阿哌沙班的合成工艺研究

Study on the synthesis of apixaban

目的研究阿哌沙班的合成工艺。方法以环戊酮肟为原料,经重排、双氯取代、缩合、亲核取代3步反应得到关键中间体3-吗啉-4-基-1-(4-硝基苯基)-5,6-二氢-1H-吡啶-2-酮(5);再以对甲氧基苯胺为起始原料,经Japp-Klingmann反应得到中间体2-氯-2-[2-(4-甲氧基苯基)腙]乙酸乙酯(6);中间体5与中间体6经过1,3-偶极环加成、脱吗啉基、还原、酰胺化、环合、胺解6步反应得到目标化合物。结果与结论目标化合物的结构经1H-NMR、MS谱确证。总收率达32.5%(以环戊酮肟计)。与文献报道的工艺相比,该路线原料易得、操作简便、条件温和、收率较高,有利于工业化生产。

Apixaban, a novel efficient oral factor X a direct inhibitor,is developed by the cooperation of Bristol-Myers Squibb and Pfizer. In this paper, a new synthetic route has been established based on the literatures. Using cyclopentanone oxime and 4-methoxybenzenamine as the starting materials, apixaban is synthesized through ten steps, including Beckmann rearrangement, a-active hydrogen dichlorination, condensation with morpholine, nucleophilic substitution, 1,3-dipolar cycloaddition, olefination, reduction, acylation by 5- chlorovalerylchloride, cyclization and aminolysis. The total yield of the procedure is 32. 5 % （according to the quantity of the cyclopentanone oxime） and the HPLC purity of the final product is 99.7 %. The structures of the finial compound and some important intermediates have been identified by 1H-NMR and MS. The improved process has several advantages over these reported procedures, such as mild conditions, short reaction time and simple operations. Anyway it＇s more suitable for industrial production.