Process for the preparatin of Citalopanm
The present invention relates to a process for (he preparation of the well known antidepres-sant drug cilalopram and intermediates used in the process.
Background of the Invention.
Citalopram is a well known antidepressant drug that has now been on the market for some years and has the following structure:

It is a selective, centrally active serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, accordingly having antidepressant activities. The antidepressant activity of the compound has been reported in several publications, eg. J. Hyttel, Prog. Neitro-Psychopharmacoi & Biol Psychiat., 1982, 6, 277-295 and A. Gravem, Acta Psychiatr, Scand, 1987, 75 , 478-486. The compound has further been disclosed to show effects in the treatment of dementia and cerebrovascular disorders, EP-A 474580.
Citalopram was first disclosed in DF 2,657,271 corresponding to US 4,136,193. This patent publication described preparation of citalopram by one method and outlines a further method which may be used for preparing citalopram.
According to the process described, the corresponding l-(4-fluorophcnyl)I.3-dihydro 5-isn-bezenefuranbonitrile is reacted with 3-(N,N-dimcthyIamino)propyl chloride in the presence of methylsulfinylmothide as condensing agent. The starting material was prepared from the corresponding 5-bromo derivative by reaction with cuprous cyanide.
According to the method which is only outlined in general terms, cilalopram may be obtained by ring closure of the compound:


in the presence of a dehydrating agent and subsequent exchange of the 5-bromo group with cuprous cyanide. The starling material of Fonnula II is obtained from 5-bromophthalide by two successive Grignard reactions, i.e. with 4-nuorophenyl magnesium chloride and N,N-dimethylaminopropyl magnesium chloride, respectively.
m
A new and surpising method and an intermediate for the preparation of citalopram were described in US Patent No 4,650,884 according to which an intermediate of the formula

is subjected to a ring closure reaction by dehydration with strong sulfuric acid in order to obtain citalopram. The intennediate of Formula III was prepared from 5-cyanophthalide by two successive Grignard reactions, i,e, with 4-fluorophenyl magnesium halogenide and N,N-dimcthylaminoprnpyl magnesium halogenide, respectively.
Finally, methods of preparing the individual enantiomers of citalopram are disclosed in US r\itcnt No 4,043,590 from which it also appears that the ring closure of the intermediate of Formula III hiny be carried out via a labile ester with a base.
It has now, surprisingly, been found that citalopram may be manufactured by a novel favourable and safe procedure using convenient starting materials.

Summary of the invention
Accordingly, the present invention relates to a novel method for the preparation of citaloprane
comprising the steps of:
a) reacting acompound of Foemula IV
M

wherein R1 is H or C1-10, alkylcarhonyl, with a Grignard reagent of 4-halogen-fluorophenyl; h) reactine the resulting compound of formula V

wherein R' is as defined above, with a Grignard reagent of 3-halogen-N,N-dimethylpropyl-
amine;
c) effecting ring closure of the resulting compound of Formula VI

wherein R' is as defined above, and
(1) converting the resulting compound of Formula VII


wherein R' is as defined above, into the corresponding 5-cyano derivative, i.e. citalopram, which is isolated as the base or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides the novel intermediates of Formula V,
In a further aspect, the present invention provides the novel intermediates of Formula VI.
In a further aspect, the present invention provides the novel intermediates of Formula VIL
In yet another aspect, the present invention relates to an antidepressant pharmaceutical composition comprising citalopram manufactured by the process of the invention.
Throughout the specification and claims, C1-6 alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2,2-dimethyl-l-ethyl and 2-methyl-l-propyl.
Grignard reagents of 4-halogen-fluorophenyl that may be used in step a) are the magnesium halogenidcs, such as the chloride, bromide or iodide. Preferably the magnesium bromide is used. Grignard reagents of 3-halogen-N,N-dimethyIpropylamine that may be used are the magnesiun) halogenidcs, such as the chloride, bromide or iodide, preferably the magnesium bromide. Preferably the two reactions arc performed successively without iso(a(ion of the intermidiate.
The ring closure of the compound of Formula VI may be effected by an acid or when R' is C1-6, alkylcarbonyl, it may alternatively be carried out via a labile ester with a base. Acidic ring closure is performed by an inorganic acid, such as a sulfuric or phosphoric acid, or an organic acid, such as mcthylsulfonic, p-tolucncsulfonic or trifluoroacetic acid. The basic ring closure i.s performed via a labile ester, such as the methane sulfonyl, p-toluene sulfonyl, 10-camphersulfornyl, trifluoroacetyl or trifluorormethanesulfonyl ester with addition of a base, such as triethyl amine, dimcthylaniline or pyridine. The basic reaction is perfomed in an

1 he reaction mixture is broken with ice water (100 ml) and acetic acid (6 g). THF is cvaporntcd off in vacuo. The aqueous phase is washed with ethyl acetate (2x50 ml). To the aqueous phase is added NH4OH to give a final pTI of 9. The aqueous layer is extracted with ethyl acetate (2x50 ml), and the organic phase is filtered and washed with water (50 ml).

W g CLAIM
I A process for the preparation of citalopram comprising the steps of
a) reacting a compound Formula IV

2. Herein R is IF or C, akylcarbonyl with a Grignard reagent of 4-halogen-fIuorophcnyl; l>) reacting the resulting compound of formula V

wherein R' is as defined above, with a Grignard reagent of 3-haIogen-N,N-dimethylpropyl-
amine;
c) effecting ring closure of the resulting compound of Formula VI

herein R' is as defined above, and
(I) converting the resulting compound of Formula VII


wherein R' is as defined above, into the corresponding 5-cyano derivative, i.e. citalopram, which is isolated as the base or a pharmaceutically acceptable salt thereof.
2. The process of Claim 1 wherein R' is H.

3- The process of Claim 1 wherein R' is C1-6 alkylcarbonyl
4. The process of Claim 3 wherein C1-6. alkyi is methyl, ethyl, propyl, or butyl.
5. The process of Claim 1-4 wherein the Grignard reagent used are magnesium halogenides, preferably the chlorides, bromides or iodides.
6. The process of Claim 5 wherein the Grignard reagents used in step a) is the magnesium
bromide.
7. Theprocess of Claim 5 wherein the Grignard reagents used in step b) is the magnesium chloride.
8. The-process of any of Claims 1-7 wherein the ring closure of the compound of Formula VI is effected by acidic ring closure performed by an inorganic acid, such as a sulfuric or phosphoric acid, or an organic acid, such as mcthylsulfonic, p-tohicnesulfonic or trifluoro acetic acid.
9. The process of Claim 3 wherein the ring closure of the compound of Formula VI is performed by a basic ring closure via a labile ester, preferably with sinuiltancons esterification and addition of base.
10. The process of Claim 9 wherein the labile ester is tbe methane sulfonyl. p-toluene sulfonyl 10-camphorsulfonyl trifluoroacetyl or trifluorometbanesulfonyl ester and the base is triefhyl amine, dimethylaniline or pyridine.

11. The process of Claim 2 wherein the conversion of the group R1-NH- into cyano is
performed by diazotation followed by reaction with CN".
12, The process of Claim 3 wherein the conversion of the group R'-NH- to cyano is
performed by hydrolysis of the C1-6 alkylcarbonyl amino group, R'-NH-, to the
corresponding amino group wherein R' is H, followed by diazotation and reaction with CN".

13. The process as claimed in claims 1 to 12, wherein the compound of formula VI obtained in step (b) of the reaction is separated into the optically active enantiomers thereby obtaining the (S)-enantiomer which is subsequently subjected to ring closure as in step (C).
14- A process for the preparation of citalopram, substantially as hereinabove described and exemplified.