Highly purified pharmaceutical grade tasimelteon

Patent metadata

Field	Value
Publication number	US-11760740-B2
Application number	US-202318149590-A
Country	US
Kind code	B2
Filing date	Jan 3, 2023
Priority date	Feb 12, 2014
Publication date	Sep 19, 2023
Grant date	Sep 19, 2023

Abstract

A process for preparing a batch of highly purified, pharmaceutical grade tasimelteon comprises analyzing a batch of tasimelteon synthesized under GMP conditions for the presence of one or more identified impurities.

First claim

What we claim is:

1. A composition comprising tasimelteon prepared by a process comprising the steps of:
contacting and reacting (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropane carboxamide with a reducing agent followed by contacting the reaction product thereof with an acid in an organic solvent to prepare ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl) methanamine or a salt thereof; and
contacting and reacting the ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methanamine with a propionylating reagent to prepare tasimelteon,
wherein the composition comprises 0.15 wt % or less of Impurity 5 (N-((2-(2,3-dihydrobenzofuran-4-yl)-1-((2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl) (propionamido)methyl) cyclopropyl)methyl)propionamide).

2. The composition of claim 1 , wherein the reducing agent comprises LiAlH 4 .

3. The composition of claim 1 , wherein the acid comprises HCl.

4. The composition of claim 1 , wherein the organic solvent comprises TBME.

5. The composition of claim 1 , wherein the propionylating agent comprises propionyl chloride.

6. The composition of claim 1 , wherein the propionylation step further includes an organic solvent and a base.

7. The composition of claim 6 , wherein the base comprises NaOH.

8. The composition of claim 1 , wherein the (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropane carboxamide is reduced to prepare ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methanamine or a salt thereof.

9. A pharmaceutical composition comprising the composition according to claim 1 and at least one pharmaceutically acceptable excipient.

10. The composition of claim 1 comprising 0.15 wt % or less of each of each of Impurity 1 (N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)-3-methylbutanamide), Impurity 2 (N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)-pentanamide), and Impurity 3 (1,3-bis(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)urea).

11. The composition of claim 1 comprising 0.15 wt % or less of each of Impurity 4 (N-(((1R,2R)-2-(benzofuran-4-yl)cyclopropyl)methyl)propionamide) and Impurity 7 (N-(((1R,2R)-2-(3-oxo-2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)propionamide).

12. The composition of claim 1 comprising 100 ppm or less of ethyl diazaoacetate (EDA).

13. The composition of claim 1 , wherein the process further comprises the steps of: crystallizing the tasimelteon; and
assaying the crystallized tasimelteon from step (b) for the presence of one or both of Impurity 5 (N-((2-(2,3-dihydrobenzofuran-4-yl)-1-((2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl) (propionamido)methyl) cyclopropyl)methyl)propionamide) and Impurity 6 (2-hydroxy-6-(2-(propionamidomethyl)cyclopropyl)phenethyl 2-(2-hydroxyethyl)-3-(2-(propionamidomethyl)cyclopropyl)phenyl carbonate).

14. The composition of claim 13 , wherein the reducing agent comprises LiAlH 4 , the acid comprises HCl, or both.

15. The composition of claim 13 , wherein the propionylating agent comprises propionyl chloride.

16. The composition of claim 13 , wherein the (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropane carboxamide is reduced to prepare ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methanamine or a salt thereof.

17. The composition of claim 13 comprising 0.15 wt % or less of each of each of Impurity 1 (N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)-3-methylbutanamide), Impurity 2 (N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)-pentanamide), and Impurity 3 (1,3-bis(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)urea).

18. The composition of claim 13 comprising 0.15 wt % or less of each of Impurity 4 (N-(((1R,2R)-2-(benzofuran-4-yl)cyclopropyl)methyl)propionamide) and Impurity 7 (N-(((1R,2R)-2-(3-oxo-2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)propionamide).

19. The composition of claim 13 comprising 100 ppm or less of ethyl diazaoacetate (EDA).

20. A pharmaceutical composition comprising the composition according to claim 13 and at least one pharmaceutically acceptable excipient.

21. A composition comprising tasimelteon prepared by a process comprising the steps of:
contacting and reacting (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropane carboxamide with a reducing agent followed by contacting the reaction product thereof with an acid in an organic solvent to prepare ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl) methanamine or a salt thereof; and
contacting and reacting the ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methanamine with a propionylating reagent to prepare tasimelteon,
wherein the composition comprises 0.15 wt % or less of each of Impurity 6 (2-hydroxy-6-(2-(propionamidomethyl)cyclopropyl)phenethyl 2-(2-hydroxyethyl)-3-(2-(propionamidomethyl)cyclopropyl)phenyl carbonate).

22. The composition of claim 21 , wherein the reducing agent comprises LiAlH 4 .

23. The composition of claim 21 , wherein the acid comprises HCl.

24. The composition of claim 21 , wherein the organic solvent comprises TBME.

25. The composition of claim 21 , wherein the propionylating agent comprises propionyl chloride.

26. The composition of claim 21 , wherein the propionylation step further includes an organic solvent and a base.

27. The composition of claim 26 , wherein the base comprises NaOH.

28. The composition of claim 21 , wherein the (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropane carboxamide is reduced to prepare ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methanamine or a salt thereof.

29. A pharmaceutical composition comprising the composition according to claim 21 and at least one pharmaceutically acceptable excipient.

30. The composition of claim 21 comprising 0.15 wt % or less of each of each of Impurity 1 (N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)-3-methylbutanamide), Impurity 2 (N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)-pentanamide), and Impurity 3 (1,3-bis(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)urea).

31. The composition of claim 21 comprising 0.15 wt % or less of each of Impurity 4 (N-(((1R,2R)-2-(benzofuran-4-yl)cyclopropyl)methyl)propionamide) and Impurity 7 (N-(((1R,2R)-2-(3-oxo-2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)propionamide).

32. The composition of claim 21 comprising 100 ppm or less of ethyl diazaoacetate (EDA).

33. The composition of claim 21 , wherein the process further comprises the steps of: crystallizing the tasimelteon; and
assaying the crystallized tasimelteon from step (b) for the presence of one or both of Impurity 5 (N-((2-(2,3-dihydrobenzofuran-4-yl)-1-((2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl) (propionamido)methyl) cyclopropyl)methyl)propionamide) and Impurity 6 (2-hydroxy-6-(2-(propionamidomethyl)cyclopropyl)phenethyl 2-(2-hydroxyethyl)-3-(2-(propionamidomethyl)cyclopropyl)phenyl carbonate).

34. The composition of claim 33 , wherein the reducing agent comprises LiAlH 4 , the acid comprises HCl, or both.

35. The composition of claim 33 , wherein the propionylating agent comprises propionyl chloride.

36. The composition of claim 33 , wherein the (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropane carboxamide is reduced to prepare ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methanamine or a salt

Assignees

• Vanda Pharmaceuticals Inc

Inventors

• Phadke Deepak
• Platt Natalie M
• Pandrapragada Ravi K

Classifications

• C07D307/81 Primary

  Radicals substituted by nitrogen atoms not forming part of a nitro radical · CPC title

• C07D307/79

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring · CPC title

• A61P25/20

  Hypnotics; Sedatives · CPC title