小编有幸负责开发过Nirmatrelvir的工艺，并于2022年上半年完成了车间的生产放大。感谢曾经的平台、感谢曾经的客户、感谢项目团队的所有人员，特别感谢生产方的人员。看到商业化工艺信息，尤其伯酰胺脱水步骤的工艺，有一点开心、因为我们当时开发的工艺条件和原研商业化工艺条件基本一样，三氟乙酸酐、NMM、乙酸异丙酯，当时文献信息采用Burgess 试剂。 最初路线如下 商业化路线一 商业化路线二 商业化路线一和二的对比 研究历程（筛选过程） 杂质谱 文献实验操作 酸胺缩合Compound 5 (750 kg, 1.0 equiv) and MEK (3000 L, 4 L/kg) were combined and stirred at 25 °C. HOPO (171 kg, 0.75equiv) and TEA (312 kg, 1.50 equiv) were added, followed by charging with MEK (375 L, 0.5 L/kg) to rinse the lines and reactor walls. The resulting mixture was stirred for 30 min and turned a pale yellow color. Compound 6 (447.75 kg, 1.05 equiv) and EDCI hydrochloride (511.5 kg, 1.30 equiv) were charged in this order, and the reactor walls were washed with MEK (375 L, 0.5 L/kg). Stirring was maintained for at least 10h. Upon completion of the reaction, the mixture was quenched by the addition of aqueous NaCl (2250 L of a 14 wt % brine solution, 3 L/kg). After agitating for 30 min, stirring was stopped and the layers were permitted to settle. The lower aqueous phase was removed. The upper organic phase was washed with a second portion of aqueous NaCl (2250 L of a 14 wt % brine solution, 3 L/kg) following the same protocol. The organic phase was then concentrated by vacuum distillation at 0.3 bar while adding iPrOAc (9750 L, 13 L/ kg) to maintain a constant volume of ∼6 L/kg. Additional iPrOAc (1125 L, 1.5 L/kg) was charged, ending the distillation at 7.5 L/kg. A sample was analyzed for water content (Karl Fischer) with a target of NMT 0.2 wt % water. The resulting organic solution of 7 was used in Step 4 without further purification.
伯酰胺脱水A warm iPrOAc solution of 7 prepared as described above(assuming a quantitative conversion, 1065 kg, 1.0 equiv) resulting from the distillation step was combined with NMM(916 kg, 4.4 equiv) at 30 °C. The line was washed with additional iPrOAc (375 L, 0.5 L/kg), and the mixture was cooled to 10 °C, which resulted in a thin slurry. TFAA (951 kg, 2.2 equiv) was charged over 60 min, maintaining the reaction temperature below 20 °C. The resulting mixture was stirred for 1 h. Upon completion of the reaction, the tan-colored solution was quenched with water (2250 L, 3.0 L/kg) and stirred for 30 min. Once stirring was complete, the layers were allowed to settle. The aqueous phase was removed, and the organic phase was washed with another 3750 L of water. The resulting organic phase was then concentrated by vacuum distillation (0.1 bar) to a volume of 2625 L (3.5 L/kg). iPrOAc (3750 L, 5.0 L/kg) was added, and the solution was concentrated by vacuum distillation to 2625 L (3.5 L/kg). This solution was stirred at 50 °C followed by the addition of MTBE (1500 L, 2 L/kg) over 60 min to initiate nucleation. An additional portion of MTBE (4500 L, 6 L/kg) was then added over 3 h. The resulting slurry was stirred at 50 °C for 1 h, cooled to 20 °C at a rate of 0.1 °C/min, and stirred at 20 °C for 2 h. Solids were collected by filtration, rinsed with 2.0 L/kg of an 80:20 MTBE/iPrOAc solution, and dried at 50 °C to isolate crystalline compound 8 (968 kg, 80% yield).参考文献 https://doi.org/10.1021/acs.oprd.3c00250
