Process for preparation of saxagliptin and its hydrochloride salt
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.
1. A process for the preparation of saxagliptin of formula [I] or its hydrochloride salt,
comprising:
a. reacting (1S,3S,5S)-2-[(2S)-2-tritylamino-2-(3-hydroxyadamantan-1-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 (1 S,3S,5S)-2-[(2S)-2-tritylamino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile [V]; and
b. removing the trityl group from (1S,3S,5S)-2-[(2S)-2-tritylamino-2-(3-hydroxyadamantan-1-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 (1S,3S,5S)-2-[(2S)-2-tritylamino-2-(3-hydroxyadamantan-1-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-1-yl-tert-butoxycarbonylamino acetic acid [II]
with a methanesulfonic acid salt of (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide [III],
followed by BOC deprotection and reaction with trityl chloride to obtain (1S,3S,5S)-2-[(2S)-2-tritylamino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide [IV].
8. The process of claim 7 , wherein the reaction of 3-hydroxyadamantan-1-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 a coupling agent selected from the group consisting of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N,N′-dicyclohexylcarbodiimide (DCC), and N,N′-diisopropylcarbodiimide (DIC).
9. The process of claim 7 , wherein the reaction of 3-hydroxyadamantan-1-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 1-hydroxy-7-azabenzotriazole.
10. The process of claim 7 , wherein the reaction of 3-hydroxyadamantan-1-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-1-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-1-yl-tritylamino acetic acid [IIA]
with a methanesulfonic acid salt of (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide [III],
to obtain (1S,3S,5S)-2-[(2S)-2-tritylamino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide [IV].
16. The process of claim 15 , wherein the reaction of 3-hydroxyadamantan-1-yl-tritylamino acetic acid [IIA] 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 a coupling agent selected from the group consisting of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N,N′-dicyclohexylcarbodiimide (DCC), and N,N′-diisopropylcarbodiimide (DIC).
17. The process of claim 15 , wherein the reaction of 3-hydroxyadamantan-1-yl-tritylamino acetic acid [IIA] 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 1-hydroxy-7-azabenzotriazole.
18. The process of claim 15 , wherein the reaction of 3-hydroxyadamantan-1-yl-tritylamino acetic acid [IIA] 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.
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-1-yl-tritylamino acetic acid [IIA] 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.
21. A process for the preparation of saxagliptin of formula [I] or its hydrochloride salt,
comprising:
providing (1S,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 (1S,3S,5S)-2-[(2S)-2-tritylamino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile [V] to obtain saxagliptin hydrochloride, and optionally converting the hydrochloride salt to saxagliptin.
22. A compound selected from:
and pharmaceutically acceptable salts, solvates and hydrates thereof.