富马酸比索洛尔的合成工艺改进

Improved synthesis of bisoprolol fumarate

目的改进富马酸比索洛尔的合成方法。方法以3-(异丙基氨基)丙烷-1,2-二醇为起始原料,经成环、对甲苯磺酰化、偶合、开环及成盐5步反应制得富马酸比索洛尔。结果与结论目标化合物及中间体的结构经1H-NMR、MS谱等确证。新合成路线操作简便,反应条件温和,总收率为36%,适合工业化生产。目标物经HPLC法检测纯度达99.4%,单个杂质含量小于千分之一,符合中华人民共和国药典标准。

Bisoprolol fumarate is a kind of highly selective fll cardiac receptor blockers, which is used for the treatment of hypertension, angina and arrhythmia. An improved preparation method was designed to synthe size the target compound in this paper. Bisoprolol fumarate was obtained from 3-（isopropylamino）-1,2-diol as starting material through cyclization, sulfonylation, coupling, ring cleavage, salification with an overall yield of 36%. 3-（Isopropylamino）-1,2-diol was reacted with dimethyl carbonate under certain conditions to give intermediate 2. Compound 2 was reacted with 4-toluenesulfonyl chloride in dichloromethane to obtain compound 3. Intermediate 3 was coupled with compound 4 under the condition of sodium hydride to give key intermediate 5. After ring cleavage （6）and salification ,fumarate salt 1 was given. The structure of target compound was identified by 1H-NMR and MS. The improved process is facile with relatively convenient op eration procedures and suitable for industrial production.