Process for the preparation of 5-substituted isobenzofurans

A process for the preparation of citalopram which comprises:

• (a) treating 5-formylphthalide of formula
• with a hydroxylamine of formula
• R—O—NH2 (II)
• wherein R represents a hydrogen atom or a substituent R′ inert under the conditions of a Grignard reaction selected from the group consisting of (C1–C6)alkyl, (C1–C3)alcoxy(C2–C4)alkyl, a benzyl, diphenylmethyl and triphenylmethyl group, unsubstituted or substituted on the benzene rings with one or more groups independently selected from the groups consisting of (C1–C6)alkyl, (C1–C3)alcoxy and nitro groups or with a 2,3- or 3,4-methylenedioxy group, to obtain an oxime of formula
• wherein R is as defined above;
• (b) reacting the oxime thus obtained with a 4-fluorophenylmagnesium halide;
• when R═R′ (IIIb) or after substitution of R by R′ when R═H (IIIa) to form an intermediate ketone of formula
• wherein R′ is as defined above and R″ represents MgHal (IVa) wherein Hal is halogen, or hydrogen (IVb);
• (c) reacting the intermediate ketone of formula IV with a [3-(dimethylamino)propyl]magnesium halide to form an intermediate diol of formula
• wherein R′ is as defined above;
• and
• (d) cyclizing the intermediate diol of formula V to form a substituted oxime of formula
• wherein R′ is as defined above;
• (e) optionally, when R is not H removing the group R′ of the substituted oxime of formula VI to form an unsubstituted oxyamino group of the oxime of formula
• (f) converting the unsubstituted oxyamino group of the oxime of formula VII into a nitrile group to give citalopram or one of its pharmaceutical acceptable salts;
• or
• (e′) optionally, when R′ is triphenylmethyl or diphenylmethyl, converting the substituted oxyamino group of the oxime of formula VI into nitrile by treatment with a mixed anhydride of formula
• H—CO—O—CO—R′″ (VIII)
• wherein R′″ represents a C1–C6 alkyl group, an aralkyl group or an aryl group, to give citalopram or a pharmaceutical acceptable salt thereof.