Synthesis Of The New Calcium Antagonits Nilvadipine

In this paper, the present situation of application and classfication of pharmaceutical for treatment of hypertesion were introduced. Calcium antagonists has been accepted for the treatment of cardiovascular diseases in clinical. It has many predominace such as the better for decreasing of blood pressure, high selectivity for distal blood vessel, and no side affection for all kinds of metabolism, small taboo symptom and affection for vascular expand etc.. Nilvadipine is the second generation of dihydropyridine calcium antagonists. Its cohesion with the special location of calcium ion is 10 times stronger than previous Nifeddipine and affect lasting 2 to 3 times longer than that. The blood pressure decreasing can be maintained well for 24 hours because of its steady pharmceutical concentrationin blood. So Nilvadipine is a safe, efficacious and first-selective pharmceutical in treatment of hypertension. Therefor it has a wild potential in the market.The synthesis process of Nilvadipine and its five intermediates were designed. The optimum reaction conditions were obtained as followry:(1) A new process has been developed to synthesize dimethoxyacetic acid methyl ester with the 50% solution of glyoxylic acid and methylorthoformate in the presence of concentrated sulfuric acid. The reaction conditions have been optimized by orthogonal experimental design. The yield of dimethoxyacetic acid methyl ester was to 92.16%.(2) A new process has been developed to synthesize dimethoxy methyl aceto acetate with dimethoxyacetic acid methyl ester and methyl acetate in the presence of sodium methanol. On the basis of investigating effects of the mole ratio of raw material, amount of catalyst, reaction temperature and time, the optimum reaction conditions were obtained by using uniform design, and the yield of dimethoxy methyl aceto acetate was to 43.56%.(3) A new process has been developed to synthesize mehtyl 2-(3-nitrobenzyliene)-4,4-dimethoxyacetoacetate with dimethoxy methyl aceto acetate and 3-nitrobenzal dehyde in the presence of piperidine and acetic acid ylacial. The effects of the mole ratio of raw material, the amount and feeding method of catalyst, reaction time on the yield were investigated. The optimum reaction conditions were obtained. The rate of production of methyl 2-(3-nitrobenzyliene)-4,4-dimethoxyacetoacetate was to 112.30%, which was used in the following reaction without purification.(4) A new process has been developed to synthesize 2,2-dimethoxyme-thyl-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-methyl 5-(l-methylethyl) diester with methyl 2-(3-nitrobenzyliene) -4,4-dimethoxyacetoacetate and 3-aminocaotonic acid isproxycarbonyl ester. The optimum reaction conditions were obtained by investigating effects of the mole ratio of raw material, reaction temperature and time on the yield. The yield of 2,2-dimemoxymethyl-ls4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-methyl 5-(l-methylethyl) diester was to83.52%.(5) A new process has been developed to synthesize 2-formyl-l,4- dihy-dro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-mehtylethyl diester with 2,2-dimethoxymethyl-l,4-dihydro-6-methyl-4-(3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3-methyl 5-(l-methylethyl) diester and 6mol/L hydrochloric acid in the presence of acetone as solvent. The optimum reaction conditions were obtained by investigating the effects of mole ratio of raw material, reaction temperature and time on the yield. The yield of 2-formyl-l,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-methylethyl diester was to 85.44%.(6) A new process has been developed to synthesize Nilvadipine with 2-formyl-l,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-methylethyl diester and hydroxylamine hydrochloride in the presence of sodium acetate anhydrous as dehydrate. The optimum reaction conditions were obtained by investigating effects of the mole ratio of raw material, amount of dehydrate, re...