Synthesis Of Diltiazem And Process For The Recycle Of Its By-product

Diltiazem is a benzothiazepine calcium antagonist widely used for the treatment ofcardiovascular diseases. Through consulting a great deal of relevant literatures about thesynthesis of Diltiazem hydrochloride, comparing and analyzing the synthetic routes andprocess of several methods, We finally confirmed the experimental routes： Withp-methoxybenzaldehyde and methyl chloroacetate as raw materials, Diltiazem isprepared through Darzens condensation, ring-opening of epoxide, resolution, cyclization,N-alkylation, O-acetylation and salification.The synthetic improvement focused on some reactions, such as the Darzenscondensation, ring-opening of epoxide, resolution and cyclization. The yield of Darzenscondenstion raised to93%from previous70%, and the yields of ring-opening of epoxidereached85%from75%, and the yield of resolution by L-(+)-tartaric acid improvedfrom77.2%to82%, as well as the condition is easier to control with the acetonitrile as asolvent, also the yield of cyclization added up to92%from84%. The overall yield hasbeen increased to53%from28%reported in former document.At the same time, we studied the recycle process of L-cis-ester isomer includingfour steps--cyclization, oxidation, reduction and ring-oping reaction. IBX was used asnew green oxidant in the oxidation process and can be recycled repeatedly, reduction andring-opening using the “one pot preparation”. The racemization yield increased from63.4%to78%.The structure of the intermediates and products are confirmed by1H NMR, MS, IR.And the improved synthetic route of Diltiazem was suitable for the industrialization.