Improved Synthesis Research Of Diltiazem Hydrochloride

The dissertation mainly studied the improved synthesis of calcium antagonist diltiazem hydrochloride.This dissertation includes two chapters as following.First chapter introduced the research progress of calcium antagonist and diltiazem hydrochloride briefly,it also outlined the synthetic methods of diltiazem hydrochloride and analyzed the advantages and disadvantages of these methods.The second chapter studied the synthetic efforts towards the improved synthesis of diltiazem hydrochloride.Diltiazem hydrochloride was synthesized from anisaldehyde and methyl chloroacetate through darzens condensation giving dl-trans-(4-methoxy phenyl)-2,3-epoxy acrylic acid methyl ester 4 with yield of 72.0%.Then2-Aminobenzenethiol was used to react with compound 4 to afford thedl-cis-3-(4-methoxy phenyl)-3-(2-amino benzene sulfonium)-2-hydroxy methyl propionate 6.Under the optimal conditions,the total yield could be reached to 82.0 %.Then compound 6 was hydrolyzed under alkaline conditions to afford dl-cis-3-(4-methoxy phenyl)-3-(2-amino benzene sulfonium)-2-hydroxy acrylic acid 7’ with 99.5% yield.We further studied the resolution of compound 7’ with L-lysine,resulted in d-cis-3-(4-methoxy phenyl)-3-(2-amino benzene sulfonium)-2-hydroxy acrylic acid 7 with 38.0 % yield.Then compound 7 was subjected to dehydration condition to give compound 8 with 78.0 % yield.Then compound 8 was used to react with N,N-dimethyl ethyl chloride hydrochloride to afford Desacetyldiltiazem 10,with high yield(91.0%).Moreover the compound of diltiazem could be achived by the esterification reaction.Finally,the diltiazem was converted to hydrochloride salt 87.6% yield.We investigated the reaction conditions including various reagents,solvents,bases,reaction temperature,feeding ratio,addition sequences and so on.The improved synthesis of diltiazem hydrochloride was completed in nine steps with an overall yield of13.9 %.Compared to the traditional craft,the improved process obtained in higher yield,lower amount of by-products,less expenses and easier to operate.All above mentioned advantage make this improved method more suitable for industrial production.