Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-09-09
2004-04-06
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
06717000
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-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-(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 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 also provides high yields.
SUMMARY OF THE INVENTION
The present invention relates to a method for the preparation of citalopram, comprising reduction of a compound of formula
wherein X is a cyano group, or a group which can be converted to a cyano group,
and where X is not a cyano group followed by conversion of X to a cyano group, and isolation of citalopram base or a pharmaceutically acceptable acid addition salt thereof.
In one embodiment of the invention, the compound of formula (III) may be prepared by reaction of a compound of formula
wherein X is as defined above, with a compound of formula
and if X is not cyano, optionally followed by conversion of the group X to a cyano group, thereafter dehydration to form a compound of formula (III) and if X is not cyano, optionally conversion of the group X to a cyano group.
In a second embodiment, the compound of formula (III) may be prepared by reaction of a compound of formula (I) with a compound of formula
and if X is not cyano, optionally followed by conversion of the group X to a cyano group, thereafter dehydration to form a compound of formula (III) and if X is not cyano, optionally followed by conversion of the group X to a cyano group.
In a third embodiment, the compound of formula (III) is prepared by reaction of a compound of formula (I) with a compound of formula
wherein Y is a suitable leaving group, to form a compound of formula
and if X is not cyano, optionally followed by conversion of the group X to a cyano group, thereafter peroxidation of the double bond to form an epoxide and if X is not cyano, optionally conversion of the group X to a cyano group, thereafter reaction with dimethylamine or a salt thereof followed by dehydration to form a compound of formula (III) and if X is not cyano, optionally followed by conversion of the group X to a cyano group
In another aspect, the present invention provides the novel intermediates of the general formula (III) and (V).
In yet another aspect, the present invention relates to an antidepressant pharmaceutical composition comprising citalopram manufactured by the process of the invention.
Suitable leaving groups, Y may be a halogenide or a sulphonate of formula —O—SO
2
—R
0
, wherein R
0
is alkyl, alkenyl, alkynyl or optionally alkyl substituted aryl or aralkyl. Conventionally, R
0
is methyl or p-methylphenyl.
Groups X, which can be converted to a cyano group may be selected from halogen, —O—SO
2
—(CF)
n
—CF
3
, wherein n is 0-8, —CHO, —COOR′, —CONR′R″, —NHR′″ wherein R′ and R″ are hydrogen, alkyl, alkenyl or alkynyl, or optionally alkyl substituted aryl or aralkyl and R′″ is hydrogen or alkylcarbonyl or X is an oxazoline or thiazoline group of the 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.
X may be any other group which can be converted to a cyano group.
The alkylation step where the compound of formula I is reacted with a compound of formula (IIa), (IIb) or (IIc) 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) and metalalkoxides such as NaOMe, KOMe, LiOMe, NaOtertBu, KOtertBu and 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 (IIa), (IIb) or (IIc).
The reaction of the compound of formula (I) with a compound of formula (IIa), (IIb) or (IIc) is suitably carried out under non-aqueous conditions.
The dehydration of the intermediate alcohol, formed by reaction of the compound of formula (I) with a compound of formula (IIa) or (IIb), to form a compound of formula (III) may be carried out with any suitable dehydrating agent, e.g. with p-toluenesulfonic acid in toluene or with SOCl
2
, POCl
3
, PCl
5
, mineral acids etc.
The peroxidation of the alkene double bond in a compound of formula (V) to form an epoxide may be carried out using tertBuOOH, organic peracids, dimethyldioxirane, NaOCl, I
2
/Ago, microorganisms etc. After reaction with dimethylamine or a salt thereof, the resulting compound is subjected to dehydration using any suitable dehydrating agent, e.g. with p-toluenesulfonic acid in toluene or with SOCl
2
, POCl
3
, PCl
5
, mineral acids etc.
The reduction of the compound of formula (III) is suitably carried out in presence of Pd/C, Pt/C or Rh/C as catalyst.
When X is halogen or CF
3
—(CF
2
)
n
—SO
2
—O—, wherein n is 0-8, the conversion to a cyano group may be carried out by reaction with a cyanide source, for example KCN, NaCN, CuCN, Zn(CN)
2
or (R
15
)
4
NCN, where (R
15
)
4
indicates four groups, which may be the same or different, and are selected from hydrogen and straight chain or branched alkyl, in the presence of a palladium catalyst and a catalytic amount of Cu
+ or Zn
2+
, or with Zn(CN)
2
in the presence a palladium catalyst. The conversion of a compound wherein X is halogen or CF
3
—(CF
2
)
n
—SO
2
—O—, wherein n is 0-8, by reaction with a cyanide source in presence of a palladium catalyst, may
Darby & Darby
H. Lundbeck A/S
Owens Amelia
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