心脏保护剂右雷佐生的合成

Synthesis of Cardioprotective Agent Dexrazoxane

本研究设计以下路线合成右雷佐生。(S)-1,2-丙二胺盐酸盐在氢氧化钠溶液中与氯乙酸经亲核取代制得(S)-(+)-1,2-丙二胺-N,N,N',N'-四乙酸,在浓硫酸作用下直接与甲醇成酯得(S)-(+)-1,2-丙二胺-N,N,N',N'-四乙酸甲酯,在室温下以甲醇钠为碱,与甲酰胺进行环化,所得粗品经二噁烷重结晶即得目标化合物,总收率52.4%,纯度99.88%,未检出左雷佐生。本工艺条件温和,可避免形成杂质A和杂质B,收率高,业已应用于商业化生产。

Dexrazoxane was prepared according to the following route.（S）-Propane-1,2-diamine dihydrochloride was subjected to a nucleophilic substitution with chloroacetic acid in sodium hydroxide solution to give（S）-（＋）-1,2-diaminopropane-N,N,N＇,N＇-tetraacetic acid. The latter was reacted with methanol directly in the presence of sulfuric acid to afford tetramethyl（S）-（＋）-1,2-diaminopropane-N,N,N＇,N＇-tetraacetate, which was followed by a cyclization with formamide in the presence of sodium methoxide at room temperature to give crude dexrazoxane. After a recrystallization from 1,4-dioxane, the target compound was obtained with a total yield of 52.4%, and a purity of 99.88%. The reaction conditions in this study are mild, and the formation of impurities A and B in the process are avoided. It has been applied to commercial production.