Process for preparing heterocyclic derivatives

Abstract: A process for the preparation of compounds of formula (I) in which R₁ and R₄ independently represent a C₁₋₄ alkyl group, R₂ and R₃ independently represent a straight or branched C₁₋₆ alkyl chain optionally interrupted by an oxygen atom; and R₅ represents a straight or branched chain C₁₋₁₃ alkyl group or a C₅₋₈ cycloalkyl group optionally substituted by C₁₋₃ alkyl; which comprises esterification of an acid of formula (II) wherein the groups R₁, R₂, R₃ and R₄ have the meanings given above in formula (I) by reaction with an amide acetal capable of introducing the group R₅.

Description: This invention relates to a novel process for preparing dihydropyridine derivatives useful in the treatment of cardiovascular disorders. United Kingdom Published Specification GB 2164336A describes compounds of formula (I) wherein R 1 and R 4 independently represent C 1 - 4 alkyl; R 2 and R 3 independently represent a straight or branched C 1 - 6 alkyl chain optionally interrupted by an oxygen atom; and R 5 represents a tertiary butyl group. The group CH=CHCO 2 R 5 in the compounds of formula (I) can exist in the cis (Z) or the trans (E) configuration and formula (I) is intended to refer to the (Z) end (E) forms individually as well as to mixtures of the two forms. The compounds are useful for the treatment of cardiovascular disorders such as hypertension, angina pectoris, myocardial ischaemia, congestive heart failure, cerebral vascular and peripheral disorders. A number of process for preparing the compounds of formula (I) are described in UK Specification GB 2164336A, including esterification of the corresponding acid of formula (I) in which R 5 represents a hydrogen. More particularly the specification teaches that the esterification may be effected by treating a compound of formula (I) in which R 5 is a hydrogen atom with an alkylating agent R 5 X where R 5 is as defined in formula (I) and X is a leaving group such as a chloride, bromide, iodide or mesylate. Alternatively the specification teaches that the esterification may be carried out by converting the acid corresponding to the compound of formula (I) into an activated derivative thereof such as a mixed anhydride which is then reacted with an alcohol R 5 OH or the corresponding alkoxide thereof in which R 5 is as defined in formula (I). We have now found that the compounds of formula (I) may be advantageously prepared by reacting the corresponding acid of formula (II) with an appropriate amide acetal of the general formula R a R b NCR c (OR 5 ) 2 (III) in which R 5 is as defined in formula (I) and R a and R b independently represent a C 1-4 alkyl group or together they form a stright alkylene chain containing 4 to 6 carbon atoms or the group (CH 2 ) 2 O(CH 2 ) 2 -; R c represents a hydrogen atom, a C 1-3 alkyl group or R a and R c are linked together to form an alkylene chan containing 3 to 5 carbon atoms. This process has the particular advantage of giving the required ester in good yield. The invention therefore provides a process for the preparation of compounds of formula (I) in which the groups R 1 , R 2 , R 3 , R 4 and R 5 have the meanings given above, which comprises esterification of an acid of formula (II) in which the groups R 1 , R 2 , R 3 and R 4 have the meanings defined above in formula (I) by reaction with said amide acetal capable of introducing the group R 5 . Particularly preferred acetals are those in which R a and R b are C 1-3 alkyl, especially methyl and R c represents hydrogen. The reaction is conveniently carried out in an asprotic solvent such as a hydrocarbon e.g. benzene or toluene, a halohydrocarbon such as methylene chloride, acetonitrile or dimethylformamide and preferably with heating e.g. 40-120°C. The acetals of formula (III) are either known compounds or can be prepared by analogous methods to those described for the known compounds. The process of the present invention is particularly useful for the preparation of compounds of formula (I) wherein R 1 and R 4 represents methyl, R 2 and R 3 independently represent C 1-4 alkyl e.g. methyl, ethyl, isopropyl or isobutyl or ethyl substituted by C 1-3 alkoxy e.g. methoxy or propoxy and R 5 represents a tertiary butyl group. A specific compound which may be conveniently prepared by the processes of the present invention is (E)-4-(2-(3-(1,1-dimethylethoxy)-3-oxo-1-propenyl)phenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedi- carboxylic acid, diethyl ester. The acids of formula (II) may be prepared by the process described in UK Specification GB 2164336A. More advantageously however the acids of formula (II) and more particularly the E isomers thereof, may be prepared in good yield from the reaction compound of formula (IV). wherein R 1 and R 2 are as previously defined; X 1 represents a halogen atom e.g. chlorine, bromine or iodine and R 6 is a hydrogen atom or a carboxyl protecting group, with an amino ester (V), with subsequent deprotection as appropriate. The reaction is conveniently carried out in a suitable solvent such as an alkanol e.g. ethanol or isopropanol, in the presence of a base, such as a trialkylamine e.g. triethylamine and preferably with heating e.g. 40-150°C. If the carboxyl protecting group R 6 is not cleaved under the conditions of the reaction then this may be subsequently removed by conventional procedures. Examples of suitable protecting groups include C 1-6 alkyl e.g. tertiary butyl, tetrahydropyranyl, tetrahydrofuranyl, trimethylsilyl, or activated methyl esters such as phthalimidomethyl, benzyloxymethyl or methoxyethoxymethyl groups. Preferably the reaction is carried out using a haloketoester of formula (IV) where X represents chlorine and the group R 6 represents a C 1-6 alkyl group, conveniently a tertiary butyl group. The haloketoester (IV) may be prepared from the reaction of the aldehyde (VI) wherein R 6 is as defined above, with the ketoester (VII) wherein R 1 and R 2 are as defined above in the presence of the appropriate hydrogen halide (HX). The reaction is conveniently carried out in a suitable non-aqueous solvent such as a hydrocarbon e.g. benzene, toluene or xylene. The reaction may be carried out at a temperature within the range -30° to 100°, more preferably between -10° to 30°C. The aldehyde (VI) and the ketoesters (VII) are either known compounds or may be prepared by analogous methods to those described for the known compounds. The following examples illustrate the invention. Throughout the examples reference to t.l.c. means thin layer chromatography on silica plates (Merck 60F-254). Intermediate 1 (E)-2-(α-Chloro-2-(carboxyethenyl)phenylmethyl)-3-oxo-butanoic acid, ethyl ester A mixture of 2-formylcinnamic acid (0.76g) and ethyl acetoacetate (0.56g) in toluene was treated with HCl gas, at 0°C, for 15 minutes, then was left standing with sealing at room temperature for 20 hrs. The solid was collected by filtration, washed quickly with toluene, then with petrol and dried in vacuo over P 2 O 5 . The title compound was obtained as a white solid (0.9g). m.p. 171-173°C. T.l.c. (methylene chloride/methanol, 9:1) Rf. = 0.53 Intermediate 2 (E)-4-(2-(2-Carboxyethenyl)phenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid, diethyl ester A solution of Intermediate (1) (1.4g), ethyl 3-aminocrotonate (0.57g) and triethylamine (0.88g) in isopropanol (10ml) was refluxed for 18 hrs. The solvent was evaporated and the residue taken up with water and made alkaline with potassium bicarbonate. The mixture was washed with ethyl acetate, then treated with 10% HCl (pH 2-3) and extracted with ethyl acetate. The organic phase was washed with water, dried over MgSO 4 and the solvent evaporated to give a solid, which was recrystallised from petrol ether/ethyl acetate (1:1). The title compound was obtained as a white solid (1.4g). m.p. 175-180°C (dec.) T.l.c. (Methlene chloride/ethyl acetate/acetic acid, 8:2:1) (Rf = 0.4) Example 1 (E)-4-(2-(3-(1,1-Dimethylethoxy)-3-oxo-1-propenyl)phenyl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester The compound of Intermediate 2 (1g) was suspended in toluene (10ml) and stirred at 80°C N,N-dimethylformamide di-tert-butyl acetal (4g) was added dropwise to the mixture at 80°C, in 15 minutes. The solution was stirred at 80°C for 4 hrs, then cooled, washed with water, sodium bicarbonate 5%, brine and dried over sodium sulphate. The solvent was evaporated and the residue (1.5g) was eluted on a silica gel column (ethyl acetate/cyclohexane, 7:3) to give the title compound as a white solid, (1g). m.p. 173-175°C T.l.c. (Methylene chloride/ethyl acetate, 9:1) Rf. = 0.40.

Claims: A process for the preparation of compounds of formula (I) in which R 1 and R 4 each represent a methyl group, R 2 and R 3 each represent an ethyl group and R 5 represents a tertiary butyl group; which comprises esterification of an acid of formula (II) wherein the groups R 1 , R 2 , R 3 and R 4 have the meanings given above in formula (I) by reaction with an amide acetal of the general formula R a R b NCR 2 (OR 5 ) 2 (III) in which R 5 is as defined in formula (I) and R a and R b independently represent a C 1-4 alkyl group or together they form a straight alkylene chain containing 4 to 6 carbon atoms or the group -(CH 2 ) 2 O(CH 2 ) 2 -; R c represents a hydrogen atom, a C 1-3 alkyl group or R a and R c are linked together to form an alkylene chain containing 3 to 5 carbon atoms. A process as claimed in claim 1 using an amide acetal of formula (III) in which the groups R a and R b independently represent a C 1-3 alkyl group. A process as claimed in claims 1 or 2 using an amide acetal of formula (III) in which the groups R a and R b each represent a methyl group. A process as claimed in any of claims 1 to 3 using an amide acetal of formula (III) in which the group R c represents a hydrogen atom. A process as claimed in any of claims 1 to 4 in which the reaction is carried out in an aprotic solvent. A process as claimed in any of claims 1 to 5 in which the reaction is carried out in a hydrocarbon solvent. A process as claimed in any of claims 1 to 6 in which the reaction is carried out with heating. A process as claimed in any of claims 1 to 7 for preparing the E-isomer of the compound of formula (I).

Inventors: PIERACCIOLI DANIELE, PIERACCIOLI, DANIELE
Applicants: GLAXO WELLCOME SPA, GLAXO WELLCOME S.P.A.
Application year: 1989
Main classification: C07D211
IPC codes: C07D211