盐酸屈他维林的合成工艺改进

Improved Synthetic Process of Drotaverine Hydrochloride

用盐酸多巴胺(12)经Boc酸酐保护得N-Boc-多巴胺(13),13经硫酸二乙酯醚化制得(3,4-二乙氧基苯乙基)氨基甲酸叔丁酯(14),最后水解得到3,4-二乙氧基苯乙胺(4)。另用邻苯二酚(15)经硫酸二乙酯醚化得1,2-二乙氧基苯(16),16经傅-克酰基化反应制得3,4-二乙氧基苯乙酮酸乙酯(17),17在KOH/水合肼作用下经黄鸣龙反应得3,4-二乙氧基苯乙酸(5)。5经酰氯化后,再与4经缩合、成环制得盐酸屈他维林(1)。该路线工艺比较简单、安全易操作,总收率60.4%(以12计),且反应过程避免使用高温、高压和剧毒原料,三废处理简单,适合工业化生产。

Compound N-Boc-dopamine(13)prepared by protecting dopamine hydrochloride(12)with(Boc)_(2)O was ethylated with diethyl sulfate to obtain tert-butyl(3,4-diethyloxyphenylethyl)carbamate(14),and then 14 was hydrolyzed to obtain 3,4-diethyloxyphenylethylamine(4).In addition,1,2-diethoxybenzene(16)was obtained by ethylation of catechol(15)with diethyl sulfate.Ethyl 2-(3,4-diethoxyphenyl)-2-oxoacetate(17)was prepared by Friedel-Crafts acylation of compound 16.The key intermediate 2-(3,4-diethoxyphenyl)acetic acid(5)was obtained from compound 17 by Huangminglong reaction in the presence of KOH/hydrazine hydrate.The acyl chloride compound of 5 was condensed with compound 4 for a further cyclization reaction to obtain drotaverine hydrochloride(1)with an overall yield of 60.4%(based on 12).The synthetic route was simple,safe and easy to operate,without high temperature,high pressure and highly toxic raw materials,and it was suitable for industrial production.