Two‐step flow synthesis of Olaparib in microreactor: Route design, process development and kinetics research

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.