Olaparib is a top-selling pharmaceutical approved for the treatment of ovarian cancer. Herein, a two-step cascaded flow process was developed to synthesize Olaparib in microreactor. Since two different acyl groups are in the piperazine ring of Olaparib, a highly selective monoacylation route of piperazine is crucial for the efficient synthesis of Olaparib. For the first step (i.e., the monoacylation of piperazine), N,N'-carbonyldiimidazole was screened as coupling reagent due to its excellent selectivity, safety and greenness, a high monoacylation yield of 83 % was obtained in the microreactor. To understand the selective monoacylation reaction more deeply, the intrinsic kinetics was investigated based on mechanism cognition and experimental data. The established kinetic model was in good agreement with the experimental results in validation experiments. To further realize continuous manufacturing, the following step (i.e., amidation) was cascaded with the monoacylation in a microreactor system, Olaparib was continuously synthesized in the two-step cascaded microreactor with an overall yield of 78 % within 25 min. Relative to existing processes, the reaction steps were reduced, the economy and efficiency were remarkably improved, indicating efficient process intensification.

奥拉帕尼是一种经批准用于治疗卵巢癌的最畅销药物。本文开发了一种两步级联流程在微反应器中合成奥拉帕尼。由于奥拉帕尼的哌嗪环上有两个不同的酰基，因此哌嗪的高选择性单酰化路线对于奥拉帕尼的高效合成至关重要。对于第一步（即哌嗪的单酰化），N , N'β-羰基二咪唑因其优异的选择性、安全性和绿色性而被筛选作为偶联剂，在微反应器中获得了高达83%的单酰化产率。为了更深入地理解选择性单酰化反应，基于机理认知和实验数据研究了其内在动力学。建立的动力学模型与验证实验结果吻合较好。为了进一步实现连续化生产，将后续步骤（即酰胺化）与单酰化在微反应器系统中级联，在两步级联微反应器中连续合成奥拉帕尼，25分钟内总产率为78%。相对现有工艺，减少了反应步骤，经济性和效率显着提高，