摘要
目的改进米罗那非的合成工艺。方法以2-羟基苯甲酸甲酯为原料,经醚化、氯磺化、N-酰化得到中间体2-丙氧基-5-[[4-(2-羟乙基)-1-哌嗪基]磺酰基]苯甲酸甲酯,水解后与4-丙基-1-苄基-3-氨基-1H-吡咯-2-甲酰胺发生酰化反应,再经O-乙酰化、N-脱苄基、N-乙基化、酯水解"一锅法"得到1-乙基-4-丙基-3-[5-[[4-(2-羟乙基)-1-哌嗪基]磺酰]-2-丙氧基苯甲酰胺基]-1H-吡咯-2-甲酰胺,最后经环合生成米罗那非。关键中间体4-丙基-1-苄基-3-氨基-1H-吡咯-2-甲酰胺的合成以甘氨酸为原料,经甲酯化、还原胺化、烯胺化、氨解、环合反应得到。结果与结论经5步反应合成目标化合物,收率为25.9%(以2-羟基苯甲酸甲酯计)。关键中间体经6步反应合成,收率为36.5%,目标化合物和中间体的结构经1H-NMR和MS谱确证。
Mirodenafil, an inhibitor of phosphodiesterase type 5 （ PDE5 ）, which was developed by SK Chemi- cals and approved by the Korea FDA in November 2007 with the trade name Mvix. A synthetic route to mi- rodenafil was designed on the basis of references and the synthetic process was also investigated and opti- mized. Mirodenafil was synthesized from methyl 2-hydroxybenzoate via etherification, chlorosulfonation, N- acylation, hydrolysis, N-acylation, the one-pot method of O-acetylation, N-debenzylation, N-ethylation, hy- drolysis, and cyclization and the yield was 25.9 % （calculated from methyl 2-hydroxybenzoate）. Wherein the important intermediate of 3-amino-1-benzyl-4-propyl-1H-pyrrole-2-carboxamide was prepared from glycine with a yield of 36. 5% （calculated from glycine） via methyl esterification, reductive amination, Schiff reac- tion, ammonolysis, and cyclization. The structures of mirodenafil and some intermediates were confirmed by 1H-NMR spectra and MS, and the purity of mirodenafil was determined by HPLC. The synthetic route is more suitable for industrial production owing to the simple operations ,less by-products and high yields.
出处
《中国药物化学杂志》
CAS
CSCD
2015年第1期35-39,共5页
Chinese Journal of Medicinal Chemistry
