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-hydroxyadamantan-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.

DETAILED DESCRIPTION It is desirable to reduce the formation of the saxagliptin cyclic amidine impurity. It has been found that a triphenylmethyl (trityl) group is superior to other protecting groups in reducing the formation of the cyclic amidine impurity. Moreover, the trityl group is less expensive, easily available, and easy to handle by being in a solid state, thus making it industrially feasible. Further, it is easier to monitor the reaction using TLC or high performance liquid chromatography ("HPLC"), since it absorbs UV light. Moreover, removing a trityl protecting group can directly yield saxagliptin hydrochloride salt and does not involve formation of saxagliptin which is highly unstable and prone to intramolecular cyclization. The methanesulfonic acid salt of (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide [III] used in the present process can be obtained by reacting tert-butyl (lS,3S,5S)-3-carbamoyl- 2-azabicyclo[3.1.0]hexane-2-carboxylate with methanesulfonic acid in the presence of an organic solvent. Organic solvents that may be used include, but are not limited to, methanol, ethanol, isopropanol, n-butanol, iso-butanol, tert-butanol, and the like. Useful temperatures for conducting the reaction are above about 50°C, such as about 60-70°C, or other temperatures. 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- :tyl]-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], - CONH N H [HI]. The compound [IIA] can be prepared by reacting (lS)-a-amino-3-hydroxyadamantane- acetic acid with triphenylmethyl chloride in the presence of a suitable solvent such as dichloromethane and base such as triethylamine at a temperature of about 25-35°C. The reaction of compound [IIA] and compound [III] can be carried out in the presence of one or more halogenated solvents, such as dichloromethane, 1,2-dichloroethane, 1,1- dichloroethane, chloroform, carbon tetrachloride, and the like, at temperatures about 20-40°C or about 25-35°C. The amide formation can be carried out in the presence of a carbodimide coupling agent, such as l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), Ν,Ν'- dicyclohexylcarbodiimide (DCC), or Ν,Ν'-diisopropylcarbodiimide (DIC). Further, an additional auxiliary nucleophile, such as 1-hydroxybenzotriazole, N-hydroxysuccinimide, or 1- hydroxy-7-azabenzotriazole, can be added to the reaction mixture to prevent loss of optical purity. The amide bond formation can be carried out in the presence of a tertiary amine base such as N-methylmorpholine (NMM), Ν,Ν-diisopropylethylamine (DIPEA or Hiinig' s base), and triethylamine (TEA). In another embodiment, (lS,3S,5S)-2-[(2S)-2-tritylamino-2-(3-hydroxyadamantan-l- yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide [Γν ] is prepared by: 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],

H [HI] followed by BOC deprotection and reaction with trityl chloride. The reaction of compound [II] and compound [III] can be carried out in the presence of one or more halogenated solvents, such as dichloromethane, 1,2-dichloroethane, 1,1- dichloroethane, chloroform, carbon tetrachloride, and the like, at temperatures about 20-40°C or about 25-35°C. The amide formation can be carried out in the presence of a carbodimide coupling agent, such as l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), Ν,Ν'- dicyclohexylcarbodiimide (DCC), or Ν,Ν'-diisopropylcarbodiimide (DIC). Further, an additional auxiliary nucleophile, such as 1-hydroxybenzotriazole, N-hydroxysuccinimide, or 1- hydroxy-7-azabenzotriazole, can be added to the reaction mixture to prevent loss of optical purity. The amide bond formation can be carried out in the presence of a tertiary amine base such as N-methylmorpholine (NMM), Ν,Ν-diisopropylethylamine (DIPEA or Hiinig's base), and triethylamine (TEA). The removal of BOC protecting group after completion of the reaction of the compound [II] and [III] can be carried out with a solution of hydrochloric acid, such as an aqueous solution having a concentration of HC1 about 34-36% by weight followed by treatment with hydrogen chloride in isopropanol in concentration of about 14.2% w/w. The formation of compound [IV] can be carried out by treatment of reaction mass with trityl chloride in presence of suitable base such as triethylamine and suitable solvent such as acetonitrile at a temperature of about 10-20°C. The conversion of compound [IV] to compound [V] involves treatment with trifluoroacetic anhydride in the presence of an organic solvent and a base. Useful organic solvents include, but are not limited to, methanol, ethanol, n-propanol, isopropyl alcohol, isobutanol, n-butanol, tert-butanol, amyl alcohol, isoamyl alcohol, hexanol, tetrahydrofuran, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate, ethyl formate, and mixtures of two or more thereof. The base is an organic or inorganic base. Exemplary organic bases include, without limitation, triethyl amine, tributyl amine, ammonia, diisopropyl amine, dimethyl amine, diisopropyl ethyl amine, pyridine, and the like. Trifluoroacetic acid generated during the conversion of compound [IV] to compound [V] can be scavenged using an aqueous solution of alkali metal carbonates or bicarbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and the like. In one embodiment, trifluoroacetic acid generated during the reaction can be scavenged using a 20% aqueous potassium carbonate solution. Completion of scavenging can be confirmed by TLC. The compound (lS,3S,5S)-2-[(2S)-2-tritylamino-2-(3-hydroxyadamantan-l-yl)acetyl]- 2-azabicyclo[3.1.0]hexane-3-carbonitrile [V] can optionally be further purified using an alcohol, such as methanol. The removal of the trityl protecting group from compound [V] can be carried out with a solution of hydrochloric acid, such as an aqueous solution having a concentration of HC1 about 34-36% by weight. Examples of solvents that can be used in the deprotection step include methanol, ethanol, isopropanol, n-butanol, and iso-butanol. The deprotection step can be carried out at temperatures about 20-35°C, or about 25-30°C. Saxagliptin hydrochloride, obtained as a residue after distilling the solvent in the deprotection step, can be further purified using an ester, such as methyl acetate, ethyl acetate, and isopropyl acetate as antisolvents. In a preferred embodiment, saxagliptin hydrochloride is recovered as saxagliptin hydrochloride dihydrate. The recovered saxagliptin hydrochloride can optionally be converted to saxagliptin using methods known in the art. In yet another aspect, the present invention provides a process for preparation of saxagliptin hydrochloride as depicted in the scheme-I below. Scheme-I

In yet another aspect, the present invention provides a process for preparation of saxagliptin hydrochloride as depicted in the scheme-II below. Scheme-II

Potassium Carbonate The following examples are provided only for the purpose of illustrating certain specific aspects and embodiments of the present invention and should not be considered as limiting the scope or spirit of the invention in any manner.

Example 1 Preparation of (lS)-a-amino-3-hydroxyadamantane-acetic acid hydrochloride A solution of (lS)-l-[[(l,l-Dimethylethoxy)carbonyl]amino]-3-hydroxyadamantane-l-acetic acid (1.0 g) in dichloromethane (10 ml) at 10-20°C was mixed with 20-25% isopropanol-HCl (2 ml) and stirred at 25-35°C for 8 hours. Solvent was evaporated from the reaction mixture to give the product (lS)-a-amino-3-hydroxyadamantane-acetic acid hydrochloride as a solid (0.72 g). (Yield: 90.0%)

Example 2 Preparation of (lS)-l-[triphenylmethyl amino]-3-hydroxyadamantane-l-acetic acid A solution of (lS)-a-amino-3-hydroxyadamantane-acetic acid (1.0 g) in dichloromethane (10 ml) at 15-25°C was mixed with triethylamine (1.18 ml) and triphenylmethyl chloride (1.2 g). The reaction mixture was stirred at 25-35°C for 4 hours. Solvent was evaporated from the reaction mixture to give the product (lS)-l-[triphenylmethyl amino]-3-hydroxyadamantane-l- acetic acid (1.24 g). (Yield: 70.0%)

Example 3 Preparation of methanesulfonic acid salt of (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3- carboxamide Tert-butyl (lS,3S,5S)-3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate (100 g, 0.442 mole) was combined with isopropyl alcohol (600 ml), with stirring at 25-30°C. The mixture was heated to 60-70°C and methanesulfonic acid (55.2 g, 0.575 mole) was added in small amounts over 60 minutes. The mixture was stirred for 4 hours at 60-70°C. Completion of the reaction was confirmed using TLC. The mixture was cooled to 5-15°C and stirred for 1 hour. The mixture was filtered and the solid was washed with chilled isopropyl alcohol (2x50 ml). The filtrate was dried under vacuum to obtain the methanesulfonic acid salt of (lS,3S,5S)-2- azabicyclo[3.1.0]hexane-3-carboxamide. (Yield=96.7%; HPLC purity= 96%) Mass: 434 [M+H] + δ 1H-NMR (CDCI 3) : 6.96 ( 1 H, s), 5.68 ( 1 H, s), 5.39-5.42 ( 1 H, d), 4.88-4.91 ( 1 H, dd), 4.52- 4.54 ( 1 H, d), 3.67-3.70 ( 1 H, m), 2.50-2.53 ( 1 H, dd), 2.22 (2 H, s), 2.03 ( 1 H, s), 1.47-1.75

(15 H, m), 1.41 (9 H, s), 1.24 ( 1 H, s), 0.81-0.95 (2 H, m)

Example 4 Preparation of (lS,3S,5S)-2-[(2S)-2-triphenylmethylamino-2-(3-hydroxyadamantan-l- yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide A solution of (lS)-l-[triphenylmethyl amino] -3-hydroxyadamantane-l -acetic acid (1.0 g),

(1S,3S, 5S)-2-azabicyclo [3.1.0]-hexane-3-carboxamide methanesulphonate (0.47 g), 1- hydroxybenzotriazole monohydrate (HOBt H20) (0.08 g), dichloromethane (5 ml), and triethyl amine (0.4 ml) at 5-15°C was combined with triethylamine (0.65 ml) and l-ethyl-3-(3- dimethylaminopropyl) carbodiimide hydrochloride (EDC.HC1) (0.5 g) and stirred at ambient temperature (25-35°C) for 12 hours. Completion of the reaction was verified using TLC. The reaction mixture was successively washed with water (5 ml), IN HC1 (5 ml), 5% aqueous sodium bicarbonate solution (3x5 ml), and then with brine (5 ml). The solvent from the organic phase was evaporated to give a residue. To the residue was added toluene (5 ml) and water (5 ml) and the mixture was heated to 45-55°C and maintained for 1 hour. The mixture was cooled to 25°C, stirred for 2 hours and filtered. The solid was washed with toluene (2 ml) and dried at 50-60°C in an oven to give the title compound (0.984 g). (Yield: 80.0%)

Example 5 Preparation of (lS,3S,5S)-2-[(2S)-2-(tritylamino)-2-(3-hydroxyadamantan-l-yl)acetyl]-2- azabicyclo[3.1.0]hexane-3-carboxamide l-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HC1) (1.2 eq., 12.3 g) was added in portions to a solution of 3-hydroxyadamantane-l-yl (lS)-tritylamino-acetic acid (25.0 g) in tetrahydrofuran (175 ml) and stirred for 15 minutes. 1-Hydroxybenzotriazole monohydrate (HOBt H20) (1.0 eq., 8.2 g) and (1S,3S, 5S)-2-azabicyclo [3.1.0]-hexane-3- carboxamide methanesulphonate (1.0 eq., 11.88 g) were added to the mixture in portions. Triethyl amine (3.2 eq., 17.28 g) was added dropwise to the reaction mixture over 20 minutes. The reaction mixture was stirred at 25°C for 5 hours. Completion of the reaction was verified using TLC. The solvent was distilled from the reaction mixture to give a residue. Dichloromethane (250 ml) and water (100 ml) were mixed with the residue and the organic phase was separated. The organic phase was washed with aqueous dilute HC1 (100 ml), aqueous 10% sodium bicarbonate solution (100 ml), and then with brine (100 ml). The organic phase was dried over sodium sulfate and the solvent evaporated to give a residue, which was dried under high vacuum at 30-40°C for 2 hours to obtain (lS,3S,5S)-2-[(2S)-2-(tritylamino)- 2-(3-hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide (18.0 g). (Yield: 59%)

Example 6 Preparation of (lS,3S,5S)-2-[(2S)-2-tritylamino-2-(3-hydroxyadamantan-l-yl)acetyl]-2- azabicyclo[3.1.0]hexane-3-carboxamide Tert-butoxycarbonylamino-(3-hydroxy-adamantan-l-yl)-acetic acid (100 g; 0.307 mole) was added to dichloromethane (500 ml) with stirring. The methanesulfonic acid salt of (1S,3S,5S)- 2-azabicyclo[3.1.0]hexane-3-carboxamide (64.8 g; 0.292 mole) was added, and the reaction mixture was stirred for 15 minutes at 25-35°C. In a separate flask, 1-hydroxybenzotriazole monohydrate (11.8 g; 0.077 mole) and triethylamine (34.2 g) were added to dichloromethane (500 ml) and stirred to form a solution. This solution was added to the reaction mixture gradually over 30 minutes at 25-30°C. The reaction mixture was then cooled to 5-15°C, 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1) (70.6 g) was added, and the mixture was stirred for 15 minutes at 5-15°C. Triethylamine (65.2 g) was added to the reaction mixture and stirred for 30 minutes. Temperature of the reaction mixture was raised to 25-35°C and stirred continuously for 12 hours. Reaction completion was confirmed by HPLC. Water (500 ml) was added, the mixture was stirred, and the organic layer was separated. The organic layer was washed with dilute hydrochloric acid solution (500 ml, prepared by adding concentrated hydrochloric acid (60 ml) to water (440 ml)), and further washed with sodium bicarbonate solution (3 times), followed by washing with sodium chloride solution. Hydrogen chloride in isopropanol (14.2% w/w, 315.6 g) was added over 60 minutes, and the mixture was stirred for 4 hours. Completion of the reaction was confirmed by HPLC. The mixture was distilled under vacuum to remove dichloromethane. Toluene was added to the residue and distilled under vacuum. Acetonitrile (400 ml) was added to the residue followed by addition of triethylamine (79.2 g) over 15 minutes with stirring. The reaction mixture was cooled to 10- 20°C, and trityl chloride (72.7 g) was added gradually, followed by stirring for 2 hours. Completion of the reaction was confirmed by HPLC. The mixture was distilled under vacuum to remove acetonitrile. Toluene was added to the residue and distilled under vacuum. Toluene (500 ml) followed by water (500 ml) were added to the residue, the mixture was heated at 45- 55°C and filtered and dried to obtain the product. (Yield=60.3%; HPLC purity=94%) Mass: 576 [M+H] + δ 1H-NMR (CD3OD) : 7.43-7.45 (5 H, d), 7.06-7.17 (10 H, m), 4.50 ( 1 H, s), 3.84-3.87 ( 1 H, dd), 3.42 ( 1 H, s), 3.09-3.13 ( 1 H, m), 2.87-2.91 ( 1 H, m), 2.15-2.23 ( 1 H, m), 2.09 ( 1 H, s),

1.90-1.92 ( 1 H, d), 1.42-1.77 (13 H, m), 1.19-1.22 ( 1 H, t), 0.72-0.76 ( 1 H, m), 0.50-0.55 (1H, m)

Example 7 Preparation of (lS,3S,5S)-2-[(2S)-2-tritylamino-2-(3-hydroxyadamantan-l-yl)acetyl]-2- azabicyclo[3.1.0]hexane-3-carbonitrile A solution of (lS,3S,5S)-2-[(2S)-2-tritylamino-2-(3-hydroxyadamantan-l-yl)acetyl]-2- azabicyclo[3.1.0]hexane-3-carboxamide (15.0 g) in tetrahydrofuran (150 ml) was mixed with pyridine (12.3 g) and cooled to 0-10°C. Trifluoroacetic anhydride (19.1 g) was added to the reaction mixture slowly over 30 minutes. The reaction mixture was stirred at 0-10°C for 3 hours. Completion of the reaction was confirmed by HPLC. Aqueous potassium carbonate solution (20%, 240 ml) was added to the reaction mixture over 30 minutes to obtain pH 10-11. Methanol (50 ml) was added, and the reaction mixture was stirred at 25°C for 3 hours. Completion of the reaction was verified using TLC. The reaction mixture was cooled to 0°C and stirred for 30 minutes. The solid was filtered and washed with water (2x15 ml). The solid was dried under vacuum at 50-60°C for 8 hours to give the title compound (10.0 g). (Yield=79%; HPLC purity=99%) Mass: 558 [M+H] + δ 1H-NMR (DMSO d6) : 7.47-7.49 (6 H, d), 7.24-7.28 (6 H, t), 7.16-7.19 (3 H, t), 4.46 ( 1 H, s), 4.05-4.08 ( 1 H, dd), 3.10-3.13 ( 1 H, m), 2.95-2.98 ( 1 H, d), 2.20-2.26 ( 1 H, m), 2.12-2.18 (2 H, m), 1.88-1.95 (3 H, m), 1.38-1.75 ( 1 H, m), 0.75-0.80 ( 1 H, q), 0.42-0.46 ( 1 H, m)

Example 8 Preparation of saxagliptin hydrochloride A mixture of aqueous hydrochloric acid (34.5% w/w) (2.3 g) and methanol (20 ml) was added to a mixture of (lS,3S,5S)-2-[(2S)-2-tritylamino-2-(3-hydroxyadamantan-l-yl)acetyl]-2- azabicyclo[3.1.0]hexane-3-carbonitrile (10.0 g) in methanol (80 ml), and the mass was stirred at 25°C for 3 hours. Completion of the reaction was verified by HPLC. Solvent was distilled from the reaction mixture to give a residue. Ethyl acetate (100 ml) was mixed with the residue for 30 minutes at ambient temperature. The solid was filtered and washed with ethyl acetate (2x5 ml). The solid was dried under vacuum at 50-60°C for 8 hours to give the title product (6.0 g). (Yield=90%; HPLC purity=99.5%) Mass: 316 [M+H] + δ 1H-NMR (DMSO d6) : 8.29 (3 H, s), 5.21-5.24 ( 1 H, dd), 4.63 ( 1 H, s), 4.23 ( 1 H, s), 4.09- 4.12 ( 1 H, m), 2.54-2.57 ( 1 H, m), 2.23-2.27 ( 1 H, dd), 2.15 ( 1 H, s), 1.93-1.98 ( 1 H, m), 1.40-

1.67 (12 H, m), 1.00-1.05 ( 1 H, m), 0.73-0.77 ( 1 H, m) What is claimed is:

1. A process for the preparation of saxa liptin of formula [I] 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.

2. The process of claim 1, wherein carbonate salt in step (a) is potassium carbonate. 3. The process of claim 1, wherein step (a) is carried out in the presence of an organic or inorganic base.

4. The process of claim 3, wherein the organic or inorganic base is selected from the group consisting of triethyl amine, tributyl amine, ammonia, diisopropyl amine, dimethyl amine, diisopropyl ethyl amine, pyridine, and mixtures thereof.

5. The process of claim 1, wherein removal of 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] is carried out in a solution of hydrochloric acid and organic solvent at a temperature of about 20-35°C.

6. The process of claim 1, wherein saxagliptin hydrochloride obtained is in the form of saxagliptin hydrochloride dihydrate.

7. The process of claim 1, further 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],

H [HI] followed by BOC deprotection and reaction with trityl chloride to obtain (lS,3S,5S)-2-[(2S)-2-tritylamino-2-(3-hydroxyadamantan-l-yl)acetyl]-2- azabicyclo[3. 1.0]hexane-3-carboxamide [IV] .

8. The process of claim 7, wherein the reaction of 3-hydroxyadamantan-l-yl-tert- butoxycarbonylamino acetic acid [II] and themethanesulfonic acid salt of (lS,3S,5S)-2- azabicyclo[3.1.0]hexane-3-carboxamide [III] is carried out in the presence of a coupling agent selected from the group consisting of l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC), Ν,Ν'-dicyclohexylcarbodiimide (DCC), and Ν,Ν'-diisopropylcarbodiimide (DIC).

9. The process of claim 7, wherein the reaction of 3-hydroxyadamantan-l-yl-tert- butoxycarbonylamino acetic acid [II] and the methanesulfonic acid salt of (1S,3S,5S)- 2-azabicyclo[3.1.0]hexane-3-carboxamide [III] is carried out in the presence of an auxiliary nucleophile selected from the group consisting of 1-hydroxybenzotriazole, N- hydroxysuccinimide, and l-hydroxy-7-azabenzotriazole.

10. The process of claim 7, wherein the reaction of 3-hydroxyadamantan-l-yl-tert- butoxycarbonylamino acetic acid [II] and the methanesulfonic acid salt of (1S,3S,5S)- 2-azabicyclo[3.1.0]hexane-3-carboxamide [III] is carried out in the presence of an organic or inorganic base.

11. The process of claim 10, wherein the organic or inorganic base is selected from the group consisting of triethyl amine, tributyl amine, ammonia, diisopropyl amine, dimethyl amine, diisopropyl ethyl amine, pyridine, and mixtures thereof.

12. The process of claim 7, wherein the reaction of 3-hydroxyadamantan-l-yl-tert- butoxycarbonylamino acetic acid [II] and the methanesulfonic acid salt of (1S,3S,5S)- 2-azabicyclo[3.1.0]hexane-3-carboxamide [III] is carried out in the presence of one or more halogenated solvents and at a temperature of about 20-40°C.

13. The process of claim 7, wherein BOC deprotection is carried out in a solution of hydrochloric acid.

14. The process of claim 7, wherein reaction with trityl chloride is carried out in the presence of an organic solvent and base.

15. The process of claim 1, further comprising: 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],

[III] to obtain (lS,3S,5S)-2-[(2S)-2-tritylamino-2-(3-hydroxyadamantan-l-yl)acetyl]-2- azabicyclo[3. 1.0]hexane-3-carboxamide [IV] .

16. The process of claim 15, wherein the reaction of 3-hydroxyadamantan-l-yl-tritylamino acetic acid [IIA] and themethanesulfonic acid salt of (lS,3S,5S)-2- azabicyclo[3.1.0]hexane-3-carboxamide [III] is carried out in the presence of a coupling agent selected from the group consisting of l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC), Ν,Ν'-dicyclohexylcarbodiimide (DCC), and Ν,Ν'-diisopropylcarbodiimide (DIC).

17. The process of claim 15, wherein the reaction of 3-hydroxyadamantan-l-yl-tritylamino acetic acid [IIA] and the methanesulfonic acid salt of (lS,3S,5S)-2- azabicyclo[3.1.0]hexane-3-carboxamide [III] is carried out in the presence of an auxiliary nucleophile selected from the group consisting of 1-hydroxybenzotriazole, N- hydroxysuccinimide, and l-hydroxy-7-azabenzotriazole.

18. The process of claim 15, wherein the reaction of 3-hydroxyadamantan-l-yl-tritylamino acetic acid [IIA] and the methanesulfonic acid salt of (lS,3S,5S)-2- azabicyclo[3.1.0]hexane-3-carboxamide [III] is carried out in the presence of an organic or inorganic base. 19. The process of claim 18, wherein the organic or inorganic base is selected from the group consisting of triethyl amine, tributyl amine, ammonia, diisopropyl amine, dimethyl amine, diisopropyl ethyl amine, pyridine, and mixtures thereof.

20. The process of claim 1, wherein the reaction of 3-hydroxyadamantan-l-yl-tritylamino acetic acid [IIA] and the methanesulfonic acid salt of (lS,3S,5S)-2- azabicyclo[3.1.0]hexane-3-carboxamide [III] is carried out in the presence of one or more halogenated solvents and at a temperature of about 20-40°C.

21. A process for the preparation of saxa liptin of formula [I] or its hydrochloride salt,

comprising: providing (lS,3S,5S)-2-[(2S)-2-tritylamino-2-(3-hydroxyadamantan-l-yl)acetyl]-2- azabicyclo[3.1.0]hexane-3-carbonitrile [V]; and

22. A compound selected from: 2 1 A. CLASSIFICATION OF SUBJECT MATTER C07D 209/52(2006.01)i, A61K 31/403(2006.01)i

According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) C07D 209/52; C07D 209/49; C07D 209/04; A61K 3 1/403; C07D 209/02

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Korean utility models and applications for utility models Japanese utility models and applications for utility models

Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) eKOMPASS(KIPO internal), STN(REGISTRY, CAPLUS) & Keywords: saxagliptin, amidine, preparation, process, hydrochloride, salt, trityl, triphenylmethyl

DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

A SAVAGE, SCOTT A . e t a l ., Preparation o f Saxagliptin, a Novel DPP-IV 1 --22 Inhibi tor , Organic Process Research & Development, Vol. 13, pp. 1169-1176 (2009) See the whole document

A US 2005-0090539 Al (VU, TRUC e t al.) 28 April 2005 1 --22 See the whole document

A US 2005-0267191 Al (SHARMA, PADAM N.) 01 December 2005 1 --22 See the whole document

A US 2013-0023671 Al (KOVI, RAVISHANKER e t al.) 24 January 2013 1 --22 See the whole document

A WO 01-68603 A2 (BRISTOL-MYERS SQUIBB CO.) 20 September 2001 1 --22 See the whole document

A WO 2011-140328 A l (TEVA PHARMACEUTICAL INDUSTRIES LTD. e t al.) 10 November 2 1 --22 011 See the whole document

Further documents are listed in the continuation of Box C. See patent family annex.

* Special categories of cited documents: "T" later document published after the international filing date or priority "A" document defining the general state of the art which is not considered date and not in conflict with the application but cited to understand to be of particular relevance the principle or theory underlying the invention "E" earlier application or patent but published on or after the international "X" document of particular relevance; the claimed invention cannot be filing date considered novel or cannot be considered to involve an inventive "L" document which may throw doubts on priority claim(s) or which is step when the document is taken alone cited to establish the publication date of another citation or other "Y" document of particular relevance; the claimed invention cannot be special reason (as specified) considered to involve an inventive step when the document is "O" document referring to an oral disclosure, use, exhibition or other combined with one or more other such documents,such combination means being obvious to a person skilled in the art "P" document published prior to the international filing date but later "&" document member of the same patent family than the priority date claimed

Date of the actual completion of the international search Date of mailing of the international search report 12 December 2014 (12. 12.2014) 12 December 2014 (12.12.2014)

Name and mailing address of the ISA/KR Authorized officer International Application Division Korean Intellectual Property Office LEE, Jeong A 189 Cheongsa-ro, Seo-gu, Daejeon Metropolitan City, 302-701, Republic of Korea Facsimile No. +82-42-472-7140 Telephone No. +82-42-481-8738 Form PCT/ISA/210 (second sheet) (July 2009) C (Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

A WO 2008-131149 A2 (BRISTOL-MYERS SQUIBB COMPANY e t a l . ) 30 Oct ober 2008 1-22 See the whol e document

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US 2005-0267191 Al 01/12/2005 EP 1751102 Al 14/02/2007

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01-68603 A2 20/09/2001 AR 027634 Al 02/04/2003 AT 396176 T 15/06/2008 AU 2001-245466 B2 12/05/2005 AU 2001-45466 Al 24/09/2001 AU 4546601 A 24/09/2001 BR 0109115 A 30/12/2003 CA 2402894 Al 20/09/2001 CA 2402894 C 17/04/2012 CN 1213028 CO 03/08/2005 CN 1427826 AO 02/07/2003 CN 1698601 A 23/11/2005 CN 1698601 CO 23/11/2005 CO 5280198 Al 30/05/2003 cz 304355 B6 26/03/2014 DE 122010000008 11 01/07/2010 DE 122012000023 11 09/08/2012 DE 60134122 Dl 03/07/2008 D 1261586 T3 29/09/2008 EG 25854 A 11/09/2012 EP 1261586 A2 04/12/2002 EP 1261586 Bl 21/05/2008 EP 1559710 A2 03/08/2005 EP 1559710 A3 22/07/2009 EP 1559710 Bl 26/02/2014 EP 2272825 A2 12/01/2011 EP 2272825 A3 04/05/2011 ES 2305062 T3 01/11/2008 ES 2456667 T3 23/04/2014 H 1049330 Al 14/11/2008 HU 0302792 A2 29/12/2003 HU 0302792 A3 28/03/2007 HU 228110 Bl 28/11/2012 IL 151372 A 24/12/2009 IL 151372 DO 10/04/2003 IL 177018 DO 11/02/2009 IL 177019 A 28/02/2013 IL 177019 DO 10/12/2006 JP 04-460205 B2 12/05/2010 JP 05-427047 B2 26/02/2014 JP 2003-531118 A 21/10/2003 JP 2003-531118 T 21/10/2003 JP 2010-077163 A 08/04/2010

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WO 2011-140328 Al 10/11/2011 CN 103140475 A 05/06/2013 EA 201291169 Al 30/04/2013 EP 2539321 Al 02/01/2013 IL 222649 DO 31/12/2012 JP 05-373996 B2 18/12/2013 JP 2013-528592 A 11/07/2013 KR 10-2013-0038258 A 17/04/2013 US 2011-275687 Al 10/11/2011 US 8501960 B2 06/08/2013

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