Process for preparing apalutamide

Patent metadata

Field	Value
Publication number	US-2018201601-A1
Application number	US-201815873207-A
Country	US
Kind code	A1
Filing date	Jan 17, 2018
Priority date	Jan 18, 2017
Publication date	Jul 19, 2018
Grant date	—

Abstract

The present invention provides efficient, economical, and environmentally friendly processes for synthesizing apalutamide and intermediates thereof. Also provided herein are novel compounds and intermediates thereof.

First claim

1 . A process for the preparation of apalutamide

the process comprising:
contacting a compound of Formula II

with a compound of Formula III

to provide apalutamide;

wherein R is C 1 -C 6 alkyl.

2 . The process of claim 1 , wherein the reaction is conducted at a temperature above 50° C.

3 . The process of claim 2 , wherein the reaction is conducted at a temperature above 70° C.

4 . The process of claim 2 , wherein the reaction is conducted at a temperature from about 75-85° C.

5 . The process of claim 1 , wherein 1.5-5 equiv. of the compound of Formula III is used relative to the compound of Formula II.

6 . The process of claim 5 , wherein 4.5 equiv. of the compound of Formula III is used.

7 . The process of claim 5 , wherein the compound of Formula III is added incrementally.

8 . The process of claim 1 , wherein the reaction is conducted in an organic solvent.

9 . The process of claim 8 , wherein the organic solvent is selected from the group consisting of dimethylacetamide (DMAc), acetonitrile (MeCN), tetrahydrofuran (THF) and mixtures thereof.

10 . The process of claim 9 , wherein the organic solvent is acetonitrile.

11 . The process of claim 1 , wherein the compound of Formula II is prepared from a process comprising:
contacting the compound of Formula I with an O-alkylating agent

to provide a compound of Formula II,
wherein R is C 1 -C 6 alkyl.

12 . The process of claim 11 , further comprising a base selected from the group consisting of Li 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , Na 2 CO 3 and combinations thereof.

13 . (canceled)

14 . The process of claim 12 , wherein the base is K 2 CO 3 .

15 . The process of claim 11 , wherein O-alkylating agent is selected from the group consisting of RI, RBr, and RCl, wherein R is C 1 -C 6 alkyl.

16 . The process of claim 15 , wherein the O-alkylating agent is RI.

17 . The process of claim 1 , wherein R is methyl.

18 . A process for the preparation of apalutamide

the process comprising:
(a) contacting Starting Material 1 (SM1)

with Starting Material 2 (SM2)

to provide a compound of Formula I

(b) contacting the compound of Formula I with an O-alkylating agent to provide a compound of Formula II

wherein R is C 1 -C 6 alkyl; and

(c) contacting the compound of Formula II with a compound of Formula III

to provide apalutamide.

19 . The process of claim 18 , wherein step (a) is conducted in the presence of a metal catalyst.

20 . The process of claim 19 , wherein the metal catalyst is a copper salt selected from the group consisting of CuCl, CuI, and mixtures thereof.

21 . A compound of Formula II

wherein R is C 1 -C 6 alkyl.

Assignees

• Scinopharm Taiwan Ltd

Inventors

• Chen Shang-Hong
• Guo Jiunn-Cheh
• Shih Wen-Li

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07C2601/04

  with a four-membered ring · CPC title

• C07C237/30

  having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms · CPC title

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title