Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-02-26
2002-07-16
Owens, Amelia (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C514S469000
Reexamination Certificate
active
06420574
ABSTRACT:
The present invention relates to a method for the preparation of the well-known antidepressant drug citalopram,1-[3-(dimethylamino)propyl]-1-(4fluorophenyl)-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 2,657,013 , 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-(4fluorophenyl)-1,3dihydro-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 alkylamninocarbonyl)-2-hydroxymethylphenyl-(4-fluorophenyl)methanol compound is subjected to ring closure. The resulting 5-(alkyloxycarbonyl or alkylaminocarbonyl)-1-(4fluorophenyl)-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 used is made possible. In addition, the process of the invention provides high yields.
SUMMARY OF THE INVENTION
The present invention relates to a method for the preparation of citalopram comprising reaction of a compound of formula (I)
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(OR
1
)(OR
2
), —C(OR
4
)(OR
5
)(OR
6
), —COOR
3
, —CH
2
—CO—NH
2
, —CH═CHR
7
or —CO—NHR
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 or aralkyl groups or R
1
and R
2
together form a chain of 2 to 4 carbon atoms, R
3
, R
4
, R
5
, R
6
and R
7
are independently selected from alkyl, alkenyl, alkynyl and optionally alkyl substituted aryl or aralkyl and R
8
is hydrogen or methyl; to form a compound of the formula
wherein R is as defined above; followed by conversion of the group R to a dimethylaminomethyl group and isolation of citalopram in the form of the base or as a pharmaceutically acceptable salt thereof.
In a first embodiment of the invention, the compound of formula (I) is reacted with a compound of formula (II) wherein R is —CH
2
—O—Pg, wherein Pg is a protection group for an alcohol group, followed by removal of the protection group to form the corresponding alcohol of the formula
The alcohol group is then converted to a feasible leaving group such as halogen or —O—SO
2
—R
0
wherein R
0
is alkyl, or optionally alkyl substituted aryl or aralkyl, and the resulting compound is then
a) reacted with dimethylamin or a metal salt thereof to form citalopram,
b) reacted with methylamin to form a compound of formula (XII) below followed by reductive amination to form citalopram, or
c) reacted with an azide followed by reduction to form the corresponding amino compound of formula (VI) below and thereafter methylation or reductive amination to form citalopram.
In a second embodiment, the compound of formula (I) is reacted with a compound of formula (II) wherein R is —CO—N(CH
3
)
2
, followed by reduction of the resulting compound of the formula
to form citalopram.
In a third embodiment, the compound of formula (I) is reacted with a compound of formula (II) wherein R is —CH
2
—N(Pg
1
)(Pg
2
) where Pg
1
or Pg
2
are protection groups for an amino group and thereafter removal of the protection groups to form a compound of formula
followed by methylation of the free amino group or reductive amination to form citalopram.
In a fourth embodiment, citalopram may be prepared by reaction of a compound of formula (I) with a compound of formula (II) wherein R is —CH(OR
1
)(OR
2
) or —C(OR
4
)(OR
5
)(OR
6
) where R
1
, R
2
, R
4
, R
5
and R
6
are as defined above to form a compound of the formula (VII
a
) or (VII
b
)
wherein R
1
, R
2
, R
4
, R
5
and R
6
are as defined above, followed by deprotection of the compound of formula (VII
a
) or (VII
b
) and consecutively reductive amination of the resulting aldehyde with dimethylamin to form citalopram.
In a fifth embodiment, citalopram may be prepared by reaction of a compound of formula (I) with a compound of formula (II) wherein R is —COOR
3
and R
3
is as defined above to form a compound of the formula
wherein R
3
is as defined above, which is then converted to an amide of formula (V) or an alcohol of formula (IV) which is converted to citalopram as described above.
In a sixth 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 —CH
2
—CONH
2
to form a compound of formula
which is treated with hypohalide to form a compound of formula
followed by methylation of the free amino group or reductive amination to form citalopram.
In a seventh embodiment, the invention relates to a method for the preparation of citalopram by reaction of a compound of formula (I) with a compound of formula (II) wherein R is —CH═CHR
7
to form a compound of formula
wherein R
7
is as defined above, which is oxidised to form a compound of formula
followed by reductive amination with dimethylamin to form citalopram.
In a eight embodiment, the invention relates to a process for the preparation of citalopram wherein the compound of formula (I) is reacted with a compound of formula (II) wherein R is —CH
2
—Me(Pg
1
) followed by removal of the protection group to form a compound of formula
and thereafter methylation of the amino group or reductive amination to form citalopram.
In a final 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—NHR
8
wherein R
8
is hydrogen or methyl, followed by reduction of the resulting compound of the formula
wherein R
8
is as defined above, to form a compound of formula
wherein R
8
is as defined above, followed by methylation or reductive amination to form citalopram.
In another aspect, the present invention provides the novel intermediates of the general formula (III), (IV), (VI), (XI) and (XII).
In yet another aspect, the present invention relates to an antidepressant pharmaceutical composition comprising citalopram manufactured by the process of the invention.
The alkylation step where the compound of formula (I) is reacted with a compound of formula (II) is suitably carried out by treatment of the compound of formula (I) with a base such as for example LDA ( lithiumdiisopropylamine), LiHMDS (hexamethyldisilasan lithium), N
Ahmadian Haleh
Petersen Hans
Rock Michael Harold
Darby & Darby
H. Lundbeck A/S
Owens Amelia
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