The Synthesis Of Nilvadipine And Etoricoxib

This thesis contains three parts:1.The synthesis of nilvadipine.Nilvadipine,a very potent calcium channel antagonist,is clinically used for the treatment of hypertension.At first,the 5-isopropyl 3-methyl 2-(dimethoxymethyl)-6-methyl-4-(3-nitro-phenyl)-1,4-dihydropyridine-3,5-dicarboxylate(5)was obtained from 3-nitrobenzaldehyde,isopropyl 3-aminocrotonate and 4,4-dimethoxy-methyl acetoacetate by one-pot reaction,then compound 5 was hodrolyzed by hydrochloric acid to get 5-isopropyl 3-methyl 2-formyl-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxyl ate(6).and then 5-isopropyl 3-methyl 2-((hydroxyimino)methyl)-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate(7)was prepared by oximation of aldehydes 6.Finally,nilvadipine was obtained from the dehydration of aldoxime7 under weak alkaline condition.The mild reaction conditions,simple experimental procedure and the 99.8%purity of final product after one recrylstallization are advatanges of the current route.Finally the imourity profile of nilvadipine was investigated and the possible impurities in nilvadipine were also synthesized.2.The Synthesis of nitriles.Nitrile is an important synthetic intermediate for pharmacellticals,pesticides dyes and material sciences.The transformation of aldoximes to nitriles using acetic anhydride as dehydration agent under mild reaction conditions is reported.The reaction,which proceeds under weak alkaline condition,allows for the conversion of a range of aldoximes including aromatic aldoximes,alphatic aldoximes,and heterocyclic aldoximes in good to excellent yields.This method has also been successfully applied to the synthesis of calcium channel blocker nilvadipine in pilot scale.3.The synthesis of etoricoxib was studied.Etoricoxib,a selective COX-2 inhibitor,is clinically used for the treatment of acute or chronic osteoarthritis and gouty arthritis.Firstly 4-(methylsulphonyl)-phenyl-acetic acid(27)was prepared by 4-(methylsulphonyl)acetophenone by Willgerodt-Kindler reaction.Then the key intermediate 2-[4-(methyl-sulfonyl)phenyl]-1-(6-methyl-pyridin-3-yl)-ethanone(22)was obtained from 4-(methylsulphonyl)phenylacetic acid and methyl 6-methylni-cotinate through condensation reaction.After addition and cyclization with hexafluorophosphate salt(24),etoricoxib was synthesized in high yield.With 99.8%purity after purification.Finally the possible impurities in etoricoxib were identified and synthesized.