Patent EA-002977-B1 (EA)
Title: Method for the preparation of citalopram
Inventor: DALL ASTA LEONE
IPC: C07D263/52
Filed: 1999-10-19
Abstract: 1. A method for the preparation of citalopram or any of its enantiomers and acid addition salts thereof comprising treatment of a compound of formula IV   wherein X is O or S; R<1> - R<2> are each independently selected from hydrogen and C1-6 alkyl, or R<1> and R<2> together form a C2-5 alkylene chain thereby forming a spiro-ring; R<3> is selected from hydrogen and C1-6 alkyl, R<4> is selected from hydrogen, C1-6 alkyl, a carboxy group or a precursor group therefore, or R<3> and R<4> together form a C2-5 alkylene chain thereby forming a spiro-ring, with a dehydration agent or alternatively where X is S, thermally cleavage of the thiazoline ring, or treatment in presence of a radical initiator, to form citalopram having the formula   and thereafter optionally converting the free base or an acid addition salt thereof thus obtained to a pharmaceutically acceptable salt thereof. 2. A method according to claim 1 comprising: a) reacting a 5-carboxyphthalide of formula V   with a 2-hydroxy- or 2-mercaptoethanamine of formula VI   in which X, R<1> - R<4> are as defined above, (b) submitting the amide of formula VII thus obtained   in which X, R<1> - R<4> are as defined above, to a ring closure by dehydration; (c) submitting the 2-(1-oxo-1,3-dihydroisobenzofuran-5-yl)oxazoline or thiazoline of formula VIII thus obtained to two subsequent Grignard reactions,   in which X, R<1> - R<4> are as defined above, the first with a fluorophenyl magnesium halide and the second in situ with a [3-(dimethyl-amino)propyl]magnesium halide; (d) submitting the 2-[3-hydroxymethyl-4-[(1-(4-fluorophenyl)-1-hydroxy-[4-(dimethyl-amino)butyl]phenyl]oxazoline or -thiazoline of formula IX thus obtained   in which X, R1 - R4 are as defined above, to a ring closure by dehydration; (e) reacting the 2-[1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzo-furan-5-yl]oxazoline or -thiazoline thus obtained of formula IV   in which X, R<1> - R<4> are as defined above, with a dehydration reagent or alternatively if X is S subjecting the compound of formula IV to a thermal decomposition reaction, or treatment with a radical initiator; and isolating the thus obtained citalopram in form of the free base or of a salt thereof; and (f) optionally converting the compound obtained into pharmaceutically acceptable salt thereof. 3. A method for the preparation of citalopram according to claims 1-2 wherein the compound of formula IV is treated with a dehydrating agent selected from phosphoroxytrichloride, thionylchloride, phosphorpentachloride, PPA (polyphosphoric acid) and P4O10 or a Vilsmeier reagent. 4. A method according to claim 3 wherein the Vilsmeier reagent is formed by reaction of a clorinating reagent with a tertiary amide. 5. A method according to claim 4 wherein the clorinating agent is an acyl chloride selected from phosgene, oxalyl chloride, thionyl chloride, phosphoroxychloride, phosphorpentachloride and trichloromethyl chloroformate and the tertiary amide is selected from N,N-dimethylformamide or a N,N-dialkylalkanamide, e.g. N,Ndimethylacetamide. 6. A method according to claims 3 to 5 wherein the Vilsmeier reagent is prepared in situ by adding the chlorinating agent to a mixture containing the starting oxazoline or thiazoline derivative of formula IV and the tertiary amide. 7. A method for the preparation of citalopram according to claims 1 to 2 wherein the termally cleavage of the thiazoline ring of a compound of formula IV where X is S is carried out in presence of oxygen or an oxidizing agent. 8. A method for the preparation of citalopram according to claims 1 to 2 wherein the thiazoline ring of a compound of formula IV where X is S and R<4> is carboxy or a precursor for carboxy is treated with a radical initiator, such as light or peroxides. 9. A method according to claim 2 wherein step b) is carried out by subjecting the amide of formula VII to a ring closure reaction by dehydration, preferably by treatment with thionyl chloride at low temperature, namely at less than 10 degree C, preferably less than 0 degree C, most preferably at -10 degree C whereafter the temperature is allowed to rise to 20 degree C and the reaction is completed at a temperature of 20-40 degree C, preferably at 25-35 degree C, most preferred at 28 to 30 degree C. 10. A method according to any of claims 1-6 wherein the compound of formula IV is in the form of the S-enantiomer. 11. A method according to claim 2 wherein the compound of formula IX used is in the form of the S-enantiomer. 12. A compound of the general formula VIII   in which X, R<1> - R<4> are as defined above in claim 1, or any of its enantiomers and acid addition salts thereof. 13. A compound of the general formula IX   in which X, R<1> - R<4> are as defined in claim 1, or any of its enantiomers and acid addition salts thereof. 14. A compound of the general formula IV   in which X, R<1> - R<4> are as defined in claim 1, or any of its enantiomers and acid addition salts thereof. 15. The method according to claim 2 wherein step a) and b) is carried out as a one-pot process.