(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/120111 A2 13 August 2015 (13.08.2015) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07D 487/04 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (21) International Application Number: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, PCT/US2015/014548 DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, 5 February 2015 (05.02.2015) KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (25) Filing Language: English PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (26) Publication Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 61/936,291 5 February 2014 (05.02.2014) US (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant: STEREOKEM, INC. (USA) [US/US]; 2507 GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, Kingwood Drive, Santa Clara, CA 9505 1 (US). TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (72) Inventors: JANAGANI, Satyanarayana; 2507 Kingwood DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Drive, Santa Clara, CA 9505 1 (US). THADURI, Ven- LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, kateshwar, Kumar; 3-1-353/2, SBH Colony, Venture III, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Maitrinagar, LB Nagar, Hyderabad, 500074 (IN). VAMA- GW, KM, ML, MR, NE, SN, TD, TG). RAJU, Ravisankar; 3-1-353/2, SBH Colony, Venture III, Maitrinagar, LB Nagar, Hyderabad, 500074 (IN). Published: (74) Agent: JACKSON, David, A.; Klauber & Jackson L.L.C., — without international search report and to be republished 25 East Spring Valley Avenue-Suite 160, Maywood, NJ upon receipt of that report (Rule 48.2(g)) 07607 (US). < © o (54) Title: EXPEDIENT SYNTHESIS OF SITAGLIPTIN (57) Abstract: Novel intermediates are disclosed as intermediates for preparation of a Sitagliptin. A novel synthetic method to pre pare Sitagliptin using the said intermediates is also disclosed. EXPEDIENT SYNTHESIS OF SITAGLIPTIN PRIORITY [0001] The present application claims priority from U.S. Provisional Application Serial No. 61/936,291, entitled " Expedient synthesis of Sitagliptin" and filed on February 5, 2014. The content of this application is hereby incorporated herein by reference in its entirety. FIELD OF THE INVENTION [0002] The present invention provides novel intermediates and their use in the preparation of (R)-3-amino-l-(3-trifluoromethyl-5,6-dihydro-8H-[l,2,4]triazolo[4,3-a]pyrazin-7-yl)-4-(2,4,5- trifluoro-phenyl)-butan-l-one (Sitagliptin). Furthermore, the present invention provides processes for the preparation of Sitagliptin and related compounds useful, for example, in Type II diabetes therapy. BACKGROUND OF THE INVENTION [0003] ((R)-3-amino-l-(3-trifluoromethyl-5,6-dihydro-8H-[l,2,4]triazolo[4,3-a]pyrazin-7- yl)-4-(2,4,5-trifluoro-phenyl)-butan-l-one, is a dipeptidyl peptidase-4 (DPP-IV) enzyme modulator and is useful in Type 2 diabetes therapy. The compound is also known as Sitagliptin. Sitagliptin also exists as its acid salts. The salt of sitagliptin has the following chemical structure: .HX IV [0004] The phosphate salt of sitagliptin has the following chemical structure: IV [0005] In a specific embodiment, sitagliptin is a monohydrate of the phosphate salt of sitagliptin, and has the following chemical structure: .H3P0 4 .H2 IV [0006] Sitagliptin is used either alone or in combination with other oral antihyperglycemic agents (such as metformin or a thiazolidinedione) for treatment of diabetes mellitus type II. The benefit of this medicine is its lower side-effects (e.g., less hypoglycemia, less weight gain) in the control of blood glucose values. [0007] Sitagliptin works to competitively inhibit the enzyme dipeptidyl peptidase 4 (DPP-4). This enzyme breaks down the incretins GLP-1 and GIP, gastrointestinal hormones that are released in response to a meal {J Clin Pharmacol 46 (8): 876-86). By preventing GLP-1 and GIP inactivation, GLP-1 and GIP are able to potentiate the secretion of insulin and suppress the release of glucagon by the pancreas. This drives blood glucose levels towards normal. As the blood glucose level approaches normal, the amounts of insulin released and glucagon suppressed diminish, thus tending to prevent an "overshoot" and subsequent low blood sugar (hypoglycemia) that is seen with some other oral hypoglycemic agents (Wikipedia). [0008] International Application Publication No. WO2003/004498 and U.S. Patent No. 6,699,871, describe the use of sitagliptin and analogs, and the composition thereof. [0009] Several processes for the synthesis of sitagliptin are known. For example, International Application Publication WO2004/085661 discloses the preparation of sitagliptin using S-phenylglycine amide as a chiral auxiliary. [0010] International Application Publication No. WO2004/087650 discloses the preparation of sitagliptin using the chiral benzyloxylazetidinone as an intermediate. [0011] International Application Publication Nos. WO2004/085378, WO2005/097733, and WO2006/081 151 disclose the preparation of sitagliptin which involves an enantioselective reduction of the intermediate chiral enamine in the presence of specific catalysts. [0012] International Application Publication No. WO2009/085990 discloses the preparation of sitagliptin using various chiral auxiliaries, such as chiral resolving agents. [0013] While these methods are useful for preparing Sitagliptin, alternative methods of the preparation, particularly for manufacturing scale production, are desirable. [0014] Citation of any reference in this application is not to be construed as an admission that such reference is prior art to the present application. SUMMARY OF THE INVENTION [0015] Novel intermediates, and use thereof, in the preparation of Sitagliptin are described herein. [0016] Accordingly, in one aspect of the invention, the novel intermediates are provided as useful synthons for preparation of Sitagliptin and pharmaceutically acceptable salt thereof. [0017] In particular aspects, the present invention provides processes for the preparation of an intermediate compound of formula I : or a salt thereof; wherein each R1 and R2 is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocycloalkyl, or substituted 3 3 3 3 or unsubstituted cycloalkyl, -C(0)-R , -C(0)-OR , -0-C(0)-R , -S(0) 2-R , -Si(R )3, and -O- 3 Si(R )3; each R is independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or R1 and R2 are joined together to form a heterocycle; and the wavy bond represents that the compound is in R-, S- or racemic form; wherein the process comprises the steps of: providing an intermediate compound of formula II A2) reacting the intermediate compound of formula II with a Michael donor of formula III: N H wherein R1 and R2 are as described above; to obtain the intermediate compound of formula I. [0018] In another aspect, the present invention provides stereoselective processes for the preparation of a pharmaceutically acceptable salt of sitagliptin of the formula IV: .HX IV or a solvate, or polymorph thereof; wherein HX is a pharmaceutically acceptable acid; comprising the steps of: Bl) reacting the compound of formula II or an isomer thereof: with a Michael donor of formula III: N H III wherein each R1 and R2 is H; or R is H, and R2 is t-butyl, 1,1,1-triphenylmethyl, or -C(0)-0-t- Bu; to form a mixture of isomers according to Va or V b B2) separating the compound of formula Vb from the mixture of isomers; B3) reacting the compound of formula Vb with HX to produce the pharmaceutically acceptable salt of sitagliptin of the formula IV or a solvate, or polymorph thereof. [0019] In one embodiment, R1 and R2 are as described in the context of formula I. [0020] In yet another aspect, the present invention provides stereoselective process for the preparation of a pharmaceutically acceptable salt of sitagliptin of the formula IV: .HX IV or a solvate, or polymorph thereof; wherein HX is a pharmaceutically acceptable acid; comprising the steps of: CI) reacting the compound of formula II or an isomer thereof: with a Michael donor of formula III: N H III wherein R1 is H, and R2 is substituted or unsubstituted benzyl, -C(0)0-benzyl, CH(Me)-Ph, CH(Me)-naphth-2-yl, or -CH(Ph)-C(0)OR 4a, -CH(Ph)-C(0)NR 4aR4 ; each R4a and R4 is independently H, substituted or unsubstituted alkyl, benzyl, or substituted or unsubstituted cycloalkyl; or R1 and R2 are joined together to form a heterocycle; and Ph is substituted or unsubstituted phenyl; to form a mixture of isomers according to Va or V b separating the compound of formula Vb from the mixture of isomers reacting the compound of formula Vb with HX to obtain the salt of formula VI: .HX V I C4) hydrogenolysis of the compound of formula VI or a solvate or polymorph, thereof; to produce the pharmaceutically acceptable salt of sitagliptin of the formula IV or a solvate, or polymorph thereof.