Processes for the preparation of an apoptosis-inducing agent

Patent metadata

Field	Value
Publication number	US-9238652-B2
Application number	US-201514637639-A
Country	US
Kind code	B2
Filing date	Mar 4, 2015
Priority date	Mar 4, 2014
Publication date	Jan 19, 2016
Grant date	Jan 19, 2016

Abstract

Provided herein is a process for the preparation of an apoptosis-inducing agent, and chemical intermediates thereof. Also provided herein are novel chemical intermediates related to the process provided herein.

First claim

What is claimed is:

1. A process for the preparation of Compound 2 of the formula:

which comprises:
(a) combining a compound of formula (K):

wherein R is C 1 to C 12 alkyl, with a tert-butoxide salt, an aprotic organic solvent, and water to provide a compound of formula (L):

(b′) combining the compound of formula (L) with a compound of formula (P):

 and 1 -ethyl-3 -(3 -dimethylaminopropyl)carbodiimide hydrochloride (EDAC), 4-dimethylaminopyridine (DMAP), and an organic solvent to provide the compound of formula (2).

2. The process of claim 1 , wherein in step (a) the tert-butoxide salt is selected from the group consisting of sodium tert-butoxide and potassium tert-butoxide.

3. The process of claim 2 , wherein the process further comprises:
(c′) combining a compound of formula (M):

with a tertiary amine base, an organic solvent, and (1R,4R)-4(aminomethyl)-1methylcyclohexanol or a salt thereof, to provide the compound of formula (P).

4. The process of claim 3 , wherein in step (c′) the tertiary amine base is N,N-diisopropylethylamine.

5. The process of claim 1 , wherein the process further comprises:
(d) combining a compound of formula (D):

with a compound of formula (I):

a source of palladium, a tert-butoxide salt, and a phosphine ligand in an aprotic organic solvent to provide the compound of formula (K).

6. The process of claim 5 , wherein the compound of formula (I) is combined with a base prior to the combining of step (d).

7. The process of claim 5 , wherein in step (d) the source of palladium is Pd 2 dba 3 or [(cinnamyl)PdC1] 2 .

8. The process of claim 5 , wherein the phosphine ligand of step (d) is a compound of formula (J):

9. The process of claim 7 , wherein the source of palladium is Pd 2 dba 3 , a catalytic amount of Pd 2 dba 3 is used relative to the amount of compound (I), and wherein the catalytic amount of Pd 2 dba 3 is from about 0.5 mole percent to about 2 mole percent.

10. The process of claim 9 , wherein a catalytic amount of the compound of formula (J) is used relative to the amount of compound (I), and wherein the catalytic amount of the compound of formula (J) is from about 1 mole percent to about 5 mole percent.

11. The process of claim 5 , wherein in step (d) the tert-butoxide salt is selected from the group consisting of sodium tert-butoxide and potassium tert-butoxide.

12. The process of claim 5 , wherein the process further comprises:
(e) combining a compound of formula (B) with a compound of formula (C):

and a tert-butoxide salt in an organic solvent to provide the compound of formula (D).

13. The process of claim 12 , wherein in step (e) the tert-butoxide salt is selected from the group consisting of sodium tert-butoxide and potassium tert-butoxide.

14. The process of claim 12 , wherein the process further comprises:
(f) combining a compound of formula (A):

with R 1 MgX in an aprotic organic solvent; wherein R 1 is C 1 to C 6 alkyl and X is Cl, Br, or I;
(g) combining a C 1 to C 12 alkyl chloroformate or a di-(C 1 to C 12 alkyl)dicarbonate with the product of step (f), to provide the compound of formula (C).

15. The process of claim 14 , wherein in step (f), R 1 is isopropyl.

16. The process of claim 14 , wherein in step (f), R is tert-butyl and the di-(C 1 to C 12 alkyl)dicarbonate is di-tert-butyl dicarbonate.

17. The process of claim 5 , wherein the process further comprises:
(h) combining a compound of formula (E):

with dimethylformamide and POC1 3 to provide a compound of formula (F):

(i) combining the compound of formula (F) with a source of palladium and 4chlorophenylboronic acid in an organic solvent to provide a compound of formula (G):

(j) combining the compound of formula (G) with BOC-piperazine and sodium triacetoxyborohydride in an organic solvent to provide a compound of formula (H):

 and
(k) combining the compound of formula (H) with hydrochloric acid to provide the compound of formula (I).

18. The process of claim 17 , wherein in step (i) the source of palladium is Pd(OAc) 2 .

19. The process of claim 17 , wherein step (i) comprises combining tetrabutylammonium bromide with the compound of formula (F), the source of palladium and 4chlorophenylboronic acid in the organic solvent.

20. The process of claim 17 , wherein step (j) further comprises producing the compound of formula (H) as a crystalline solid.

21. The process of claim 17 , wherein step (k) further comprises producing the compound of formula (I) as a crystalline solid.

22. The process of claim 1 , wherein R is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl and neo-butyl.

23. The process of claim 1 , wherein R is tert-butyl.

Assignees

• Abbvie Inc

Inventors

• Barkalow Jufang
• Califano Jean-Christophe
• Chan Vincent S
• Christesen Alan C
• Grieme Timothy A
• Ku Yi-Yin
• Mulhern Mathew M
• Pu Yu-Ming M

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title