美托洛尔有关物质E和J的合成

目的为更好地对美托洛尔的产品质量进行控制,合成美托洛尔有关物质E和J。方法以2-羟基苯乙酸为起始原料,经过羧基还原、酚羟基保护、甲基化、酚羟基脱保护,再依次与环氧氯丙烷、异丙胺反应得到1-异丙胺基-3-2-(2-甲氧乙基)苯氧基]-2-丙醇(E),总收率为49%。以4-(2-甲氧乙基)苯酚为起始原料,与环氧氯丙烷、丙烯醇反应后得到1-烯丙氧基-3-4-(2-甲氧基乙基)苯氧基]-2-丙醇,再经环氧化、异丙胺化反应制得1-(2-羟基-3-异丙胺基)丙氧基-3-4-(2-甲氧乙基)苯氧基]-2-丙醇(J),总收率为53%。结果与结论美托洛尔合成中的两个相关物质E、J的结构经核磁共振氢谱、质谱确证。两种合成路线原料易得、操作简便、条件温和、收率高,可为美托洛尔的质量评价和相关杂质的控制提供帮助。

Synthesis of related substances E and J of metoprolol

Metoprolol is a commercially marked pharmaceutically active substance known to be useful for the treatment of hypertension and the angina pectoris. To perform the quality control of metoprolol, two related substances were prepared. They are 1 - （ isopropylamino ） -3- 2- （ 2-methoxyethyl ） phenoxy ] propan-2-ol （ E ） and 1- （ 2-hydroxy-3-isopropylamino ） propoxy-3-E 4-（ 2-methoxyethyl ） phenoxy ] propan-2-ol （ J ）. Related substance E was synthesized from 2- （ 2-hydroxyphenyl ） acetic acid by reduction of carboxyl group, protection of phenolic hydroxyl, methylation, deprotection of phenolic hydroxyl, and then reacted successively with epichlorohydrin and isopropylamine with an overall yield about 49%. 4-（2-Methoxyethyl）phenol was reacted with epichlorohydrin and allyl alcohol successively to afford 1-（allyloxy）-3-（4-（2-methoxyethyl） phenoxy） propan-2-ol, which was converted to related substance J by epoxidation and isopropylamination with an overall yield about 53%. Their structures were confirmed by 1H-NMR and MS.