Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-08-14
2003-01-21
Dentz, Bernard (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06509483
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 the Formula
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-dihydroisobenzofuiran 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 HI 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:
reacting 5-carboxyphthalide successively with a Grignard reagent of 4-halo-fluorophenyl and a Grignard reagent of 3-halo-N,N-dimethyl-propylamine and then effecting ring closure of the resulting compound of Formula XI
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 an 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, heteroarylacyloxy 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 reaction of 5-carboxyphthalide successively with a Grignard reagent of 4-halo-fluorophenyl and a Grignard reagent of 3-halo-N,N-dimethyl-propylamine and then effecting ring closure of the resulting compound of Formula XI
to a compound of Formula IV
The Grignard reagent of 4-halogen-fluorophenyl is a magnesium halide, such as the chloride, bromide or iodide. Preferably the magnesium bromide is used. The Grignard reagent of 3-halogen-N,N-dimethylpropylamine is a magnesium halide, such as the chloride, bromide or iodide, preferably the magnesium chloride. Preferably, the two reactions are performed successively without isolation of the intermediate resulting from the first Grignard reaction.
The ring closure of the compound of Formula XI is effected by an acid or via a labile ester with or without a base. Acidic ring closure is performed by an inorganic acid, such as a sulfuric or phosphoric acid, or an organic acid, such as methylsulfonic, p-toluenesulfonic or trifluoroacetic acid. The basic ring closure is performed via a labile ester, such as the methane sulfonyl, p-toluene sulfonyl, b
10
-camphorsulfonyl, trifluoroacetyl or trifluoromethanesulfonyl ester with addition of a base, such as triethyl amine, dimethylaniline, pyridine, etc. The reaction is performed in an inert solvent, preferably with cooling, in particular about 0° C., and is preferably carried out by a one-pot procedure, i.e. with esterification and simultaneous addition of the base.
The 5-carboxyphthalide used as a starting material may be obtained by the methods described in U.S. Pat. No. 3,607,884 or German patent No. 2630927, i.e. by reacting a concentrated solution of terephthalic acid with formaldehyde in liquid S03 or by electrochemical hydrogenation of trimellithic acid.
In yet another aspect, the invention relates to a method for the preparation of citalopram
comprising reacting a compound of Formula IV
with a dehydrating agent and a sulfonamide of the formula H
2
N—SO
2
—R wherein R is
a)
Ahmadian Haleh
Dancer Robert
Petersen Hans
Darby & Darby
Dentz Bernard
H. Lundbeck A/S
LandOfFree
Method for the preparation of citalopram does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method for the preparation of citalopram, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method for the preparation of citalopram will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3047561