Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-05-03
2001-09-18
Dentz, Bernard (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C558S423000, C560S057000, C564S171000
Reexamination Certificate
active
06291689
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 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 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.
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 comprising the steps of:
a) reduction of a compound of Formula IV
wherein R
1
is CN, C
1-6
alkyloxycarbonyl or C
1-6
alkylaminocarbonyl,
b) effecting ring closure of the resulting compound of Formula V
wherein R
1
is as defined above thereby obtaining a compound of Formula VI
wherein R
1
is as defined above
c) then if R
1
is cyano using the compound of Formula VI directly in the next step and if R
1
is C
1-6
alkyloxycarbonyl or C
1-6
alkylaminocarbonyl, converting the compound of Formula VI to the corresponding compound wherein R
1
is cyano; and
d) alkylating the resulting 5-cyano compound of formula VI (R
1
=CN) with 3-dimethyl-aminopropylhalogenid in basic conditions thereby obtaining 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.
A further aspect of the invention relates to the novel intermediate for preparation of citalopram of Formula VI wherein R
1
is C
1-6
alkoxycarbonyl or C
1-6
alkylaminocarbonyl.
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.
The 3-dimethylaminopropylhalogenide used may be the chloride, bromide or iodide, preferably the chloride.
The reduction of the compound of Formula IV may be performed with any convenient reducing agent, preferably by NaBH
4
in an alcohol, such as ethanol or methanol in basic conditions or with zink in aqueous acetic acid.
The ring closure of the compound of Formula V may be 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 ring closure may be 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 R
1
is an alkylaminocarbonyl group, the conversion to cyano may be performed by conventional nitril synthesis. Thus, the amide of Formula V wherein R
1
is an alkylaminocarbonyl group is preferably converted to the cyano compound, i.e. citalopram, by reaction with a dehydrating agent, most preferably thionyl chloride or phosphor pentachloride.
When R
1
is an alkyloxycarbonyl group, the conversion 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 R
1
is an alkylaminocarbonyl group.
The reaction of alkyloxycarbonyl 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 (R
1
is an alkyloxycarbonyl group) with ammonia or an alkylamine under pressure and heating. The amide obtained is converted to the cyano group as described above.
Alternatively, an ester, i.e. a compound of Formula VI wherein R
1
is an alkyloxycarbonyl group may be hydrolysed and then reacted with chlorosulfonyl isocyanate in order to form the nitrile.
The alkylation in step d) is carried out by addition of the 3-dimethylaminopropylhalogenide to the compound of formula VI (R
1
=CN) in a proper solvent, such as an ether, preferably 1,2-dimethoxyethane (DME), THF, diglyme or diethylether, in the presence of a base, preferably lithiumdiisopropylamine (LDA).
The process of the invention may be carried out with or without isolation of the intermediates.
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 may be prepared from the corresponding phthalide compound by reaction with a Grignard reagent of 4-halogen-fluorophenyl as exemplified with the magnesiumhalogenide in the following reaction scheme:
wherein R
1
is as defined above.
When R
1
is a cyano group, the starting materials of formula VII may be prepared as described in Tirouflet, J.; Bull. Soc. Sci. Bretagne 26, 1959, 35.
Other starting materials of formula IV may be prepared from 5-carboxyphtalide by reaction with thionyl chloride and then C
1-6
alkanol or C
1-6
alkylamine. 5
Bech Sommer Michael
Bøgesø Klaus Peter
Petersen Hans
Darby & Darby
Dentz Bernard
H. Lundbeck A/S
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