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WO 2015/031595 Al 5 March 2015 (05.03.2015) P O P C T

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WO 2015/031595 Al 5 March 2015 (05.03.2015) P O P C T (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 2015/031595 Al 5 March 2015 (05.03.2015) P O P C T (51) International Patent Classification: garden, Ajab road, Mendarda, Junagadh, Gujarat 362260 C07D 209/52 (2006.01) A61K 31/403 (2006.01) (IN). SURESHBHAI, Patel Hitesh; C-103, Galaxy resid ency, Nr. Nilsagar tenement, Naroda-Kathvada Road, (21) International Application Number: Ahmedabad, Gujarat 382330 (IN). BADHABHAI, Sond- PCT/US20 14/053 123 harava Lalit; At post Kolda, Tal-Kunkavav, Dist-Amreli, (22) International Filing Date: Amreli, Gujarat 365455 (IN). 28 August 2014 (28.08.2014) (74) Agent: SMIRK, Rebecca; Servilla Whitney, 33 Wood Av (25) Filing Language: English enue South, Second Floor, Suite 210, Iselin, New Jersey 08830 (US). (26) Publication Language: English (81) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of national protection available): AE, AG, AL, AM, 2813/MUM/2013 28 August 2013 (28.08.2013) IN AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (71) Applicant: AMNEAL PHARMACEUTICALS LLC BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, [US/US]; 400 Crossing Boulevard, Third Floor, Bridgewa- DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, ter, New Jersey 08807-2863 (US). HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (72) Inventors: KUMAR, Agarwal Virendra; A14, Vishal MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, Residency, Anandnagar Char-rasta, Satellite, Ahmedabad, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, Gujarat 380015 (IN). BADRULHUSAN, Siddiqui Arif; SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, 50, Ketki society, Nr. Sonal Cinema, Vejalpur road, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, Ahmedabad, Gujarat 380055 (IN). KESHAV, Kataria ZW. Lalit; 30, Krishna Bungalow, Opp. Shyam Villa, Bopal, Ahmedabad, Gujarat 380058 (IN). SUBODHBHAI, Ma- (84) Designated States (unless otherwise indicated, for every heta Abhay; Plot No. 1358/7, Daxinamurti Society, Near kind of regional protection available): ARIPO (BW, GH, Shramjivi akhada, Ghogha circle, Bhavnagar, Gujarat GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, 364001 (IN). CHANGANBHAI, Butani Pankaj; TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, "Kuldeep", Gundala Road, Nr. Railway crossing, Jayesh- TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, nagar, Gondal, Rajkot, Gujarat 3603 11 (IN). DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, PRABHAKARRAO, Patil Shashikant; At post Morane LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Pre. Ner Tal and Dist-Dhule, Dhule, Maharashtra 424302 GW, KM, ML, MR, NE, SN, TD, TG). (IN). YASHWANT, Patil Tushar; At post Ghodade, B/h. Bank of Maharashtra, Tal-Sakri, Dist-Dhule, Dhule, Mah a Published: rashtra 424304 (IN). SURYAKANT, Deore Ganesh; New — with international search report (Art. 21(3)) Plot, Bhagwat Road, Nr. Petrol pump, Tal-Amalner, Dist- Jalgaon, Jalgaon, Maharashtra 425401 (IN). JAHY- ANTIBHAI, Pansuriya Ketan; "Kalyan", Nr. Public © o (54) Title: A PROCESS FOR PREPARATION OF SAXAGLIPTIN AND ITS HYDROCHLORIDE SALT (57) Abstract: Described is an improved and industrially feasible process for the preparation of Saxagliptin or its hydrochloride salt. Also described are the novel intermediates and their use in the preparation of Saxagliptin or its hydrochloride salt. A PROCESS FOR PREPARATION OF SAXAGLIPTIN AND ITS HYDROCHLORIDE SALT TECHNICAL FIELD The present invention relates to processes for the preparation of saxagliptin and its hydrochloride salt. The present invention also relates to intermediate compounds and their use in processes for preparing saxagliptin. BACKGROUND Dipepeptidyl peptidase IV inhibitors (DPP-IV inhibitors) are a class of oral hypoglycemic agents that block the enzyme DPP-rV and have been used to treat diabetes mellitus type 2. Saxagliptin has the chemical names (l S',3 S,,5 S,)-2-[2( S,)-2-amino-2-(3-hydroxy- adamantan-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile or (lS,3S,5S)-2-[(2S)-2- amino-2-(3-hydroxytricyclo[3.3.1.1 3'7]dec-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3- carbonitrile and the structural formula [I] . It is an orally active reversible DPP-IV inhibitor that is the active ingredient in the form of its hydrochloride salt in the ONGLYZA® tablet products originally developed by Bristol-Myers S uibb, and now marketed by AstraZeneca. Saxagliptin and its hydrochloride and trifluoroacetic acid salts are disclosed in U.S. Patent 6,395,767. U.S. Patent 7,420,079 and U.S. Patent 8,278,462 disclose a process for the preparation of saxagliptin, its hydrochloride salt, trifluoroacetate, and benzoate salts, and saxagliptin monohydrate. U.S. Patent 7,705,033 discloses a process for the preparation of saxagliptin monohydrate. U.S. Patent 7,214,702 discloses a process for the preparation of saxagliptin or its hydrochloride salt. The above documents disclose a process for the preparation of saxagliptin, which involves condensation of 2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid amide with adamantan- 1-yl-tert-butoxycarbonylamino acetic acid. U.S. Patent 7,186,846 discloses a process for the preparation of saxagliptin which involves reacting 2-aza-bicyclo[3.1.0]hexane-3-carbonitrile with trifhioroacetic acid 3- [carboxy-(2,2,2-trifluoroacetylamino)-methyl]adamantan-l-yl ester, followed by reductive cleavage of protected saxagliptin. Hiroshi Fukushima et al., "Synthesis and Structure- Activity Relationships of Potent 1- (2-Substituted-aminoacetyl)-4-fluoro-2-cyanopyrrolidine Dipeptidyl Peptidase IV Inhibitors," Chemical and Pharmaceutical Bulletin, Vol. 56(8), pages 1110-1117 (2008), reports the instability of 2-cyanofluoropyrrolidine derivatives at pH 6-8, due to intramolecular cyclization of basic nitrogen to a cyano group, leading to the formation of cyclic amidine which further transforms to diketopiperazine derivatives. Saxagliptin, being a 2-cyanopyrrolidine derivative, may undergo intramolecular cyclization to form a cyclic amidine. The above reported processes suffer from the drawback that the tert-butyloxy carbonyl ("BOC") group is too sensitive in acidic conditions, which exist during the condensation of 2- aza-bicyclo[3.1.0]hexane-3-carboxylic acid amide with adamantan-l-yl-tert- butoxycarbonylamino acetic acid, which leads to formation of unwanted impurities. Further, deprotection of BOC requires harsh and more acidic conditions. Moreover, using BOC as a protecting group makes the reaction monitoring difficult using thin layer chromatography ("TLC" ) and tedious since it is less sensitive to ultraviolet ("UV"). BOC also is relatively expensive, making the process not viable industrially. Indian Application 2065/CHE/2012 discloses a process for the preparation of saxagliptin which involves the use of the benzyloxy carbonyl group ("CBZ") for protection of the amino group. However, CBZ deprotection would eventually lead to saxagliptin, which by itself is unstable and prone to intramolecular cyclization. Moreover, CBZ is difficult to handle on an industrial scale because of its liquid state and lacrimating properties. Therefore, there is a need for improved and industrially feasible processes for the preparation of saxagliptin. SUMMARY OF THE INVENTION In one aspect, the present invention provides a process for the preparation of saxagliptin or its hydrochloride salt, comprising: (a) reacting (lS,3S,5S)-2-[(2S)-2-tritylamino-2-(3-hydroxyadamantan-l-yl)acetyl]-2- azabicyclo[3. 1.0]hexane-3-carboxamide [IV] with trifluoroacetic anhydride followed by treatment with a carbonate or bicarbonate salt to obtain (lS,3S,5S)-2-[(2S)-2-tritylamino-2-(3- hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile [V]; and (b) removing the trityl group from (lS,3S,5S)-2-[(2S)-2-tritylamino-2-(3- hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile [V] to obtain saxagliptin hydrochloride, and optionally converting the hydrochloride salt to saxagliptin. In one embodiment, (lS,3S,5S)-2-[(2S)-2-tritylamino-2-(3-hydroxyadamantan-l yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide [IV] is prepared by: reacting 3-hydroxyadamantan-l-yl-tritylamino acetic acid [IIA] with a methanesulfonic acid salt of (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3 carboxamide [III], H [HI]. In another embodiment, lS,3S,5S)-2-[(2S)-2-tritylamino-2-(3-hydroxyadamantan-l- :tyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide [IV] is prepared by a process, comprising: reacting 3-hydroxyadamantan-l-yl-tert-butoxycarbonylamino acetic acid [II] with a methanesulfonic acid salt of (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3- carboxamide [III], [III] followed by BOC deprotection and reaction with trityl chloride. In a preferred embodiment, saxagliptin hydrochloride is in the form of saxagliptin hydrochloride dihydrate. In another aspect, the present invention provides a process for the preparation of saxagliptin or its hydrochloride salt, comprising: providing (lS,3S,5S)-2-[(2S) -2-tritylamino-2- (3-hydroxyadamantan- 1-yl)acetyl]-2- azabicyclo[3.1.0]hexane-3-carbonitrile [V]; and removing the trityl group from (lS,3S,5S)-2-[(2S)-2-tritylamino-2-(3- hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile [V] to obtain saxagliptin hydrochloride, and optionally converting the hydrochloride salt to saxagliptin. In additional aspects, the present invention provides intermediate compounds: 3- hydroxyadamantan-l-yl-tritylamino acetic acid [IIA]; (lS,3S,5S)-2-[(2S)-2-tritylamino-2-(3- hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide [IV]; and (lS,3S,5S)-2-[(2S)-2-tritylamino-2-(3-hydroxyadamantan-l-yl)acetyl]-2- azabicyclo[3.1.0]hexane-3-carbonitrile [V], and their pharmaceutically acceptable salts, solvates and hydrates thereof; processes for their preparation; and their uses for the preparation of saxagliptin or hydrochloride salt thereof.
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