Process for the preparation of citalopram

A process for the synthesis of citalopram comprising:

• (a) converting a compound of Formula (I):
• wherein R represents a C2 to C5 alkylene group which may be unsubstituted or substituted by one or more of the groups selected from:
• C1 to C6 alkyl, which may be unsubstituted or substituted by halo, C1 to C6 alkoxy, or C6 to C15 aryl;
• C3 to C10 cycloalkyl, which may be unsubstituted or substituted by halo, C1 to C6 alkyl, C1 to C6 alkoxy, or C6 to C15 aryl;
• C5 to C10 heterocycloalkyl;
• C6-C15 aryl, which may be unsubstituted or substituted by halo, C1 to C6 alkoxy, or C1 to C6 alkyl;
• C7 to C10 aralkyl;
• C1 to C6 alkoxy and heteroaryl;
• or the alkylene group can be substituted by one or more C3 to C7 cycloalkyl groups attached to the alkylene group via a spiro-carbon atom;
• or the alkylene group may contain a C6-C15 aryl group fused to two alkylene carbon atoms;
• to a compound of Formula (II):
• wherein R1 represents a carboxylic acid group or a salt or an ester thereof, and
• (b) converting the compound of Formula (II) to form citalopram or a pharmaceutically acceptable salt thereof wherein said step (b) is carried out via an amide intermediate of Formula (III).
• wherein R2 and R3 independently represent H or C1 to C6 alkyl, C5 to C10 cycloalkyl, aralkyl or aryl.

A process for the preparation of citalopram comprising the steps of:

• (a) subjecting the compound of Formula (I) having the structure:
• to a ring-closure reaction with aqueous sulfuric acid followed by a hydrolysis reaction with aqueous sodium hydroxide to produce a compound of formula (II) having the structure:
• (b) subjecting the compound of Formula (II) to reaction with thionyl chloride followed by reaction with ammonia to form the compound of Formula (III) having the structure:
• (c) subjecting the compound of Formula (III) to a reaction with POCl3 to form citalopram.

A process for the direct conversion of a compound of Formula (I):

• wherein R represents a C2 to C5 alkylene group which may be unsubstituted or substituted by one or more of the groups selected from:
• C1 to C6 alkyl, which may be unsubstituted or substituted by halo, C1 to C6 alkoxy, or C6 to C15 aryl;
• C3 to C10 cycloalkyl, which may be unsubstituted or substituted by halo, C1 to C6 alkyl, C1 to C6 alkoxy, or C6 to C15 aryl;
• C5 to C10 heterocycloalkyl;
• C6-C15 aryl, which may be unsubstituted or substituted by halo, C1 to C6 alkoxy, or C1 to C6 alkyl;
• C7 to C10 aralkyl;
• C1 to C6 alkoxy and heteroaryl;
• or the alkylene group can be substituted by one or more C3 to C7 cycloalkyl groups attached to the alkylene group via a spiro-carbon atom;
• or the alkylene group may contain a C6-C15 aryl group fused to two alkylene carbon atoms;
• to citalopram, the process comprising subjecting the compound of Formula (I) to a one-pot reaction with two or more acidic dehydrating agents.