Methods for preparation of quinazoline derivatives

• US 9,988,357 B2
• Filed: 12/09/2016
• Issued: 06/05/2018
• Est. Priority Date: 12/09/2015
• Status: Active Grant

• Current Assignee: Araxes Pharma LLC
• Original Assignee: Araxes Pharma LLC
• Inventors: Mani, Neelakandha S., Allison, Brett D., Sales, Zachary S., Liang, Jimmy T., Deng, Xiaohu, Li, Liansheng, Long, Yun Oliver, Liu, Yuan, Ren, Pingda
• Primary Examiner(s): Ward, Paul V
• Application Number:
  US15/373,832
• Publication Number:
  US 20170190672A1
• Time in Patent Office: 543 Days
• CPC Class Codes: C07D 235/06 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
• CPC Class Codes: C07D 239/86 with hetero atoms directly attached in position 4
• CPC Class Codes: C07D 239/94 Nitrogen atoms
• CPC Class Codes: C07D 401/00 Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
• CPC Class Codes: C07D 403/00 Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
• CPC Class Codes: C07D 417/00 Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
• CPC Class Codes: C07D 487/00 Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
• CPC Class Codes: C07F 3/06 Zinc compounds

Abstract

Methods for preparing compounds having the following structure (I):

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R¹, R^2a, R^2b, R^3a, R^3b, R^4a, R^4b and R^4c, are as defined herein are provided. Related compounds and methods for making the same are also provided.

Claims

1. A method for preparing a compound having the following structure (I):

2. The method of claim 1, wherein the compound of structure (II) is prepared by reaction of a mixed-metal, heterocyclyl base with a compound having the following structure (IV):

3. The method of claim 2, wherein the mixed metal, heterocyclyl base comprises Zn, Mg and Li.

4. The method of claim 2, wherein the mixed metal, heterocyclyl base comprises a piperidinyl heterocycle.

5. The method of claim 2, wherein the mixed metal, heterocyclyl base comprises a 2,2,6,6-Bis(tetramethylpiperidine)zinc, magnesium chloride, lithium chloride complex ((tmp)₂Zn.2MgCl₂.2LiCl).

6. The method of claim 1, wherein the mixture comprising a compound of structure (II) and a compound of structure (III) further comprises a metal catalyst or metal precatalyst.

7. The method of claim 6, wherein the metal is palladium.

8. The method of claim 7, wherein the metal precatalyst is CPhos 3^rd generation.

9. The method of claim 1, wherein the mixture comprising a compound of structure (II) and a compound of structure (III) comprises a polar, aprotic solvent.

10. The method of claim 9, wherein the solvent is tetrahydrofuran.

11. The method of claim 1, wherein R¹ and R^1′

are each independently C₁-C₆ alkyl, carbocyclyl or heterocyclyl.

12. The method of claim 11, wherein R¹ and R^1′

are each independently heterocyclyl.

13. The method of claim 12, wherein heterocyclyl is piperazinyl.

14. The method of claim 1, wherein R¹ and R^1′

each have the following structure;

15. The method of claim 14, wherein P is butyloxycarbonyl (Boc).

16. The method of claim 1, wherein R^2a and R^2b are each independently halo.

17. The method of claim 1, wherein R^2a′

and R^2b′

are each independently halo.

18. The method of claim 1, wherein R^3a and R^3b are each independently halo, hydroxyl or C₁-C₆ alkoxy.

19. The method of claim 1, wherein R^3a′

and R^3b′

are each independently halo or C₁-C₆ alkoxy.

20. The method of claim 1, wherein R^4a, R^4b and R^4c are each independently H.

21. The method of claim 1, wherein R^4a′

, R^4b′

and R^4c′

are each independently H.

22. The method of claim 1, wherein X is halo.

23. The method of claim 22, wherein halo is bromo.

24. The method of claim 1, wherein the compound of structure (II) has one of the following structures:

25. The method of claim 1, wherein the compound of structure (III) has one of the following structures:

26. The method of claim 1, comprising the following steps (a) and (b):

27. The method of claim 26, wherein P is butyloxycarbonyl.

28. The method of claim 26, wherein R^2a, R^2b, R^2a′

and R^2b′

are each independently chloro or fluoro.

29. The method of claim 26, wherein R^2a and R^2b′

are each chloro, and R^2b and R^2b′

are each fluoro.

30. The method of claim 26, wherein R^3a, R^3bR^3a′

and R^3b′

are each independently halo or C₁-C₆ alkoxy.

31. The method of claim 30, wherein halo is fluoro and C₁-C₆ alkoxy is methoxy.

32. The method of claim 31, wherein R^3a and R^3a′

are each fluoro, and R^3b and R^3b′

are each methoxy.