Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-06-25
2002-06-18
Dentz, Bernard (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C558S044000, C558S058000, C558S415000
Reexamination Certificate
active
06407267
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.
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 2,657,271, 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 11 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-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 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 comprising reaction of a compound of Formula IV
wherein R is C
1-6
alkyl, acyl, C
1-6
alkylsulfonyl or arylsulfonyl, with 3-(N, N-dimethylamino)-propyl magnesium halide, preferably of 3-(N,N-dimethylamino)propyl magnesium chloride to afford 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 IV.
In a further aspect, the invention relates to methods for preparing the intermediates of Formula IV.
In yet another aspect of the invention, the compounds of Formula IV are used for the preparation of the racemic compound of Formula III.
In yet another aspect, the present invention relates to an antidepressant pharmaceutical composition comprising citalopram manufactured by the process of the invention.
By the process of the invention, citalopram is obtained by a single step Grignard reaction from the compounds of Formula IV, wherein R is C
1-6
alkyl, acyl, C
1-6
alkylsulfonyl or arylsulfonyl
Surprisingly, the product of the Grignard reaction ring closes spontaneously and directly to citalopram, and accordingly the reaction of compound of Formula IV with the Grignard reagent leads to citalopram in one step.
Furthermore, according to the invention the compounds of Formula IV may be prepared by three different methods.
One of these methods includes protection of the hydroxymethylalcohol of (4-cyano-2-hydroxymethylphenyl)(4-fluorophenyl)methanol of Formula VI:
followed by an oxidation to afford the compounds of Formula IV, wherein R is C
1-6
alkyl, acyl, C
1-6
alkylsulfonyl or arylsulfonyl.
The oxidation of the compounds of Formula V, may be performed by any convenient oxidation agent, preferably performed by Na
2
WO
4
.
The starting material of the compound of Formula VI may be prepared as described in International Patent Application No. PCT/DK97/00511.
Another method for preparing the compounds of Formula IV includes the reaction of 5-cyanophthalide with 4-fluorophenylmagnesiumhalide, preferably 4-fluorophenyl-magnesiumbromide followed by the reaction with R-X, wherein R is as defined above and X is a leaving group, preferably R-X is pivaloylchloride, 3,5-dimethoxybenzoylchloride, methyliodide, ethylbromide, tosyichloride, Me
2
SO
4
or MeSO
2
Cl.
The reaction is illustrated below:
The starting material, 5-cyanophthalide, may be prepared as described in Tirouflet, J.; Bull.Soc.Sci. Bretagne 26, 1959,35.
According to the third method for preparing the compound of Formula IV, one of the enantiomers of the compound of Formula III, i.e. the R-enantiomer, is subjected to protection and dehydration to give the compound of Formula VII, which is oxidised to give the ketone of Formula IV.
In this way, the R-enantiomer of Formula III may be used in the preparation of racemic citalopram.
The oxidative cleavage of the compound of Formula VII is effected by oxidation, preferably performed by MnO
4
−
(permanganates), or ozone, RuCl
3
, OsO
4
.
Citalopram is on the market as an antidepressant drug in the form of the racemate. However, in the near future the active S-enantiomer of citalopram is also going to be introduced to the market.
The active S-enantiomer of citalopram may be prepared from the compound of Formula III by separation of the S-enantiomer and the R-enantiomer followed by ring closure of the S-enantiomer as described in U.S. Pat. No. 4,943,590. The R-enantiomer of the compound of Formula III has previously not been used after separation.
Furthermore, according to a further aspect of the invention, after conversion of the R-enantiomer of Formula III to the non-optically active compound of Formula IV, the racemic compound of Formula III may be prepared as illustrated below:
The racemic compound of Formula III may be separated into the optically active enantiomers by the procedure described in U.S. Pat. No. 4,943,590 thereby obtaining the S-enantiomer of the compound of Formula III, which is used in the preparation of S-citalopram. The R-enantiomer of the compound of Formula III can be recycled once more in the process cycle described above.
In this way, the R-enantiomer of Formula III may be converted to S-citalopram.
Other reaction conditions, solvents, etc. for the reactions described above are conventional conditions for such reactions and may easily be d
Ellegaard Peter
Petersen Hans
Rock Michael Harold
Dentz Bernard
H. Lundbeck A/S
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