组胺H3受体拮抗剂／反向激动剂pitolisant的合成

目的对组胺H3受体拮抗剂／反向激动剂pitolisant进行合成工艺研究。方法以对氯氯苄、丙二酸二乙酯为起始原料,经过缩合、水解、脱羧、还原、酯化、取代反应制得pitolisant。结果与结论经过6步反应合成目标化合物pitolisant,其结构经1H—NMR及MS确证。对其中多步反应条件进行了工艺考察及优化,总收率为31．4％（以对氯氯苄计）。

Synthesis of pitolisant as a histamine H3 receptor antagonist/inverse agonist

Pitolisant, discovered by Bioprojet,is an orally bioavailable histamine H3 receptor competitive antagonist and inverse agonist in phase Ⅲ clinical studies for the oral treatment of excessive daytime sleepiness in parkinson＇s disease patients. It will probably be the first histamine H3 receptor antagonist/inverse agonist on sale in the future. According to the synthetic method of pitolisant in patent,its synthetic route was established,and the synthetic process was investigated and optimized thoroughly. Starting from 4-chlorobenzyl chloride and diethyl malonate, the key intermediate 3-（4-chlorophenyl） propyl methanesulfonate was obtained by the steps of condensation, hydrolization, decarbolization, reduction and esterification. Another key intermediate 3-（piperidin-1-yl） propan-1-ol was prepared from methyl 3-chloropropanoate via reduction and condensation. Then 3-（4-chlorophenyl） propyl methanesulfonate was condensated with 3-（ piperidin-1-yl ） propan-1-ol to give pitolisant and the overall yield was 31.4% （calculated by 4-chlorobenzyl chloride）. Its structure and some intermediates were confirmed by 1H-NMR and MS. In this procedure, the yield of intermediate 3- （4-chlorophenyl） propanoic acid, was increased by 15 %, intermediate 3- （ piperidin-1 -yl） propan- 1-ol, was obtained in a shortened reaction time by adding a catalytic amount of PEG 400. The improved synthetic process is more convenient for industrial application.