Process for preparation of dronedarone by Grignard reaction

Patent metadata

Field	Value
Publication number	US-9238636-B2
Application number	US-201314403528-A
Country	US
Kind code	B2
Filing date	May 23, 2013
Priority date	May 31, 2012
Publication date	Jan 19, 2016
Grant date	Jan 19, 2016

Abstract

The invention relates to a novel process for the preparation of dronedarone (I) and pharmaceutically acceptable salts thereof, which comprises reacting of compound of formula (IV) with compound of formula (VI) in a Grignard reaction, and the obtained product is isolated and, if desired, converted into a pharmaceutically acceptable salt thereof. The invention also relates to some novel intermediary compounds and processes for the preparation thereof.

First claim

The invention claimed is:

1. A process for the preparation of dronedarone (I)

or a pharmaceutically acceptable salt thereof, comprising the steps of:
a) reacting a compound of formula (IV)

wherein X is Cl or Br, with a compound of formula (VI)

or a salt thereof, in a Grignard reaction,
wherein R is a group of formula —NR 1 R 2 ,
wherein R 1 and R 2 are independently selected from the group consisting of H, alkyl, alkyloxy and aryl;

b) isolating dronedarone (I); and
c) optionally converting dronedarone (I) into a pharmaceutically acceptable salt thereof.

2. A compound of formula (VI),

or a salt thereof, wherein R is a group of formula —NR 1 R 2 ,
wherein R 1 and R 2 are independently selected from the group consisting of H, alkyl, alkyloxy and aryl.

3. A process for the preparation of the compound of formula (VI))

or a salt thereof,
comprising the steps of:
a) reacting a compound of formula (V)

or a salt thereof, with an amine of formula H—R, or a salt thereof, in a solvent or in a mixture of solvents, wherein R is a group of formula —NR 1 R 2 , wherein R 1 and R 2 are independently selected from the group consisting of H, alkyl, alkyloxy and aryl;
b) isolating the compound of formula (VI); and
c) optionally converting the compound of formula (VI) into a salt thereof.

4. A compound of formula (IV)

wherein X is Cl or Br.

5. A process for the preparation of the compound of formula (IV)

comprising reacting a compound of formula (III)

with Mg in an anhydrous solvent, wherein X is Cl or Br.

6. A compound of formula (III)

wherein X is Cl or Br.

7. A process for the preparation of the compound of formula (III)

wherein X is Cl or Br,
comprising halogenating a compound of formula (II)

8. The process
of claim 1 further comprising a process for the preparation of the compound of formula (IV), wherein:
a compound of formula (II)

is halogenated to obtain a compound of formula (III)

wherein X is Cl or Br; and
the obtained compound (III) is converted into the compound of formula (IV);
and further comprising a process for the preparation of the compound of formula (VI), wherein:
a compound of formula (V)

is reacted with an amine of formula H—R, wherein R is as defined in claim 1 , to obtain the compound of formula (VI).

9. The process of claim 1 , wherein step a) further comprises an anhydrous solvent and a catalyst.

10. The process of claim 9 , wherein the solvent is THF and the catalyst is FeCl 3 .

11. The compound of claim 2 , wherein R 1 and R 2 are independently selected from the group consisting of H, methyl, ethyl, methoxy, and phenyl.

12. The process of claim 3 , wherein the solvent is dichloromethane or n-hexane and wherein step a) further comprises a catalyst.

13. The process of claim 3 , wherein the amine is selected from the group consisting of ammonia, dimethylamine, diethylamine, N,O-dimethyl hydroxylamine, and aniline.

14. The compound of claim 4 , wherein X is Cl.

15. The compound of claim 4 , wherein X is Br.

16. The compound of claim 6 , wherein X is Cl.

17. The compound of claim 6 , wherein X is Br.

Assignees

• Sanofi Sa

Inventors

• Huszár Csaba
• Hegedus Adrienn
• Dombrády Zsolt

Classifications

• C07D307/80 Primary

  Radicals substituted by oxygen atoms · CPC title

• C07C231/02

  from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines · CPC title

• C07C233/65

  having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals · CPC title

• C07D307/79

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring · CPC title