Preparation of 4-((6BR,10AS)-3-methyl-2,3,6B,9,10, 10A-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo [1,2,3-de]quinoxalin-8-(7H)-yl)-1-(4-fluorophenyl)-1-butanone or a pharmaceutically acceptable salt thereof

Patent metadata

Field	Value
Publication number	US-9315504-B2
Application number	US-201414323545-A
Country	US
Kind code	B2
Filing date	Jul 3, 2014
Priority date	Mar 12, 2007
Publication date	Apr 19, 2016
Grant date	Apr 19, 2016

Abstract

The present invention provides methods for the preparation of 4-(3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido-[3′,4′:4,5]-pyrrolo[1,2,3-de]quinoxalin-8-(7H)-yl)-1-(4-fluorophenyl)-1-butanone in free form or a salt thereof.

First claim

What is claimed is:

1. A method for preparing a compound of Formula 2J:

or a pharmaceutically acceptable salt thereof, wherein:
(i) k is 1;
(ii) m is 1;
(iii) n is 1;
(iv) R 1 is 4-(4-fluorophenyl)-4-oxobutyl;
(v) R 5 is H;
(vi) R 6a and R 6b are H;
(vii) R 7 , R 8 and R 9 are H;
(viii) R 10 is —CH 3 ; and
(ix) X is N;
comprising the steps of:
a) deprotecting a compound of Formula 2H:

wherein:
(i) k is 1;
(ii) m is 1;
(iii) n is 1;
(iv) B is benzyl or triphenylmethyl; or
B is a compound of the Formula:

wherein:
(a) P is —C(O)—, —C(O)O— or —S(O) 2 —; and
(b) Z is C 1-6 alkyl, C 1-6 alkylaryl, aryl or —OR, where R is C 1-6 alkyl, aryl, arylC 1-6 alkyl or heteroarylC 1-6 alkyl;

(v) R 5 is H;
(vi) R 6a and R 6b are H;
(vii) R 7 , R 8 and R 9 are H;
(viii) R 10 is —CH 3 ; and
(ix) X is N;

to give a compound of Formula 2I:

wherein:
(i) k is 1;
(ii) m is 1;
(iii) n is 1;
(iv) R 5 is H;
(v) R 6a and R 6b are H;
(vi) R 7 , R 8 and R 9 are H;
(vii) R 10 is —CH 3 ; and
(viii) X is N;

b) alkylating the compound of Formula 2I:

wherein:
(i) k is 1;
(ii) m is 1;
(iii) n is 1;
(iv) R 5 is H;
(v) R 6a and R 6b are H;
(vi) R 7 , R 8 and R 9 are H;
(vii) R 10 is —CH 3 ; and
(viii) X is N;

with 4-chloro-4′-fluorobutyrophenone in the presence of a base to give the compound of Formula 2J; and
c) optionally reacting the compound of Formula 2J with an acid to give a pharmaceutically acceptable salt of the compound of Formula 2J.

2. The method according to claim 1 , wherein step a) comprises potassium hydroxide.

3. The method according to claim 1 , wherein the base is triethylamine.

4. The method according to claim 1 , wherein step b) further comprises sodium iodide or potassium iodide.

5. The method according to claim 1 , wherein the acid is toluenesulfonic acid.

Assignees

• Intra Cellular Therapies Inc

Inventors

• Tomesch John Charles
• Li Peng
• Yao Wei
• Zhang Qiang
• Beard James David
• Thompson Andrew S
• Cheng Hua
• Wennogle Lawrence P

Classifications

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/26

  Psychostimulants, e.g. nicotine, cocaine · CPC title

• A61P25/20

  Hypnotics; Sedatives · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title