New process for the synthesis of agomelatine

摘要

Disclosed is a process for the industrial synthesis of agomelatine of formula (I): characterised in that 1-(4-methoxyphenyl)-4-penten-1-one of formula (II) is reacted, in the presence of a free radical initiator (such as (di)lauroyl peroxide or (di)benzoyl peroxide), with a compound of formula (III), to yield the adduct of formula (IV) (it being possible for the compound of formula (IV) optionally to be isolated, the amine function of which may optionally be deprotected and converted into an acetamide function), which is subjected to a cyclisation reaction in the presence of a free radical initiator to form the compound of formula (V), where -(N) is a deprotected amino group, or an acylated protected amine moiety; said compound of formula (V) is either subjected to reduction-esterification followed by dehydration, or converted into a vinyl halide, to yield the compound of formula (VI), wherein Y represents a halogen atom or a hydrogen atom; the amine function of the compound of formula (VI) is converted into an acetamide function where applicable, to yield the compound of formula (VI’), which is finally subjected to an aromatisation reaction to yield the compound of formula (I), which is isolated in the form of a solid. In a preferred embodiment the amino moiety -(N) is provided in the form of a phthalidimide. Also disclosed are intermediates of formula (VI) which are 2-[2-(4-chloro-7-methoxy-1,2-dihydro-1-naphthyl)ethyl]-1H-isoindole-1,3(2H)-dione, 2-[2-(4-bromo-7-methoxy-1,2-dihydro-1-naphthyl)ethyl]-1H-isoindole-1,3(2H)-dione, N-[2-(4-chloro-7-methoxy-1,2-dihydro-1-naphthyl)ethyl]acetamide, N-[2-(4-bromo-7-methoxy-1,2-dihydro-1-naphthyl)ethyl]acetamide, N-[2-(7-methoxy-1,2-dihydro-1-naphthyl)ethyl]acetamide.