I 1111111111111111 11111 111111111111111 1111111111 1111111111111111 IIII IIII IIII
`US008309724B2
`
`c12) United States Patent
`Padi et al.
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 8,309,724 B2
`Nov. 13, 2012
`
`(54) PROCESSES FOR THE PREPARATION OF
`SITAGLIPTIN 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, Krislma 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 ofthis
`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
`
`(86) PCT No.:
`
`PCT /US2008/087 491
`
`§ 371 (c)(l),
`(2), ( 4) Date:
`
`Jun.18,2010
`
`(87) PCT Pub. No.: WO2009/085990
`
`PCT Pub. Date: Jul. 9, 2009
`
`(65)
`
`Prior Publication Data
`
`US 2010/0274017 Al
`
`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
`Jan. 18,2008
`May 14, 2008
`
`(IN) ........................... 3076/CHE/2007
`(IN) ............................. 159/CHE/2008
`(IN) ........................... 1188/CHE/2008
`
`(51)
`
`Int. Cl.
`C07D471/00
`(2006.01)
`(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.
`7,265,128 B2
`9/2007 Ashton et al.
`7,326,708 B2
`2/2008 Cypes et al.
`2005/0032804 Al
`2/2005 Cypes et al.
`2006/0194977 Al
`8/2006 Xiao et al.
`2006/0287528 Al
`12/2006 Wenslow et al.
`2007/0021430 Al
`1/2007 Chen et al.
`2009/0247 532 Al
`10/2009 Huang et al.
`
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`
`FOREIGN PATENT DOCUMENTS
`10/2004
`2004/085378 Al
`10/2004
`2004/085661 A2
`10/2004
`2004/087650 A2
`3/2005
`2005/020920 A2
`4/2005
`2005/030127 A2
`8/2005
`2005/072530 Al
`3/2006
`2006/033848 Al
`3/2007
`2007 /035198 A2
`
`OTHER PUBLICATIONS
`
`David J. Ager, "Novel Chiral Chemistries Japan 2007", Platinum
`Metals Review, vol. 51, No. 4, pp. 172-175, 2007.
`
`Primary Examiner - Douglas M Willis
`(74) Attorney, Agent, or Firm - Gilman Pergament LLP;
`Edward D. Pergament; Milagros A. Cepeda
`
`(57)
`
`ABSTRACT
`
`There is provided an improved process for the preparation of
`Sitagliptin of Formula II by reduction of compound of For(cid:173)
`mula VIII to Formula IX followed by deprotectionofFormula
`IX to afford Sitagliptin of Formula II.
`
`6 Claims, 33 Drawing Sheets
`
`Merck Exhibit 2032, Page 1
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Nov. 13, 2012
`
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`Nov. 13, 2012
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
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`Nov. 13, 2012
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`Nov. 13, 2012
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`U.S. Patent
`
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

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`
`Nov. 13, 2012
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`Nov. 13, 2012
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
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`Merck Exhibit 2032, Page 14
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Nov. 13, 2012
`
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

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`Nov. 13, 2012
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`Nov. 13, 2012
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
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`Nov. 13, 2012
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
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`Merck Exhibit 2032, Page 20
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

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`U.S. Patent
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`Nov. 13, 2012
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`Merck Exhibit 2032, Page 21
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Nov. 13, 2012
`
`Sheet 21 of 33
`
`US 8,309,724 B2
`
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`Merck Exhibit 2032, Page 22
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Nov. 13, 2012
`
`Sheet 22 of 33
`
`US 8,309,724 B2
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`Merck Exhibit 2032, Page 23
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Nov. 13, 2012
`
`Sheet 23 of 33
`
`US 8,309,724 B2
`
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`Merck Exhibit 2032, Page 24
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Nov. 13, 2012
`
`Sheet 24 of 33
`
`US 8,309,724 B2
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`Merck Exhibit 2032, Page 25
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Nov. 13, 2012
`
`Sheet 25 of 33
`
`US 8,309,724 B2
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`Merck Exhibit 2032, Page 26
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Nov. 13, 2012
`
`Sheet 26 of 33
`
`US 8,309,724 B2
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`Merck Exhibit 2032, Page 27
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Nov. 13, 2012
`
`Sheet 27 of 33
`
`US 8,309,724 B2
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`Merck Exhibit 2032, Page 28
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Nov. 13, 2012
`
`Sheet 28 of 33
`
`US 8,309,724 B2
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`Merck Exhibit 2032, Page 29
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Nov. 13, 2012
`
`Sheet 29 of 33
`
`US 8,309,724 B2
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`Merck Exhibit 2032, Page 30
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Nov. 13, 2012
`
`Sheet 30 of 33
`
`US 8,309,724 B2
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`Merck Exhibit 2032, Page 31
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Nov. 13, 2012
`
`Sheet 31 of 33
`
`US 8,309,724 B2
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`Merck Exhibit 2032, Page 32
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Nov. 13, 2012
`
`Sheet 32 of 33
`
`US 8,309,724 B2
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`Merck Exhibit 2032, Page 33
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Nov. 13, 2012
`
`Sheet 33 of 33
`
`US 8,309,724 B2
`
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`Merck Exhibit 2032, Page 34
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`US 8,309,724 B2
`
`1
`PROCESSES FOR THE PREPARATION OF
`SITAGLIPTIN AND PHARMACEUTICALLY
`ACCEPTABLE SALTS THEREOF
`
`INTRODUCTION
`
`The present application relates to sitagliptin, its salts, and
`its polymorphs, and processes for the preparation of sitaglip(cid:173)
`tin, its salts, and its polymorphs.
`Sitagliptin is (R)-7-(1-oxo-3((R)-amino )-4-(2,4,5-trifluo(cid:173)
`rophenyl)-butyl)-3-(trifluoromethyl)-5,6, 7,8-tetrahydro- l ,2,
`4-triazolo[ 4,3-a ]pyrazine represented by the structural For(cid:173)
`mula II.
`
`Formula II
`
`F
`
`F
`
`2
`an ongoing need for simple, cost effective, and industrially
`viable processes for the production of sitagliptin and its phar(cid:173)
`maceutically acceptable salts.
`Crystalline salts of sitagliptin are known. International
`5 Application Publication No. WO 2005/072530 describes
`various crystalline salts of sitagliptin, International Applica(cid:173)
`tion Publication No. WO 2006/033848 describes amorphous
`form of the dihydrogen phosphate salt of sitagliptin. Interna(cid:173)
`tional Application Publication No. WO 2005/020920 dis-
`10 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
`15 salt of sitagliptin. International Application Publication No.
`WO 2005/072530 discloses crystalline hydrochloric acid,
`benzenesulfonic acid, p-toluenesulfonic acid, 10-camphor(cid:173)
`sulfonic acid, and tartaric acid salts of sitagliptin. Interna(cid:173)
`tional Application Publication No. WO 2007/035198 dis-
`20 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.
`
`25
`
`SUMMARY OF THE APPLICATION
`
`35
`
`Sitagliptin is an orally-active dipeptidyl peptidase-4 (DPP(cid:173)
`IV) enzyme inhibitor that improves glycemic control in 30
`patients with Type 2 diabetes mellitus by slowing the inacti(cid:173)
`vation of incretin hormones. Sitagliptin may be used as a
`monotherapy, as an adjunct to diet and exercise, or in combi(cid:173)
`nation with metformin or a PPARy agonist (e.g., thiazo(cid:173)
`lidinediones ).
`U.S. Pat. No. 6,699,871 describes a class of beta-amino(cid:173)
`tetrahydrotriazolo[4,3-a]pyrazines 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(cid:173)
`ration of sitagliptin and related compounds.
`International Application Publication No. WO 2004/
`085661 discloses a process for the preparation of sitagliptin in 45
`which S-phenyl glycine amide is used as a chiral auxilary to
`form an intermediate that subsequently provides the required
`enantiomer (i.e., sitagliptin).
`International Application Publication No. WO 2004/
`087650 discloses another process in which N-protected 50
`3-((R)-amino )-4-(2,4,5-trifluorophenyl)-butyric acid is syn(cid:173)
`thesized enantio-selectively, condensed with a pyrazine inter(cid:173)
`mediate, and deprotected to provide sitagliptin.
`U.S. Pat. No. 7,326,708 discloses the dihydrogen phos(cid:173)
`phate salt of sitagliptin and processes for the preparation 55
`thereof.
`International Application Publication No. WO 2004/
`0853 78 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(cid:173)
`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 65
`reagents, such as chloro pyrazine, dichloropyrazine, etc., and
`extensive protection and deprotection steps. Hence, there is
`
`The present invention includes processes for the prepara(cid:173)
`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-(l-oxo-3-amino-4-(2,
`4,5-trifluoropheny l)-but-2-enyl )-3-trifluoromethy 1-5, 6, 7, 8-
`tetrahydro-1,2,4-triazolo [ 4,3-a ]pyrazine;
`(ii) converting
`the 7-(1-oxo-3-amino-4-(2,4,5-trifluo(cid:173)
`rophenyl)-but-2-enyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-
`1,2,4-triazolo[4,3-a]pyrazine 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(cid:173)
`ny 1)-buty 1)-3-( trifluoromethy 1)-5 ,6, 7 ,8-tetrahydro-1,2,4-
`triazolo[ 4,3-a ]pyrazine with a third reagent to afford a dias-
`tereomeric
`salt
`of
`7-(1-oxo-3((R)-amino )-4-(2,4,5-
`trifluorophenyl )-buty 1)-3-( trifluoromethy 1)-5 ,6, 7 ,8-
`tetrahydro-1,2,4-triazolo [ 4,3-a ]pyrazine;
`(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(cid:173)
`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 1 -C4 alkyl;
`(ii) converting the compound of Formula VIII to the com-
`60 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(cid:173)
`gliptin dihydrogen phosphate of Formula I' (also referred to
`hereinafter as Form A).
`
`Merck Exhibit 2032, Page 35
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
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`

`US 8,309,724 B2
`
`3
`Form A may be characterized by differential scanning calo(cid:173)
`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 5
`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 10
`analysis (TGA) curve corresponding to a weight loss of about
`0.038% (0.01082 mg) up to a temperature ofabout 100° C. (as
`shown in FIG. 3).
`The present invention includes processes for the prepara(cid:173)
`tion ofFormA, which processes comprise the step of treating 15
`sitagliptin freebase with phosphoric acid in aqueous isopro(cid:173)
`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, 20
`fumaric acid, and lactic acid salts of sitagliptin.
`The present invention includes processes for the prepara(cid:173)
`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; 25
`(b) isolating the salt of sitagliptin from the solution of Step
`(a); and
`( c) recovering the crystalline salt of sitagliptin and option(cid:173)
`ally drying it.
`There present invention includes pharmaceutical compo- 30
`sitions comprising sitagliptin according to the present inven(cid:173)
`tion together with at least one pharmaceutically acceptable
`excipient.
`
`BRIEF DESCRIPTION OF THE DRAWING
`
`35
`
`4
`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(cid:173)
`gliptin acetate prepared according to example 17.
`FIG. 15 is an illustration ofTGA curve of crystalline sita(cid:173)
`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(cid:173)
`gliptin benzoate prepared according to example 18.
`FIG. 18 is an illustration ofTGA curve of crystalline sita(cid:173)
`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(cid:173)
`gliptin oxalate prepared according to example 19.
`FIG. 21 is an illustration ofTGA curve of crystalline sita(cid:173)
`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(cid:173)
`gliptin succinate prepared according to example 20.
`FIG. 24 is an illustration ofTGA curve of crystalline sita(cid:173)
`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(cid:173)
`gliptin mendelate prepared according to example 21.
`FIG. 27 is an illustration ofTGA curve of crystalline sita(cid:173)
`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(cid:173)
`gliptin fumarate prepared according to example 22.
`FIG. 30 is an illustration ofTGA curve of crystalline sita(cid:173)
`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-
`40 gliptin lactate prepared according to example 23.
`FIG. 33 is an illustration ofTGA curve of crystalline sita(cid:173)
`gliptin lactate prepared according to example 23.
`
`45
`
`FIG. 1 is an illustration of X-ray powder diffraction
`(XRPD) pattern of crystalline anhydrate Form A of the dihy(cid:173)
`drogen phosphate salt of sitagliptin.
`FIG. 2 is an illustration of differential scanning calorimetry
`("DSC") curve of crystalline anhydrate Form A of the dihy(cid:173)
`drogen phosphate salt of sitagliptin.
`FIG. 3 is an illustration of thermogravimetric analysis
`(TGA) curve of crystalline anhydrate Form A of the dihydro(cid:173)
`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 50
`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(cid:173)
`gliptin hydrobromide prepared according to example 15.
`FIG. 9 is an illustration of TGA curve of crystalline sita(cid:173)
`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(cid:173)
`gliptin methane sulfonate prepared according to example 16.
`FIG. 12 is an illustration ofTGA curve of crystalline sita(cid:173)
`gliptin methane sulfonate prepared according to example 16.
`
`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(cid:173)
`peratures are in Degrees Celsius unless specified otherwise.
`The present invention can comprise ( open ended) of the com(cid:173)
`ponents of the present invention as well as other ingredients or
`elements described herein.
`As used herein, "comprising" means the elements recited,
`or their equivalent in structure or function, plus any other
`55 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
`65 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.
`
`60
`
`Merck Exhibit 2032, Page 36
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`US 8,309,724 B2
`
`6
`
`Formula V
`
`F
`
`F
`
`(ii) converting the compound of Formula V to 7-(1-oxo-3-
`amino-4-(2,4, 5-trifluorophenyl )-buty 1)-3-( trifluoromethyl )-
`5 ,6, 7 ,8-tetrahydro-1,2,4-triazolo [ 4,3-a]pyrazine of Formula
`IV;
`
`Formula IV
`
`F
`
`F
`
`(iii) treating the compound of Formula IV with a reagent to
`afford a diasteromeric salt of sitagliptin of Formula III;
`
`Formula III
`
`F
`
`F
`
`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
`
`F
`
`F
`
`20
`
`5
`This document may refer to a material, such as in this
`instance, salts of sitagliptin, and its crystalline forms, sol(cid:173)
`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 5
`context, it will be appreciated that patterns, spectra, and other
`graphical data can be shifted in their positions, relative inten(cid:173)
`sities, and/or values due to a number of factors known to those
`of skill in the art. For example, in the crystallographic and
`powder X-ray diffraction arts, such shifts in peak positions or 10
`the relative intensities of one or more peaks can occur because
`of, without limitation: the equipment used, the sample prepa(cid:173)
`ration protocol, preferred packing and orientations, the radia(cid:173)
`tion source, operator error, method and length of data collec(cid:173)
`tion, and the like. However, those of ordinary skill in the art 15
`should be able to compare the figures herein with a pattern
`generated of an unknown form of, in this case, salts of sita(cid:173)
`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(cid: