Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-09-05
2004-07-13
Dentz, Bernard (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06762308
ABSTRACT:
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.
International patent application No. WO 98/019511 discloses a process for the manufacture of citalopram wherein a (4-(cyano, alkyloxycarbonyl or alkylaminocarbonyl)-2-hydroxymethylphenyl-(4-fluorophenyl)methanol compound is subjected to ring closure. The resulting 5-(alkyloxycarbonyl or alkylaminocarbonyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran is converted to the corresponding 5-cyano derivative and the 5-cyano derivative is then alkylated with a (3-dimethylamino)propylhalogenide in order to obtain citalopram.
It has now, surprisingly, been found that citalopram may be manufactured by a novel favourable process where 5-cyano-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran is alkylated with a compound which may be converted to a dimethylaminopropyl group.
The alkylation process according to the invention is particularly advantageous because the formation of by-products by polymerisation of the alkylating agent is avoided whereby a reduction in the amount of alkylating reagent to be used is made possible. The process of the invention provides high yields.
SUMMARY OF THE INVENTION
Thus, the present invention relates to a method for the preparation of citalopram comprising reaction of a compound of formula (I)
wherein Y is a group which may be converted to cyano, 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
, —CH
2
—NMePg
1
, —CO—N(CH
3
)
2
, —CH(A
1
R
1
)(A
2
R
2
), COOR
3
, —CH
2
—CO—NH
2
, —CH═CH—R
7
or —CONHR
8
, 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 independently selected from alkyl, alkenyl, alkynyl and optionally alkyl substituted aryl and aralkyl groups or R
1
and R
2
together form a chain of 2 to 4 carbon atoms, R
3
and R
7
are independently selected from alkyl, alkenyl, alkynyl and optionally alkyl substituted aryl and aralkyl, R
8
is hydrogen or methyl and A
1
and A
2
are selected from O and S;
to form a compound of the formula
wherein R and Y are as defined above, followed by, in either order, conversion of the group R to a dimethylaminomethyl group and conversion of the group Y to a cyano group, followed by isolation of the citalopram base or a pharmaceutically acceptable acid addition salt thereof.
Thus, in one embodiment, the invention relates to a method for the preparation of citalopram wherein the compound of formula (I) is reacted with a compound of formula (II) wherein R is —CH
2
—O—Pg to form a compound of formula
wherein Y is a group which may be converted to cyano and Pg is a protection group for an alcohol group, optionally followed by conversion of the group Y to a cyano group; and thereafter removal of the protecting group to form a compound of formula
wherein Y
1
is cyano or a group which may be converted to cyano, and if Y
1
is not cyano, optionally followed by conversion of the group Y
1
to a cyano group; thereafter conversion of the alcohol group to a feasible leaving group, followed by, in either order, conversion of a group Y
1
which is not cyano to cyano, and replacement of the leaving group with a dimethylamino group by reaction with
a) dimethylamine or a salt thereof,
b) methylamine followed by methylation or reductive amination, or
c) with an azide followed by reduction to form the corresponding amine and thereafter methylation or reductive amination.
In a second embodiment, the invention relates to a method for the preparation of citalopram wherein the compound of formula (I) is reacted with a compound of formula (II) wherein R is —CO—N(CH
3
)
2
to form a compound of the formula
wherein Y is as defined above, optionally followed by conversion of the group Y to a cyano group; and thereafter reduction of the resulting compound to form a compound of formula
wherein Y
1
is cyano or a compound which may be converted to cyano, and if Y
1
is not cyano conversion of the group Y
1
in the compound of formula (VII) to a cyano group.
In a third embodiment, the invention relates to a method for the preparation of citalopram wherein the compound of formula (I) is reacted with a compound of formula (II) wherein R is —CH
2
—N(Pg
1
)(Pg
2
) to form a compound of formula
wherein Y is a group which may be converted to a cyano group and Pg
1
and Pg
2
are protection groups for an amino group, optionally followed by conversion of the group Y to a cyano group; and thereafter removal of the protecting groups to form a compound having the formula
wherein Y
1
is a cyano group or a group which may be converted to a cyano group, followed by, in either order, conversion of a group Y
1
which is not cyano to a cyano group and methylation or reductive amination of the free amino group to form citalopram.
In a fourth embodiment, the invention relates to a process for the preparation of citalopram wherein a compound of formula (I) is reacted with a compound of formula (II) wherein R is —CH(A
1
R
1
)(A
2
R
2
) to form a compound of the formula
wherein Y is a group which may be converted to a cyano group, R
1
and R
2
are independently selected from alkyl, alkenyl, alkynyl and optionally alkyl substituted aryl and aralkyl groups or R
1
and R
2
together form a chain of 2 to 4 carbon atoms, and A
1
and A
2
are selected from O and S; optionally followed by conversion of the group Y to a cyano group; and thereafter deprotection of the compound of formula (X) to form a compound of formula
wherein Y
1
is cyano or a group which may be converted to a cyano group and A
1
are as defined above, followed by, in either order, reductive amination with dimethylamine of the compound of formula (XI) and if Y
1
is not cyano, conversion of the group Y
1
to form a cyano group.
In a fifth embodiment, the invention relates to a method for the preparation of citalopram wherein a compound of formula (I) is reacted with a compound of formula (II) wherein R is —COOR
3
to form a compound of the formula
wherein Y is a group which may be converted to cyano and R
3
is selected from alkyl, alkenyl, alkynyl and optionally alkyl substituted aryl and aralkyl, optionally followed by conversion of Y to a cyano group; and thereafter
i) reduction to form an alcohol of formula
wherein Y
1
is cyano or a group which may be converted to cyano, and if Y
1
is not cyano, optionally followed by conversion of the group Y
1
to a cyano group; and thereafter conversion of the alcohol group to a feasible leaving group, followed by, in either order, conversion of a group Y
1
which is not cyano to cyano, and replacement of the leaving group with a dimethylamino group by reaction with
a) dimethylamine or a salt thereof,
b) methylamine followed by methylation or reductive amination, or
c) with an azide followed by reduction to form the corresponding amine and thereafter methylation or reductive aminatio
Darby & Darby
Dentz Bernard
H. Lundbeck A/S
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