Synthesis of aranidipine
|School||Tianjin University of Technology|
|Keywords||Aranidipine Antihypertensives 1,4 - dihydropyridine calcium antagonists Synthesis|
Aranidipine is the first one with 24 hours of continuous antihypertensive effect of the third generation of 1,4 - dihydropyridine calcium antagonist with L-type and T-type calcium channel blockade. The drug is made in Japan and the United States Taiho Pharmaceutical Squibb Company jointly developed in 1996 in Japan for the first time listed. Aranidipine is an efficient, safe new antihypertensive drugs for the treatment of hypertension, coronary heart disease and hypertension in patients with angina pectoris. Because the drug, but the slow onset of action lasting effect, can effectively improve the patient's blood flow, especially for senile hypertension, it is expected to become the ideal drug for the clinical treatment of hypertension. According to literature reports, aranidipine synthetic route can be divided into the main and side chains of two parts. Sidechain propargyl alcohol and ethylene glycol as starting material, after the addition reaction with diketene, and then amination to give 3 - amino-2 - butenoic acid 2,2 - ethylenedioxy methacrylate. Main chain of o-nitrobenzaldehyde and methyl acetoacetate as a starting material, after condensation to give 2 - (2 - nitrobenzylidene) -3 - oxobutanoate, with a 3 - amino-2 - D acid 2,2 - ethylenedioxy propylene by cyclization, and then hydrolyzed to produce a pale yellow powder aranidipine. The final reaction products were detected more than 99% purity, the chemical structure characterized by elemental analysis, IR, UV, NMR, MS and other methods recognized, and with Japan Taiho Pharmaceutical granules produced by extraction of product for comparison. From the simplified operation and improve the product yield, etc., for each step of the reaction are optimized to determine the optimum conditions. Addition reaction of propargyl alcohol and ethylene glycol in a molar ratio of 1:1.1 optimal molecule, p-toluenesulfonic acid in place of boron trichloride as catalyst, while maintaining the temperature at 35 ℃ propargyl alcohol was added dropwise to the ethylene glycol , optimum reaction time 2h; esterification diketene with chloroform as solvent, the reaction temperature was controlled at 80 ~ 85 ℃, optimum reaction time 3h; amination of the ammonia at 3h after the 0 ~ 5 ℃ continue After 24h the reaction was complete sealed; condensation reaction of o-nitrobenzaldehyde was reacted at 20 ℃ 24h, isopropanol as solvent and phosphorus oxychloride as the catalyst, the solvent is not used for a class of toxic benzene; 2 - (2 - nitro benzylidene) -3 - oxobutanoate and 3 - amino-2 - butenoic acid 2,2 - ethylenedioxy cyclization of propylene molar ratio of 1:1.1 best; hydrolysis reaction with hydrochloric acid - ethanol as solvent, the reaction mother liquor can be recycled in the sample. The study also intermediates in the synthesis of esters, amides, condensates and quality ring compounds were studied to determine a reasonable and effective quality control methods. This synthesis method feedstock conversion rate, less byproducts, synthetic route to achieve 34% overall yield, higher than the current yield of 17% reported in the literature. Does not use toxic solvents and reuse of the solvent for recycling is not purified by column chromatographic separation methods, techniques easy, suitable for industrial production.