Process for the synthesis of agomelatine

Patent metadata

Field	Value
Publication number	US-9604911-B2
Application number	US-201415100782-A
Country	US
Kind code	B2
Filing date	Dec 4, 2014
Priority date	Dec 5, 2013
Publication date	Mar 28, 2017
Grant date	Mar 28, 2017

Abstract

Process for the industrial synthesis of the compound of formula (I):

First claim

The invention claimed is:

1. A process for the industrial synthesis of a compound of formula (I):

wherein 7-methoxy-naphthalen-2-ol of formula (II):

is used for reaction, and wherein the group —CH 2 —X, wherein X represents —N(CH 3 ) 2 , —CO—N(CH 2 -Ph) 2 , —CH 2 —OH, —CH═CH 2 or —CO—NH 2 , is introduced at position 1 of the compound of formula (II)
to yield a compound of formula

wherein X represents —N(CH 3 ) 2 , —CO—N(CH 2 -Ph) 2 , —CH 2 —OH, —CH═CH 2 or —CO—NH 2 ;
which compound of formula (III) is subjected to a sulphonylation reaction at the aromatic alcohol and the substituent X of which compound of formula (III) is modified, before or after the aromatic alcohol sulphonylation step, by means of customary chemical reactions to yield a compound of formula (IV):

wherein X′ represents —CN, —CO—NH 2 , —CH 2 —OH, —CHO, —CH 2 —N(CH 2 -Ph) 2 , —CH 2 —NH—CO—CH 3 , —CH(OH)—CH 2 —OH or (2,5-dioxopyrrolidin-1-yl)methyl and R represents —CH 3 , —(CH 2 ) 2 —CH 3 , —CF 3 or tolyl;
which compound of formula (IV) undergoes a deoxygenation reaction in the presence of a transition metal and a reducing agent to yield:
either, when X′ represents the group —CH 2 —NH—CO—CH 3 , the compound of formula (I) directly, which is isolated in the form of a solid;
or the compound of formula (V):

wherein X″ represents —CN, —CH 2 —N(CH 2 -Ph) 2 , —CH 2 —OH, —CH(OH)—CH 2 —OH, —CO—NH 2 , or (2,5-dioxopyrrolidin-1-yl)methyl;
which compound of formula (V) is subjected to customary chemical reactions to yield the compound of formula (I), which is isolated in the form of a solid.

2. The process according to claim 1 , wherein the conversion of the compound of formula (II) into the compound of formula (III) is accomplished by means of the action of formaldehyde and dimethylamine to yield the compound of formula (III) wherein X represents —N(CH 3 ) 2 .

3. The process according to claim 1 , wherein the conversion of the compound of formula (II) into the compound of formula (III) is accomplished by means of the action of glyoxal followed by the action of a reducing agent to yield the compound of formula (III) wherein X represents —CH 2 —OH.

4. The process according to claim 1 , wherein the conversion of the compound of formula (II) into the compound of formula (III) is accomplished by means of the action of glyoxal followed by the action of the compound of formula NHR′R wherein R′ represents H or a —CH 2 -Ph group to yield the compound of formula (III) wherein X represents —CO—NH 2 or —CO—N(CH 2 -Ph) 2 .

5. The process according to claim 1 , wherein the conversion of the compound of formula (II) into the compound of formula (III) is accomplished by means of the action of allyl bromide followed by a thermal rearrangement to yield the compound of formula (III) wherein X represents —CH═CH 2 .

6. The process according to claim 1 , wherein, in the conversion of the compound of formula (III) into the compound of formula (IV), the sulphonylation step is accomplished by means of the action of a sulphonyl chloride, a sulphonic anhydride or a sulphonimide.

7. The process according to claim 1 , wherein the conversion of the compound of formula (III) into the compound of formula (IV) consists of a step of sulphonylation of the aromatic alcohol followed by modification of the group X by means of customary chemical reactions, X being as defined for formula (III).

8. The process according to claim 1 , wherein the conversion of the compound of formula (III) into the compound of formula (IV) consists of modification of the group X by means of customary chemical reactions followed by a step of sulphonylation of the aromatic alcohol, X being as defined for formula (III).

9. The process according to claim 1 , wherein the conversion of the compound of formula (IV) into the compound of formula (V) is accomplished in the presence of nickel and a hydride.

10. The process according to claim 1 , wherein the conversion of the compound of formula (IV) into the compound of formula (V) is accomplished in the presence of palladium and dihydrogen.

11. The process according to claim 1 , wherein the conversion of the compound of formula (IV) into the compound of formula (V) is accomplished in the presence of palladium and an alkaline earth metal.

12. The process according to claim 1 , wherein the conversion of the compound of formula (IV) wherein X′ represents —CH 2 —NH—CO—CH 3 into the compound of formula (I) is accomplished in the presence of nickel and a hydride.

13. The process according to claim 1 , wherein the conversion of the compound of formula (IV) wherein X′ represents —CH 2 —NH—CO—CH 3 into the compound of formula (I) is accomplished in the presence of palladium and dihydrogen.

14. The process according to claim 1 , wherein the conversion of the compound of formula (IV) wherein X represents —CH 2 —NH—CO—CH 3 into the compound of formula (I) is accomplished in the presence of palladium and an alkaline earth metal.

Assignees

• Servier Lab

Inventors

• Briere Jean-François
• Lebeuf Raphaël
• Levacher Vincent
• Hardouin Christophe
• Lecouve Jean-Pierre

Classifications

• C07D307/92

  Naphthofurans; Hydrogenated naphthofurans · CPC title

• C07C217/60

  linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring · CPC title

• C07C217/58

  with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain · CPC title

• C07B43/06 Primary

  of amide groups · CPC title

• C07C41/26

  by introduction of hydroxy or O-metal groups · CPC title