Salts of Saxagliptin with organic acids

Patent metadata

Field	Value
Publication number	US-9994523-B2
Application number	US-201314403552-A
Country	US
Kind code	B2
Filing date	May 24, 2013
Priority date	May 24, 2012
Publication date	Jun 12, 2018
Grant date	Jun 12, 2018

Abstract

The invention relates to organic salts of Saxagliptin and processes for their preparation.

First claim

What is claimed is:

1. A salt of Saxagliptin of formula (I):

wherein HA is

2. The salt of claim 1 wherein the salt is crystalline.

3. Saxagliptin nicotinate of formula (Ia):

4. The Saxagliptin nicotinate (Ia) according to claim 3 in a crystalline monohydrate form.

5. The Saxagliptin nicotinate (Ia) according to claim 3 characterized by a XRPD diffractogram having peaks, expressed in degrees 2 theta, at approximately 7.3, 10.9, 16.3, 19.2, and 20.6.

6. The Saxagliptin nicotinate (Ia) according to claim 3 characterized by a XRPD diffractogram substantially similar to the XRPD diffractogram in FIG. 1 .

7. The Saxagliptin nicotinate (Ia) according to claim 3 characterized by a DSC thermogram having two endothermic peaks with peak maxima at approximately 88° C. and approximately 235° C. and two exothermic peaks with peak maxima at approximately 140° C. and approximately 160° C.

8. The Saxagliptin nicotinate (Ia) according to claim 3 characterized by a DSC thermogram substantially similar to the DSC thermogram in FIG. 3 .

9. The Saxagliptin nicotinate (Ia) according to claim 3 characterized by an IR spectrum having one or more adsorption peaks, expressed in cm −1 , at approximately 3336, 3046, 2134 and 1647.

10. The Saxagliptin nicotinate (Ia) according to claim 3 characterized by an IR spectrum substantially similar to the IR spectrum in FIG. 5 .

11. Saxagliptin salicylate of formula (Ib):

12. The Saxagliptin salicylate (Ib) according to claim 11 in an anhydrous crystalline form.

13. The Saxagliptin salicylate (Ib) according to claim 11 characterized by a XRPD diffractogram having peaks, expressed in degrees 2 theta, at approximately 6.7, 8.4, 13.4, 15.1, 17.5, and 21.1.

14. The Saxagliptin salicylate (Ib) according to claim 11 characterized by a XRPD diffractogram substantially similar to the XRPD diffractogram in FIG. 2 .

15. The Saxagliptin salicylate (Ib) according to claim 11 characterized by a DSC thermogram having an exothermic peak with a peak maximum at approximately 210° C. and an endothermic peak with a peak maximum at approximately 263° C.

16. The Saxagliptin salicylate (Ib) according to claim 11 characterized by a DSC thermogram substantially similar to the DSC thermogram in FIG. 4 .

17. The Saxagliptin salicylate (Ib) according to claim 11 characterized by an IR spectrum having one or more adsorption peaks, expressed in cm −1 , at approximately 3584, 3455, 3041.8, 2112, 1669 and 1630.

18. The Saxagliptin salicylate (Ib) according to claim 11 characterized by an IR spectrum substantially similar to the IR spectrum in FIG. 6 .

19. A process for the preparation of salts of Saxagliptin of formula I:

wherein HA is

the process comprising:
(a) treating, at a temperature of about 40° C. to about 65° C., (S)—N-Boc-3-hydroxyadamantylglycine-L-cis-4,5-methanoprolinenitrile with a mineral acid in either: (i) water or (ii) a mixture of water and an alcoholic solvent, thereby forming a solution;
(b) adding a water-immiscible solvent to the solution, thereby forming a bi-phasic solution;
(c) basifying the bi-phasic solution by adjusting the pH to about 9 to about 9.5, thereby forming a basified bi-phasic solution;
(d) separating an organic phase from the basified bi-phasic solution;
(e) treating the organic phase with an organic acid selected from salicylic acid and nicotinic acid, thereby forming a treated organic phase; and
(f) isolating the salt of Saxagliptin from the treated organic phase.

20. The process according to claim 19 wherein the mineral acid is hydrochloric acid.

21. The process according to claim 19 wherein the alcoholic solvent is a C 1 -C 3 alkanol selected from the group consisting of methanol, ethanol, and isopropanol.

22. The process according to claim 19 wherein the water-immiscible solvent is dichloromethane or ethyl acetate.

23. The process of claim 19 , wherein the organic acid is nicotinic acid, and the salt of Saxagliptin of formula (I) is Saxagliptin nicotinate characterized by a XRPD diffractogram having peaks, expressed in degrees 2 theta, at approximately 7.3, 10.9, 16.3, 19.2, and 20.6.

24. The process of claim 19 , wherein the organic acid is salicylic acid, and the salt of Saxagliptin of formula (I) is Saxagliptin salicylate characterized by a XRPD diffractogram having peaks, expressed in degrees 2 theta, at approximately 6.7, 8.4, 13.4, 15.1, 17.5, and 21.1.

25. The process of claim 19 , wherein the organic acid is nicotinic acid, and the salt of Saxagliptin of formula (I) is Saxagliptin nicotinate having a HPLC purity of at least 99.39%.

Assignees

• Apotex Inc

Inventors

• Akbarali Padiyath Mohammed
• Kintali Venkata Ramana
• H N Shreenivasa Murthy
• Shetty Prakash Bhaskar
• Mallya Narendra Manjeshwar
• Reddy Venkataramana Lachhi

Classifications

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• C07C65/05

  o-Hydroxy carboxylic acids · CPC title

• C07D209/52 Primary

  condensed with a ring other than six-membered · CPC title

• C07D213/80

  in position 3 · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title