摘要
目的开发一种合成富马酸沃诺拉赞的实用方法。提高收率,减少杂质、满足药品的质量要求。方法以5-(2-氟苯基)吡咯-3-甲醛为原料,经过N-磺酰化得到了5-(2-氟苯基)-1-(吡啶-3-磺酰基)-1H-吡咯-3-甲醛,采用甲醇重结晶除去了氯化物杂质,接着经过醛基的还原胺化、盐酸成盐除去二甲胺杂质,再中和形成沃诺拉赞,后经室温与富马酸成盐和甲醇/水(1∶1)重结晶后得到合格的富马酸沃诺拉赞。结果开发了一种实用的富马酸沃诺拉赞的合成工艺,可操作性高,杂质可控,收率提高4%,目标产物经过ESI-MS和1H NMR确认。结论研究得到了单杂<0.1%、纯度>99.5%的富马酸沃诺拉赞产品的合成工艺路线,该工艺适合工业化生产。
Objective To develop a practical synthetic process of vonoprazan fumarate with high-yield and lower impurities to meet the quality requirements.Methods By using 5-（2-fluorophenyl）pyrrole-3-carboxaldehyde as the starting material,the qualified vonoprazan fumarate was synthesized via the following steps：（1） N-sulfonylation and the chloride impurity was removed by recrystallization from MeOH;（2） the aldehyde was converted to amine by reductive amination,followed by forming the vonoprazan chloride to remove the dimethylamino impurity;（3） vonoprazan free base was obtained by neutralization and then converted to fumarate at room temperature and finally recrystallized from MeOH/H_2O（1∶1）.Results An impurity controllable synthetic process was developed with a 4% total yield improving.The final product was confirmed by ESI-MS and ~1H NMR.Conclusion The synthetic process with single impurity less than 0.1% and purity above 99.5% was obtained and suitable for scale production of vonoprazan fumarate.
出处
《国际药学研究杂志》
CSCD
北大核心
2017年第9期890-893,共4页
Journal of International Pharmaceutical Research
