Sharui Tan Synthesis And Process Study

The incidence of asthma in the world has been increased rapidly, now The therapeutical drugs is still focusing on the drugs of inhalant steroidal for anti-inflammatory, the drugs for the dilation of bronchiole, such as β -2 adrenoceptor agonists, and the antiallergic drugs such as leukotriene antagonist. It is important to research the medicines of new mechanism. Many pharmaceutical companies have investigated the neurokinins antagonist. Neurokinin-2 receptors are expressed in the gastrointestinal tract of both laboratory animals and humans. Selective NK-2 receptor antagonist can inhabit the asthma and release the pain of patients.This article studied the preparation and the process of an important NK-2 antagonist — Saredutant. Now it progresses to phase Ⅱ clinical trial by Senofi-Synthelabo.Based on the analysis of the synthesis described in the reference, we firstly discover a new and more direct route to prepare the key medciate 3-cyano-3-(3,4-dichlorophenyl)propionic acid. In this route saredutant was prepared from simple starting material 3,4-dichlorophenyl-benzene carbonal, through 9 steps reaction including of condensation, addition, hydrolysis, decarboxylation, reduction by borane, resoluting by D-tartaric acid, acylation, hydroxy protecting, methylation of amine, cleavage of the protective group ,condensation with side chain . the overall yield is 7.87% .In this route the cost was prohibitively expensive due to more steps and the lower yield. So, we design a whole new route. In this route Saredutant was prepared from simple starting material 1,2-dichlorobenzene, through 7 steps reaction including of Friedel-Crafts reaction, Wittig reaction, substitution, hydrogenation reduction , resolution by D-tartaric acid, acylation , condensation with side chain, the overall yield is 11.7 %. There were 3 new compounds. The key mediate of 4-(N-methyl-N-benzyl)amine-3-(3,4-dichlorophenzyl)-2-ethyl crotonate can be reduced by asymmetric hydrogen, or reduced by hydrogen and then resoluted.The side chain of saredutant was prepared starting from 4-benzylpiperidone through 3 steps reaction including of Griguard reaction, Ritter reaction, hydrogenation, the overall yield is 52.5 %.The new compounds and the main mediates are identified by ~1HNMR, MS.