2011年5月，FDA批准默克公司的丙型肝炎治疗药物Victrelis上市。Victrelis也称为Boceprevir波普瑞韦。
Boceprevir分子结构包括三个片段：P1、P2和P3。
片段P2的三条合成路线如下，Route A，Route B，Route C。
辉瑞的新冠口服药物Paxlovid，分子结构也包括片段P2。其合成方案主要围着上述三条路线，其中卡龙酸酐的火爆也是源于此。
新冠药物前两年的走势带动了卡龙酸酐的市场，作为Paxlovid原料药的一个关键片段，很多企业采用的工艺路线都用到了卡龙酸酐。
作为原研公司，从文献报道上看，开发了一条新路线，批量做到200kg左右，没有采用卡龙酸酐。
Nirmatrelvir的需求决定了新路线的报道，只有经济最优，没有技术最优。
新路线
化合物20为原料，和双甲基的双溴代物，在溴化钴/配体/锌/碘条件下制备手性环丙烷，得到化合物21
再去除Boc得到目标物
常用的[2 + 1]型环丙烷的构建方案，有一点Simmons−Smith感觉。
实验操作
To a reactor were added THF (1240 L, 4 L/kg), L1(87 kg, 0.15 equiv), CoBr2 (45 kg, 0.15 equiv), and zinc (225kg, 2.52 equiv). To this mixture was added a solution of iodine(87 kg, 0.25 equiv) in THF (310 L, 1 L/kg). This resulted in a purple-colored solution. Dehydroproline 20 (310 kg, 1 equiv) was added. 2,2-Dibromopropane (358 kg, 1.30 equiv) was then added over 4 h. The mixture was stirred at 25−30 °C for at least one more hour. Water (2325 L, 7.5 L/kg), MTBE (930 L,3 L/kg), THF (310 L, 1 L/kg), and 36% HCl (1.6−1.8 equiv) were added. The mixture was stirred for at least 2 h. The layers were separated, and the aqueous phase was discarded. Water (2325 L, 7.5 L/kg), 36% HCl (0.8−0.9 equiv), and MTBE (620 L, 2 L/kg) were added. The layers were separated. The aqueous phase was discarded (H2SO4 can be used in place of HCl during the acidic washes). The organic phase was washed twice with water (2325 L, 7.5 L/kg for each wash). The organic phase was filtered and transferred to another reactor with rinsing with MTBE (310 L, 1 L/kg). The solution was concentrated at reduced pressure to an oil and then concentrated again after charging MTBE (310 L, 1 L/kg). Additional MTBE (310 L, 1 L/kg) and THF (698 L, 2.25 L/kg) were added. Gaseous HCl (180 kg, 3.6 equiv) was added, and the mixture was stirred at 20−25 °C for at least 10 h. At 0−5 °C, MTBE (310 L, 1 L/kg) was added, and the suspension was stirred for 1−2 h. The solid was filtered and washed with THF (1240 L, 4 L/kg). The wet solid was dried under a vacuum. On average, 205 kg of 2 was isolated (73% yield). 98.0−99.1 wt % assay, 99.23−99.62% HPLC purity, and>99.9% chiral purity.
参考文献
J. Am. Chem. Soc. 2012, 134, 6467−6472
Org. Process Res. Dev. 2012, 16, 1468−1481
https://doi.org/10.1021/acs.oprd.3c00251
