure to obtain the title compound. Yield: 3.6 g.

EXAMPLE 18: Preparation of sitagliptin phosphate Form A. Sitagliptin acetate (4.0 g) and ethyl acetate (120 mL) are charged into a round bottom flask and heated at reflux to obtain a clear solution. Phosphoric acid (1.0 g) is added to the solution and the mass is maintained at reflux temperature for 1 hour. The mass is cooled to room temperature and maintained for 3 hours. The solid is collected by filtration, washed with ethyl acetate (8 mL), and dried at 45°C for 10 hours, 15 minutes under reduced pressure to obtain the title compound. Yield: 4.1 9·

EXAMPLE 19: Preparation of 7-[(3 ?)-3-amino-1-oxo-4-(2,4,5-trifluoro phenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a] pyrazine acetate. 7-[1-Oxo-(3f?)-(R-1-phenylethylamino)-4(2,4,5-trifluorophenyl)- butyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1 ,2,4-thazolo[4,3-a]pyrazine

hydrochloride (10.0 g), 10% palladium on carbon (50% wet, 0.5 g), methanol (40 mL), and water (10 mL) are charged into an autoclave vessel at 28°C. The mass is heated to 55-60°C and hydrogen gas pressure of 7-10 kg/cm² is applied and maintained until completion of reaction. The mass is allowed to cool to room temperature. The reaction mass is filtered through a Hyflow bed and washed with methanol (10 mL). Water (200 mL) and dichloromethane (200 mL) are added to the filtrate. The pH of the mass is adjusted to 9-10 by adding ammonia solution (5.4 mL) and it is stirred for 30-60 minutes. The organic and aqueous layers are separated. The aqueous layer is extracted with dichloromethane (2x30 mL). Organic layers are combined and acetic acid is added at room temperature. The solvent is evaporated off completely under vacuum below 35°C. Isopropyl alcohol (80 mL) is added to the residue. The mass is heated to 55-60°C and stirred for clear solution for about 1-2 hours at the same temperature. Acetic acid (2.6 mL) is added and the mass is maintained for 1 hour under reflux. The mass is allowed to cool to room temperature and maintained for 1 hour. Seed crystals (0.2 g) are added and the mass is stirred for about 4½ hours. The solid is collected by filtration, washed with isopropyl alcohol (20 mL), and dried at 48°C for 7 hours to obtain the title compound.

EXAMPLE 20: Preparation of 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluoro phenyl)butyl]-5,6,7,8-tetrahydro-3-(trif luoromethyl)-1 ,2,4-triazolo[4,3-a] pyrazine acetate and 7-[(3 ?)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]- 5,6,7,8-tetrahydro-3-(trifluoromethyl)-1 ,2,4-triazolo[4,3-a]pyrazine formate. 7- [1-Oxo-(3f?)-(R-1-phenylethylamino)-4(2,4,5-trifluorophenyl)-butyl)-3-trifluoro methyl-5,6,7,8-tetrahydro-1 ,2,4-triazolo[4,3-a]pyrazine hydrochloride (100.0 g), 10% palladium on carbon (50% wet, 5.0 g), methanol (400 mL), and water (100 mL) are charged into an autoclave vessel at 26°C. Hydrogen gas pressure of about 11.5-13 kg/cm² is applied to the reaction mass, heated to 55°C and maintained for 15½ hours. The mass is allowed to cool to room temperature, then is filtered through a Hyflow bed and washed with water (100 mL). Water (1800 mL) and dichloromethane (1000 mL) are added to the filtrate and stirred for 10 minutes. The pH of the reaction mass is adjusted to about 9.3 with aqueous ammonia (60 mL) and it is stirred for 20 minutes. The organic and aqueous layers are separated. The aqueous layer is extracted with dichloromethane (500 mL). Organic layers are combined and divided into two equal parts.

Part 1 : solvent in the organic layer is evaporated off at 45°C. Isopropyl alcohol (600 mL) is added to the residue at 32°C. The mass is heated at reflux and stirred for 35 minutes. Acetic acid (5.9 g) is added and the mass is

maintained for 60 minutes under reflux. The mass is allowed to cool to room temperature and maintained for 1 hour. Seed crystals (0.5 g) are added and the mass is stirred for 6 hours. The solid is collected by filtration, washed with isopropyl alcohol (100 mL), and dried at 45°C under reduced pressure for 10 hours to obtain 7-[(3 ?)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl) butyl]-5,6,7,8- tetrahydro-3-(trifluoromethyl)-1 ,2,4-triazolo[4,3-a]pyrazine acetate. Yield: 34.40 g; Purity by HPLC: 99.57%.

Part 2: solvent in the organic layer is evaporated off at 45°C. Isopropyl alcohol (600 mL) is added to the residue at 32°C. The mass is heated at reflux and stirred for 40 minutes. Acetic acid (4.5 g) is added and the mass is maintained for 65 minutes under reflux. The mass is allowed to cool to room temperature and maintained for 5 hour. The solid is collected by filtration, washed with isopropyl alcohol (100 mL), and dried at 45°C under reduced pressure for 7½ hours to obtain 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl) butyl]-5,6,7,8- tetrahydro-3-(trifluoromethyl)-1 ,2,4-triazolo[4,3-a]pyrazine formate. Yield: 33.60 g; Purity by HPLC: 99.25%.

EXAMPLE 21 : Preparation of 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluoro phenyl)butyl] -5,6,7, 8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a] pyrazine acetate. 7-[1 -Oxo-(3R)-(R-1 -phenylethylamino)-4(2,4,5-trifluorophenyl)- butyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1 ,2,4-triazolo[4,3-a]pyrazine (20.0 g), 10% palladium on carbon (50% wet, 1.0 g), methanol (80 mL), and water (20 mL) are charged into an autoclave vessel at 28°C. The mass is heated to 55°C and hydrogen gas pressure of 7-10 kg/cm² is applied and maintained for 10 hours. The mass is allowed to cool to room temperature. The reaction mass is filtered through a Hyflow bed and washed with methanol (20 mL). Water (190 mL) and dichloromethane (200 mL) are added to the filtrate. The pH of the mass is adjusted to 9.3 by adding ammonia solution (10 mL) and it is stirred for 20 minutes. The organic and aqueous layers are separated. The aqueous layer is extracted with dichloromethane (2x60 mL). Organic layers are combined and evaporated at 42°C. Isopropyl alcohol (200 mL) is added to the residue at 26°C. The mass is heated at reflux and stirred for 45 minutes. Acetic acid (2.6 mL) is added and the mass is maintained for 1 hour under reflux. The mass is allowed to cool to room temperature and maintained for 1 hour. Seed crystals (0.2 g) are added and the mass is stirred for about 4½ hours. The solid is collected by filtration, washed with isopropyl alcohol (20 mL), and dried at 48°C for 7 hours to obtain the title compound. Yield: 12.80 g; Purity by HPLC: 99.87%.

EXAMPLE 22: Preparation of 7-[(3/?)-3-amino-1-oxo-4-(2,4,5-trifluoro phenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a] pyrazine acetate. 7-[1-Oxo-(3f?)-(R-1-phenylethylamino)-4(2,4,5-trifluorophenyl)- butyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1 ,2,4-triazolo[4,3-a]pyrazine

hydrochloride (75.0 g) and methanol (300 mL) are charged into an autoclave vessel at 28°C followed by addition of 10% palladium on carbon (50% wet, 3.75 g) and water (75 mL). A hydrogen gas pressure of 7- 0 kg/cm² is applied to the reaction mass. The mass is heated to 57°C and hydrogen gas pressure of 7-10 kg/cm² is applied and maintained for about 9 hours. The mass is allowed to cool to room temperature. The reaction mass is filtered and washed with methanol (75 mL). Water (1500 mL) and dichloromethane (750 mL) are added to the filtrate and stirred for 35 minutes. The pH of the mass is adjusted to 9.4 by adding ammonia solution (62 mL). The organic and aqueous layers are separated. The aqueous layer is extracted with dichloromethane (2x225 mL). Organic layers are combined and acetic acid (9.9 g) is added. The solvent is evaporated at 40°C. Isopropyl alcohol (600 mL) is added to the residue at 34°C. The mass is heated at reflux for 2 hours. The mass is allowed to cool to room temperature. Seed crystals (0.2 g) are added and the mass is stirred for about 5 hours. The solid is collected by filtration, washed with isopropyl alcohol (75 mL), and dried at 53°C for about 7½ hours to obtain the title compound. Yield: 50.10 g; Purity by HPLC: 99.89%.

EXAMPLE 23: Preparation of sitagliptin phosphate Form A. Sitagliptin formate (30.0 g) and isopropyl alcohol (450 mL) are charged into a round bottom flask and heated at reflux to obtain a clear solution. Phosphoric acid (7.4 g) is added to the solution and the mass is maintained at reflux temperature for 1 hour. The mass is cooled to room temperature and maintained for 7 hours. The solid is collected by filtration, washed with isopropyl alcohol (60 mL), and dried at 45°C for 6 hours under reduced pressure to obtain the title compound. Yield: 31.90 g.

EXAMPLE 24: Preparation of sitagliptin phosphate Form A. Sitagliptin acetate (5.0 g) and isopropyl acetate (50 mL) are charged into a round bottom flask and heated at reflux to obtain a clear solution. Phosphoric acid (1.2 g) is added to the solution and the mass is maintained at reflux temperature for 1 hour. The mass is cooled to room temperature and maintained for 5 hours. The solid is collected by filtration, washed with isopropyl acetate (10 ml_), and dried at 47°C for 7 hours under reduced pressure to obtain the title compound. Yield: 4.8 g.

EXAMPLE 25: Preparation of sitagliptin phosphate Form A. Sitagliptin acetate (10.0 g) and isopropyl alcohol (100 mL) are charged into a round bottom flask and heated at reflux to obtain a clear solution. Phosphoric acid (2.4 g) is added to the solution and the mass is maintained at reflux temperature for 8 hours. The mass is cooled to room temperature and maintained for 1 hour. The solid is collected by filtration, washed with isopropyl alcohol (20 mL), and dried at 52°C for 4! hours under reduced pressure to obtain the title compound. Yield: 10.2 g.

EXAMPLE 26: Preparation of sitagliptin phosphate Form A. Sitagliptin acetate (40.0 g) and methanol (320 mL) are charged into a round bottom flask at 25-35°C and stirred at the same temperature for 30-60 minutes. The reaction mass is filtered and washed with methanol (40 mL). Phosphoric acid (10.4 g) in methanol (40 mL) is added to the above solution over a period of 25 minutes and maintained for about 2-3 hours. The solid obtained is collected by filtration, washed with methanol (40 mL), and dried at 50-60°C for about 10-12 hours under reduced pressure to obtain the title compound. Yield: 37.0 g; Purity by HPLC: 99.97%.

While particular aspects of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.

Claims

CLAIMS:

1. A process for the preparation of a phosphate salt of sitagliptin of Formula I, as a single enantiomer or in an enantiomerically enriched form, embodiments comprising:

H₃P0₄

Formula I

with a compound

Formula IV

Formula V

Formula VI

(iii) converting a compound of Formula VI or its salt to an enantiomerically pure acid addition salt of sitagliptin of Formula VII:

Formula VII

wherein HY is an acid moiety such as hydrochloric acid, phosphoric acid, oxalic acid, hydrobromic acid, acetic acid, formic acid, succinic acid, mandelic acid, fumaric acid, benzoic acid, or the like; and (iv) converting an acid addition salt of sitagliptin obtained in step (iii) to an enantiomerically pure or enriched phosphate salt of sitagliptin of Formula I, by treating with a source of phosphate ion.

2. The process of claim 1 , wherein the chiral reagent of Formula IV is (R)-1- phenylethyl amine.

3. The process of any one of claim 1 or of claim 2, wherein the hydride is a borohydride.

4. The process of claim 3, wherein the borohydride is sodium borohydride.

5. The process of any one of claims 1-4, wherein the sulfonic acid is

methanesulfonic acid.

6. The process of any one of claims 1-5, wherein the acid addition salt of sitagliptin in step (iii) is hydrochloric acid, phosphoric acid, oxalic acid, hydrobromic acid, acetic acid, formic acid, succinic acid, mandelic acid, fumaric acid, or benzoic acid salt.

7. A process for preparation of crystalline sitagliptin phosphate Form A, comprising converting an acid addition salt of sitagliptin to an enantiomerically pure or enriched phosphate salt of sitagliptin of Formula I, by treating with a source of phosphate ion.

8. A process for preparation of crystalline sitagliptin phosphate Form A, comprising the steps of:

(ii) adding a source of phosphate ion source to the mixture of (i); and

(iii) isolating crystalline sitagliptin phosphate Form A.

9. The process of claim 8, wherein the acid addition salt of sitagliptin is selected from hydrochloride, hydrobromide, phosphate, oxalate, acetate, formate, succinate, mandelate, fumarate, or benzoate salt.

10. The process of claim 9, wherein the acid addition salt is a sitagliptin acetate salt.

11. The process of claim 9, wherein the acid addition salt is a sitagliptin formate.

12. A process for the preparation of crystalline sitagliptin phosphate comprising;

(i) providing a mixture of an acid addition salt of sitagliptin in a suitable solvent

(ii) adding a source of phosphate ion to the above mixture

(iii) isolating a crystalline form of sitagliptin phosphate

13. The process of claim 12, wherein the acid addition salt of sitagliptin is selected from a hydrochloride, hydrobromide, phosphate, oxalate, acetate, formate, succinate, mandelate, fumarate or benzoate salt.

1^'4. The process of claim 13, wherein the acid addition salt is a sitagliptin acetate salt.

15. The process of claim 13, wherein the acid addition salt is a sitagliptin formate salt.