Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-06-01
2002-04-02
Dentz, Bernard (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S147000, C548S201000, C548S216000, C548S238000, C549S467000
Reexamination Certificate
active
06365747
ABSTRACT:
The present invention relates to a method for the preparation of the well known antidepressant drug citalopram, 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile.
BACKGROUND OF THE INVENTION
Citalopram is a well-known antidepressant drug that has now been on the market for some to years and has the following structure:
It is a selective, centrally acting serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, having antidepressant activities. The antidepressant activity of the compound has been reported in several publications, e.g. J. Hyttel, Prog. Neuro-Psychopharmacol. & Biol.
Psychiat
., 1982, 6, 277-295 and A. Gravem, Acta Psychiatry. Scand., 1987, 75, 478-486. The compound has also been disclosed to show effects in the treatment of dementia and cerebrovascular disorders, EP-A 474580.
Citalopram was first disclosed in DE 2,657,271 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 that 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 second 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 cyano using 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 98/019511, WO 98/019512 and WO 98/019513. WO 98/019512 and WO 98/019513 relate to methods wherein a 5-amino-, 5-carboxy- 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 98/019511 discloses a process for the manufacture of citalopram wherein a (4-substituted-2-hydroxymethylphenyl-(4-fluorphenyl)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 and 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 been found that citalopram may be obtained in a high yield as a very pure product by a new process in which an optionally substituted 2-[1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-yl]oxazoline or -thiazoline is converted in one step to citalopram substantially without any occurrence of undesired side-reactions.
It has also been found that it is possible to prepare the optionally substituted 2-[1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)- 1,3-dihydroisobenzofuran-5-yl]oxazoline or -thiazoline intermediate directly starting from 5-carboxyphthalide, by formation of its amide with an optionally substituted 2-hydroxy-ethylamine or 2-mercapto-ethylamine and ring closure. The intermediate oxazolines and thiazolines are stable under the Grignard reaction conditions.
SUMMARY OF THE INVENTION
Accordingly, the present invention relates to a novel method for the preparation of citalopram, its enantiomers and acid addition salts thereof comprising treatment of a compound of formula IV
wherein X is O or S;
R
1
-R
2
are each independently selected from hydrogen and C
1-6
alkyl, or R
1
and R
2
together form a C
2-5
alkylene chain thereby forming a spiro-ring; R
3
is selected from hydrogen and C
1-6
alkyl, R
4
is selected from hydrogen, C
1-6
alkyl, a carboxy group or a precursor group therefore, or R
3
and R
4
together form a C
2-5
alkylene chain thereby forming a spiro-ring; with a dehydration agent or alternatively where X is S, thermally cleavage of the thiazoline ring or treatment with a radical initiator, such as peroxide or with light, to form citalopram having the formula
as the base or an acid addition salt thereof, and thereafter optionally converting said base or said acid addition salt to a pharmaceutically acceptable salt thereof.
The dehydration agent may be any suitable dehydration agent conventionally used in the art, such as phosphoroxytrichloride, thionylchloride, phosphorpentachloride, PPA (polyphosphoric acid), and P
4
O
10
. The reaction may be carried out in the presence of an organic base, such as pyridine.
Alternatively, the dehydration agent may be a Vilsmeier reagent, i.e. a compound which is formed by reaction of a chlorinating agent, preferably an acid chloride, e.g. phosgene, oxalyl chloride, thionyl chloride, phosphoroxychloride, phosphorpentachloride, trichloromethyl chloroformate, also briefly referred to as “diphosgene”, or bis(trichloromethyl) carbonate, also briefly referred to as “triphosgene”, with a tertiary amide such as N,N-dimethylformamide or a N,N-dialkylalkanamide, e.g N,N-dimethylacetamide. A classic Vilsmeyer reagent is the chloromethylenedimethyliminium chloride. The Vilsmeier reagent is preferably prepared in situ by adding the chlorinating agent to a mixture containing the starting oxazoline or thiazoline derivative of formula IV and the tertiary amide.
When X is S and the conversion of the thiazoline group into the cyano group is made by thermal transformation, the thermal decomposition of compound IV is preferably carried out in an anhydrous organic solvent, more preferably an aprotic polar solvent, such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide or acetonitrile. The temperature at which the thermal decomposition transforms the 2-thiazolyl group to a cyano group is between 60° C. and 140° C. The thermal decomposition may conveniently be carried out by reflux in a suitable solvent, preferably acetonitrile. The thermal cleavage may conveniently be carried out in the presence of oxygen or an oxidation agent. Compounds of formula IV where X is S and R
4
is a carboxy group or a precursor for a carboxy group can also be converted to citalopram by treatment with a radical initiator such as light or peroxides.
In a further aspect, the invention relates to the above process in which the compound of formula IV is in the form of the S-enantiomer.
In yet another aspect, the present invention relates to citalopram and S-citalopram manufactured by the process of the invention and an antidepressant pharmaceutical composition comprising citalopram or S-citalopram manufactured by the process of the invention.
According to the present invention, it has surprisingly been found that the oxazoline or thiazoline group may be introduced into the 5-position of phthalide and that remain stable during the subsequent reactions.
Furthermore, it has been found that the 1,1-disubstituted isobenzofurancarbonyl group in the intermediate of formula IV is surprisingly stable and that the reaction of the 2-[1-[3-(dimethyla
Casazza Umberto
Dall'Asta Leone
Petersen Hans
Darby & Darby
Dentz Bernard
H. Lundbeck A/S
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