Process for the preparation of a chiral compound

• US 9,493,428 B2
• Filed: 06/14/2012
• Issued: 11/15/2016
• Est. Priority Date: 06/16/2011
• Status: Active Grant

• Current Assignee: Sandoz Ag (Novartis Ag)
• Original Assignee: Sandoz Ag (Novartis Ag)
• Inventors: Wilhelm, Thorsten, Langner, Martin
• Primary Examiner(s): SAEED, KAMAL A
• Application Number:
  US14/125,341
• Publication Number:
  US 20140303184A1
• Time in Patent Office: 1,615 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: C07D 249/08 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 249/12 Oxygen or sulfur atoms

Abstract

The present invention relates to a process for the preparation of a compound of formula (V), in particular posaconazole, wherein said process comprises the steps of (1) providing a mixture comprising a compound of formula (IV), a protic solvent system, and a suitable base; and (2) heating the mixture of (1) to obtain a mixture comprising the compound of formula (V).

Claims

1. A process for the preparation of an antifungal agent of formula (V)

2. The process of claim 1, wherein in (2), the mixture is heated to a temperature in the range of from 40 to 140°

C.

3. The process of claim 1, wherein in (2), the mixture is heated for a time in the range of from 0.1 to 10 h.

4. The process of claim 1, wherein the protic solvent system comprises water and/or an alcohol, and optionally at least one further organic solvent.

5. The process of claim 1, wherein the protic solvent system comprises water and an alcohol, or comprises water and a ketone.

6. The process of claim 4, wherein the alcohol comprises 1to 5 carbon atoms, and wherein the ketone comprises 3 to 9 carbon atoms.

7. The process of claim 1, wherein the protic solvent system comprises water wherein the water content of the protic solvent system is at most 25 vol-%.

8. The process of claim 1, wherein the protic solvent system is a mixture of water and isopropanol, wherein the volume ratio of water relative to isopropanol is in the range of from 1:

12 to 3;

1.

9. The process of claim 1, wherein the suitable base has a pK_b of less than 7.

10. The process of claim 1, wherein the suitable base is at least one hydroxide, or at least one carbonate, or at least one alcoholate, or a mixture of at least one hydroxide and at least one carbonate, or a mixture of at least one hydroxide and at least one alcoholate, or a mixture of at least one carbonate and at least one alcoholate, or a mixture of at least one hydroxide and at least one carbonate and at least one alcoholate.

11. The process of claim 10, wherein the hydroxide is selected from the group consisting of an alkali metal hydroxide and an alkaline earth metal hydroxide;

wherein the carbonate is selected from the group consisting of an alkali metal carbonate and an alkaline earth metal carbonate;

wherein the alcoholate is selected from the group consisting of an alkali metal alcoholate and an alkaline earth metal alcoholate.

12. The process of claim 10, wherein the alcoholate is selected from the group consisting of a methanolate, an ethanolate, an isopropanolate, and an n-butanolate.

13. The process of claim 1, wherein in the mixture provided in (1), the molar ratio of the suitable base relative to the compound of formula (IV) is in the range of from 0.1:

1 to 3;

1.

14. The process of claim 1, wherein step (2) of heating the mixture of (1) is carried out in the absence of bis-trimethylsilyl acetamide (BSA) and a trimethylsilyl (TMS) halide.

15. The process of claim 1, wherein X₂ is a residue according to formula (X2)

16. The process of claim 15, wherein R₁ is an alkyl residue having from 1 to 4 carbon atoms, and wherein —

R′

is —

O—

R wherein —

R is —

H or a hydroxyl protecting group selected from the group consisting of —

Si(CH₃)₃ and benzyl.

17. The process of claim 1, wherein the residue X₂ is

18. The process of claim 1, wherein the compound of formula (IV) is a compound of formula (IVa)

19. The process of claim 18, wherein the compound of formula (IV) is a compound of formula (IVb)

20. The process of claim 18, wherein the compound of formula (IV) is a compound of formula (IVb)

21. The process of claim 17, wherein the compound of formula (IV'"'"') is a compound of formula (IVa)

22. The process of claim 21, wherein the compound of formula (IV'"'"') is a compound of formula (IVb)

23. The process of claim 21, wherein the compound of formula (IV'"'"') is a compound of formula (IVb)

24. The process of claim 21, wherein X₁ is a residue according to formula (X1)

25. The process of claim 1, further comprising

(3) crystallizing the compound of formula (V) from the mixture obtained in (2);

(4) optionally separating the crystallized compound.

26. The process of claim 24 further comprising

(3) crystallizing the compound of formula (V) from the mixture obtained in (2);

(4) optionally separating the crystallized compound.

27. The process of claim 25, wherein after (2) and before (3), the compound of formula (V) is not subjected to an extraction stage.

28. The process of claim 25, wherein in (3), the compound of formula (V) is crystallized in the presence of a ketone.

29. The process of claim 25, wherein in (3), the compound of formula (V) is crystallized in the presence of water and an alcohol.

30. The process of claim 25, wherein in (3), the compound of formula (V) is crystallized in the presence of seed crystals.

31. The process of claim 30, wherein the compound of formula (V) is the compound of formula (Vb)

32. The process of claim 25, wherein crystallizing in (3) is carried out at a temperature of 35 °

C. or less, and at a pH in the range of from 5to 14.

33. The process of claim 25, wherein the crystallized compound obtained from (3) or (4) is not subjected to a subsequent chromatography purification stage.

34. The process of claim 25, wherein the crystallized compound obtained from (3) or (4),

wherein at least 95% of the molecules of said crystalline compound are present as isomer of formula (Vd)

36. The process of claim 1, wherein in the mixture provided in (1), the molar ratio of the suitable base relative to the compound of formula (IV) is in the range of from 0.75:

1 to 1.5;

1.

37. The process of claim 1, wherein in the mixture provided in (1), the molar ratio of the suitable base relative to the compound of formula (IV) is in the range of from 0.5:

1 to 1.05;

1.

38. The process of claim 1, wherein step (2) of heating the mixture of (1) is carried out in the absence of bis-trimethylsilyl acetamide (BSA) and trimethylsilyl iodide (TMSI) and/or trimethylsilyl chloride (TMSCI).

39. The process of claim 1, wherein step (2) of heating the mixture of (1) is carried out in the absence of trialkylsilyl halide.

40. The process of claim 1, wherein step (2) of heating the mixture of (1) is carried out in the absence of silylating agent.

41. The process of claim 15, wherein R₁ is an alkyl residue having from 1to 62 carbon atoms.

42. The process of claim 15, wherein R₁ is an alkyl residue having from 1or 2 carbon atoms, and wherein —

R′

is —

O—

R wherein —

R is —

H or a hydroxyl protecting group selected from the group consisting of —

Si(CH₃)₃ and benzyl.

43. The process of claim 1, wherein the residue X₂ is

44. The process of claim 1, wherein the compound of formula (IV) and/or of formula (IV′

) is a crystalline compound of formula (IVb)

45. The process of claim 1, wherein the compound of formula (IV) and/or of formula (IV'"'"') is a crystalline compound of formula (IVb)

46. The process of claim 25, wherein crystallizing in (3) is carried out at a temperature of from 0 to 20 °

C. and at a pH in the range of from 5 to 9.

47. The process of claim 25, wherein crystallizing in (3) is carried out at a temperature of from 10 to 15 °

C. and at a pH in the range of from 6 to 8.

48. The process of claim 25, wherein the crystallized compound obtained from (3) or (4) is the compound of formula (Vb)

49. The process of claim 25, wherein the crystallized compound obtained from (3) or (4) is the compound of formula (Vb)

35. A method of using a protic solvent system for the preparation of an antifungal agent of formula (V)