Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-08-14
2002-07-30
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C558S423000
Reexamination Certificate
active
06426422
ABSTRACT:
The present invention relates to a method for the preparation of the well-known anti-depressant drug citalopram, 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile, methods for the preparation of intermediates used in the preparation of citalopram, and methods for conversion of said intermediates into citalopram.
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 acting 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. Neuro
-
Psychopharmacol.
&
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 DE 2,657,013, corresponding to U.S. Pat. No. 4,136,193. This patent publication describes the 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 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile is reacted with 3-(N,N-dimethylamino)propyl-chloride in the presence of methylsulfinylmethide 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, citalopram 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 starting material of Formula II is obtained from 5-bromophthalide by two successive Grignard reactions, i.e. with 4-fluorophenyl magnesium chloride and N,N-dimethylaminopropyl magnesium chloride, respectively.
A new and surprising method and an intermediate for the preparation of citalopram were described in U.S. Pat. No. 4,650,884, according to which an intermediate of Formula III
is subjected to a ring closure reaction by dehydration with strong sulfuric acid in order to obtain citalopram. The intermediate of Formula III was prepared from 5-cyanophthalide by two successive Grignard reactions, i.e. with 4-fluorophenyl magnesium halogenide and N,N-dimethylaminopropyl magnesium halogenide, respectively.
Further processes are disclosed in international patent application Nos. WO 98019511, WO 98019512 and WO 98019513. WO 98019512 and WO 98019513 relate to methods wherein a 5-amino-, 5-alkoxycarbonyl- or 5-(sec. aminocarbonyl)phthalide is subjected to two successive Grignard reactions, ring closure and conversion of the resulting 1,3-dihydroisobenzofuran derivative to the corresponding 5-cyano compound, i.e. citalopram. International patent application No. WO 98019511 discloses a process for the manufacture of citalopram wherein a (4-substituted-2-hydroxymethylphenyl-(4-fluorophenyl)methanol compound is subjected to ring closure and the resulting 5-substituted 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran converted to the corresponding 5-cyano derivative, which is alkylated with a (3-dimethylamino)propylhalogenide in order to obtain citalopram.
Finally, methods of preparing the individual enantiomers of citalopram are disclosed in U.S. Pat. No. 4,943,590 from which it also appears that the ring closure of the intermediate of Formula III may 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 citalopram having the Formula I
comprising:
conversion of a compound of Formula VIII
wherein Z is halogen,
to a compound of Formula IV
followed by conversion of the compound of Formula IV into citalopram.
In particular the invention relates to such a method comprising:
i) reaction of the compound of Formula IV with a dehydrating agent and a sulfonamide of the Formula H
2
N—SO
2
—R wherein R is:
a) An optionally substituted NH
2
, or C
1-6
alkyloxy,
b) aryloxy or heteroaryloxy optionally substituted with halogen, C
1-4
-alkyl, cyano, hydroxy, C
1-4
-alkoxy, trifluoromethyl, nitro, amino, C
1-4
-alkylamino or di-C
1-4
-alkylamino, or
c) aryl or heteroaryl optionally substituted with halogen, C
1-4
-alkyl, cyano, hydroxy, C
1-4
-alkoxy, trifluoromethyl, nitro, amino, C
1-4
-alkylamino or di-C
1-4
-alkylamino; or
ii) conversion of the compound of Formula IV to the corresponding amide of Formula V
in which R
1
and R
2
are independently hydrogen, C
1-6
alkyl, C
1-6
alkyl substituted with one or more substituents selected from the group comprising aryl and heteroaryl, hydroxy, C
1-6
-alkoxy, aryloxy, heteroaryloxy, aryl-C
1-6
-alkoxy, or trisubstituted silyl wherein the substituents are independently C
1-6
alkyl, aryl, heteroaryl or aryl-C
1-6
-alkyl and then reacting the amide of Formula V with a dehydrating agent
thereby obtaining citalopram as the base or a pharmaceutically acceptable salt thereof.
The conversion of the 5-carboxy derivative of Formula IV to the amide of Formula V may be carried out via activated acid derivative of Formula VI:
wherein R
3
is halogen, C
1-6
alkoxy,aryloxy, heteroaryloxy, aryl-C
1-6
-alkoxy, heteroaryl-C
1-6
-alkoxy, alkylcarbonate, arylcarbonate, alkylcarbamate, arylcarbamate, alkylthiocarbonate, arylthiocarbonate, alkylthiocarbamate, arylthiocarbamate, alkylacyloxy, arylacyloxy, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
In another aspect, the invention relates to methods for the preparation of the intermediate of Formula IV comprising conversion of a compound of Formula VIII, wherein Z is halogen to compound of Formula IV.
In yet another aspect, the invention relates to methods for the preparation of the intermediate of Formula VII
wherein X is selected from halide, CN, OR
5
or SR
6
where R
5
and R
6
are independently selected from C
1-6
alkyl, aryl, heteroaryl or benzyl and each of these C
1-6
alkyl, aryl, heteroaryl or benzyl groups are unsubstituted or substituted with halogen, C
1-4
alkyl, cyano, hydroxy, C
1-4
alkoxy, trifluoromethyl, nitro, amino, C
1-4
alkylamino or di-C
1-4
alkylamino, NR
7
R
8
where R
7
and R
8
are independently selected from hydrogen, C
1-6
alkyl, aryl, heteroaryl or benzyl and each of these C
1-6
alkyl, aryl, heteroaryl or benzyl groups are unsubstituted or substituted with halogen, C
1-4
alkyl, cyano, hydroxy, C
1-4
alkoxy, trifluoromethyl, nitro, amino, C
1-4
alkylamino or di-C
1-4
alkylamino;
Y is O, S, or NR
9
where R
9
is selected from hydrogen, C
1-6
alkyl, aryl, heteroaryl or benzyl and each of these C
1-6
alkyl, aryl, heteroaryl or benzyl groups are unsubstituted or substituted with halogen, C
1-4
alkyl, cyano, hydroxy, C
1-4
alkoxy, trifluoromethyl, nitro, amino, C
1-4
alkylamino or di-C
1-4
-alkylamino;
comprising
conversion of a compound of Formula VIII
wherein Z is halogen,
to a compound of Formula VII.
In yet another aspect, the present invention relates to an antidepressant pharmaceutical composition comprising citalopram as the base or any convenient salt thereof manufactured by the process of the invention.
Throughout the specification and claims, the term ‘dehydrating agent’ refers to any suitable dehydrating agent, and a person skilled in the art may easily determine the optimal agent. Examples of suitable dehydrating agents are SOCl
2
, POCl
3
, PCl
5
, SOBr
2
, POBr
3
, PBr
5
, SOI
2
, POI
3
, PI
5
, P
4
O
10
, oxalylchloride, carbonyldiimidazole and Vilsmeier reagents. Preferably a chloro-containing agent, most preferably SOCl
2
or POCl
3
, is used. Vilsmeier reagents are reagents formed by mixing of N,N-dimethylformamide (DMF) and dehydrating agents, examples of which are DMF/SOCl
2
and DMF
Ahmadian Haleh
Petersen Hans
Covington Raymond
Darby & Darby
H. Lundbeck A/S
Rotman Alan L.
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