Process for the preparation of dihydropyridinecarboxylic acids

Details Process for the preparation of dihydropyridinecarboxylic acids Process for the preparation of dihydropyridinecarboxylic acids

1993-08-17

1995-12-12

Ivy, C. Warren

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

546270, 546271, 546321, C07D21190

Patent

active

054751110

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP91/02476 filed Dec. 20, 1991.


AREA OF APPLICATION OF THE INVENTION

The invention relates to a novel process for the preparation of dihydropyridinecarboxylic acids. The compounds prepared according to the invention are employed as precursors in the pharmaceutical industry.


KNOWN TECHNICAL BACKGROUND

Since the fact was made known that, in the area of calcium antagonists of the 1,4-dihydropyridine type, in the case of chiral compounds one enantiomer usually has a distinctly more strongly pronounced cardiovascular action that the other, the need for a suitable, stereoselective synthesis or for a resolution into the enantiomers which also works on the industrial scale has continuously grown. This is seen in the multiplicity of publications and published patent applications, in which resolutions or enantioselective syntheses of chiral 1,4-dihydropyridinecarboxylic acid derivatives are described.
In D. Enders et al. [Tetrahedron Letters 29, 6437 (1988)], an enantioselective synthesis of 1,4-dihydropyridine is described in which the intermediate condensation with a chiral hydrazine leads to a product which is greatly enriched (84 to 98% purity) in one enantiomer. B. Lamm and R. Simonsson [Tetrahedron Letters 30, 6423 (1989)] describe the resolution of felodipine into the enantiomers with the aid of an optically active alcohol. In attempts to obtain manidipine [Drugs of the future 15, 311 (1990)] or alternatively other pharmacologically interesting 1,4-dihydropyridines [such as, e.g., YM-09730, J. Med. Chem. 29, 2504 (1986)] in optically pure form, the synthesis has usually still been carried out recently by the method described in Shibanuma et al. [Chem. Pharm. Bull. 28, 2809 (1980)], in which the monocarboxylic acid regarded as the key compound is prepared from the diester by hydrolysis using sodium 1-dimethylamino-2-propanolate and 2% water. Novel routes to corresponding monocarboxylic acids are described in International Patent Applications WO88/07524 and WO88/09931.


DESCRIPTION OF THE INVENTION

Surprisingly, a route which is particularly problem-free and can easily be used on the industrial scale for the preparation and processing of the 1,4-dihydropyridinemonocarboxylic acids described in Shibanuma et al. (see above) and regarded as key intermediates has now been found. The invention thus relates to a process for the preparation of optically pure 1,4-dihydropyridinemonocarboxylic acids of the formula I ##STR2## in which R1 denotes 1-4C-alkyl, 2-nitrophenyl, 3-nitrophenyl, benzoximidazolyl (4-benzofurazanyl), 2-trifluoromethylphenyl, 2,3-methylenedioxyphenyl or 2-difluoromethoxyphenyl radical, or 2-nitrophenyl, 3-nitrophenyl, benzoximidazolyl (4-benzofurazanyl), 2-trifluorobenzoimidazolyl (4-benzofurazanyl), 2-trifluoromethylphenyl, 2,3-methylenedioxyphenyl or 2-difluoromethoxyphenyl radical and
The process in a first aspect comprises hydrolysing a compound of the formula II ##STR3## in which R1, R2, R3, A and B have the abovementioned meanings, in an alcohol R1--OH using aqueous alkali metal hydroxide and resolving the resultant acid III ##STR4## into the enantiomers in the customary manner. In a further aspect, the process comprises employing the undesired enantiomer, after ester formation with the compound R1--X in which R1 has the abovementioned meaning and X represents a leaving group or a halocarbonyloxy group, again as the starting compound II.
1-4C-alkyl represents methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl and tert-butyl. Preferred 1-4C-alkyl radicals R1 are isobutyl, isopropyl and in particular ethyl and methyl. Preferred 1-4C-alkyl radicals R2 are ethyl and methyl. A preferred 1-4C-alkyl radical R3 is ethyl.
The hydrolysis in the alcohol R1--OH is advantageously carried out at a dilution ratio (compound II:alcohol) of 1:3 to 1:40, preferably 1:5 to 1:10.
A suitable aqueous alkali metal hydroxide is in particular 0.3- or 10-molar, preferably 0.5- to 2-molar, sodium hydroxide solution or potassium hydroxide solution, where--relative to the

REFERENCES:
patent: 4769465 (1988-09-01), Antoncic et al.
Chemistry of heterocyclic compounds, vol. 14, No. 2, Feb. 1978, p. 225.
Chem. Pharm. Bull. vol. 28, No. 9, 1980, pp. 2809-2812.
Chem. Pharm. Bull 37(8), 1989, pp. 2225-2228.

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