Patent EA-003132-B1 (EA)
Title: Method for the preparation of citalopram
Inventor: PETERSON HANS
IPC: C07C231/12
Filed: 1997-11-10
Abstract: 1. A method for the preparation of citalopram comprising the steps of a) reduction of a compound of Formula IV wherein R<1> is CN, C1-6 alkyloxycarbonyl or C1-6 alkylaminocarbonyl, b) effecting ring closure of the resulting compound of Formula V wherein R<1> is as defined above thereby obtaining a compound of Formula VI wherein R<1> is as defined above; c) then if R<1> is cyano using the compound of Formula VI directly in the next step and if R<1> is C1-6 alkyloxycarbonyl or C1-6 alkylaminocarbonyl, converting the compound of Formula VI to the corresponding compound wherein R<1> is cyano; and d) alkylating the resulting 5-cyano compound of formula VI (R<1>=CN) with 3-(N,N-dimethylamino) propyl halogenide in basic conditions thereby obtaining citalopram, which is isolated as citalopram as such or as a pharmaceutically acceptable salt thereof. 2. The method of claim 1, wherein R<1> is CN. 3. The method of claim 1, wherein R<1> is C1-6 alkyloxycarbonyl. 4. The method of claim 1, wherein R<1> is C1-6 alkylaminocarbonyl. 5. The method of claim 3 or 4, wherein C1-6 alkyl is ethyl-, propyl- or butyl, preferably ethyl-, 2-propyl- or t-butyl, and the most preferable is t-butyl. 6. The method of any one of claims 1 to 5, wherein the reduction of the compound of Formula IV is performed by use of NaBH4 in an alcohol in basic conditions. 7. The method of any one of claims 1 to 6, wherein the ring closure of the compound of Formula V is effected by acidic ring closure performed by an inorganic acid such as sulfuric or phosphoric acid or an organic acid such as methylsulfonic, p-toluenesulfonic or trifluoroacetic acid. 8. The method of any one of claims 1 to 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 a base. 9. The method of claim 8, wherein the labile ester is the methane sulfonyl, p-toluene sulfonyl, 10-camphor-sulfonyl, trifluoroacetyl or trifluoromethanesulfonyl ester and the base is triethyl amine, dimethylaniline or pyridine. 10. The method of claim 3, wherein the conversion of the C1-6 alkyloxycarbonyl to cyano is performed via the corresponding amide group. 11. The method of claim 10, wherein the reaction of C1-6 alkyloxycarbonyl to amide is carried out by hydrolysis with an acid or a base, subsequent conversion to acid chloride and amidation by reaction with ammonia or an alkylamine, preferably by t-butyl amine. 12. The method of claim 11, wherein the hydrolysis is performed with a corresponding acid, such as HBr, HCl or HBr/acetic acid. 13. The method of claim 11, wherein the hydrolysis is performed with a corresponding base, preferably K2CO3, NaOH or KOH. 14. The method of claim 10, wherein the reaction of C1-6 alkyloxycarbonyl to amide is carried out by reaction of the ester with ammonia or an alkylamine under pressure and heating. 15. The method of any one of claims 6 and 10 to 14, wherein the amide is converted to the cyano group by reaction with a dehydrating agent, preferably thionyl chloride or phosphorous pentachloride. 16. The method of any one of claims 1 to 15, wherein the 3-(N,N-dimethylamino) propyl halogenide used as alkylation agent in step d) is chloride, bromide or iodide, preferably chloride. 17. The method of any one of claims 1 to 16, wherein the alkylation in step d) is carried out in an ether, preferably 1,2dimethoxyethane, THF, diglyme or diethylether. 18. The method of any one of claims 1 to 17, wherein the alkylation in step d) is carried out in the presence of a base, preferably lithiumdiisopropylamine. 19. The method of any one of claims 1 to 18, wherein the starting material of formula IV is prepared from the corresponding phthalide compound by reaction with a Grignard reagent of 4-halogen-fluorophenyl, preferably fluorophenylmagnesiumhalogenide, most preferable is magnesiumbromide. 20. The method of claim 1, wherein R<1> is cyano, the starting material of formula IV is prepared from the corresponding phthalide compound by reaction with a fluorophenylmagnesiumhalogenide, the reduction in a) is performed by NaBH4 in an alcohol, the ring closure in b) is effected by an inorganic acid and the alkylation in d) is carried out by use of dimethylaminopropylchloride in an ether in the presence of lithiumdiisopropylamine. 21. A compound of Formula V wherein R<1> is CN, C1-6 alkyloxycarbonyl or C1-6 alkylaminocarbonyl. 22. A compound of formula VI wherein R<1> is C1-6 alkyloxycarbonyl or C1-6 alkylaminocarbonyl. 23. A method for the preparation of citalopram comprising alkylating a compound of formula VI wherein R<1> is C1-6 alkyloxycarbonyl or C1-6 alkylaminocarbonyl, with 3-(N,N-dimethylamino) propyl halogenide in basic conditions, in which the reaction is carried out in an ether in the presence of lithiumdiisopropylamine.