Patent EA-005315-B1 (EA)
Title: Method for the preparation of citalopram
Inventor: PETERSEN HANS
IPC: C07D307/87
Filed: 2001-02-22
Abstract: 1. A method for the preparation of citalopram comprising reaction a compound of formula (I) with a compound having the formula wherein X is a suitable leaving group and R is -CH2-O-Pg, -CH2-NPg1Pg2, -CH2NMePg1, -CO-N(CH3)2, -CH(OR<1>)(OR<2>), -C(OR<4>)(OR<5>)(OR<6>), -COOR<3>, -CH2-CO-NH2, -CH=CHR<7> or -CONHR<8>, wherein Pg is a protection group for an alcohol group, Pg1 and Pg2 are protection groups for an amino group, R<1> and R<2> are independently selected from C1-6 alkyl, C1-6 alkenyl, C1-6 alkynyl and optionally C1-6 substituted phenyl, C1-6 substituted naphthyl, phenyl-C1-6 alkyl or naphthyl-C1-6alkyl or R<1> and R<2> together form a chain of each of R<3>,R<4>,R<5>,R<6> and R<7> are independently selected from C1-6alkyl, C1-6alkenyl, C1-6 and optionally C1-6 substituted phenyl, C1-6 substituted naphthyl, phenyl-C1-6alkyl or naphthyl-C1-6alkyl, and R<8> is hydrogen or methyl, to form a compound of the formula wherein R is as defined above; followed by conversion of the group R to form a dimethylaminomethyl group and isolation of citalopram base or a pharmaceutically acceptable salt thereof. 2. The method according to claim 1 wherein the compound of formula (I) is reacted with a compound of formula (II) wherein R is -CH2-O-Pg followed by removal of the protection group to form the corresponding alcohol of the formula and thereafter conversion of the alcohol group to a feasible leaving group and reaction of the resulting compound a) with dimethylamin or a metal salt thereof to form citalopram, b) with methylamin followed by reductive amination to form citalopram, or c) with an azide followed by reduction to form the corresponding amino compound and thereafter methylation or reductive amination to form citalopram. 3. The method according to claim 1 wherein the compound of formula (I) is reacted with a compound of formula (II) wherein R is -CO-N(CH3)2, followed by reduction of the resulting compound of the formula to form citalopram. 4. The method according to claim 1 wherein the compound of formula (I) is reacted with a compound of formula (II) wherein R is -CH2-N(Pg1)(Pg2) followed by removal of the protection groups to form a compound of formula and thereafter reductive amination or methylation of the free amino group to form citalopram. 5. The method according to claim 1 wherein a compound of formula (I) is reacted with a compound of formula (II) wherein R is -CH(OR<1>)(OR<2>) or -C(OR<4>)(OR<5>)(OR<6>) to form a compound of the formula (VIIa) or (VIIb) wherein R<1>, R<2>, R<4>, R<5> and R<6> are as defined above, followed by deprotection of the compound of formula (VIIa) or (VIIb) and consecutive reductive amination of the resulting aldehyde to form citalopram. 6. The method according to claim 1 wherein a compound of formula (I) is reacted with a compound of formula (II) wherein R is -COOR<3> to form a compound of the formula which is converted to an amide of formula (V) followed by reduction to form citalopram, or the compound of formula (VIII) is reduced to form the corresponding alcohol of formula (IV) followed by conversion of the alcohol group to feasible leaving group and consecutively reaction a) with dimethylamine or a metal salt thereof to form citalopram, b) with methylamine followed by reductive amination to form citalopram, or c) with an azide followed by reduction to form the corresponding amino compound and thereafter methylation or reductive amination to form citalopram. 7. The method according to claim I wherein a compound of formula (I) is reacted with a compound of formula (II) wherein R is -CH2-CONH2 to form a compound of formula which is treated with hypohalide to form a compound of formula followed by methylation of the free amino group or reductive amination to form citalopram. 8. The method according to claim 1 wherein a compound of formula (I) is reacted with a compound of formula (II) wherein R is -CH=CHR<7> to form a compound of formula wherein R<7> is as defined above, which is oxidised to form a compound of formula followed by reductive amination to form citalopram. 9. The method according to claim 1 wherein the compound of formula (I) is reacted with a compound of formula (II) wherein R is -CH2-Me(Pg1) followed by removal of the protection group to form a compound of formula and thereafter methylation of the amino group or reductive amination to form citalopram. 10. The method according to claim 1 wherein the compound of formula (I) is reacted with a compound of formula (II) wherein R is -CO-NHR<8> wherein R<8> is hydrogen or methyl, followed by reduction of the resulting compound of the formula wherein R<8> is as defined above, to form a compound of formula wherein R<8> is as defined above, followed by methylation or reductive amination to form citalopram. 11. The method according to claim 1 wherein the reaction of the compound of formula (I) with a compound of formula (II) is carried out in presence of a base selected from LDA (lithiumdiisopropylamine), LiHMDS (hexamethyldisilasan lithium), NaH, NaHMDS (hexamethyldisilasan sodium) and metalalkoxides such as NaOMe, KOMe, LiOMe, NaOtertBu, KOtertBu and LiOtertBu. 12. An intermediate having the general formula wherein R is -CH2-O-Pg, -CH2-NPg1Pg2, -CH2NmePg1, -CO-N(CH3)2, -CH(OR<1>)(OR<2>), -C(OR<4>)(OR<5>)(OR<6>), -COOR<3>, -CH2-CO-NH2, -CH=CHR<7> or -CONHR<8>, wherein Pg is a protection group for an alcohol group, Pg1 and Pg2 are protection groups for an amino group, R<1> and R<2> are independently selected from C1-6alkyl, C1-6alkenyl, C1-6alkynyl and optionally C1-6 substituted phenyl, C1-6 substituted naphthyl, phenyl-C1-6 alkyl or naphthyl-C1-6alkyl or R<1> and R<2> together form a chain of each of R<3>,R<4>,R<5>,R<6> and R<7> are independently selected from C1-6alkyl, C1-6alkenyl, C1-6 and optionally C1-6 substituted phenyl, C1-6 substituted naphthyl, phenyl-C1-6 alkyl or naphthyl-C1-6alkyl, and R<8> is hydrogen or methyl, and acid addition salts thereof. 13. An intermediate having the formula and acid addition salts thereof. 14. An intermediate having the formula