放大异常：加料速度的问题
文摘
科学
2024-11-26 07:02
天津
- 碱拔烯丙位质子，产生杂质A，温度很关键，THF用量也会影响杂质A，虽然THF多，甲苯少不利于杂质A控制，但是搅拌状态好。
- 放大60kg规模，相比30kg规模收率低了8%，主要是杂质B明显变大
- 30kg规模，杂质B大约13%；60kg规模，杂质B大约18%
- 小编：滴加反应，一定要研究滴加时间绝对快和绝对慢的极端情况，关注时温度决定还是速率（体系浓度）决定。
![]()
A 5000 L glass-lined reactor was charged with 3 (124.00 kg, 406.06 mol), 2,6-lutidine (74.00 kg, 690.62 mol, 1.7 equiv), DMAP (7.44 kg, 60.90 mol, 0.15 equiv), and DME (1344.3 kg). AcCl (54.20 kg, 690.45 mol, 1.7 equiv) was added to the mixture, followed by a DME wash (53.90 kg), and the mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with toluene (2150.10 kg) and washed with a mixture of NaCl (31.00 kg) and water (589 L). The separated organic layer was washed with a mixture of 35% aqueous HCl (6.20 kg), NaCl (31.00 kg), and water (620.2 L). The organic layer was washed with a mixture of NaHCO3 (15.50 kg), NaCl (62.00 kg), and water (558 L). The organic layer was concentrated to 600 L under vacuum and azeotroped twice with toluene (1610.00 and 1610.05 kg) under vacuum (each final volume was 590 and 660 L) at not more than 60 °C. The concentrate was transferred to a 5000 L stainless steel cryogenic reactor through a filter, followed by a toluene wash (323.35 kg) and cooling to −70 °C.
LHMDS (20.2 wt % solution in THF, 706.00 kg, 852.28 mol, 2.1 equiv) was added to the reactor, followed by a THF wash (55.10 kg). After the reaction mixture was stirred at −70 °C for 9 h, EtOH (97.85 kg) was added to the reaction mixture at −70 °C. The mixture was heated to 0 °C and diluted with water (1180 L). The aqueous layer was separated and transferred to a 5000 L glass-lined crystallization reactor, followed by a water wash (62.05 kg). The aqueous layer was neutralized with a mixture of 35% aqueous HCl (88.90 kg) and water (67.25 kg) at 5 °C. After the resulting slurry was stirred at 5 °C for 2 h, the crystals were filtered, washed with water (620 L), and dried at not more than 60 °C for 23 h under vacuum to give 5 (64.25 kg, 213.21 mol, 53% yield). HPLC purity: 99.6 area %https://doi.org/10.1021/acs.oprd.3c00317
