| 摘要 |
1. A method for the preparation of citalopram comprising the steps of reacting a compound of Formula IV wherein R<1> is C1-6 alkyl and X is O or NH, successively with a Grignard reagent of 4-halogenfluorophenyl, thereby obtaining a compound of Formula IVa wherein R<1> and X are as defined above, and a Grignard reagent of 3-halogen-N,N-dimethylpropylamine, effecting ring closure of the resulting compound of Formula V wherein R<1> and X are as defined above, and converting the resulting compound of Formula VI wherein R<1> and X are as defined above, to citalopram, which is isolated as the base or a pharmaceutically acceptable salt thereof. 2. The method of Claim 1 wherein X is O. 3. The method of Claim 1 wherein X is NH. 4. The method of Claim 2 or 3 wherein R<1> is ethyl, propyl, or butyl, preferably ethyl, 2-propyl or tert-butyl, most preferably tert-butyl. 5. The method of Claim 1-4 wherein the Grignard reagent used is a magnesium halogenide, preferably the chloride, bromide or iodide. 6. The method of Claim 5 wherein the Grignard reagent used in the first step is the magnesium broride salt. 7. The method of Claim 5 wherein the Grignard reagent used in the second step is the magnesium chloride. 8. The method of any of Claims 1-7 wherein the ring-closure of the compound of Formula V is effected by acidic ring closure performed by an inorganic acid, such as a sulfuric or phosphoric acid, or an organic acid, such as a methylsulfonic, p-toluenesulfonic or trifluoroacetic acid. 9. The method of any of Claims 1-6 wherein the ring-closure of the compound of Formula V is performed by a basic ring-closure via a labile ester preferably with simultaneous esterification and addition of base. 10. The method of Claim 9 wherein the labile ester is the methanesulfonyl, p-toluenesulfonyl, 10-camphorsulfonyl, trifluoroacetic or trifluoromethanesulfonyl ester and the base is triethylamine, dimethylaniline or pyridine. 11. The method of Claim 2 wherein X is O and the conversion of the group R<1>-X-CO- to cyano is performed via the corresponding amide group. 12. The method of Claim 11 wherein the reaction of R<1>-X-CO- to amide is carried out by hydrolysis with an acid or a base, subsequent conversion to acid chloanhydride and amidation by reaction with ammonia or an alkylamine, preferably tert-butylamine. 13. The method of Claim 12 wherein the hydrolysis is performed by use of a suitable acid, such as HBr, HCl, HBr/acetic acid. 14. The method of Claim 12 wherein the hydrolysis is performed by use of a suitable base, preferably K2CO3, NaOH or KOH. 15. The method of Claim 9 wherein the reaction of R<1>-X-CO- to amide is carried out by reaction of the ester with ammonia or an alkylamine under pressure and heating. 16. The method of any of Claims 11-14 wherein amide is converted to the cyano group by reaction with a dehydrating agent, preferably thionylchloride or phosphor pentachloride. 17. The method of any of Claims 1-16 characterised in that before it is used in the ring closure reaction, the compound of Formula V is separated into the optically active enantiomers thereby obtaining the (S)-enantiomer. 18. An intermediate for preparation of citalopram having Formula IVa Formula IVa wherein R<1> is C1-6 alkyl and X is O or NH. 19. An intermediate for preparation of citalopram of Formula V wherein R<1> is C1-6 alkyl and X is O or NH. 20. An intermediate for preparation of citalopram of Formula VI wherein R<1> is C1-6 alkyl and X is O or NH. |
