Citalopram → 2-Hydroxymethyl-4-bromo-4'-fluorobenzophenone

Participants

Reaction Steps

The preparation of citalopram and its hydrobromide salt from 5-bromophthalide and the properties of such compounds was first reported in U.S. Pat. No. 4,136,193, which corresponds to German Offenlegungsschrift No. 2,657,013. U.S. Pat. No. 4,136,193 discloses a synthesis of citalopram starting from 5-bromophthalide, which involves the use of two successive Grignard reactions. In a first reaction, a Grignard reagent prepared from p-fluorobromobenzene and magnesium turnings in ether was reacted with 5-bromophthalide to give 2-hydroxymethyl-4-bromo-4′-fluorobenzophenone. The latter was isolated as a crude oil before, in a second reaction, being added to N,N-dimethylaminopropylymagnesium chloride to give (4-bromo-2-(hydroxymethyl)phenyl)-(4′-fluorophenyl)-(3-dimethylaminopropyl)-methanol. The latter was dehydrated with 60 aqueous phosphoric acid to yield 1-(4′-fluorophenyl)-1-(3-dimethylaminopropyl)-5-bromophthalane, which was then refluxed with cupric cyanide in dimethylformamide to give citalopram.

Provenance & Evidence