Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
1999-11-12
2002-01-01
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C548S333500, C514S323000
Reexamination Certificate
active
06335463
ABSTRACT:
This Application is a 371 PCT/DK98/00183 filed May 7, 1998 which claims benefit of Provisional application Ser. No. 60/046,011, filed May 9, 1997.
BACKGROUND OF THE INVENTION
Sertindole is a well known antipsychotic drug having the formula
The compound was disclosed in U.S. Pat. No. 4,710,500 and the antipsychotic activity thereof was described in U.S. Pat. No. 5,112,838. Sertindole is a potent centrally acting 5-HT
2
receptor antagonist in vivo and has further been disclosed to be active in models indicative of effects in the treatment of anxiety, hypertension, drug abuse and cognitive disorders. Recently, it has been reported to show antipsychotic effect in clinical studies,
Psychopharmacology
(1996) 124:168-175.
U.S. Pat. No. 4,710,500 covered a class of 1-aryl-3-(piperazinyl-, tetrahydropyridyl or piperidyl)indole compounds including sertindole. A number of methods of preparing the compounds were generically disclosed, some of which could be used in the preparation of sertindole. The methods were:
a) reaction of a properly substituted 1-arylindole with a proper 1-substituted 4-piperidone and subsequent reduction of the resulting tetrahydropyridyl compound;
b) arylation of the corresponding 1-unsubstituted indole compound;
c) reduction of the corresponding compound having an oxo group in the 2-position of the indole ring.
Sertindole was specifically exemplified, however, no experimental procedure for its preparation was given.
Perregaard et al.,
J Med. Chem
, 1992, 35, 1092-1101, disclosed a new method of preparing sertindole. This method comprises reaction of the intermediate 5-chloro-1-(4-fluorophenyl)indole with 4-piperidone in a mixture of trifluoroacetic acid and acetic acid, reduction of the resulting 5-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)indole in order to obtain 5-chloro-1-(4-fluorophenyl)-3-(piperidin-4-yl)indole which in turn is reacted with 1-(2-chloroethyl)-2-imidazolidinon in the presence of K
2
CO
3
and KI in methyl isobutyl ketone (MIBK). The 5-chloro-1-(4-fluorophenyl)indole was obtained from the corresponding 3-acetoxy-indole by NaBH
4
reduction in methanol and subsequent elimination of H
2
O under acidic conditions. The 3-acetoxy-indole was prepared from the N-(4fluorophenyl)-N-(2-carboxy-4-chlorophenyl)glycine following literature procedures.
A procedure for preparing the N-(4fluorophenyl)-N-(2-carboxy-4-chlorophenyl)glycine is described in Perregaard et al.,
Dansk Kemi
, 95, 3. p. 6-9. By this method the glycine is obtained by a copper catalyzed reaction of 2,5-dichlorobenzoic acid with N-(4-fluorophenyl)glycine. The potassium salts of the two acids are used in the presence of K
2
CO
3
in the solvent N-methylpyrrolidone (NMP).
However, it has been found that the above processes are not useful in technical scale. The total yields are too low and the processes involve the use of reactants or solvents that are not suitable and in some cases not allowed in large scale for environmental or safety reasons. Furthermore, due to the aqueous solubility of NMP, the work-up of the reaction is tedious, and regeneration of NMP is costly and time consuming.
Consequently, the present invention relates to a new process useful in technical scale production of sertindole.
It has now been found that the main limiting steps of the process are the preparation of N-(4-fluorophenyl)-N-(2-carboxy-4-chlorophenyl)glycine and the reaction of 5-chloro-1 -(4-fluorophenyl)indole with 4piperidone.
Accordingly, the present invention provides a process for the preparation of N-(4-fluorophenyl)-N-(2-carboxy-4chlorophenyl)glycine comprising reaction of an alkalimetal salt of 2,5-dichlorobenzoic acid with an alkalimetal salt of N-(4-fluorophenyl)glycine in an aqueous, alkaline environment in the presence of a copper catalyst followed by treatment with an aqueous acid, as illustrated in the following reaction scheme:
wherein M, and M
2
are alkali metal ions.
According to Perregaard et al.,
Dansk Kemi
, 95, a reaction using the potassium salts of the reactants is carried out in NMP. However, the use of NMP necessitated a time consuming extractive work-up, and the reaction afforded substantial amounts of tarry by-products. The reaction temperature was 120-130° C.
By carrying out the reaction in aqueous environment instead of NMP, a higher yield and only a negligible amount of tarry by-products are obtained. Furthermore, the work-up procedure is simple and the use of an aqueous medium causes substantial environmental advantages. Finally, the reaction temperature is lowered to the reflux temperature of the aquous medium or below.
In another aspect the invention provides a novel process for preparing 5-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)indole comprising reaction of the 5-chloro-1-(4-fluorophenyl)indole with 4-piperidone in a mixture of a mineral acid and acetic acid, as illustrated in the following reaction scheme:
By using a mixture of acetic acid and a mineral acid instead of a trifluoroacetic acid-acetic acid mixture, substantial environmental advantages are obtained. Furthermore, trifluoro acetic acid is very volatile and aggressive, accordingly being undesirable for large scale production. Also, the formation of the undesired bis-substituted piperidine may be avoided:
In yet another aspect, the invention provides a novel process of manufacturing sertindole comprising preparation of N-(4fluorophenyl)-N-(2-carboxy4-chlorophenyl)glycine by a reaction comprising a copper catalysed reaction of an alkalimetal salt of 2,5-dichlorobenzoic acid with an alkali metal salt of N-(4-fluorophenyl)glycine in an aqueous, alkaline environment in the presence of a copper catalyst and/or in which 5-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)indole is obtained by a reaction comprising reaction of the 5-chloro-1-(4-fluorophenyl)indole with 4-piperidone in a mixture of a mineral acid and acetic acid.
The reaction of the alkalimetal salt of 2,5-dichlorobenzoic acid with the alkalimetal salt of N-(4-fluorophenyl)glycine is carried out at an elevated temperature, conveniently at a temperature between 80° C. and the reflux temperature of the medium, preferably at about the reflux temperature. Throughout the specification and claims the term aqueous medium is intended to include water and water to which a cosolvent such as ethyleneglycol is added as reaction medium. Preferably water such as demineralised, deionised or destined water is used.
Preferred alkali metal salts of the reactants are the lithium, sodium or potassium salts and conveniently the same salts of the reactants are used. Most preferably the potassium salts are used.
It is important that the HCl formed during the reaction is neutralised in order to avoid undesired side reactions. The reaction medium is made alkaline by addition of a base such as an alkali metal hydroxide, alkali metal acetate, alkali metal carbonate, alkali metal hydrogen carbonate, alkali metal phosphate or alkali metal citrate. Preferably an alkali metal carbonate, such as Li
2
CO
3
, Na
2
CO
3
or K
2
CO
3
, is used. Conveniently, the same alkali metal as included in the reactants is used. Preferably the base is potassium carbonate. The amount of base is preferably larger than the stoechiometric amount of 2,5-dichlorobenzoic acid. On the other hand, increased [OH] may cause hydrolysis of 2,5-dichlorobenzoic acid, thereby decreasing the yield. Thus, the base may conveniently be added gradually during the process.
The catalyst may be any Cu(0)-catalyst, preferably copper-bronze. It is added in catalytic amounts. The specific amount is not critical and may easily be determined by a person skilled in the art.
The ratio between the amounts of the alkali metal salt of N-(4-fluorophenyl)glycine and the alkali metal salt of 2,5-dichlorobenzoic acid is conveniently from 0.5 to 3.0, preferably 1.0 to 2.5 and most preferably 2.0 to 2.3 mol/mol. Excess N-(4-fluorophenyl)glycine may be regenerated.
The reaction is conveniently carried out in a minimal amount of aqueous solvent still technically feasible. Thus
H. Lundbeck A/S
Killos Paul J.
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