Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-11-08
2003-12-09
Owens, Amelia (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06660873
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-isobenzofuran-carbonitrile.
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 applications 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-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 for 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
with an appropriate oxidising agent such as copper(I) and O
2
; or NiSO
4
and K
2
S
2
O
8
to afford citalopram
which is isolated as the base or a pharmaceutically acceptable salt thereof.
In another aspect, the invention relates to methods for preparing the intermediates of Formula IV.
In yet another aspect, the present invention relates to an antidepressant pharmaceutical composition comprising citalopram as the base or any convenient salt thereof manufactured by the process of the invention.
Furthermore, according to the invention, the compounds of Formula IV may be prepared by different methods.
One of these methods includes the following steps:
6-carboxy-3-(4-fluorophenyl)phthalide is reacted with an alcohol, R-OH, wherein R is preferably lower alkyl, most preferably Me, in the presence of a dehydrating agent, preferably SOCl
2
.
The resulting compound of Formula VI is alkylated with
wherein X is a leaving group in the presence of a suitable base. X is preferably halogen or sulphonate.
Optionally, the alkylating reaction is a stepwise alkylation. In this case, the resulting compound of Formula VI is alkylated with a compound having the formula
wherein X′ is a suitable leaving group and R′ is —CH
2
—O-Pg, —CH
2
-NPg
1
Pg
2
, —CO—N(CH
3
)
2
, —CH(OR
1
)(OR
2
), —C(OR
4
)(OR
5
)(OR
6
) or —COOR
3
; wherein Pg is a protection group for an alcohol group, Pg
1
and Pg
2
are protection groups for an amino group, R
1
and R
2
are alkyl groups or R
1
and R
2
together form a chain of 2 to 4 carbon atoms and R
3
, R
4
, R
5
and R
6
are alkyl, alkenyl, alkynyl, aryl or aralkyl;
to form a compound of Formula XVIII
wherein R′ is as defined above; followed by conversion of the group R′ to a dimethylaminomethyl group.
The resulting compound of Formula VII is reacted with a reducing agent such as LiAlH
4
, Red-Al, AlH
3
or activated forms of NaBH
4
, e.g. NaBH
4
, Me
2
SO
4
; NaBH
4
, I
2
; NaBH
4
, BF
3
. Et
2
O; or B
2
H
6
; followed by treatment with acid or another dehydrating agent to perform ring closure to form the compound of Formula VIII.
The alcohol of Formula VIII is conveniently activated by tosylchloride or mesylchloride to form the corresponding substituted sulphonate; or the alcohol is converted into the corresponding benzylic halide. This conversion is preferably carried out with SOBr
2
or SOCl
2
.
The corresponding sulphonate or halide is either converted directly to the compound of Formula IV by reaction with liquid ammonia;
or by a reaction with a metal salt of phthalimide, preferably potassium phthalamide followed by treatment with NH
2
NH
2
or by treatment with an amine in an alcohol, i.e. R
8
NH
2
/R
9
—OH, wherein R
8
and R
9
are lower alkyl, preferably methyl or ethyl, e.g. methylamine in ethanol;
or by a reaction with metal azide, MN
3
, M preferably being Na or K; followed by treatment with a reducing agent such as Pd/C and H
2
or a hydrate source such as LiAlH
4
or NaBH
4
or an activated form of it.
Another method for preparing the compound of Formula IV includes the following steps:
6-carboxy-3-(4-fluorophenyl)phthalide is conveniently reacted with a dehydrating agent such as thionylchloride, followed by aminolysis of the resulting activated acid derivative.
The resulting compound of Formula IX is alkylated with
wherein X is a leaving group in the presence of a suitable base. X is preferably halogen or sulphonate.
Optionally, the alkylating reaction is a stepwise alkylation analogous to the stepwise alkylation described above.
The resulting compound of Formula X is reacted with a reducing agent such as LiAlH
4
, Red-Al, AlH
3
or activated forms of NaBH
4
, e.g. NaBH
4
, Me
2
SO
4
; NaBH
4
, I
2
; NaBH
4
, BF
3
.Et
2
O; or B
2
H
6
; followed by treatment with acid or another dehydrating agent to perform ring closure to form the compound of Formula IV.
According to a third method for preparing the compound of Formula IV, the corresponding 6-cyano substituted derivative of 6-carboxy-3-(4-fluorophenyl)phthalide is prepared.
The carboxy derivative is either reacted with SOCl
2
followed by treatment with ammonia and finally a dehydrating agent such as SOCl
2
to prepare the cyano derivative of Formula XI; or reacted with an alcohol R—OH in the presence of acid followed by trea
Dancer Robert
Petersen Hans
Darby & Darby
H. Lundbeck A/S
Owens Amelia
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