阿哌沙班的合成新工艺

New synthetic process of apixaban

目的:对目前阿哌沙班的合成路线进行优化,以获得适合工业化生产的工艺路线。方法:以硝基化合物6为原料,依次经铁粉还原-酰胺化、环合-水解反应得阿哌沙班酸2;2与廉价绿色试剂CDI反应所得活性酰胺经氨水氨解得目标化合物阿哌沙班。结果:所得阿哌沙班经HPLC检测纯度为99.88%以上,总收率为67.2%。结论:此方法克服了文献报道的方法中原料价格昂贵,反应条件苛刻,反应过程不易监测,产品收率低等缺点。具有原料易得、生成成本低,反应条件温和、操作简便,工艺稳定性高,阿哌沙班纯度和收率高等优点,适合工业化生产。

Objective： To develop a new synthetic route for apixaban by optimizing the reported synthesis routes. Methods： Nitro-compound 6 was used as starting material and it was subjected to the reactions of iron reduction, acylation, cyclization and hydrolysis to generate apixaban acid 2. Apixaban acid 2 was reacted with CDI to afford an active amide, followed by aminolysis with aqueous ammonia to produce the target compound apixaban. Results： Apixaban was synthesized with a total yield of 67.2% , and the purity was 〉 99.88% as determined by HPLC. Conclusion ： This route has overcome the shortcomings of the reported synthesis methods for apixaban, such as the expensive materials, harsh and not easy to be monitored reaction conditions, low yield, et al. In this paper, a significantly improved strategy has been developed to meet the requirement for industrial production, with the ad- vantages of low production cost, simple operation, mild reaction conditions, high process stability, and high purity of the target product, et al