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A Process For The Preparation Of (1 S, 3 S, 5 S) 2 (2(s) 2 Amino 2 (3 Hydroxy 1 Adamantan 1 Yl)acetyl] 2 Azabicyclo [3.1.0] Hexane 3 Carbonitrile

Abstract: The present invention relates to an improved process for the preparation of (1S, 3S, 5S)-2-[2(S)-2-amino-2-(3-hydroxy-1-adamantan-1-yl) acetyl]-2-azabicyclo [3.1.0] hexane-3-carbonitrile and its intermediates.

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Notices, Deadlines & Correspondence

Patent Information

Application #
Filing Date
23 May 2012
Publication Number
34/2012
Publication Type
INA
Invention Field
CHEMICAL
Status
Email
Parent Application
Patent Number
Legal Status
Grant Date
2018-05-11
Renewal Date

Applicants

DIVI'S LABORATORIES LTD.,
7-1-77/E/1/303, DIVI TOWERS, DHARAM KARAN ROAD, AMEERPET, HYDERABAD - 500 016

Inventors

1. MURALI KRISHNA PRASAD DIVI
7-1-77/E/1/303, DIVI TOWERS, DHARAM KARAN ROAD, AMEERPET, HYDERABAD - 500 016
2. GUNDU RAO PADAKANDLA
7-1-77/E/1/303, DIVI TOWERS, DHARAM KARAN ROAD, AMEERPET, HYDERABAD - 500 016
3. NAGESWARA RAO BOLNENI
7-1-77/E/1/303, DIVI TOWERS, DHARAM KARAN ROAD, AMEERPET, HYDERABAD - 500 016
4. GOPINARAYANA BODALA
7-1-77/E/1/303, DIVI TOWERS, DHARAM KARAN ROAD, AMEERPET, HYDERABAD - 500 016

Specification

Field of Invention: The present invention relates to an improved process for the preparation of (1S, 3S, 5S)-2-[2(S)-2-amino-2-(3-hydroxy-1 -adamantan-1 -yl) acetyl]-2-azabicyclo [3.1.0] hexane-3-carbonitrile and its intermediates. Background of the Invention : Saxagliptin, (1S,3S,5S)-2-[2(S)-2-amino-2-(3-hydroxy-1 -adamantan-1 -yl)acetyl]-2-azabicyclo[3.1.0] hexane-3-carbonitrile of Formula I or its hydrochloride salt of Formula-II is an orally active reversible dipeptidyl peptidase-4 (DPP-4) inhibitor, which is a therapeutic agent for treatment of type-2 diabetes mellitus, obesity or related diseases and is disclosed in US 6395767 example 60. Saxagliptin is marketed under the trade name ONGLYZA ® by Bristol-Myers Squibb. Saxagliptin, its hydrochloride and trifluoro acetate salts are disclosed in US Pat No. 6395767B2. US Pat No. 7420079B2 and its continuation US Pat.No.2010/0274025 A1 disclosed process for preparing Saxagliptin and its hydrochloride, trifluoro acetate and benzoate salts, as well as Saxagliptin monohydrate. US Pat No. 7705033 B2 disclosed process for preparing Saxagliptin monohydrate. US Pat. No. 7214702 B2 also disclosed similar processes for the preparation of Saxagliptin and its hydrochloride salt. The essential steps of the processes disclosed in all the above said patents are summarized as Scheme-I below. Scheme -1 Tertiary butyloxy carbonyl (BOC) protected Saxagliptin of formula-VI was deprotected with aqueous hydrochloric acid, converted into Saxagliptin hydrochloride salt of formula-ll, which was further treated with an alkali solution and extracted with an organic solvent to obtain the free base (1S,3S,5S)-2-[2(S)-2-amino-2-(3-hydroxy-1 -adamantan-1 -yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile of formula-l. The above process suffers from the drawback that the tertiary- butyloxy carbonyl (BOC) protecting group was sensitive towards acidic experimental conditions during the condensation of compounds of formula-Ill and IV and transformation of the amide group to cyano group subsequently. Without this protection, the amino group is available for interaction with the cyano group leading to undesirable products as explained later. US Pa, No 7,86846B2 disclosed a process .or the preparation of Saxagliptin base through the reductive cleavage of a protected Saxagliptin (protected with tritluoro acetyl group) as shown in Scheme-II below. Scheme - II Hiroshi Fukushima et al (Chem. Pharm. Bull., 56(8), 1110-1117, 2008) reported the instability of 2-cyano fluoro pyrrolidine derivatives at pH 6-8 due to intramolecular attachment of basic nitrogen to the cyano group which leads to the formation of cyclic amidine, with subsequent further transformation into diketopiperazine derivatives. Saxagliptin can also be viewed as a derivative of 2-cyano pyrrolidine which may undergo formation of the cyclic amidine through intramolecular cyclisation. The acid salts of Saxagliptin are generally stable in solution. However, isolation of the free base (1S, 3S, 5S)-2-[2(S)-2-amino-2-(3-hydroxy-l-adamantan-1-yl) acetyl]-2-azabicyclo [3.1.0] hexane-3-carbonitrile of formula-l from its hydrochloride salt of formula-II is difficult. Scott Jones et al (OPRD 13,1169-1176, 2009) have shown (Scheme- III below) that Saxagliptin base underwent intramolecular cyclisation to form cyclic amidine of formula-X under alkaline conditions. Scheme - III Further Scott Jones et a/(JOC, 76, 10332-10337, 2011) reported that, "during the development of Saxagliptin manufacturing process, it was observed that the rate of cyclisation increases monotonically with pH". Since the resultant cyclic amidine [CA] of formula - VIII is not therapeutically active; its formation is not desirable. All the methods disclosed in the literature and patents employ treatment of Saxagliptin hydrochloride with an alkali solution to prepare Saxagliptin base, which process is not preferable because it leads to the formation of the cyclic amidine impurity under the basic pH conditions. Therefore there is a need for an improved, industrially applicable process to overcome the above problems. The present invention provides new methods and compounds for use in the process for making of Saxagliptin free base of formula-l. Summary of the Invention : Because of the drawbacks associated in the conversion of the Saxagliptin hydrochloride into Saxagliptin free base such as formation of cyclic amidine impurity under alkaline conditions, the present inventors investigated other possible protecting groups. After considerable experimentation with various protecting groups, it was found that the benzyloxy carbonyl group (CBZ) is a preferable choice. The selected benzyloxy carbonyl group (GBZ) is quite stable under the reaction conditions. Our studies showed that the benzyloxy carbonyl group of CBZ-protected Saxagliptin can be easily cleaved under mild hydrogenation in neutral medium to yield Saxagliptin free base of formula-l and formation of the cyclic amidine impurity was minimized to the specified limit of < 0.1%, as shown below in Scheme-IV. Further the base could be directly converted to Saxagliptin HCI or other salts if desired. A simple and convenient approach has been developed for the direct formation of the Saxagliptin free base of formula-l using CBZ protected Saxagliptin without the intermediate hydrochloride salt as in prior art processes. Scheme-IV In accordance with the present invention a process is provided for preparing Saxagliptin free base of formula-l which include the steps of a) providing a compound of formula-XIV b) coupling the compound of formula-XIV with a compound of formula-XIII to form the compound of formula-XI c) defecting the compound of formula-X using hydrogen source to give compound of formula-l Formula-I Alternately in accordance with the present invention, a process is provided for preparing compound of formula-l using compound of formula-Ill, which includes the steps of a) Coupling of compound of formula-XIV with compound of formula-Ill to give compound of formula-XV Formula-XV b) dehydration followed by hydrolysis of the formula-XV to give compound of formula-XI formula AI c) deprotecting the compound of formula-XI using hydrogen source to give compound of formula-l The process has the following advantages over the earlier processes: amenable for large scale industrial production, direct formation of Saxagliptin free base from CBZ-protected Saxagliptin of Formula-XI and minimizes the formation of the cyclic amidine of formula-X by employing mild conditions. The invention is also useful to prepare Saxagliptin hydrates and its salts, as for example Saxagliptin mono hydrate, Saxagliptin HCI and its hydrates. Detailed Description of the Invention: The invention relates to direct synthesis of Saxagliptin free base of formula-l from benzyl N-[(1S)-2-[(1S, 3S, 5S)-3-cyano-2-azabicyclo [3.1.0] hexan-2-yl]-1-(3-hydroxyadamantan-1-yl)-2-oxo-ethyl] carbamate of formula-XI, which is depicted by the following reaction Scheme-V. The base so obtained may be optionally converted to its hydrate or hydrochloride salt and its hydrate. Scheme-V In one embodiment the present invention refers to the process for preparing Saxagliptin of formula-l comprising deprotection of the benzyloxy carbonyl group of benzyl N-[(1S)-2-[(1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl]-1-(3-hydroxyadamantan-1-yl)-2-oxo-ethyl] carbamate of formula-XI by dissolving it in a suitable solvent or mixtures of solvents, treating with a hydrogen source in presence of a metal catalyst to yield Saxagliptin free base of formula-l. The reaction is carried out with solvents which may include but are not limited to methanol, ethanol, isopropyl alcohol, butanol, acetonitrile, tetrahdyrofuran, ethyl acetate, acetic acid or water, preferably in methanol or more preferably in acetonitrile. The reaction is carried out with hydrogen source, which may include but are not limited to hydrogen gas, formic acid, ammonium formate, ammonium acetate or ammonium chloride preferably hydrogen gas. The hydrogen gas used may be atmosphere of hydrogen gas, bubbling of hydrogen gas or hydrogen gas under pressure, preferably bubbling of hydrogen gas. The reaction is carried out at 0°C to 50°C temp, preferably at 15-30°C temperature. The reaction is carried out in presence of a metal catalyst such as palladium on carbon (Pd/C). The duration of the reaction is about 1 to 6 hr, preferably 2 hrs. In another embodiment the present invention refers to deprotection of benzyl N-[(1S)-2-[(1S, 3S, 5S)-3-cyano-2-azabicyclo [3.1.0] hexan-2-yl]-1-(3-hydroxyadamantan-1-yl)-2-oxo ethyl] carbamate of Formula-XI to give the [(1S,3S,5S)-2- [2(S)-2-amino-2-(3- hydroxy-1- adamantan-1-yl) acetyl]-2- azabicyclo [3.1.0]hexane-3-carbonitrile] monohydrate of Formula-XII. The process for preparing Saxagliptin monohydrate of formula-XII comprises, deprotection of the benzyloxy carbonyl group of benzyl N-[(1S)-2- [

Documents

Application Documents

# Name Date
1 2065-CHE-2012 FORM-2 23-05-2012.pdf 2012-05-23
1 296708-Correspondence_Renewal Fee_06-03-2023.pdf 2023-03-06
2 2065-CHE-2012 FORM-1 23-05-2012.pdf 2012-05-23
2 296708-Correspondence_Renewal Fee_09-03-2022.pdf 2022-03-09
3 296708-Correspondence_Renewal Fee_18-03-2021.pdf 2021-03-18
3 2065-CHE-2012 DESCRIPTION (COMPLETE) 23-05-2012.pdf 2012-05-23
4 2065-CHE-2012-Renewal Fee_08-05-2020.pdf 2020-05-08
4 2065-CHE-2012 CORRESPONDENCE OTHERS 23-05-2012.pdf 2012-05-23
5 Correspondence by Applicant_ Form-13_18-09-2019.pdf 2019-09-18
5 2065-CHE-2012 CLAIMS 23-05-2012.pdf 2012-05-23
6 Form13_Address of service Change_18-09-2019.pdf 2019-09-18
6 2065-CHE-2012 ABSTRACT 23-05-2012.pdf 2012-05-23
7 Correspondence by Applicant_Restoration_03-09-2019.pdf 2019-09-03
7 2065-CHE-2012 FORM-9 06-08-2012.pdf 2012-08-06
8 Correspondence by Applicant_Form 15_30-04-2019.pdf 2019-04-30
8 2065-CHE-2012 CORRESPONDENCE OTHERS 06-08-2012.pdf 2012-08-06
9 2065-CHE-2012 FORM-5 06-08-2012.pdf 2012-08-06
9 Form 15_Restoration_30-04-2019.pdf 2019-04-30
10 2065-CHE-2012 FORM-18 06-08-2012.pdf 2012-08-06
10 Form 27_License_01-04-2019.pdf 2019-04-01
11 2065-CHE-2012 CORRESPONDENCE OTHERS 06-08-2012.pdf 2012-08-06
11 Correspondence by Applicant_Form 3_18-05-2018.pdf 2018-05-18
12 2065-CHE-2012 FORM-3 11-12-2014.pdf 2014-12-11
12 Form 3_After Filing_18-05-2018.pdf 2018-05-18
13 2065-CHE-2012-Form 3-290316.pdf 2016-06-08
13 2065-CHE-2012-IntimationOfGrant11-05-2018.pdf 2018-05-11
14 2065-CHE-2012-FER.pdf 2018-01-23
14 2065-CHE-2012-PatentCertificate11-05-2018.pdf 2018-05-11
15 2065-CHE-2012-OTHERS [05-05-2018(online)].pdf 2018-05-05
15 Abstract_Granted 296708_11-05-2018.pdf 2018-05-11
16 2065-CHE-2012-FER_SER_REPLY [05-05-2018(online)].pdf 2018-05-05
16 Claims_Granted 296708_11-05-2018.pdf 2018-05-11
17 Description_Granted 296708_11-05-2018.pdf 2018-05-11
18 Claims_Granted 296708_11-05-2018.pdf 2018-05-11
18 2065-CHE-2012-FER_SER_REPLY [05-05-2018(online)].pdf 2018-05-05
19 2065-CHE-2012-OTHERS [05-05-2018(online)].pdf 2018-05-05
19 Abstract_Granted 296708_11-05-2018.pdf 2018-05-11
20 2065-CHE-2012-FER.pdf 2018-01-23
20 2065-CHE-2012-PatentCertificate11-05-2018.pdf 2018-05-11
21 2065-CHE-2012-Form 3-290316.pdf 2016-06-08
21 2065-CHE-2012-IntimationOfGrant11-05-2018.pdf 2018-05-11
22 2065-CHE-2012 FORM-3 11-12-2014.pdf 2014-12-11
22 Form 3_After Filing_18-05-2018.pdf 2018-05-18
23 2065-CHE-2012 CORRESPONDENCE OTHERS 06-08-2012.pdf 2012-08-06
23 Correspondence by Applicant_Form 3_18-05-2018.pdf 2018-05-18
24 Form 27_License_01-04-2019.pdf 2019-04-01
24 2065-CHE-2012 FORM-18 06-08-2012.pdf 2012-08-06
25 2065-CHE-2012 FORM-5 06-08-2012.pdf 2012-08-06
25 Form 15_Restoration_30-04-2019.pdf 2019-04-30
26 2065-CHE-2012 CORRESPONDENCE OTHERS 06-08-2012.pdf 2012-08-06
26 Correspondence by Applicant_Form 15_30-04-2019.pdf 2019-04-30
27 2065-CHE-2012 FORM-9 06-08-2012.pdf 2012-08-06
27 Correspondence by Applicant_Restoration_03-09-2019.pdf 2019-09-03
28 2065-CHE-2012 ABSTRACT 23-05-2012.pdf 2012-05-23
28 Form13_Address of service Change_18-09-2019.pdf 2019-09-18
29 2065-CHE-2012 CLAIMS 23-05-2012.pdf 2012-05-23
29 Correspondence by Applicant_ Form-13_18-09-2019.pdf 2019-09-18
30 2065-CHE-2012 CORRESPONDENCE OTHERS 23-05-2012.pdf 2012-05-23
30 2065-CHE-2012-Renewal Fee_08-05-2020.pdf 2020-05-08
31 296708-Correspondence_Renewal Fee_18-03-2021.pdf 2021-03-18
31 2065-CHE-2012 DESCRIPTION (COMPLETE) 23-05-2012.pdf 2012-05-23
32 296708-Correspondence_Renewal Fee_09-03-2022.pdf 2022-03-09
32 2065-CHE-2012 FORM-1 23-05-2012.pdf 2012-05-23
33 296708-Correspondence_Renewal Fee_06-03-2023.pdf 2023-03-06
33 2065-CHE-2012 FORM-2 23-05-2012.pdf 2012-05-23

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