Methods for preparation of quinazoline derivatives
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.
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.