To a 300 L reactor were charged with 4-bromo-2-fluoro-1-iodobenzene 33 (15.0 kg, 49.9 mol, 1.0 equiv) and THF (67 kg). The mixture was stirred at 20 °C for 15 min, and the resulting solution was cooled to −5 °C. To the cooled solution was slowly added the 2 Μ isopropyl magnesium chloride in THF (31.6 kg, d =0.975 g/mL, 64.8 mol, 1.3 equiv) maintaining the internal temperature below 0 °C. The mixture was stirred at 0 °C for 1 h.To the mixture was slowly added a solution of di-tert-butyl dicarbonate (16.4 kg, 75.2 mol, 1.5 equiv) in THF (27 kg) maintaining the internal temperature of no more than (NMT) 5°C. The solution was mixed at 0 °C for 1 h. The reaction mixture was quenched by addition of 10% citric acid aq. solution (30 kg) slowly maintaining the internal temperature of NMT 20 °C followed by addition of 25% NaCl aq. solution (30 kg). The internal temperature of the quenched mixture was adjusted to 25 °C, and mixed for no less than (NLT) 1 h. The layers were separated. The upper organic layer was concentrated under vacuum to 20 L, and chased three times with THF (27 kg) to a final volume of 25 L. The product solution was filtered and the solid was rinsed with THF (13 kg). The filtrate was concentrated under vacuum to 20 L to obtain a concentrated THF solution of the desired product (32c) (18.3 kg, 66 wt % assayed by HPLC, 88% yield). This product solution was taken to the next step without further purification. DOI: 10.1021/acs.joc.8b02750
J. Org. Chem. 2019, 84, 4814−4829
- 目标物19是合成AZD7518的关键中间体，其合成路线如下：
- 底物18在锂试剂作用下，得到中间态24后，经烷氧羰基化反应得到目标物19，研究数据如下
- 二聚杂质27形成原理：滴加氯甲酸乙酯淬灭中间态24过程放热，不能一次性加入，滴加过程，体系形成的目标物19和没有淬灭的中间态24反应形成二聚杂质27，滴加速率越慢，该二聚杂质27越大（entry 5）。
- 淬灭方式策略：为避免二聚杂质27，最好的淬灭方式就是反向淬灭，把中间态24滴加到氯甲酸乙酯中，但需要解决中间态24高于-40度不稳定的问题，工业生产规模，挑战很大，寻找其它淬灭试剂。
- 尝试锂化反应制备中间态24在碳酸二乙酯和甲基叔丁基醚的混合溶剂中进行，滴加HDMSLi过程，一旦有中间态24产生，就会有亲电试剂碳酸二乙酯去捕获，得到目标物19。
- 为降低二聚杂质27的风险，采用大过量的12eq.碳酸二乙酯，尽管二聚杂质27可以降到1.4%，但有底物18产生，也有水解杂质19c，目标物19纯度只有90%（entry6），
- 尝试用大过量的二氧化碳气体淬灭中间态24（entry7），尽管可以抑制开环杂质和二聚杂质，但是19c明显大，影响后续工艺。
- 尝试滴加Boc酸酐淬灭中间态24，没有发现底物18，也没有发现二聚杂质（推测与叔丁基的位阻有关）和开环杂质，目标物19d占100%（entry8），结果很理想。
18 (320.3 kg, 1.00 equiv), anhydrous tBME (3200 L), and Boc2O (319 kg, 1.50 equiv) were charged to vessel 1. The batch was agitated at 20 °C for 30 min before being cooled to 0 °C. LiHMDS (1140 L, 1.0 M in tBME, 1.20 equiv) was charged to vessel 1 over 1 h (internal batch temperature does not exceed 5 °C). The batch was kept at 0 °C for 1 h before being transferred to vessel 2. Water (2958 L) was charged to vessel 2, and the batch was agitated for 1 h at 20 °C. Org. Process Res.Dev. 2015, 19, 721−734https://doi.org/10.1021/acs.oprd.0c00533
