CRBN调节剂Avadomide的合成工艺优化

Avadomide是处于Ⅱ期临床阶段用于治疗晚期实体瘤的潜在药物,本文对其合成工艺进行了研究,并对重要中间体的合成工艺进行了优化。以3-硝基邻苯二甲酰亚胺为起始原料,依次经开环、霍夫曼降解、环化、酯的氨解反应、氢氧化钯/碳加氢还原反应得到Avadomide,总收率为46.9%,产物结构经~1H NMR、~(13)C NMR和HRMS表征,纯度经HPLC检测为99.5%。优化后的工艺路线具有反应条件温和、后处理简单、产率高、可操作性强等特点,更适合Avadomide的工业化生产。

Optimization of Synthetic Process for The CRBN Regulator Avadomide

Avadomide is a potential drug for the treatment of advanced solid tumors in phase II clinical trials. In this work, the synthesis technique for preparation of Avadomide was optimized and improved. Using 3-nitrophthalimide as the starting material, Avadomide was obtained by ring-cleavage, Hoffman degradation, cyclization, ester aminolysis reaction and Pd(OH)2/C hydrogenation reduction. The overall yield was 46.9% and the target compound was identified by 1HNMR, 13CNMR and HRMS, whose purity was 99.5% through HPLC test. In comparison with literature methods, this synthetic route has the advantages of mild reaction conditions, simple post-treatment, high yield and easy work-up, so it is suitable for industrial production of Avadomide.