Studies On The Synthesis Of Azelnidipine

Azelnidipine is a kind of the dihydropyridine calcium antagonists,it is mainly used to treat hypertension and angina pectoris in cilinc,and also can treat congestive heart failure.It is an very important hypotensor which was put on market by a Japanese company(Daiichi Sankyo Company Limited)in 2003.Compared with other dihydropyridine drugs,this drug has strong vascular specificity,less adverse reactions and long-lasting effect,so it has very important research value.Synthesis is presented in this paper,the process is startedwith benzhydrylamine,epoxy chloropropane,nitrobenzene formaldehyde and isopropyl acetoacetic ester.The first intermediate 1-2 benzyl-3-nitrogen(hybrid)ring butanol(Ⅰ)is synthesized,then it reactions with cyanoacetic acid,and gets intermediate(1-2(hybrid)ring butyl benzyl-3-nitrogen)cyanoacetic acid ester(Ⅱ),intermediate(1-2 nitrogen heterocyclic butyl benzyl-3-)-3,3-2 amino acrylic ester acetate(Ⅲ)is synthesised by intermediate(Ⅱ),alchohol and,ammonium acetate,the intermediate 2-(3-nitro benzyl)acetyl(Ⅳ)is synthesised by m-nitrobenzaldehyde and isopropyl acetoacetate,Azelnidipine is synthesised by intermediate(Ⅲ)and Ⅳ finally.The main work of this paper is as follows:1.The synthesis1-diphenylmethyl-3-n(mixed)cyclobutanol(I)was determined,and the materials used were diphenylamine and epichlorohydrin.The optimal conditions in the reaction process are: the solvent used is methanol,which is mixed with 32 h and the process should be treated with dark treatment.After treatment,the intermediate(I)is obtained after extraction.The structure of intermediate(I)was characterized by melting point apparatus and mass spectrometer.Yield is 72.6%.2.The synthesis of(1-diphenyl-3-n(mixed)cyclobutyl)cyanoacetate(Ⅱ),using intermediate(I)and cyanoacetic acid as reaction raw material synthesis.Optimization in the process of reaction condition is: use the solvent is tetrahydrofuran(THF),the catalyst is dicyclohexyl carbon 2 imine(DCC),feeding way is batch,intermediate(Ⅱ)after the recrystallization of alcohol.The structure of intermediate(Ⅱ)was characterized by melting point apparatus and mass spectrometer.Yield is 94.6%3.The synthesis method of(1-diphenyl-3-azobutyl)-3,3-diaminoacrylate acetate(Ⅲ)was determined,and the materials used were intermediates(Ⅱ),ethanol and ammonium acetate.The optimization conditions in the reaction process were: the intermediate products of toluene and hydrogen chloride were obtained,and the intermediate(Ⅲ)was obtained by the dissolution of the intermediate products with acetonitrile.The structure of intermediate(Ⅲ)was characterized by melting point apparatus and mass spectrometer.Yield is 90.1%4.The synthesis method of 2-(3-nitrobenzyl)acetoacetate(Ⅳ)was determined,and the material used was m-nitrobenzaldehyde and isopropyl acetoacetate,and the important intermediate(Ⅳ)was prepared.The optimum conditions in the reaction process were: the solvent used was isopropyl alcohol,and the catalyst used was piperidine acetate,which was condensed and cooled after 48 minutes stirring,and the product was obtained.The structure of intermediate(Ⅳ)was characterized by melting point apparatus and mass spectrometer.Yield is 73.6%5.(Ⅴ)synthesis technology was studied,using the intermediate(Ⅲ)and intermediate(Ⅳ)for synthesis of Michael addition get products,the optimization in the process of reaction condition is: the solvent is isopropyl alcohol,the catalyst of sodium hydroxide,after the return of products.The crude products were recrystallized with toluene and the product was obtained.and the product was obtained.The structure of Azelnidipine was characterized by melting point apparatus and mass spectrometer.Yield is 92.6%.The yield of all synthetic processes for azelnidipine is significantly higher than that of known reports.