`
`(12) United States Patent
`Padi et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,309,724 B2
`Nov. 13, 2012
`
`(54) PROCESSES FOR THE PREPARATION OF
`STAGLIPTN AND PHARMACEUTICALLY
`ACCEPTABLE SALTS THEREOF
`(75) Inventors: Pratap Reddy Padi, Hyderabad (IN);
`Babu Ireni, Nizamabad (IN); Srinivas
`Polavarapu, Hyderabad (IN); Shailaja
`Padamata, Hyderabad (IN); Kavitha
`Nerella, Krishna District (IN); Vijaya
`Anand Ramasamy, Virudhunagar (IN);
`Ranga Reddy Vangala, Hyderabad (IN)
`(73) Assignees: Dr. Reddy's Laboratories Limited,
`Hyderabad, Andhra Pradesh (IN), Dr.
`Reddy's Laboratories, Incorporated,
`Bridgewater, NJ (US)
`
`(*) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 40 days.
`
`(21) Appl. No.:
`
`12/809,200
`
`(22) PCT Filed:
`
`Dec. 18, 2008
`
`PCT/US2008/087491
`
`(86). PCT No.:
`S371 (c)(1),
`Jun. 18, 2010
`(2), (4) Date:
`(87) PCT Pub. No.: WO2009/085990
`PCT Pub. Date: Jul. 9, 2009
`
`(65)
`
`Prior Publication Data
`US 2010/O274O17 A1
`Oct. 28, 2010
`Related U.S. Application Data
`(60) Provisional application No. 61/058,764, filed on Jun.
`4, 2008, provisional application No. 61/058,975, filed
`on Jun. 5, 2008, provisional application No.
`61/097.910, filed on Sep. 18, 2008.
`
`(30)
`
`Foreign Application Priority Data
`
`Dec. 20, 2007 (IN) ........................... 3O76/CHFA2007
`Jan. 18, 2008 (IN) ............................. 1597CHEA2008
`May 14, 2008 (IN).
`... 118.8/CHFA2008
`
`
`
`(51) Int. Cl.
`(2006.01)
`C07D 47L/00
`(52) U.S. Cl. ....................................................... 544/350
`(58) Field of Classification Search ................... 544/350
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`6,699,871 B2
`3/2004 Edmondson et al.
`75-6 R:
`358. Allen t il.
`ypes et al.
`- 4 W
`2005/0032804 A1
`2/2005 Cypes et al.
`2006, O194977 A1
`8, 2006 Xiao et al.
`2006/0287528 A1 12/2006 Wenslow et al.
`2007/0021430 A1
`1/2007 Chen et al.
`2009/0247532 A1 10/2009 Huang et al.
`FOREIGN PATENT DOCUMENTS
`2004/085378 A1 10, 2004
`2004/085661 A2 10, 2004
`2004/087650 A2 10, 2004
`2005/020920 A2
`3, 2005
`2005/030127 A2
`4/2005
`2005, O72530 A1
`8, 2005
`2006/033848 A1
`3f2006
`2007/035198 A2
`3, 2007
`
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`
`OTHER PUBLICATIONS
`David J. Ager, “Novel Chiral Chemistries Japan 2007”. Platinum
`Metals Review, vol. 51, No. 4, pp. 172-175, 2007.
`
`Primary Examiner — Douglas MWillis
`(74) Attorney, Agent, or Firm — Gilman Pergament LLP:
`Edward D. Pergament; Milagros A. Cepeda
`
`ABSTRACT
`(57)
`There is provided an improved process for the preparation of
`Sitagliptin of Formula II by reduction of compound of For
`mula VIII to Formula IX followed by deprotection of Formula
`IX to afford Sitagliptin of Formula II.
`
`6 Claims, 33 Drawing Sheets
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`Nov. 13, 2012
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`N
`cy
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`(%) LHSIM
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`US 8,309,724 B2
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`1.
`PROCESSES FOR THE PREPARATION OF
`STAGLIPTN AND PHARMACEUTICALLY
`ACCEPTABLE SALTS THEREOF
`
`INTRODUCTION
`
`The present application relates to Sitagliptin, its salts, and
`its polymorphs, and processes for the preparation of Sitaglip
`tin, its salts, and its polymorphs.
`Sitagliptin is (R)-7-(1-oxo-3((R)-amino)-4-(2,4,5-trifluo
`rophenyl)-butyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,
`4-triazolo 4,3-alpyrazine represented by the structural For
`mula II.
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`Formula II
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`an ongoing need for simple, cost effective, and industrially
`viable processes for the production of sitagliptin and its phar
`maceutically acceptable salts.
`Crystalline salts of Sitagliptin are known. International
`Application Publication No. WO 2005/072530 describes
`various crystalline salts of Sitagliptin, International Applica
`tion Publication No. WO 2006/033848 describes amorphous
`form of the dihydrogen phosphate salt of Sitagliptin. Interna
`tional Application Publication No. WO 2005/020920 dis
`closes two crystalline anhydrous forms of the dihydrogen
`phosphate salt of sitagliptin namely Form I and Form III, and
`a crystalline desolvated anhydrate Form II. International
`Application Publication No. WO 2005/030127 discloses a
`crystalline anhydrate Form IV of the dihydrogen phosphate
`salt of sitagliptin. International Application Publication No.
`WO 2005/072530 discloses crystalline hydrochloric acid,
`benzenesulfonic acid, p-toluenesulfonic acid, 10-camphor
`Sulfonic acid, and tartaric acid salts of Sitagliptin. Interna
`tional Application Publication No. WO 2007/035198 dis
`closes dodecylsulfate salt of Sitagliptin.
`There remains a need for further improvement in properties
`of solid Sitagliptin, such as Stability, purity, flowability, vapor
`impermeability, solubility, and bioavailability.
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`
`SUMMARY OF THE APPLICATION
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`Sitagliptin is an orally-active dipeptidyl peptidase-4 (DPP
`IV) enzyme inhibitor that improves glycemic control in
`30
`patients with Type 2 diabetes mellitus by slowing the inacti
`vation of incretin hormones. Sitagliptin may be used as a
`monotherapy, as an adjunct to diet and exercise, or in combi
`nation with metformin or a PPARY agonist (e.g., thiazo
`lidinediones).
`U.S. Pat. No. 6,699,871 describes a class of beta-amino
`tetrahydrotriazolo 4,3-alpyrazines that are potent inhibitors
`of DPP-IV and therefore useful for the treatment of Type 2
`diabetes. Specifically disclosed in U.S. Pat. No. 6,699,871 is
`Sitagliptin. Pharmaceutically acceptable salts of this com
`40
`pound are generically encompassed within the scope of U.S.
`Pat. No. 6,699.871. It also discloses a process for the prepa
`ration of Sitagliptin and related compounds.
`International Application Publication No. WO 2004/
`085661 discloses a process for the preparation of sitagliptin in
`which S-phenylglycine amide is used as a chiral auxilary to
`forman intermediate that Subsequently provides the required
`enantiomer (i.e., sitagliptin).
`International Application Publication No. WO 2004/
`087650 discloses another process in which N-protected
`3-((R)-amino)-4-(2,4,5-trifluorophenyl)-butyric acid is syn
`thesized enantio-selectively, condensed with a pyrazine inter
`mediate, and deprotected to provide Sitagliptin.
`U.S. Pat. No. 7,326,708 discloses the dihydrogen phos
`phate salt of Sitagliptin and processes for the preparation
`thereof.
`International Application Publication No. WO 2004/
`085378 discloses a process for the preparation of sitagliptin,
`wherein the reduction of the sitagliptin intermediate is carried
`out by using rhodium metal and a chiral ferrocenyl diphos
`phine.
`Although several processes have been reported in the prior
`art for the preparation of Sitagliptin, they suffer from one or
`more drawbacks such as involving the use of hazardous
`regents, like platinum oxide, rhodium catalyst, etc., costly
`reagents, such as chloro pyrazine, dichloropyrazine, etc., and
`extensive protection and deprotection steps. Hence, there is
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`The present invention includes processes for the prepara
`tion of Sitagliptin, which processes comprise at least one of
`the steps of:
`(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 with a first reagent to afford 7-(1-oxo-3-amino-4-(2,
`4,5-trifluorophenyl)-but-2-enyl)-3-trifluoromethyl-5,6,7,8-
`tetrahydro-1,2,4-triazolo 4.3-alpyrazine;
`(ii) converting the 7-(1-oxo-3-amino-4-(2,4,5-trifluo
`rophenyl)-but-2-enyl)-3-trifluoromethyl-5,6,7,8-tetrahydro
`1,2,4-triazolo 4.3-alpyrazine with a second reagent to 7-(1-
`oxo-3-amino-4-(2,4,5-trifluorophenyl)-butyl)-3-
`(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo 4.3-a
`pyrazine;
`(iii) treating the 7-(1-oxo-3-amino-4-(2,4,5-trifluorophe
`nyl)-butyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-
`triazolo 4.3-alpyrazine with a third reagent to afford a dias
`tereomeric
`salt
`of 7-(1-oxo-3((R)-amino)-4-(2,4,5-
`trifluorophenyl)-butyl)-3-(trifluoromethyl)-5,6,7,8-
`tetrahydro-1,2,4-triazolo 4.3-alpyrazine;
`(iv) isolating the diastereomeric salt;
`(v) treating the diastereomeric salt with an acid or a base to
`afford sitagliptin freebase; and
`(vi) optionally treating the Sitagliptin freebase with an acid
`to afford an acid addition salt of Sitagliptin.
`The present invention includes processes for the prepara
`tion of Sitagliptin, which processes comprise at least one of
`the steps of:
`(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 with a chiral reagent to produce the compound of the
`Formula VIII, wherein R is an C-C alkyl:
`(ii) converting the compound of Formula VIII to the com
`pound of Formula IX, wherein wherein R is as defined above:
`(iii) converting the compound of Formula VIII using an
`acid or base or a catalyst to afford Sitagliptin freebase
`(iv) optionally treating the Sitagliptin freebase with an acid
`to afford an acid addition salt of Sitagliptin.
`The present invention includes anhydrous crystalline sita
`gliptin dihydrogen phosphate of Formula I" (also referred to
`hereinafter as Form A).
`
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`Form A may be characterized by differential scanning calo
`rimetry (DSC) thermogram with onset at about 201° C. and
`endotherm peak at about 205.5°C.
`Form A may also be characterized by its X-ray diffraction
`pattern with characteristic peaks at diffraction angles 2-theta
`of about 4.58, 9.23, 12.24, 13.88, 18.23, 23.63, 24.24, and
`26.68+0.2 degrees.
`Form A may also be characterized by X-ray diffraction
`pattern substantially as shown in FIG. 1.
`Also, Form A may be characterized by thermo gravimetric
`analysis (TGA) curve corresponding to a weight loss of about
`0.038% (0.01082 mg) up to a temperature of about 100° C. (as
`shown in FIG. 3).
`The present invention includes processes for the prepara
`tion of Form A, which processes comprise the step of treating
`Sitagliptin freebase with phosphoric acid in aqueous isopro
`panol having a water content of less than about 6%.
`In addition to Form A, the present invention includes the
`Sulfuric acid, hydrobromic acid, methanesulfonic acid, acetic
`acid, benzoic acid, oxalic acid, Succinic acid, mandelic acid,
`fumaric acid, and lactic acid salts of Sitagliptin.
`The present invention includes processes for the prepara
`tion of salts of Sitagliptin, which processes comprise at least
`one of the steps of:
`(a) providing a solution of a salt of Sitagliptin in a solvent;
`(b) isolating the salt of sitagliptin from the solution of Step
`(a); and
`(c) recovering the crystalline salt of Sitagliptin and option
`ally drying it.
`There present invention includes pharmaceutical compo
`sitions comprising sitagliptin according to the present inven
`tion together with at least one pharmaceutically acceptable
`excipient.
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`BRIEF DESCRIPTION OF THE DRAWING
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`FIG. 1 is an illustration of X-ray powder diffraction
`(XRPD) pattern of crystalline anhydrate Form A of the dihy
`drogen phosphate salt of Sitagliptin.
`FIG. 2 is an illustration of differential scanning calorimetry
`(“DSC) curve of crystalline anhydrate Form A of the dihy
`drogen phosphate salt of Sitagliptin.
`FIG. 3 is an illustration of thermogravimetric analysis
`(TGA) curve of crystalline anhydrate Form A of the dihydro
`gen phosphate Salt of Sitagliptin.
`FIG. 4 is an illustration of powder X-ray diffraction
`(“PXRD) pattern of crystalline sitagliptin sulfate prepared
`according to example 14.
`FIG.5 is an illustration of differential scanning calorimetry
`(“DSC) curve of crystalline sitagliptin sulfate prepared
`according to example 14.
`FIG. 6 is an illustration of thermogravimetric analysis
`("TGA) curve of crystalline sitagliptin sulfate prepared
`according to example 14.
`FIG. 7 is an illustration of PXRD pattern of crystalline
`Sitagliptin hydrobromide prepared according to example 15.
`FIG. 8 is an illustration of DSC curve of crystalline sita
`gliptin hydrobromide prepared according to example 15.
`FIG. 9 is an illustration of TGA curve of crystalline sita
`gliptin hydrobromide prepared according to example 15.
`FIG. 10 is an illustration of PXRD pattern of crystalline
`Sitagliptin methane Sulfonate prepared according to example
`16.
`FIG. 11 is an illustration of DSC curve of crystalline sita
`gliptin methane Sulfonate prepared according to example 16.
`FIG. 12 is an illustration of TGA curve of crystalline sita
`gliptin methane Sulfonate prepared according to example 16.
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`US 8,309,724 B2
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`FIG. 13 is an illustration of PXRD pattern of crystalline
`Sitagliptin acetate prepared according to example 17.
`FIG. 14 is an illustration of DSC curve of crystalline sita
`gliptin acetate prepared according to example 17.
`FIG. 15 is an illustration of TGA curve of crystalline sita
`gliptin acetate prepared according to example 17.
`FIG. 16 is an illustration of PXRD pattern of crystalline
`Sitagliptin benzoate prepared according to example 18.
`FIG. 17 is an illustration of DSC curve of crystalline sita
`gliptin benzoate prepared according to example 18.
`FIG. 18 is an illustration of TGA curve of crystalline sita
`gliptin benzoate prepared according to example 18.
`FIG. 19 is an illustration of PXRD pattern of crystalline
`Sitagliptin oxalate prepared according to example 19.
`FIG. 20 is an illustration of DSC curve of crystalline sita
`gliptin oxalate prepared according to example 19.
`FIG. 21 is an illustration of TGA curve of crystalline sita
`gliptin oxalate prepared according to example 19.
`FIG. 22 is an illustration of PXRD pattern of crystalline
`Sitagliptin Succinate prepared according to example 20.
`FIG. 23 is an illustration of DSC curve of crystalline sita
`gliptin Succinate prepared according to example 20.
`FIG. 24 is an illustration of TGA curve of crystalline sita
`gliptin Succinate prepared according to example 20.
`FIG. 25 is an illustration of PXRD pattern of crystalline
`Sitagliptin mendelate prepared according to example 21.
`FIG. 26 is an illustration of DSC curve of crystalline sita
`gliptin mendelate prepared according to example 21.
`FIG. 27 is an illustration of TGA curve of crystalline sita
`gliptin mendelate prepared according to example 21.
`FIG. 28 is an illustration of PXRD pattern of crystalline
`Sitagliptin fumarate prepared according to example 22.
`FIG. 29 is an illustration of DSC curve of crystalline sita
`gliptin fumarate prepared according to example 22.
`FIG. 30 is an illustration of TGA curve of crystalline sita
`gliptin fumarate prepared according to example 22.
`FIG. 31 is an illustration of PXRD pattern of crystalline
`Sitagliptin lactate prepared according to example 23.
`FIG. 32 is an illustration of DSC curve of crystalline sita
`gliptin lactate prepared according to example 23.
`FIG.33 is an illustration of TGA curve of crystalline sita
`gliptin lactate prepared according to example 23.
`
`DETAILED DESCRIPTION
`
`All percentages and ratios used herein are by weight of the
`total composition and all measurements made are at 25°C.
`and normal pressure unless otherwise designated. All tem
`peratures are in Degrees Celsius unless specified otherwise.
`The present invention can comprise (open ended) of the com
`ponents of the present invention as well as otheringredients or
`elements described herein.
`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 “hav
`ing” 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, but does not read on the prior art. 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.
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`US 8,309,724 B2
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`This document may refer to a material. Such as in this
`instance, salts of Sitagliptin, and its crystalline forms, Sol
`Vates, or optical isomers by reference to patterns, spectra, or
`other graphical data, 'substantially as shown in a Figure, or
`by one or more data points. By “substantially used in such a
`context, it will be appreciated that patterns, spectra, and other
`graphical data can be shifted in their positions, relative inten
`sities, and/or values due to a number of factors knownto those
`of skill in the art. For example, in the crystallographic and
`powder X-ray diffraction arts, such shifts in peak positions or
`the relative intensities of one or more peaks can occur because
`of without limitation: the equipment used, the sample prepa
`ration protocol, preferred packing and orientations, the radia
`tion source, operator error, method and length of data collec
`tion, and the like. However, those of ordinary skill in the art
`should be able to compare the figures herein with a pattern
`generated of an unknown form of, in this case, salts of sita
`gliptin, and confirm its identity as one of the forms disclosed
`and claimed herein. The same holds true for other techniques
`which may be reported herein.
`In addition, where a reference is made to a figure, it is
`permissible to, and this document includes and contemplates,
`the selection of any number of data points illustrated in the
`figure that uniquely define that crystalline form, salt, or opti
`cal isomer.
`When a molecule or other material is identified herein as
`"pure', it generally means, unless specified otherwise, that
`the material is 99% pure or more, as determined by methods
`conventional in art Such as high performance liquid chroma
`tography (HPLC) or optical methods. In general, this refers to
`purity with regard to unwanted residual solvents, reaction
`byproducts, 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% pure or more and likewise, “essentially pure'
`means the same as “pure' except that the lower limit is about
`95% pure.
`As used herein, the terms 'salt(s) of sitagliptin,” “sitaglip
`tin salt(s)' and other similar phrases encompass crystalline
`and amorphous forms, Solvates, hydrates, stereoisomers, both
`individual and in mixtures thereof, racemates, enantiomers,
`and the like
`The present invention includes processes for the prepara
`tion of Sitagliptin, which processes comprise at least one of
`45
`the steps of:
`(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 VI
`
`F
`
`F
`
`Formula V
`
`CF
`
`(ii) converting the compound of Formula V to 7-(1-oxo-3-
`amino-4-(2,4,5-trifluorophenyl)-butyl)-3-(trifluoromethyl)-
`5,6,7,8-tetrahydro-1,2,4-triazolo 4,3-alpyrazine of Formula
`IV;
`
`NH2
`
`Formula IV
`
`CF
`
`(iii) treating the compound of Formula IV with a reagent to
`afford a diasteromeric salt of sitagliptin of Formula III;
`
`Formula III
`
`wherein X is the reagent used for the preparation of said
`diasteromeric salt;
`(iv) isolating the diasteromeric salt of Sitagliptin;
`(v) treating the diasteromeric salt of sitagliptin with an acid
`or a base to afford sitagliptin freebase of Formula II:
`
`Formula II
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`Formula VI
`
`F
`
`F
`
`F
`
`O
`
`O
`
`--
`N- -K
`
`with a reagent, optionally in the presence of a solvent, to
`afford
`7-(1-oxo-3-amino-4-(2,4,5-trifluorophenyl)-but-2-
`enyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo4.
`3-alpyrazine of Formula V:
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`and
`(vi) optionally treating the Sitagliptin freebase with an acid
`to afford an acid addition salt of sitagliptin of Formula I
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`Formula I
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`pyl acetate, isopropyl acetate, and the like; hydrocarbon Sol
`vents, such as, for example, toluene, Xylene, n-hexane, n-hep
`tane, cyclohexane, and the like; ethers. Such as, for example,
`1,4-dioxane, tetrahydrofuran, and the like: aprotic polar Sol
`vents, such as, for example, N,N-dimethylformamide (DMF),
`dimethylsulfoxide (DMSO), dimethylacetamide (DMA):
`water; or mixtures thereof.
`A suitable temperature for the reaction of Step (ii) may be
`less than about 250°C., or less thanabout 200°C., or less than
`about 150° C., or less than about 100° C., or less than about
`80° C., or less than about 60°C., or any other suitable tem
`perature.
`The reaction may be carried out for any desired time period
`ranging from about 30 minutes to about 10 hours or longer.
`Step (iii) involves treating the compound of Formula IV
`with a reagent to afford a diasteromeric salt of Sitagliptin of
`Formula III
`Suitable reagents that may be used include and are not
`limited to: S-(+)-mandelic acid, R-(-)-mandelic acid, (1S)-
`(+)-camphor-10-Sulfonic acid, (1R)-(-)-camphor-10-Sul
`fonic acid, L-malic acid, D-malic acid, L-maleic acid, D-ma
`leic acid, (-)-naproxen, (+)-naproxen, (-)-ibuprofen, (+)-
`ibuprofen, (1R)-(+)-3-bromocamphor-10-sulfonic acid,
`(1S)-(-)-3-bromocamphor-10-sulfonic acid, L-(+)-tartaric
`acid, D-(-)-tartaric acid, (+)-dibenzoyl-D-tartaric acid, (-)-
`dibenzoyl-L-tartaric acid, (+)-dipara-tolyl-D-tartaric acid,
`(-)-dipara-tolyl-L-tartaric acid, L-(-)-pyroglutamic acid,
`L-(+)-pyroglutamic acid, (-)-lactic acid, L(+)-lactic acid,
`L-lysine, D-lysine, and mixtures of thereof. For example, the
`reagent may be (-)-di-para-tolyl-L-tartaric acid
`Suitable solvents that may be used include and are not
`limited to, alcohols, such as, for example methanol, ethanol,
`isopropanol, n-butanol, and the like: nitriles like acetonitrile,
`propionitrile, and the like, ketones, such as, for example,
`acetone, methyl isobutyl ketone, methyl ethyl ketone, n-bu
`tanone, and the like; halogenated Solvents. Such as, for
`example, dichloromethane, ethylene dichloride, chloroform,
`and the like; esters, such as, for example ethyl acetate, n-pro
`pyl acetate, isopropyl acetate, and the like; hydrocarbon Sol
`vents, such as, for example, toluene, Xylene, n-hexane, n-hep
`tane, cyclohexane, and the like; ethers. Such as, for example,
`1,4-dioxane, tetrahydrofuran, and the like: aprotic polar Sol
`vents, such as, for example, N,N-dimethylformamide (DMF),
`dimethylsulfoxide (DMSO), dimethylacetamide (DMA):
`water; or mixtures thereof.
`A suitable temperature for the reaction of Step (iii) may be
`less than about 150°C., or less thanabout 120°C., or less than
`about 80°C., or less than about 60° C., or any other suitable
`temperatures.
`The reaction may be carried out for any desired time peri
`ods ranging from about 30 minutes to about 30 hours or
`longer.
`Step (iv) involves isolating the diasteromeric salt of sita
`gliptin of Formula III
`The diastereomeric salt formed in Step (iii) may be recov
`ered by conventional methods including decantation, cen
`trifugation, gravity filtration, Suction filtration, or other tech
`niques known in the art for the recovery of solids. The
`recovered solid may be further dried. Drying may be suitably
`carried out using a tray dryer, Vacuum oven, air oven, fluid
`ized bed drier, spin flash dryer, flash dryer, and the like at
`atmospheric pressure or under reduced pressure. Drying may
`be carried out at a temperature of less than about 150° C., or
`less than 120° C., or less than 100° C., or less than about 60°
`C., or less than about 40°C., or any other suitable tempera
`ture, 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 period to achieve the desired quality
`of the product, such as, for example, about 1 to about 15 hours
`or longer.
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`wherein Y is an acid residue.
`Step (i) involves reacting the compound of Formula VI
`with a reagent, optionally in a solvent, to afford the compound
`of the formula (V)
`Suitable reagents include and are not limited to ammonia
`Sources, such as, for example, ammonium chloride, ammo
`nium bromide, ammonium iodide, ammonium carbonate,
`ammonium formate, ammonium acetate, formamide, ammo
`25
`nium formate in combination with methanolic ammonia or
`ethanolic ammonia, ammonium formate in combination with
`isopropanol ammonia, ammonium formate in combination
`with aqueous ammonia, ammonium formate in combination
`with formic acid, formamide in combination with formic
`acid, formamide in combination with formic acid and isopro
`panol ammonia, formamide in combination with formic acid
`and methanolic ammonia, formamide in combination with
`formic acid and aqueous ammonia, or a mixture thereof. For
`example, the ammonia Source may be ammonium acetate in
`combination with aqueous ammonia.
`Suitable solvents that may be used include and are not
`limited to, alcohols, such as, for example methanol, ethanol,
`isopropanol, n-butanol, and the like: nitriles like acetonitrile,
`propionitrile, and the like; ketones, such as, for example,
`acetone, methyl isobutyl ketone, methyl ethyl ketone, n-bu
`tanone, and the like; halogenated Solvents, such as, for
`example, dichloromethane, ethylene dichloride, chloroform,
`and the like; esters, such as, for example ethyl acetate, n-pro
`pyl acetate, isopropyl acetate, and the like; hydrocarbon Sol
`vents, such as, for example, toluene, Xylene, n-hexane, n-hep
`tane, cyclohexane, and the like; ethers. Such as, for example,
`1,4-dioxane, tetrahydrofuran, and the like: aprotic polar Sol
`vents, such as, for example, N,N-dimethylformamide (DMF),
`dimethylsulfoxide (DMSO), dimethylacetamide (DMA);
`water; or mixtures thereof.
`A suitable temperature for the reaction of Step (i) may be
`less than about 150°C., or less thanabout 120°C., or