New Generation Dihydropyridine Calcium Channel Blockers - Hydrochloric Lercanidipine Synthesis Method

Lercanidipine is a new 1 ,4-dihydropyridme calcium channel blocker.It was developed and launched in 1997 in the Netherlands by Recordati Co. of Italy for the treatment of hypertension, with the characteristics of long-lasting , high vascular-selectivity and minimal effects.The project aims to study synthesis of Lercanidipine. A thirteen-step route for the preparation of target compound was designed and investigated.The intermediate 3,3 -diphenyl- 1 -propanol( 1 2)was prepared by directly reducing 3,3-diphenyl-1 -propanoic acid with NaBH4H2S04, Compared with the method in the literature, a two-step route of esterfication of acid and reducing ester with alcohol and sodium,this new method was simple and the yield was raised from 60% to 94.4%.The intermediate N-methyl-3 ,3 -diphenylpropylamine(4) was prepared by methylaminolysis of 3,3 -diphenylpropylbromide(5 a) with the yield of 74.4%.This method has not been reported by far.To avoid using NaBH4 and lower cost, the other three-step route for the preparation of intermediate(4) was investigated, which starts from cinnamylalcohol(20). This method has not been reported either.Added bromine and sodium hydroxide to the desposed mixture of the preparation of the intermediate(6a),the material NBS was recovered by 50%,which could be directly used in the next reaction. As a result, the cost was lowered.3AbstractThe critical intermediate1 -[N-(3 ,3-diphenylpropyl)-N-methylaminoj -2-methyl-2-propanol(2) was prepared by using sodium hydroxide as absorbing-acid reagent. Compared with the method in the literature, this new method not only lowered the consumption of intermediate(4) but also became simple.The Hantzsch Reaction of using animoniuni-bicarbonate in stead of ammonia for the preparation of the intermediate(17)was investigated. With the same product yield, the new method reduced reaction time from 7?8h to 2?h.