Process for the preparation of chiral hydrazides

• US 9,199,919 B2
• Filed: 05/18/2011
• Issued: 12/01/2015
• Est. Priority Date: 05/19/2010
• Status: Active Grant

• Current Assignee: Sandoz Ag (Novartis Ag)
• Original Assignee: Sandoz Ag (Novartis Ag)
• Inventors: Albert, Martin, De Souza, Dominic, Salchenegger, Joerg, Oberhuber, Michael
• Primary Examiner(s): Gonzalez, Porfirio Nazario
• Assistant Examiner(s): Adzamli, Kofi
• Application Number:
  US13/697,800
• Publication Number:
  US 20130203993A1
• Time in Patent Office: 1,658 Days
• Field of Search: 544/366
• US Class Current: 1/1
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: C07C 241/04 Preparation of hydrazides
• CPC Class Codes: C07C 243/28 to hydrogen atoms or to carbon atoms of a saturated carbon skeleton
• CPC Class Codes: C07C 249/16 of hydrazones
• CPC Class Codes: C07C 251/76 to carbon atoms of a saturated carbon skeleton
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07F 7/1804 Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896
• CPC Class Codes: C07F 7/188 by reactions involving the formation of Si-O linkages

Abstract

The present invention relates to a process for the preparation of a chiral compound according to formula (V) wherein R₁ is preferably an alkyl residue preferably having from 1 to 6 carbon atoms, in particular to a process for the preparation of a chiral compound the crystalline chiral compounds as such, and their use for the preparation of an antifungal agent, in particular posaconazole.

Claims

1. An optionally crystalline chiral compound of formula (II)

3. The optionally crystalline chiral compound of claim 1, wherein Y is an optionally substituted phenyl moiety.

4. The optionally crystalline chiral compound of claim 1, wherein Y is an unsubstituted phenyl.

5. The optionally crystalline chiral compound of claim 1, wherein at least 97% of the molecules of said optionally crystalline compound are present as isomer of formula (IIa).

6. The optionally crystalline chiral compound of claim 1, wherein at least 99% of the molecules of said optionally crystalline compound are present as isomer of formula (IIa).

2. A chiral compound of formula (IV)

7. The optionally crystalline chiral compound of claim 2, wherein Y is an optionally substituted phenyl moiety.

8. The optionally crystalline chiral compound of claim 2, wherein Y is an unsubstituted phenyl.

9. The optionally crystalline chiral compound of claim 2, wherein at least 97% of the molecules of said chiral compound are present as isomer of formula (IVa).

10. The optionally crystalline chiral compound of claim 2, wherein at least 99% of the molecules of said chiral compound are present as isomer of formula (IVa).

11. A process for the preparation of a chiral compound, comprising

(1) providing a chiral compound of formula (I)

12. The process of claim 11, wherein in (1), the compound of formula (I) is provided by reacting propionaldehyde in a solvent with a compound of formula (i)

O═

N—

Y  

 

(i),

in the presence of a catalyst system, said catalyst system optionally further comprising a promoter.

13. The process of claim 12, wherein the reaction of propionaldehyde with the compound of formula (i) is carried out at a temperature in the range of from −

15 to +5°

C. in dichloromethane (DCM) as solvent.

14. The process of claim 12, wherein the reaction of propionaldehyde with the compound of formula (i) is carried out in the presence of a catalytical amount of an acid.

15. The process of claim 11, wherein in (2), the compound of formula (I) is reacted with H₂N—

NH—

CHO in the presence of a molecular sieve.

16. The process of claim 11, wherein in (2), the compound of formula (I) is reacted with H₂N—

NH—

CHO at a temperature in the range of from −

10 to +20°

C. in dichloromethane (DCM) as solvent.

17. The process of claim 11, wherein after (1), the compound of formula (I) is not separated from the reaction mixture obtained from (1) prior to reaction with H₂N—

NH—

CHO in (2).

18. The process of claim 11, further comprising

(3) separating the compound of formula (II) from the reaction mixture obtained from (2) by solvent extraction, wherein prior to (3), a solvent exchange is carried out.

19. The process of claim 11, further comprising

(4) reacting the compound of formula (II) in a solvent with a silylating agent comprising the residue —

SiR_aaR_bbR_cc to obtain a compound of formula (III)

20. The process of claim 19, wherein the silylating agent is hexamethyldisilazane, trimethylchlorosilane, bistrimethylsilylacetamide or a mixture of two or three of these compounds.

21. The process of claim 19, wherein the reaction in (4) is carried out at a temperature in the range of from 15 to 70°

C.

22. The process of claim 11, further comprising

(5) reacting the compound of formula (II) or reacting the compound of formula (III) with a nucleophilic compound comprising a nucleophilic residue R₁ in a solvent to obtain a compound of formula (IV)

23. The process of claim 22, wherein the nucleophilic compound is a Grignard compound R₁MgX wherein X is selected from the group consisting of Cl, Br, and I, and wherein R₁ is an alkyl residue having from 1 to 6 carbon atoms.

24. The process of claim 22, wherein the nucleophilic compound is CH₃CH₂MgCl.

25. The process of claim 22, wherein in (5), the compound of formula (II) or the compound of formula (III) is reacted with the nucleophilic compound at a temperature in the range of from −

80 to 0°

C.

26. The process of claim 22, wherein for the reaction of the compound of formula (II) or of the compound of formula (III) with the nucleophilic compound in (5), toluene or at least one ether is used as solvent.

27. The process of claim 22, wherein after (4), the compound of formula (III) is not separated from the reaction mixture obtained from (4) prior to reaction with the nucleophilic compound in (5).

28. The process of claim 22, further comprising

(6) reducing the compound of formula (IV) by hydrogenation, to obtain a compound of formula (V)

29. The process of claim 28, wherein in (6), the hydrogenation is carried out at a temperature in the range of from 15 to 35°

C., at a hydrogen pressure in the range of from 0.5 to 50 bar, in the presence of a precious metal containing catalyst.

30. The process of claim 28, wherein for reducing the compound of formula (IV) in (6), a solvent mixture comprising at least one alcohol comprising 1 to 4 carbon atoms.

31. The process of claim 30, further comprising crystallizing the compound of formula (V).

32. The process of claim 31, wherein the compound of formula (V) is crystallized from a mixture of MTBE and cyclohexane (CHX).

33. The process of claim 28, wherein the compound of formula (V) is not subjected to purification by chromatography.

34. The process of claim 28, further comprising

(7) reacting the compound of formula (V) in a solvent with a silylating agent comprising the residue —

SiR_aR_bR_c to obtain a compound of formula (VI)

35. The process of claim 11, wherein at least 95%, of the molecules of the chiral compound of formula (I) provided in (1) are present as isomer of formula (Ia)