Water → (-)-1-Ethoxymethyl-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine

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Reaction Conditions

Reaction Steps

Optically active dihydropyridine acid derivatives are prepared as described by T. Shibanuma, et al., Chem. Pharm. Bull., 28, 2809-2812 (1980). 2,6-Dimethyl-3,5-di(carbomethoxy)-4-(3-nitrophenyl)-1,4-dihydropyridine is prepared by the Hantzsch method (Ann. Chim., 215, 1 (1882)), then reacted with chloromethoxyethane and NaH to produce 1-ethoxymethyl-2,6-dimethyl-3,5-di(carbomethoxy)-4-(3-nitrophenyl)-1,4-dihydropyridine. Sodium (13.3 g) is added to 1-dimethylamino-2-propanol (150 mL) and the mixture stirred for 1 h. A solution of H2O (3.8 mL) in 1-dimethylamino-2-propanol (40 mL) is added dropwise, and the solution heated to dissolve any remaining sodium. A solution of 1-ethoxymethyl-2,6-dimethyl-3,5-di(carbomethoxy)-4-(3-nitrophenyl)-1,4-dihydropyridine (38 g) in benzene (190 mL) is then added with cooling to 0° C., and the mixture stirred for 3 h. The solvent is then removed by evaporation and the residue acidified to pH 2 by adding 3N HCl in a dry ice-acetone bath. The aqueous solution is then extracted with CHCl3, and the extract washed with water, dried, and concentrated to yield racemic 1-ethoxymethyl-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine. The product is then dissolved in methanol (200 mL) and cinchonidine and the solvent removed. The resulting salt is then dissolved in hot ethanol (150 mL) and allowed to stand at room temperature overnight. The crystals formed are recrystallized from EtOH, treated with 0.1N HCl, and extracted with CHCl3 to produce (-)-1-ethoxymethyl-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine (mp=134°-135°, αD22 =-16.00°). The other isomer may be recovered from the original crystallization solvent.

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