Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-09-06
2004-10-19
Owens, Amelia A. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S469000
Reexamination Certificate
active
06806376
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.
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 alkylaminocarbony)-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 a 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
The present invention relates to a method for the preparation of citalopram comprising subjecting, in either order, a compound of formula
wherein Y is a cyano group or a group which may be converted to a cyano group, R is hydrogen, —O—R
1
, NH
2
, NHCH
3
or —N(CH
3
)
2
wherein R
1
is selected from hydrogen, alkyl, alkenyl, alkynyl and optionally alkyl substituted aryl or aralkyl; to
i) reduction of the double bond in the side chain of formula —CH═CH—COR; and
ii) conversion of the group —COR or a reduced form thereof to a dimethylaminomethyl group; and
iii) if Y is not cyano, conversion of the group Y to a cyano group;
followed by isolation of citalopram base or a pharmaceutically acceptable acid addition salt thereof. The conversions mentioned under i), ii) and iii) above may be carried out in any order.
In a particular embodiment of the invention, the reduction of the double bond mentioned under i) above is carried out before the group —COR or a reduced form thereof is converted to a dimethylaminomethyl group as under ii) above.
Conversion of the group Y to a cyano group may be carried out at any suitable point during the reaction. In a particular embodiment, the compound of formula (III) used is a compound wherein Y is cyano.
According to a preferred embodiment of the invention, the compound of formula (III) is prepared by reaction of a compound of formula
wherein Y is a cyano group or a group which may be converted to a cyano group, with a compound having the formula
wherein R is hydrogen, —O—R
1
, —NH
2
, —NHCH
3
, —N(CH
3
)
2
wherein R
1
is selected from h alkyl, alkenyl, alkynyl, and optionally alkyl substituted aryl or aralkyl; to form a compound of formula (III).
In another aspect, the present invention provides the novel intermediates of the general formula (III).
In yet another aspect, the present invention relates to an antidepressant pharmaceutical composition comprising citalopram manufactured by the process of the invention.
The group Y which may be converted to a cyano group may be selected from halogen, —O—SO
2
—(CF
2
)
n
—CF
3
, wherein n is 0-8, —CHO, —COOR′, —CONR′R″ or —NHR′″ wherein R′ and R″ is selected from hydrogen, alkyl, alkenyl, alkynyl or optionally alkyl substituted aryl or aralkyl and R′″ is hydrogen or alkylcarbonyl, or Y is a group of formula
wherein U is O or S;
R
12
-R
13
are each independently selected from hydrogen and alkyl, or R
12
and R
13
together form a C
2-5
alkylene chain thereby forming a spiro ring; R
10
is selected from hydrogen and alkyl, R
11
is selected from hydrogen, alkyl, a carboxy group or a precursor group therefore, or R
10
and R
11
together form a C
2-5
alkylene chain thereby forming a spiro ring. Y may be any other group, which may be converted to a cyano group.
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), NaH, NaHMDS (hexamethyldisilasan sodium) or metalalkoxides such as NaOMe, KOMe, LiOMe, NaOtertBu, KOtertBu or LiOtertBu in an aprotic organic solvent such as THF (tetrahydrofuran), DMF (dimethylformamide), NMP (N-methylpyrrolidon), ethers such as diethylether or dioxalane, toluene, benzene, or alkanes and mixtures thereof. The anion formed is then reacted with a compound of formula (II) whereby a group of formula —CH═CH—COR is introduced into position 1 of the isobenzofuranyl ring system.
Compounds wherein the group —COR is —CON(CH
3
)
2
may be converted to the corresponding compound wherein this group is a dimethylaminomethyl group by reduction, suitably in toluene using Red-Al as a reducing agent
When —COR is —CONHCH
3
or —CONH
2
, conversion to the dimethylaminomethyl group may be carried out by, in either order, reduction to form an amine and methylation or reductive amination form a dimethylaminomethyl group.
The reduction of the amide may be carried out in toluene using Red-Al as a reducing agent.
The methylation of the amine may be carried out with methylating agents such as MeI or Me
2
SO
4
, wherein Me is methyl. The methylation is carried out using conventional procedures for carrying out such reactions.
Alternatively, methylation to form a dimethylaminomethyl group is carried out by reductive amination. According to this procedure, the compound carrying a —NH
2
or a —NHCH
3
group is reacted with compounds such as formaldehyde, paraformaldehyde or trioxane in presence of a reducing agent such as NaBH
4
or NaBH
3
CN. The reductive amination is carried out using conventional procedures for carrying out such reactions.
When R is —CHO, conversion to the dimethylaminomethyl group may be carried out by reductive amination with dimethylamine or a salt thereof. Suitably by reaction with dimethylamine in the presence of a reducing agent such as NaBH
4
or NaBH
3
CN. Dimethylamine may be added to the reaction in the form of the dimethylammonium chloride salt or as a metal salt of dimethylamine.
When R is —COOR
1
, the conversion to the dimethylaminomethyl group may be carried out by conversion to the corresponding amide followed by reduction, and optionally methylation or reductive amination to form a dimethylaminomethyl group.
The amide may be prepared by reaction of the ester with an amine, preferably NH(Me)
2
or a salt thereof.
When R is —COOR
1
, the conversion of this group to the dimethylaminomethyl group may also be carri
Darby & Darby
H. Lundbeck A.S
Owens Amelia A.
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