Patent EA-004033-B1 (EA)
Title: Method for the preparation of citalopram
Inventor: PETERSEN HANS
IPC: C07D307/78
Filed: 1999-04-14
Abstract: 1. A method for the preparation of citalopram comprising the steps of: a) a reductive hydrolysis of compound of Formula IV wherein R is a group wherein R1 and R2 are independently selected from C1-6 alkyl, mono- or bicyclic carbocyclic aromatic group, and bicyclic heterocyclic aromatic group, or R1 and R2 are linked and together designate a 4- or 5-membered chain optionally comprising an S, O or N atom, 4,5-dihydro-1,3-oxazol-2-yl optionally substituted in the 4- and/or 5-position with C1-6 alkyl, mono- or bicyclic carbocyclic aromatic group, and bicyclic heterocyclic aromatic group, and b) converting the resulting 5-formyl compound of Formula V to the corresponding 5-cyano compound, citalopram which is isolated as the base or a pharmaceutically acceptable salt thereof. 2. The method of claim 1, wherein the conversion of the 5-formyl compound of Formula V to citalopram is carried out by conversion of the formyl group by reaction with a reagent R3-X-NH2 wherein R3 is hydrogen, C1-6 alkyl, mono- or bicyclic carbocyclic aromatic group, and bicyclic heterocyclic aromatic group, and X is O, N or S, followed by dehydration with a dehydrating agent. 3. The method of claim 1 or 2, wherein R is a group 4. The method of claim 3, wherein R1 and R2 are C1-6 alkyl or R1 and R2 are linked and together designate a 4- or 5-membered chain optionally comprising an S, O or N atom. 5. The method of claim 4, wherein R1 and R2 are both methyl or R1 and R2 together with the N-atom to which they are linked form a morpholinyl group. 6. The method of claim 1, wherein R is an optionally substituted 4,5-dihydro-1,3-oxazol-2-yl group. 7. The method of claim 6, wherein R is 4,5-dihydro-4,4,-dimethyl-1,3-oxazol-2-yl. 8. The method of claim 1-7, wherein the intermediate of Formula IV is prepared by ring closure of the corresponding compound of Formula VI: wherein R is as defined in claim 1. 9. The method of claim 8, wherein the compound of Formula VI is obtained from the corresponding 5-substituted phthalide derivative by reaction with a Grignard reagent of 4-halogen-fluorophenyl followed by reaction with a Grignard reagent of 3-halogen-N,N-dimethyl-propylamine. 10. The method of claim 6 or 8, wherein the compound of Formula VI is prepared from 4-dimethylamino-1-(4-fluorophenyl)-butan-1-one by Grignard reaction with a protected 2-(hydroxymethyl)-4-(1,3-oxazol-2-yl)-phenyl magnesium halogenide derivative. 11. The method of claim 8-10, wherein the ring closure of the compound of Formula VI is effected by acidic ring closure performed by an inorganic acid, such as sulfuric acid or phosphoric acid or an organic acid, such as methylsulfonic acid, p-toluenesulfonic acid or trifluoroacetic acid. 12. The method of claim 8-10, wherein the ring closure of the compound of Formula VI is performed by a basic ring closure via a labile ester, preferably with simultaneous esterification and addition of a base. 13. The method of claim 12 wherein the labile ester is a methane sulfonyl, p-toluene sulfonyl, 10-camphorsulfonyl, trifluoroacetyl or trifluoromethanesulfonyl ester and the base is triethyl amine, dimethylaniline or pyridine. 14. The method of claim 11-13, wherein, before further reaction, the intermediate of Formula VI is separated into its enantiomers, thereby, obtaining the enantiomer giving S-citalopram. 15. An intermediate compound for the preparation of citalopram having Formula V 16. The intermediate compound for the preparation of citalopram having Formula IV wherein R has the values, defined in claim 1. 17. Use of intermediate compound, according to claim 15, for preparation of citalopram. 18. Use of intermediate compound, according to claim 16, for preparation of citalopram.