The following specification particularly describes the nature of the invention and the manner in which it is to be performed.

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-(trifluoromethyl)-1 2 4-triazolo[4 3-a]pyrazine phosphate (1:1); or (2R)-4-oxo-4-[3-(trifluoromethyl) -5 6-dihydro[1 2 4]triazolo[4 3-a]pyrazin-7(8H)-yl]-1-(2 4 5-trifluorophenyl)butan-2-amine phosphate; and is represented by structural 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)-1-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:

(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 

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

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

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

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.

(ii) reacting the compound of Formula X with 3-trifluoromethyl-5 6 7 8-tetrahydro-1 2 4-triazolo[4 3a]pyrazine hydrochloride of Formula XI  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 

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 enantiomerically enriched form  each step of which is separately contemplated. Embodiments of processes include the steps:

(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 

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

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

(iii) converting a compound of Formula VI or its salt to an addition salt of sitagliptin of 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 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 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  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  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-dimethylformamide (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 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.
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  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 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  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 triethylamine  dicyclohexylamine  diisopropylethylamine  morpholine  ammonium hydroxide  and the like.
Typically  the compound of Formula VI 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 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 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 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  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 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.
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 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.
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;

(ii) reacting the compound of Formula X with 3-trifluoromethyl-5 6 7 8-tetrahydro-1 2 4-triazolo[4 3a]pyrazine hydrochloride of Formula XI  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 C1-C4 alkyl.

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: nitriles such as acetonitrile; alcohols  such as  for example  methanol  ethanol  isopropanol  n-butanol  and the like; halogenated hydrocarbons  such as  for example  dichloromethane  ethylene dichloride  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  N N- dimethylformamide (DMF)  dimethylsulfoxide (DMSO)  and dimethylacetamide (DMA); and any mixtures thereof.
Suitable temperatures for the reaction of step (i) may be less than about 120°C  less than about 100°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 preparation of the compound of Formula lII by reacting the compound of Formula X with 3-trifluoromethyl-5 6 7 8-tetrahydro-1 2 4-triazole[4 3-a]pyrazine hydrochloride of Formula XI  in the presence of diisopropylethylamine  in an organic solvent.
The 3-trifluoromethyl-5 6 7 8-tetrahydro-1 2 4-triazole[4 3-a]pyrazine hydrochloride of Formula XI may be prepared  e.g.  using the process disclosed by J. Balsells et al.  “Synthesis of [1 2 4]Triazolo[4 3-]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 XI 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: nitriles 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 120°C  less than about 80°C  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 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 (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  tricalcium 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 cyclodextrins 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 K 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 250°C.
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-(trifluoromethyl)-5 6-dihydro[1 2 4]triazolo [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-triazolo[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 50°C 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-trifluorophenylacetic acid (25 g)  Meldrums acid (20.5 g)  N N-dimethylaminopyridine (1.28 g)  and acetonitrile (75 mL). Diisopropylethylamine (47.28 mL) is added drop-wise  while maintaining the temperature below 50°C. The mixture is heated to 50°C  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 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 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 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)-(+)-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 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 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-trifluoromethyl-5 6 7 8-tetrahydro-1 2 4-triazolo[4 3a]pyrazine (5 g) 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 cooling to 0 oC 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 -40°C  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 -50°C. 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 40°C 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 borohydride (7.4 g) are charged into a flask and cooled to -40°C. To this mixture  methanesulfonic acid (31.02 mL) is slowly added with constant stirring at -40°C  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 0°C  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 40°C to obtain a residue.
Dimethoxyethane (240 mL) and sodium borohydride (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 -40°C  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 -40°C  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% NaCl solution (150 mL). The solvent is distilled at 40°C. 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 50°C 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-trifluorophenyl)-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 30°C 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-trifluorophenyl) 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 70-80°C 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 40°C to afford the title compound (1.48 g  33% yield). Purity by chiral HPLC: R-isomer = 97.83%  S-isomer = 2.17%.

CLAIMS:
1. A process for preparing a compound of Formula VI  or a salt thereof  where Ph is a phenyl group and R is a C1-C4 alkyl group  comprising:

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

(ii) optionally  purifying a compound of Formula VI or its salt  to enhance diastereomeric excess.
2. The process of claim 1  wherein a borohydride is selected from sodium borohydride  lithium borohydride  sodium cyanoborohydride.
3. The process of claim 1  wherein a sulfonic acid is selected from methanesulfonic acid  toluenesulfonic acid.
4. The process of claim 1  wherein purifying the compound of Formula VI or its salt comprises crystallization  or any combination of acidifying and basifying.
5. 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-triazolo [4 3-a]pyrazine of Formula III 

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

6. The process of claim 5  wherein R in Formula IV is a methyl group.
7. A process for purifying a compound of Formula VI or a salt thereof  where Ph is a phenyl group and R is a C1-C4 alkyl group  to enhance the diastereomeric purity  comprising crystallizing  or any combination of acidifying and basifying  of a compound of Formula VI or its salt.

8. The process of claim 7  wherein crystallization is carried out by cooling  combining a solution with an anti-solvent  seeding  partial removal of the solvent  or any combination thereof.
9. The process of claim 8  wherein a solvent for purification of a compound of Formula VI or its salt is an alcohol  an ester  a ketone  an ether  a nitrile  a hydrocarbon  a halogenated hydrocarbon  water  or any mixture thereof.
10. The process of claim 9  wherein a solvent for purification of a compound of Formula VI or its salt comprises ethyl acetate  n-propyl acetate  or isopropyl acetate.
12. The process of claim 7  wherein crystallizing is carried out at temperatures about 0°C to 45°C.
13. A process for preparation of salt of Formula VI comprising treatment of free base of Formula VI with a source of anion in a suitable solvent.
14. A process of claim 13 wherein source of anion is selected from free acid like hydrochloric acid  sulfuric acid  oxalic acid or salts like sodium chloride.
15. A crystalline compound of Formula VI  or a salt thereof  where Ph is a phenyl group and R is a C1-C4 alkyl group.