1种新的依普利酮合成工艺研究

Investigation on a New Synthetic Process of the Eplerenone

针对依普利酮原有磺酰化工艺吡啶用量大、后处理繁琐、产物分离复杂等问题,采用二甲氨基吡啶作为磺酰化反应催化剂,以依普利酮羟酯物为起始原料,经过甲磺酰化、消除及环氧化等步骤制备得到依普利酮。结果表明,磺化反应以二氯甲烷作为反应溶剂,二甲氨基吡啶(2 mmol)作为催化剂,三乙胺(20 mmol)为缚酸剂,回流温度下反应,最高收率可达98%;环氧化反应以二氯甲烷为反应溶剂,双氧水为环氧化试剂,三氯乙酰胺(12 mmol)为活化剂,室温下反应,最高收率可达80%。在此优化条件下,总收率达到64.3%,产物结构经^(1)H NMR及^(13)C NMR确认无误。改进后的合成工艺更为绿色环保,避免了吡啶的使用,并具有操作简单、碱用量少和产物易分离等优点。

Aiming at the problems of large amount of pyridine, complicated post-treatment and complex product separation in the original sulfonylation process of eplerenone, eplerenone was prepared by using dimethylaminopyridine as the sulfonylation reaction catalyst and eplerenone hydroxy ester as the starting material through methylsulfonylation, elimination and epoxidation. The results showed that the sulfonation reaction used dichloromethane as the reaction solvent, dimethylaminopyridine(2 mmol) as the catalyst,triethylamine(20 mmol) as the acid binding agent, and the reaction was carried out at the reflux temperature. The highest yield can reach 98%;the epoxidation reaction uses dichloromethane as the reaction solvent, hydrogen peroxide as the epoxidation reagent, and trichloroacetamide(12 mmol) as the activator. At room temperature, the highest yield can reach 80%. Under the optimized conditions, the total yield was 64.3%. The structure of the product was confirmed by ^(1)H NMR and ^(13)C NMR. The improved synthesis process is more environmentally friendly, avoids the use of pyridine, and has the advantages of simple operation, less alkali consumption and easy separation of products.