Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-01-07
2001-05-08
Owens, Amelia (Department: 1612)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C514S456000, C560S062000, C564S171000
Reexamination Certificate
active
06229026
ABSTRACT:
BACKGROUND OF THE INVENTION
Citalopram is a well known antidepressant drug that has now been on the marked 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. 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 2,657,271 corresponding to U.S. Pat. No. 4,136,193. This patent publication describes the preparation of citalopram 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 is 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.
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 in basic conditions.
It has now surprisingly been found that citalopram may be manufactured by a 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 comprising the steps of reacting a compound of Formula IV
wherein R
1
is C
1-6
alkyl and X is O or NH, successively with a Grignard reagent of 4-halogen-fluorophenyl, thereby obtaining a compound of Formula IVa
wherein R
1
and X are as defined above, and a Grignard reagent of 3-halogen-N,N-dimethylpropylamine, effecting ring closure of the resulting compound of Formula V
wherein R
1
and X are as defined above, and converting the resulting compound of Formula VI
where R
1
and X are as defined above, to 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 Formulas IVa and V, respectively.
In a further aspect the present invention provides the novel intermediates of Formula VI.
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, C
1-6
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-1-ethyl and 2-methyl-1-propyl.
Grignard reagents of 4-halogen-fluorophenyl that may be used in the first step are the magnesium halogenides, such as the chloride, bromide or iodide. Preferably the magnesium bromide is used. Grignard reagents of 3-halogen-N,N-dimethylpropylamine that may be used are the magnesium halogenides, such as the chloride, bromide or iodide, preferably the magnesium bromide. The intermediate of Formula IVa may or may not be isolated Preferably the two reactions are performed successively without isolation of the intermediate.
The ring-closure of the compound of Formula V is effected by an acid or 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 methylsulfonic, p-toluenesulfonic or trifluoroacetic acid. The basic ringclosure is performed via a labile ester, such as the methane sulfonyl, p-toluene sulfonyl, 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.
When X is O, the conversion of the group R
1
—X—CO— to cyano is preferably performed via the corresponding amide group which is then converted to the cyano group in the same way as compounds of Formula VI wherein X is NH.
The reaction of R
1
—X—CO— (X═O) to amide is carried out by hydrolysis with an acid or a base and subsequent conversion to acid chloride and amidation by reaction with ammonia or an alkylamine, preferably t-butyl amine. Acid hydrolysis may be performed by use of any suitable acid, such as HBr, HCl, HBr/acetic acid. Basic hydrolysis may be performed with any suitable base, such as K
2
CO
3
, NaOH, KOH, etc. The conversion to amide may also be obtained by reaction of the ester (X═O) with ammonia or an alkylamine under pressure and heating.
The amide is converted to the cyano group by conventional nitril synthesis. So, the resulting amide or the amide of Formula V wherein X is NH is preferably converted to the cyano compound, i.e. citalopram, by reaction with a dehydrating agent, most preferably thionyl chloride, phosphor pentachloride, etc.
Alternatively, an ester, i.e. a compound of Formula VI wherein X is O may be hydrolysed and then reacted with chlorosulfonyl isocyanate in order to form the nitrile.
The process of the invention may be carried out with or without isolation of the intermediates.
The process of the invention may also be used to prepare the active (S)-enantiomer of citalopram. In that case, the compound of formula V is separated into the optically active enantiomers by a procedure analogous to the one described in U.S. Pat. No. 4,943,590 thereby obtaining the (S)-nantiomer of the compound of formula V which is used in the ring closure reaction in step c). Accordingly, the individual enantiomers of the intermediates of formulas V and VI, respectively, are embraced by the formulas.
Other reaction conditions, solvents, etc. are conventional conditions for such reactions and may easily be determined by a person skilled in the art.
The starting materials of formula IV are commercially available or may be prepared from 5-carboxyphtalide by reaction with thionyl chloride and then C
1-6
alkanol or C
1-6
alkylamine. 5-carboxyphtalide is commercially available and may be prepared by well known procedures (Tirouflet, J.; Bull.Soc.Sci. Bretagne 26, 1959,35).
In one embodiment of the invention X is O and R
1
is ethyl, propyl, or butyl, preferably ethyl, 2-propyl or t-butyl.
In another embodiment of the invention X is NH and R
1
is ethyl, propyl, or butyl, preferably ethyl, 2-propyl or t-butyl, most preferably t-butyl.
The compound of general Formula I may be used as the free base or as a pharmacologically acceptable acid addition salt thereof. As acid addition salts such salts formed with organic or inorganic acids may be used. Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascor
Darby & Darby
H. Lundbeck A/S
Owens Amelia
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