WO2011025932A2

WO2011025932A2 - Preparation of sitagliptin and salts thereof

Info

Publication number: WO2011025932A2
Application number: PCT/US2010/046938
Authority: WO
Inventors: Rakeshwar Bandichhor; Nagaraju Gudimalla; Namrata Dwivedi; Kiran Kumar Chetluru; Srinivas Reddy Gade; Venkateswarlu Muvva; Bindu Srivastava
Original assignee: Dr. Reddy's Laboratories Ltd.; Dr. Reddy's Laboratories, Inc.
Priority date: 2009-08-28
Filing date: 2010-08-27
Publication date: 2011-03-03
Also published as: EP2470542A2; WO2011025932A3; EP2470542A4

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.

The drug compound having the adopted name "sitagliptin phosphate" has chemical names: 7-[(3R)-3-amino-1 -oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8- tetrahydro-3-(thfluoromethyl)-1 ,2,4-thazolo[4,3-a]pyrazine phosphate (1 :1 ); or (2R)-4-oxo-4-[3-(thfluoromethyl) -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.

Formula I

Sitagliptin is a glucagon like peptide 1 metabolism modulator, hypoglycemic agent and dipeptidyl peptidase IV inhibitor, and is believed to exert its action in patients with type 2 diabetes by slowing the inactivation of incretin hormones. An oral tablet product containing sitagliptin phosphate monohydrate as the active ingredient 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 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. International Application Publication No. WO 2004/085661 A2 discloses a process for the preparation of sitagliptin, in which (S)-phenylglycine amide is used as a chiral auxilary to form an intermediate, which subsequently provides the desired enantiomer (sitagliptin).

International Application Publication No. WO 2009/085990 A2 discloses a process for the preparation of sitagliptin in which a (R)-i -phenylalkylamine is used as a chiral auxiliary to form an intermediate, which subsequently provides the desired enantiomer (sitagliptin).

These applications disclose the use of Adam's catalyst, i.e., a platinum oxide, to promote the diastereoselective hydrogenation of the enamine carbon- carbon double bond in the chiral substrate. Platinum oxide can form a highly flammable reaction product, is a costly catalyst, and causes concerns with process scalability. Further, the diastereo selectivity in the process is low and results in low yields during subsequent process steps.

There is a need for processes for the preparation of sitagliptin and its salts that are simple, cost effective, and viable on a commercial scale, and further avoid use of hazardous regents like platinum oxide.

SUMMARY

Aspects of the present application provide processes for the preparation of enantiomerically enriched sitagliptin or a salt thereof. Each step of the processes disclosed herein are contemplated both in the context of the multi-step sequences described, and individually.

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 Il

(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 of Formula IV,

Ph

H₂N R

Formula IV

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

Formula V

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

Formula Vl

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

enantiomerically pure acid addition salt of sitagliptin of Formula VII,

Formula VIl

wherein HY is an acid moiety. In an aspect, there are provided one-pot processes for the preparation of a compound of Formula V, starting from 2,4,5-trifluorophenylacetic acid,

embodiments comprises at least one of the steps:

(i) reacting 2,4,5-trifluorophenylacetic acid of Formula VIII with 2,2- dimethyl-1 ,3-dioxane-4,6-dione (Meldrums acid) of Formula IX, in the presence of a suitable base in an organic solvent, to afford the compound of Formula X.

Formula VIII Formula IX Formula X

(ii) reacting the compound of Formula X with 3-thfluoromethyl-5,6,7,8- tetrahydro-1 ,2,4-triazolo[4,3a]pyrazine hydrochloride of Formula Xl, in the presence of diisopropylethylamine, to afford the compound of Formula III; and

(iii) reacting the compound of Formula III with (R)-(+)-1-phenylethylamine, also known as (R)-(+)-α-methylbenzylamine, of Formula IVA, in the presence of an organic solvent, to afford a compound of Formula VA,

Formula IVA Formula VA

wherein Ph is a phenyl group.

In an aspect, there are provided pharmaceutical compositions that include sitagliptin or its pharmaceutically acceptable salt or anhydrate and at least one pharmaceutically acceptable excipient. BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is an illustration of a powder X-ray diffraction (PXRD) pattern of crystalline 7-[1 -oxo-(3R)-(R-1 -phenylethylamino)-4(2,4,5-trifluorophenyl)-butyl)-3- trifluoromethyl-5,6,7,8-tetrahydro-1 ,2,4-triazoleo[4,3-a]pyrazine hydrochloride, prepared according to Example 5.

Fig. 2 is an illustration of a thermogravimetric analysis (TGA) curve of crystalline 7-[1 -oxo-(3R)-(R-1 -phenylethylamino)-4(2,4,5-trifluorophenyl)-butyl)-3- trifluoromethyl-5,6,7,8-tetrahydro-1 ,2,4-triazoleo[4,3-a]pyrazine hydrochloride, prepared according to Example 5.

Fig. 3 is an illustration of a PXRD pattern of a crystalline dihydrogen phosphate salt of sitagliptin, prepared according to Example 9.

DETAILED DESCRIPTION

All percentages and ratios used herein are expressed by weight of the total composition and all measurements made are at ambient temperature 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.

As used herein, "comprising" means the elements recited, or their equivalents 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.

All ranges recited herein include the endpoints, including those that recite a range "between" two values.

Terms such as "about," "generally," "substantially," and 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 the very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.

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 using methods conventional in the art such as high performance liquid chromatography (HPLC), gas chromatography (GC), 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 higher and, likewise, "essentially pure" means the same as "pure" except that the lower limit is about 97% purity.

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

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

In embodiments, a compound of Formula I is obtained with an optical purity in excess of 95% ee. In embodiments, a compound of Formula I is obtained with an optical purity in excess of 97% ee.

In an aspect, the present patent application provides stereoselective processes for the preparation of sitagliptin of Formula II, or a salt thereof, as a single enantiomer or in an enantiomehcally enriched form, each step of which is separately contemplated. Embodiments of processes include the steps:

Formula Il

with a compound of Formula IV,

Ph

H₂N R

Formula IV

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

Formula V

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

Formula Vl

(iii) converting a compound of Formula Vl or its salt to an addition salt of sitagliptin of Formula VII,

Formula VII

wherein HY is an acid moiety.

Step (i) involves preparing an enamide of structural Formula V containing a (R)-(+)-1 -phenylalkylamine, such as (R)-(+)-1 -phenylethylamine, as a chiral auxiliary. For the reaction of step (i), the quantity of (R)-1 -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, and 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, n-hexane, n-heptane, and cyclohexane; ethers such as 1 ,4-dioxane and tetrahydrofuran; organic acids such as acetic acid, propionic acid, and the like; and 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 150⁰C, less than about 120⁰C, less than about 80°C, less than about 60⁰C, 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 to a compound of Formula Vl 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, to afford a protected chiral amine of Formula Vl. The diastereoselective reduction may be carried out in the presence of a borohydhde such as sodium borohydride, sodium cyanoborohydride, lithium borohydride, and the like, and a sulfonic acid such as methanesulfonic acid, p-toluenesulfonic, acid and 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), and the like; halogenated

hydrocarbons such as dichloromethane, ethylene dichloride, and chloroform;

hydrocarbons such as toluene, xylene, n-hexane, n-heptane, and cyclohexane; ethers such as 1 ,4-dioxane, tetrahydrofuran, and methyl t-butyl ether; aprotic polar solvents such as N,N-dimethylfornnannide (DMF), dimethylsulfoxide (DMSO), and dimethylacetamide (DMA); and any mixtures thereof. Optionally, the reaction may be carried out without a solvent.

Suitable temperatures for the reaction may be less than about 150⁰C, less than about 100⁰C, less than about 60°C, less than about 25°C, less than about 0⁰C, less than about -25°C, less than about -50⁰C, 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.

Optionally, the compound of Formula Vl 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 diastereomehc 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, and 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, and 2,2,2-trifluoroethanol (TFE); esters such as ethyl acetate, n-propyl acetate, and isopropyl acetate;

ketones such as acetone and methyl isobutyl ketone; hydrocarbons such as toluene and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as 1 ,4-dioxane and tetrahydrofuran; nitriles such as acetonitrile; water; and any mixtures thereof. An anti-solvent as used herein refers to a solvent in which a compound of Formula Vl 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, and the like; and organic acids such as acetic acid, methanesulfonic acid, oxalic acid, formic acid, and 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 thethylamine, dicyclohexylamine, diisopropylethylamine, morpholine, ammonium hydroxide, and the like. Typically, the compound of Formula Vl or its salt has a diastereomeric ratio of more than 80:20, or more than 95:5, or about 100:0.

Step (iii) in the process of the present application entails the removal of (R)- 1 -phenylalkylamine under hydrogenolytic conditions to afford sitagliptin free base of Formula Il 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 Il with a suitable acid.

The removal of the (R)-(+)-1-phenylalkylamine 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, and palladium hydroxide on carbon, or by transfer hydrogenation using ammonium formate, hydrazine, formic acid, and 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, and 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, n-hexane, n-heptane, and cyclohexane; ethers such as 1 ,4-dioxane and tetrahydrofuran; aprotic polar solvents such as N,N-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 150⁰C, less than about 100⁰C, less than about 80°C, less than about 60⁰C, 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 Il 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, and 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, and 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, n-hexane, n-heptane, and cyclohexane; ethers such as 1 ,4-dioxane and tetrahydrofuran; aprotic polar solvents such as N,N-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 100⁰C, less than about 80⁰C, 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.

An acid addition salt 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. 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, and the like or any other suitable techniques. The solids that are isolated may carry a small proportion of occluded mother liquor containing a higher percentage of impurities. If desired, the solids may be washed with a solvent to wash out the mother liquor and/or impurities and the resulting wet solids 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 including, but not limited to, tray drying, spray drying, fludized bed drying, and thin film drying, under reduced pressure or 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, and the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 200⁰C, or about 20⁰C to about 80°C, or about 30⁰C 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.

In an aspect, the present invention includes one-pot processes, where one or more intermediate compounds are not isolated, for preparing a compound of Formula V, starting from 2,4,5-trifluorophenylacetic acid, embodiments of which comprise at least one of the steps:

(i) reacting 2,4,5-trifluorophenylacetic acid of Formula VIII with 2,2- dimethyl-1 ,3-dioxane-4,6-dione (Meldrums acid) of Formula IX, in the presence of a suitable base in an organic solvent, to afford the compound of Formula X;

Formula VlIl Formula IX Formula X (ii) reacting the compound of Formula X with 3-thfluoromethyl-5,6,7,8- tetrahydro-1 ,2,4-triazolo[4,3a]pyrazine hydrochloride of Formula Xl, in the presence of diisopropylethylamine, to afford the compound of Formula III; and

(iii) reacting the compound of Formula III with a (R)-(+)-1 - phenylalkylamine of Formula IV, in the presence of an organic solvent, to afford a compound of Formula V, where Ph is phenyl and R is Ci-C₄ alkyl.

Formula IV

Formula V

Step (i) involves condensation of 2,4,5-trifluorophenyl acetic acid with 2,2- dimethyl-1 ,3-dioxane-4,6-dione (Meldrums acid) of Formula IX.

The quantity of Meldrums acid that may be used in step (i) may be less than about 2, or less than about 3, or less than about 5 molar equivalents, per mole of the compound of Formula VIII.

Bases that may be used in step (i) include, but are not limited to: organic bases, such as, for example, triethylamine, diisopropylethylamine, pyridine, imidazole, N-methylmorpholine, sodium methoxide, diisopropylamine, and the like, inorganic bases, such as, for example, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate; and any mixtures thereof.

Organic solvents that may be used in step (i) include, but are not limited to: nithles such as acetonitrile; alcohols, such as, for example, methanol, ethanol, isopropanol, n-butanol, and the like; halogenated hydrocarbons, such as, for example, dichloromethane, ethylene dichlohde, chloroform, and the like; esters, such as, for example, ethyl acetate, n-propyl acetate, isopropyl acetate, and the like; hydrocarbons, such as, for example, toluene, xylene, n-hexane, n-heptane, cyclohexane, and the like; ethers, such as, for example, 1 ,4-dioxane, tetrahydrofuran, and the like; aprotic polar solvents, such as, for example, N₁N- dimethylformamide (DMF), dimethylsulfoxide (DMSO), and dimethylacetamide (DMA); and any mixtures thereof.

Suitable temperatures for the reaction of step (i) may be less than about 120⁰C, less than about 100⁰C, less than about 60°C, or any other suitable temperatures.

Step (ii) involves preparation of the compound of Formula III by reacting the compound of Formula X with 3-thfluoromethyl-5,6,7,8-tetrahydro-1 ,2,4- triazole[4,3-a]pyrazine hydrochloride of Formula Xl, in the presence of

diisopropylethylamine, in an organic solvent.

The 3-trifluoromethyl-5,6,7,8-tetrahydro-1 ,2,4-thazole[4,3-a]pyrazine hydrochloride of Formula Xl may be prepared, e.g., using the process disclosed by J. Balsells et al., "Synthesis of [1 ,2,4]Thazolo[4,3-α]piperazines via Highly Reactive Chloromethyloxadiazoles," Organic Letters, Vol. 7(6), pp. 1039-1042, 2005.

The quantities of 3-trifluoromethyl-5,6,7,8-tetrahydro-1 ,2,4-triazole[4,3- a]pyrazine hydrochloride of Formula Xl may be less than about 3, or less than about 2, or less than about 1 molar equivalents, per mole of the compound of Formula X.

The quantities of diisopropylethylamine may be less than about 3, or less than about 2, or less than about 1 , molar equivalents, per mole of the compound of Formula X.

Solvents that may be used in step (ii) include, but are not limited to: nithles such as acetonitrile; halogenated hydrocarbons, such as dichloromethane, ethylene dichloride, and chloroform; hydrocarbons, such as toluene, xylene, n- hexane, n-heptane, and cyclohexane; ethers, such as 1 ,4-dioxane and

tetrahydrofuran; aprotic polar solvents, such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), and dimethylacetamide (DMA); and any mixtures thereof. Suitable temperatures for the reaction of step (ii) may be less than about 120⁰C, less than about 80⁰C, less than about 60°C, or any other suitable temperatures.

Suitable times for the reaction of step (ii) may be from about 30 minutes to about 10 hours, or longer.

Step (iii) involves reacting the compound of Formula III with a (R)-(+)-1- phenylalkylamine of Formula IV, to afford a compound of Formula V.

For the reaction of step (iii), the quantities of (R)-(+)-1-phenylalkylamine may range from about 1 to about 2 molar equivalents, per mole of the compound of Formula III.

The reaction of step (iii) may be conducted in a solvent. Solvents that may be used include, but are not limited to: nitriles such as acetonitrile, alcohols such as methanol, ethanol, isopropyl alcohol, and n-butanol; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone, and n-butanone; 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, n-hexane, n-heptane, and cyclohexane; ethers such as 1 ,4-dioxane and tetrahydrofuran; and any mixtures thereof.

Suitable temperatures for the reaction of step (iii) may be less than about 150⁰C, less than about 120°C, less than about 80°C, less than about 60⁰C, or any other suitable temperatures.

Suitable times for the reaction of step (iii) may be from about 30 minutes to about 10 hours, or longer.

In an aspect, 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 as determined using HPLC, together with one or more pharmaceutically acceptable excipients.

Pharmaceutical compositions that include sitagliptin or a salt thereof 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 using any of techniques such as direct blending, dry granulation, wet granulation, and 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 starches,

pregelatinized starches, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, thcalcium phosphate, mannitol, sorbitol, sugar, and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starch, and the like; disintegrants such as starches, sodium starch glycolate,

pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, and the like; glidants such as colloidal silicon dioxide and the like;

solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodexthns and resins; and release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethyl celluloses, methylcelluloses, various grades of methyl methacrylates, waxes, and 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, and the like.

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

Crystalline forms obtained by the present application, unless stated otherwise, can be characterized by their XRPD patterns, thermal analyses, and sprctroscopic methods such as infrared absorption spectrophotometry. PXRD data reported herein were obtained using copper Ka radiation, and were obtained using a Bruker AXS D8 Advance powder X-ray diffractometer.

TGA analyses were carried out using a TGA Q500 instrument with a ramp of 10°C/minute, up to 250⁰C.

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. EXAMPLE 1 : Preparation of 4-oxo-4-[3-(thfluoromethyl)-5,6-dihydro[1 ,2,4]thazolo [4,3,a]pyrazin-7(8H)-yl]-1 -(2,4,5-trifluorophenyl)butane-2-one (Formula III).

A round bottom flask is charged with 3-trifluoromethyl-5,6,7,8-tetrahydro- 1 ,2,4-thazolo[4,3a]pyrazine hydrochloride (144.6 g) and ethyl acetate (2000 ml_) at 28°C, then N-methylmorpholine (67.2 g) is added. 5-[1 -hydroxy-2-(2,4,5- trifluorophenyl)ethyledine]-2,2-dimethyl-1 ,3 dioxane-4,6-dione (200 g) is added and the mixture is heated to reflux for 6 hours. The mixture is slowly cooled to room temperature. Water (1000 ml_) is added, the mixture is stirred for 15 minutes, and the organic layer is separated. The aqueous layer is extracted with ethyl acetate (200 ml_). The two organic layers are combined and solvent is distilled at 37°C. Toluene (400 ml_) is added to the residue and stirred for 3 hours. The solid is filtered, washed with toluene (200 ml_), and dried under reduced pressure at 50⁰C for 12.5 hours, to afford the title compound. (252.0 g, 98.1 % yield). EXAMPLE 2: Preparation of (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 [4,3- a]pyrazine (Formula V).

A round bottom flask is charged with 4-oxo-4-[3-(trifluoromethyl)- 5,6dihydro[1 ,2,4] triazolo[4,3,a]pyrazin-7(8H)-yl]-1 -(2,4,5-trifluorophenyl)butane-2- one (25 g) and toluene (250 mL) at 26°C, then (R)-(+)-1 -phenylethylamine (9.0 g) and acetic acid (5.5 g) are added. The mixture is heated to reflux for 4 hours. Acetic acid (0.5 g) is added and the mixture is further refluxed for 1 hour. The solvent is distilled to afford the title compound (28.0 g, 92.07% yield). EXAMPLE 3: Preparation of (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 [4,3- a]pyrazine (Formula V).

A round bottom flask is charged with 2,4,5-thfluorophenylacetic acid (25 g),

Meldrums acid (20.5 g), N,N-dimethylaminopyhdine (1.28 g), and acetonitrile (75 ml_). Diisopropylethylamine (47.28 ml_) is added drop-wise, while maintaining the temperature below 50⁰C. The mixture is heated to 50⁰C, followed by drop-wise addition of pivalolyl chloride (17.8 ml_) over about 45 minutes. The mixture is maintained at the same temperature with stirring for 3 hours, followed by addition of thazole hydrochloride (30 g) in one portion. Subsequently, thfluoroacetic acid (2.95 ml_) is added and the mixture is maintained at 55°C for another 6 hours. The mixture is cooled to room temperature, followed by distillation to remove acetonitrile and afford a residue. Water (100 ml_) and ethyl acetate (500 ml_) are added to the residue, and the organic layer is separated. The organic layer is washed with 5% sodium bicarbonate, then brine solution (50 ml_), and is dried over sodium sulphate, followed by distillation at 40⁰C to form a ketoamide, i.e., 4- oxo-4-[3-(thfluoromethyl)-5,6-dihydro[1 ,2,4]thazolo[4,3a]pyrazin-7(8H)-yl]-1 -(2,4,5- trifluorophenyl)butan-2-one. lsopropyl alcohol (75 ml_) and (R)-(+)-1 - phenylethylamine (18.64 ml_) are added and the mixture is heated to 45-50°C for 4 hours. The isopropyl alcohol is distilled completely below 40°C to form a residue. Dichloromethane (200 ml_) and water (100 ml_) are mixed with the residue, 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 sulphate, and distilled to afford a residue, which, on purification results in the title compound (28.7g, 42.8% yield).

EXAMPLE 4: 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 Vl).

Dimethoxyethane (35 mL) is charged into a round bottom flask and is cooled to -40⁰C, followed by addition of sodium borohydride (1.12 g) in one portion. Methanesulfonic acid (4.7 mL) is slowly added, with continuous 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-tnfluoronnethyl-5,6,7,8- tetrahydro-1 ,2,4-triazolo[4,3a]pyrazine (5 g) are combined and stirred for 30 minutes at -40⁰C. This solution is added to the solution of sodium borohydhde and methanesulfonic acid over 30 minutes, while maintaining a temperature of -40⁰C. The mixture is stirred at the same temperature for 3-4 hours, followed by cooling to 0 ⁰C and subsequent addition of ethyl acetate (200 ml_) and water (50 ml_). The organic layer is separated, dried over sodium sulphate and distilled under vacuum at 40°C to afford the title compound (4.92 g, 98% yield).

EXAMPLE 5: 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-triazole[4,3-a] pyrazine hydrochloride.

Dimethoxyethane (171 ml_) is charged into a flask and cooled to -40⁰C, followed by addition of sodium borohydride (7.3 g) in one lot. 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, dimethoxyethane (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 -50⁰C. This solution is slowly added to the 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, the mixture is 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 sulphate and then distilled under reduced pressure at 40⁰C until 10-15% of the solvent volume remains in the flask, at which point solid begins to precipitate. The solid is filtered, 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 6: 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 hydrochloride.

Dimethoxyethane (300 ml_) and sodium borohydhde (7.4 g) are charged into a flask and cooled to -40⁰C. To this mixture, methanesulfonic acid (31.02 ml_) is slowly added with constant stirring at -40⁰C, over 40 minutes. A mixture of dimethoxyethane (330 ml_), isopropyl alcohol (30 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 (30 g) is slowly added at -40°C, over 35 minutes, and the mixture is maintained for 75 minutes. The mixture is brought to 0⁰C, followed by slow addition of ethyl acetate (300 ml_) over 30 minutes. Water (240 ml_) is added, the mixture is stirred for 30 minutes, and the organic layer is separated. The aqueous layer is extracted with ethyl acetate (60 ml_). The two organic layers are combined and washed with brine solution (240 ml_). The solvent is distilled at 42°C. Ethyl acetate (120 ml_) is added to the residue and stirred at 26°C for about 3 hours. The mass is cooled to 5°C and stirred for about 2 hours. The formed solid is filtered, washed with chilled ethyl acetate (60 ml_) and dried under reduced pressure at 45°C for 6 hours, to afford the title compound (19.0 g; chiral purity by HPLC: 99.09%).

EXAMPLE 7: 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 hydrochloride.

A round bottom flask is charged with 4-oxo-4-[3-(trifluoromethyl)- 5,6dihydro[1 ,2,4] triazolo[4,3,a]pyrazin-7(8H)-yl]-1 -(2,4,5-trifluorophenyl)butane-2- one (50 g), (R)-(+)-(1 )-phenylethylamine (8.9 g), acetic acid (4.4 g), and toluene (150 mL) at 26°C. The mixture is heated to reflux for 5 hours. The solvent is distilled at 40⁰C to obtain a residue.

Dimethoxyethane (240 mL) and sodium borohydhde (5.6 g) are charged into a flask and cooled to -40±5°C. To this mixture, methanesulfonic acid (31.02 mL) is slowly added with constant stirring at -40⁰C, over 30 minutes, and further maintained for 30 minutes. A mixture of above obtained residue, dimethoxyethane (60 mL), and isopropyl alcohol (40.5 mL) is slowly added at -40⁰C, over 30 minutes, and the mass is maintained for 1 hour. Ethyl acetate (300 mL) is added over 15 minutes, followed by addition of water (300 ml_) at 12°C. The mixture is heated to room temperature, maintained for 15 minutes and the organic layer is separated. The aqueous layer is extracted with ethyl acetate (180 ml_). The two organic layers are combined and washed with 25% NaCI solution (150 ml_). The solvent is distilled at 40⁰C. Ethyl acetate (90 ml_) is added to the residue and stirred at 26°C for about 2 hours. The solid is filtered, washed with ethyl acetate (30 ml_) and dried under reduced pressure at 50⁰C for 8 hours to afford the title compound (26.90 g; chiral purity by HPLC: 99.56%). EXAMPLE 8: 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

hydrochloride.

7-[1 -oxo-(3R)-(R-1 -phenylethylamino)-4(2,4,5-thfluorophenyl)-butyl)-3- trifluoromethyl-5,6,7,8-tetrahydro-1 ,2,4-triazolo[4,3-a]pyrazine hydrochloride (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 to reflux for about 8-10 hours. The mass is cooled to about 30⁰C and the catalyst is removed by filtration. The filtrate is distilled 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 distilled below 40°C under reduced pressure, to afford the title compound (3.7 g, 93% yield).

EXAMPLE 9: Preparation of 7-[(3R)-3-amino-1 -oxo-4-(2,4,5-thfluorophenyl) butyl]- 5,6,7,8-tetrahydro-3-(trifluoromethyl)-1 ,2,4-triazolo[4,3-a]pyrazine phosphate (Formula I).

A round bottom flask is charged with 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 hydrochloride (3.5 g), water (0.5 mL), and isopropyl alcohol (17 mL). To this mixture, 88% phosphoric acid (0.5 mL) is slowly added and the slurry is heated to 70-80⁰C for complete dissolution. The mixture is cooled to 60-65°C and seeded with milled sitagliptin phosphate monohydrate (0.03 g). The mixture is stirred for about 3 hours and then cooled to ambient temperature, followed by drop-wise addition of isopropyl alcohol (12 mL) over about 60 minutes. The precipitated solid is filtered and dried under vacuum at 40⁰C to afford the title compound (1.48 g, 33% yield). Purity by chiral HPLC: R-isomer = 97.83%, S- isomer = 2.17%.

Claims

CLAIMS:

1. A process for preparing a compound of Formula Vl, or a salt thereof, where Ph is a phenyl group and R is a CrC₄ alkyl group, comprising:

(i) reducing a compound of Formula V, with a borohydride and a sulfonic acid to form a compound of Formula Vl, or a salt thereof; and

Formula V

(ii) optionally, purifying a compound of Formula Vl or its salt, to enhance diasteromeric excess.

2. The process of claim 1 , wherein a borohydride is sodium

borohydride.

3. The process of claim 1 , wherein a sulfonic acid is methanesulfonic acid.

4. The process of claim 1 , wherein purifying the compound of Formula Vl or its salt comprises crystallization, or any combination of acidifying and basifying.

5. The process of claim 1 , wherein steps (i) and (ii) are performed in the same solvent.

6. The process of claim 1 , wherein acid addition salts of a free base of Formula Vl are prepared from a reaction mass obtained from synthesis of the compound of Formula Vl.

7. The process of claim 1 , wherein the compound of Formula V is prepared by reacting 7-(1 ,3-dioxo-4(2,4,5-trifluorophenyl)butyl)-3- trifluoromethyl-5,6,7,8-tetrahydro-1 ,2,4-thazolo [4,3-a]pyrazine of Formula III,

with a chiral reagent of Formula IV, wherein Ph and R are as described in claim 1

Ph

H₂N R

Formula IV

8. The process of claim 7, wherein R in Formula 4 is a methyl group.

9. The process of claim 1 , wherein the compound of Formula Vl or its salt is reacted with an acid HY to form an enantiomerically pure acid addition salt of sitagliptin of Formula VII.

₃

Formula VII

10. The process of claim 9, wherein HY is hydrochloric acid, phosphoric acid, oxalic acid, hydrobromic acid, acetic acid, formic acid, succinic acid, mandelic acid, fumaric acid, or benzoic acid.

11. A process for purifying a compound of Formula Vl or a salt thereof, where Ph is a phenyl group and R is a CrC₄ alkyl group, to enhance the diastereomeric purity, comprising crystallizing, or any combination of acidifying and basifying, of a compound of Formula Vl or its salt.

Formula Vl

12. The process of claim 11 , wherein crystallization is carried out by cooling, combining a solution with an anti-solvent, seeding, partial removal of the solvent, or any combination thereof.

13. The process of claim 11 , wherein a solvent for purification of a compound of Formula Vl or its salt is an alcohol, an ester, a ketone, an ether, a nitrile, a hydrocarbon, a halogenated hydrocarbon, water, or any mixture thereof.

14. The process of claim 11 , wherein a solvent for purification of a compound of Formula Vl or its salt comprises methanol, ethanol, isopropyl alcohol, hexafluoroisopropyl alcohol, phenol, or 2,2,2-trifluoroethanol.

15. The process of claim 11 , wherein a solvent for purification of a compound of Formula Vl or its salt comprises ethyl acetate, n-propyl acetate, or isopropyl acetate.

16. The process of claim 11 , wherein a solvent for purification of a compound of Formula Vl or its salt comprises acetone, or methyl iso-butyl ketone.

17. The process of claim 11 , wherein a solvent for purification of a compound of Formula Vl or its salt comprises 1 ,4-dioxane or tetrahydrofuran.

18. The process of claim 11 , wherein a solvent for purification of a compound of Formula Vl or its salt comprises acetonitrile.

19. The process of claim 11 , wherein a solvent for purification of a compound of Formula Vl or its salt comprises toluene or xylene.

20. The process of claim 11 , wherein a solvent for purification of a compound of Formula Vl or its salt comprises dichloromethane or chloroform.

21. The process of claim 11 , wherein a solvent for purification of a compound of Formula Vl or its salt comprises water.

22. The process of claim 11 , wherein crystallizing is carried out at temperatures about 0⁰C to 45°C.

23. A crystalline compound of Formula Vl, or a salt thereof, where Ph is a phenyl group and R is a Ci-C₄ alkyl group.

Formula Vl

24. A process for preparing a compound of Formula V, wherein Ph is a phenyl group and R is a Ci-C₄ alkyl group, comprising:

Formula V

(i) reacting the compound of Formula VIII with the compound of Formula IX, in the presence of a base, in an organic solvent, to afford the compound of Formula X;

Formula VIII Formula IX Formula X

(ii) reacting the compound of Formula X with the compound of Formula Xl, in the presence of diisopropylethylamine, to afford the compound of Formula III; and

Formula Xl

(iii) reacting the compound of Formula III with a compound of Formula IV, to afford a compound of Formula V;

Ph

H₂N R

Formula IV

wherein products from one or both of (i) and (ii) are not isolated from a reaction mixture before performing a following reaction step.

25. The process of claim 24, wherein a base in (i) comprises

diisiopropylethylamine.

26. The process of claim 24, wherein a solvent employed in (i) comprises acetonithle.

27. The process of claim 24, wherein products from both of (i) and (ii) are not isolated from a reaction mixture before performing a following reaction step.

28. The process of claim 24, wherein R is a methyl group.