Methods for preparation of quinazoline derivatives

Patent metadata

Field	Value
Publication number	US-9988357-B2
Application number	US-201615373832-A
Country	US
Kind code	B2
Filing date	Dec 9, 2016
Priority date	Dec 9, 2015
Publication date	Jun 5, 2018
Grant date	Jun 5, 2018

Abstract

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

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 1 , 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.

First claim

The invention claimed is:

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

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R 1 is a non-hydrogen substituent;
R 2a and R 2b are each independently halo, hydroxyl, protected hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 alkoxy;
R 3a and R 3b are each independently halo, hydroxyl, protected hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 alkoxy; or R 3a joins with R 4a to form a carbocyclyl or heterocyclyl ring, and R 3b is halo, hydroxyl, protected hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 alkoxy; and
R 4a , R 4b and R 4c are each independently H or a non-hydrogen substituent; or R 4a joins with R 3a to form a carbocyclyl or heterocyclyl ring, and R 4b and R 4c are each independently H or a non-hydrogen substituent;
wherein the method comprises preparing a mixture comprising a compound of structure (II) and a compound of structure (III), the compounds of structure (II) and (III) having the following structures, respectively:

or a salt thereof, wherein:
R 1′ is a non-hydrogen, non-acidic substituent;
R 2a′ and R 2b′ are each independently halo, protected hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 alkoxy;
R 3a′ and R 3b′ are each independently halo, protected hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 alkoxy; or R 3a′ joins with R 4a′ to form a carbocyclyl or heterocyclyl ring, and R 3b′ is halo, protected hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 alkoxy;
R 4a′ , R 4b′ and R 4c′ are each independently H or a non-hydrogen substituent; or R 4a′ joins with R 3a′ to form a carbocyclyl or heterocyclyl ring, and R 4b′ and R 4c′ are each independently H or a non-hydrogen substituent; and
X is a leaving group,
thereby forming a carbon-carbon bond between the carbon bearing the Zn moiety on compound (II) and the carbon bearing the X moiety on compound (III).

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) 2 Zn.2MgCl 2 .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 R 1 and R 1′ are each independently C 1 -C 6 alkyl, carbocyclyl or heterocyclyl.

12. The method of claim 11 , wherein R 1 and R 1′ are each independently heterocyclyl.

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

14. The method of claim 1 , wherein R 1 and R 1′ each have the following structure:

wherein P is a nitrogen protecting group.

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 C 1 -C 6 alkoxy.

19. The method of claim 1 , wherein R 3a′ and R 3b′ are each independently halo or C 1 -C 6 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:

wherein P 1 is nitrogen protecting group.

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

wherein:
R 2a , R 2b , R 2a′ and R 2b′ are each independently halo;
R 3a , R 3b , R 3a′ and R 3b′ are each independently halo, protected hydroxyl or C 1 -C 6 alkoxy; and
R 4a , R 4b , R 4c , R 4a′ , R 4b′ and R 4c′ are each independently H.

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 3b R 3a′ and R 3b′ are each independently halo or C 1 -C 6 alkoxy.

31. The method of claim 30 , wherein halo is fluoro and C 1 -C 6 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.

Assignees

• 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

Classifications

• C07D239/86

  with hetero atoms directly attached in position 4 · CPC title

• C07D239/94 Primary

  Nitrogen atoms · CPC title

• C07D235/06

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2 · CPC title

• C07D403/00

  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 title

• C07D487/00

  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 title