DK200100402A

DK200100402A - Process for removing desmethyl citalopram from a citalopram product

Info

Publication number: DK200100402A
Application number: DK200100402A
Authority: DK
Inventors: Dancer Robert; Villa Marco; Sbrogio Federico
Original assignee: Lundbeck & Co As H
Priority date: 2000-12-22
Filing date: 2001-03-08
Publication date: 2002-04-22
Also published as: DK174018B1

Abstract

The present invention relates to a process for removing desmethylcitalopram having the formula <IMAGE> from a crude product containing citalopram having the formula <IMAGE> which process comprises subjecting the crude citalopram product containing the desmethylcitalopram impurity to a preliminary purification, where appropriate, and subsequently treating the crude product with an agent which forms an amide or an amide-like group, after which the reaction mixture is subjected to an acid/base wash and/or crystallization and recrystallization of the citalopram for the purpose of removing the amides which have been formed in the crude citalopram mixture; and the resulting citalopram product is purified further, where appropriate, and worked-up and isolated as the base or a pharmaceutically acceptable salt thereof.

Description

reaktionblandingen underkastes derefter en syre/base vask og/eller krystallisering og rekrystallisering af citalopram for at fjerne amiderne, dannet i den rå citalopramblanding; og det fremkomne citalopramprodukt renses eventuelt yderligere, oparbejdes og isoleres som basen eller et farmaceutisk acceptabelt salt deraf.the reaction mixture is then subjected to an acid / base wash and / or crystallization and recrystallization of citalopram to remove the amides formed in the crude citalopram mixture; and the resulting citalopram product is optionally further purified, worked up and isolated as the base or a pharmaceutically acceptable salt thereof.

KRAVREQUIREMENTS

1. En fremgangsmåde til fjernelse af desmethyl citalopram med formlenA process for removing desmethyl citalopram of the formula

VIII) fra et råt produkt indeholdende citalopram med formlenVIII) from a crude product containing citalopram of the formula

(I) omfattende eventuelt at underkaste det rå citalopramprodukt indeholdende desmethylcitalopram urenheden en indledende rensning og efterfølgende at behandle det rå produkt med et middel, der danner en amid eller en amid-lignende gruppe, valgt blandt midlerne med formlerne (a), (b) eller (c):(I) comprising optionally subjecting the crude citalopram product containing the desmethylcitalopram impurity to initial purification and subsequently treating the crude product with an agent forming an amide or an amide-like group selected from the agents of formulas (a), (b) or (c):

hvor X er halogen eller en gruppe O-CO-R’, Hal er halogen, Y er O eller S, W er O, NH eller S og R, R’, R” og R’” hver især vælges blandt gruppen bestående af hydrogen, alkyl og eventuelt substitueret aryl eller aralkyl; reaktionblandingen underkastes derefter en syre/base vask og/eller krystallisering og rekrystal li sering af citalopram for at fjerne amiderne, dannet i den rå citalopramblanding; og det fremkomne citalopramprodukt renses eventuelt yderligere, oparbejdes og isoleres som basen eller et farmaceutisk acceptabelt salt deraf.wherein X is halogen or a group O-CO-R ', Hal is halogen, Y is O or S, W is O, NH or S and R, R', R 'and R' 'are each selected from the group consisting of hydrogen, alkyl and optionally substituted aryl or aralkyl; the reaction mixture is then subjected to an acid / base wash and / or crystallization and recrystallization of citalopram to remove the amides formed in the crude citalopram mixture; and the resulting citalopram product is optionally further purified, worked up and isolated as the base or a pharmaceutically acceptable salt thereof.

2. En fremgangsmåde ifølge krav 1, hvori det rå citalopram produkt fremstilles ved at underkaste en forbindelse med formlen ΠA process according to claim 1, wherein the crude citalopram product is prepared by subjecting a compound of formula Π

(Π) hvori Z er iod, brom, chlor eller CF3-(CF2)n-S02-0-, hvor n er 0,1, 2, 3,4,5, 6, 7 eller 8, en cyanidudskiftningsreaktion med en cyanidkilde.(Π) wherein Z is iodine, bromine, chlorine or CF3 - (CF2) n-SO2-0-, where n is 0.1, 2, 3,4,5, 6, 7 or 8, a cyanide replacement reaction with a cyanide source .

3. Processen ifølge krav 1-2 kendetegnet ved, at midlet, der danner et amid eller en amidlignende gruppe, er et middel med formlen R-CO-X, hvori R og X er som defineret i krav 1.The process according to claims 1-2, characterized in that the agent forming an amide or an amide-like group is an agent of the formula R-CO-X, wherein R and X are as defined in claim 1.

4. Processen ifølge krav 3 kendetegnet ved, at midlet, der danner et amid eller en Amid-lignende gruppe, er et carboxylsyreanhydrid eller acylhalogenid.The process according to claim 3, characterized in that the agent forming an amide or an amide-like group is a carboxylic anhydride or acyl halide.

5. Processen ifølge krav 4 kendetegnet ved, at midlet, der danner et amid eller en amid-lignende gruppe, er et eddikesyreanhydrid 6. Processen ifølge krav 4 kendetegnet ved, at midlet, der danner et amid eller en amid-lignende gruppe, er et acylchlorid, fortrinsvis acetylchlorid.The process according to claim 4 characterized in that the agent forming an amide or an amide-like group is an acetic anhydride 6. The process according to claim 4 characterized in that the agent forming an amide or an amide-like group is an acyl chloride, preferably acetyl chloride.

7. Processen ifølge et hvilket som helst af kravene 2-6 kendetegnet ved, at Z er Br og cyanidreaktionen udføres ved en reaktion med kobbercyanid i et passende opløsningsmiddel.The process according to any one of claims 2-6, characterized in that Z is Br and the cyanide reaction is carried out by a reaction with copper cyanide in a suitable solvent.

8. Processen ifølge et hvilket som helst af kravene 2-6 kendetegnet ved, at Z er iod, brom, chlor eller CF3-(CF2)n-S02-0-, hvor n er 0,1,2,3,4, 5,6,7 eller 8, og cyanidudskiftningsreaktionen udføres med en cyanidkilde i nærvær af en palladiumkatalysator og en katalytisk mængde af Cu+ eller Zn2^.The process according to any one of claims 2-6, characterized in that Z is iodine, bromine, chlorine or CF3- (CF2) n -SO2-0-, where n is 0,1,2,3,4, 5,6,7 or 8, and the cyanide replacement reaction is carried out with a cyanide source in the presence of a palladium catalyst and a catalytic amount of Cu + or Zn 2

9. Processen ifølge i hvilket som helst af kravene 2-6 kendetegnet ved, at Z er iod, brom, chlor eller CF3-(CF2)n-S02-0-, hvor n er 0,1, 2, 3,4, 5, 6, 7 eller 8, og cyanidudskifningsreaktionen udføres ved reaktion med Zn(CN)2 i nærvær af en palladiumkatalysator.The process according to any one of claims 2-6, characterized in that Z is iodine, bromine, chlorine or CF3- (CF2) n -SO2-0-, where n is 0.1, 2, 3.4, 5, 6, 7 or 8 and the cyanide exchange reaction is carried out by reaction with Zn (CN) 2 in the presence of a palladium catalyst.

10. Processen ifølge krav 9 kendetegnet ved, at Z er Br.The process according to claim 9, characterized in that Z is Br.

11. Processen ifølge et hvilket som helst af kravene 2-6 kendetegnet ved, at Z er Cl eller Br og at cyanidudskiftningsreaktionen udføres med en cyanidkilde i nærvær af en nikkelkatalysator, eventuelt i nærvær af en katalytisk mængde af Cu+ eller Zn2+.The process according to any of claims 2-6, characterized in that Z is Cl or Br and the cyanide exchange reaction is carried out with a cyanide source in the presence of a nickel catalyst, optionally in the presence of a catalytic amount of Cu + or Zn2 +.

12. Processen ifølge krav 11 kendetegnet ved, at Z er Cl.The process according to claim 11, characterized in that Z is Cl.