Processes and intermediates for the preparation of a PDE10 inhibitor

Patent metadata

Field	Value
Publication number	US-9650368-B2
Application number	US-201514696287-A
Country	US
Kind code	B2
Filing date	Apr 24, 2015
Priority date	Apr 28, 2014
Publication date	May 16, 2017
Grant date	May 16, 2017

Abstract

The present invention is directed to an improved process for the preparation of compounds of Formula (II) and Formula (III), which are useful in the inhibition of PDE10. In particular, the present invention is directed to an improved process for the preparation of 1-(5-(4-chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)ethanone, which is useful in the inhibition of PDE10.

First claim

What is claimed is:

1. A process to prepare a compound of Formula (II):

wherein
Q is S or O,
X is Cl or Br, and
R 1 , R 2 , and R 3 are each independently C (1-6) alkyl, according to the following General Scheme (I):

which process comprises:
converting boronic acid A1 to carbaldehyde B1 through activation of the boronic acid with an activating reactant A2;
converting carbaldehyde B1 to acetal C1 under acid catalysis with a suitable source of orthoformate;
converting acetal C1 to nitrile D1 through catalyzed cyanation with a metal catalyst and a cyanide source;
hydrolyzing D1 with a suitable acid to give carboxylic acid E1;
converting carboxylic acid E1 to amide F1 with a suitable base, a suitable coupling reagent, and a source amine;
converting amide F1 to a compound of Formula (II) with an anionic coupling reagent having structure H1,
wherein
M is a Group I metal, a Group II metal, Cu, or Zn;
R, R 2 , and R 3 are each independently C (1-6) alkyl;
m is 1, 2, 3, or 4;
p is 1, 2, 3, or 4; and

optionally converting the compound of Formula (II) to a salt.

2. The process of claim 1 , wherein Q is O.

3. The process of claim 1 , wherein Q is S.

4. The process of claim 1 , wherein X is Cl.

5. The process of claim 1 , wherein X is Br.

6. The process of claim 1 , wherein M is a Group II metal.

7. The process of claim 1 , wherein M is Mg.

8. The process of claim 1 , wherein R 1 is methyl, ethyl or propyl.

9. The process of claim 1 , wherein R 1 is ethyl.

10. The process of claim 1 , wherein R 2 is methyl, ethyl or propyl.

11. The process of claim 1 , wherein R 2 is methyl.

12. The process of claim 1 , wherein R 3 is methyl, ethyl or propyl.

13. The process of claim 1 , wherein R 3 is methyl.

14. The process of claim 1 , wherein R is butyl.

15. The process of claim 1 , wherein the acid catalyst used to create acetal C1 is para-toluenesulfonic acid monohydrate.

16. The process of claim 1 , wherein the suitable source of orthoformate is triethyl orthoformate.

17. The process of claim 1 , wherein the metal catalyst of the cyanation step is a cobalt salt.

18. The process of claim 1 , wherein the metal catalyst of the cyanation step is CoCl 2 .

19. The process of claim 1 , wherein the cyanide source is trimethylsilyl cyanide.

20. The process of claim 1 , wherein the suitable acid of the hydrolysis step is HCl.

21. The process of claim 1 , wherein the suitable base of the amidation step is triethylamine.

22. The process of claim 1 , wherein the suitable coupling reagent of the amidation step is propylphosphonic anhydride.

23. The process of claim 1 , wherein the source amine is N,O-dimethylhydroxylamine hydrochloride.

24. The process of claim 1 , wherein the compound of Formula (II) is:

25. The process of claim 1 , wherein the compound of Formula (II) is:

26. The process of claim 1 , wherein the compound of Formula (II) is:

27. A process to prepare a compound of Formula H1:

wherein
M is a Group I metal, a Group II metal, Cu, or Zn,
R, R 2 and R 3 are each independently C (1-6) alkyl,
X is Cl or Br,
m is 1, 2, 3, or 4, and
p is 1, 2, 3, or 4;

according to the following General Scheme (II):

which process comprises:
preparing in a solvent solution a lithium alkyl metal base from R n —Li and a metal halide comprising M, wherein n is 1, 2, 3 4, or 5; and
preparing a mixed metal lithiate H1 from G1 and the lithium alkyl metal base.

28. The process of claim 27 , wherein R 2 is methyl, ethyl, or propyl.

29. The process of claim 27 , wherein R 2 is methyl.

30. The process of claim 27 , wherein R 3 is methyl, ethyl, or propyl.

31. The process of claim 27 , wherein R 3 is methyl.

32. The process of claim 27 , wherein R is butyl.

33. The process of claim 27 , wherein X is Cl.

34. The process of claim 27 , wherein X is Br.

35. The process of claim 27 , wherein M is a Group II metal.

36. The process of claim 27 , wherein M is Mg.

37. The process of claim 27 , wherein the lithium alkyl metal base is a lithium alkylmagnesate base.

38. The process of claim 27 , wherein the lithium alkyl metal base is Bu 4 MgLi 2 .

39. The process of claim 27 , wherein the compound of Formula H1 is:

40. A process to prepare a compound of Formula (III):

wherein Q is S or O and X is Cl or Br,
according to the following General Scheme (III):

which process comprises:
converting boronic acid A1 to carbaldehyde B1 through activation of the boronic acid with an activating reactant A2;
converting carbaldehyde B1 to acetal C1-1 under acid catalysis with a suitable source of orthoformate;
converting acetal C1-1 to nitrile D1-1 through catalyzed cyanation with a metal catalyst and a cyanide source;
hydrolyzing D1-1 with a suitable acid to give carboxylic acid E1-1;
converting carboxylic acid E1-1 to amide F1-1 with a suitable base, a suitable coupling reagent, and a source amine;
converting amide F1-1 to a compound of Formula (III) with an anionic coupling reagent having structure H1-1,
wherein
M is a Group I metal, a Group II metal, Cu, or Zn;
R is C (1-6) alkyl;
m is 1, 2, 3, or 4;
p is 1, 2, 3, or 4; and

optionally converting the compound of Formula (III) to a salt.

41. The process of claim 40 , wherein Q is O.

42. The process of claim 40 , wherein Q is S.

43. The process of claim 40 , wherein X is Cl.

44. The process of claim 40 , wherein X is Br.

45. The process of claim 40 , wherein M is a Group II metal.

46. The process of claim 40 , wherein M is Mg.

47. The process of claim 40 , wherein R is butyl.

48. The process of claim 40 , wherein the acid catalyst used to create acetal C1-1 is para-toluenesulfonic acid monohydrate.

49. The process of claim 40 , wherein the suitable source orthoformate is triethyl orthoformate.

50. The pro

Assignees

• Omeros Corp

Inventors

• Cutshall Neil S
• Gage Jennifer Lynn
• Little Thomas L
• Luke Wayne Douglas
• Brot Elisabeth C A
• Jonas Marco
• Mcdermott Michael James
• Reineke Karl E

Classifications

• C07F3/02

  Magnesium compounds · CPC title

• C07F1/02

  Lithium compounds · CPC title

• C07D417/10 Primary

  linked by a carbon chain containing aromatic rings · CPC title

• C07D413/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D307/40

  Radicals substituted by oxygen atoms · CPC title