The Synthetic Technology Of Calcium Channel Blocker: Hydrochloride Verapamil And Its Novel Derivatives Research

Verapamil, as the primary CCB (Calcium Channel Blocker), was developed by Knoll Pharmaceutical Company in Germany and then was labeled Isoptin. In spite of its long history, it is still applied as the first-line agent against hypertension. It can also depress cardiac muscle and atrium-ventricular conduction, slow down the heart rate, reduce the oxygen consumption of cardiac muscle and reverse the multidrug resistance to the tumor cells. Besides, the mechanism of action and the structure-activity relationship studies fell far behind the pharmacological and biochemical research. Thus, a deeper understanding of verapamil is deserved.The industrial synthesis of verapamil has been researched thoroughly still with total yield of only 6.25% as well as the disadvantages of long reaction time, complicated conditions and difficulties in purity. Comparing the reported synthetic routes, we chose a rational and convenient one which started with 3, 4-dimethoxyl phenylacetonitrile and 3, 4-dimethoxyl benzylethylamine by 6 steps reactions to get the objective compound. We applied a novel approach to synthesize N-methyl-3, 4-dimethoxyl benzylethylamine with satisfying purity and simple operation; moreover, we modified the synthesis of 2-(3,4-dimethoxyphenyl)-3-methylbutanenitrile by employing the ordinary heat and microwave catalyze methods to get over the existing disadvantages.Two series of verapamil derivatives were designed and synthesized based on the synthetic technology. The part c was supposed to play a fundamental role in the interaction with the calcium channel, thus all objectives contained part c and were classified by bearing one, two, three of part c(See the figures below). Series I compounds were synthesized from L-amino acid protected with Boc and part c. And the novel branches were designed in view of increasing the density of the active structures. Series â…¡ reserved all the main...