Lossen重排：工艺应用案例更新
文摘
科学
2024-12-14 08:01
天津
案例一
- 底物氧肟酸16的氮已经提前被氧化，重排条件温和，无需对富电子五元环氮原子保护，在试剂CDI作用下完成lossen重排反应得到化合物17。
Hydroxamic acid 16 (19.4 g, 1.0 equiv) was charged to a reactor, followed by 2-MeTHF (388 mL), resulting in a white slurry. The slurry was warmed to 30 °C, and 1,1′-carbonyldiimidazole (16.1 g, 1.3 equiv) was added. The reaction mixture was stirred overnight, at which point the reaction was deemed to be complete by UPLC-MS. A solution of phosphoric acid (14.7 M in water, 25.5 mL, 5.0 equiv) was diluted with water (78 mL) and added slowly to the slurry. The slurry dissolved, and the reaction mixture was heated to 60 °C and held for several hours. When the reaction was deemed to be complete, sodium hydroxide (20 wt % in water, 16.4 mL, 1.45 equiv) was added to obtain 17. The reaction mixture was warmed to 80 °C and then cooled to 25 °C. 2-Propanol (58 mL) was added slowly, and the solid was filtered. The cake was washed with 2-propanol/water (1:1 v/v, 40 mL) and dried in a vacuum oven to afford 17 (19.1 g, 81% yield).- 化合物3经CDI的胺酯交换得到12a（氧肟酸），12b是醇酯交换的副产物，不参与反应，后处理去除。
- 化合物12a经CDI作用，发生Lossen重排，得到异氰酸酯5，反应过程经历了二噁唑酮13的形成。
- 手性3-喹核醇捕获异氰酸酯，得到化合物1，主要工艺杂质是异氰酸酯水解的杂质16、CDI活性酯15和手性3-喹核醇反应的杂质17。小编推测杂质脲11也会存在，至少工艺研究角度需要研究。
To a stirred solution of 12a (2.11 kg, 7.5 mol) in toluene (17.3 kg) at 20 °C was added carbonyl diimidazole (1.34 kg, 8.3mol., 1.1 equiv). The reaction was stirred at 20 °C for 3 h to form a clear solution which was then heated to 60 °C and stirred for another 16 h. (S)-(+)-Quinuclidinol (1.13 kg, 8.9 mol, 1.2 equiv) was added, and the reaction was heated at reflux for 16 h. The solution was cooled to room temperature and then partitioned with toluene (10 L) and water (20 L).Org. Process Res. Dev. 2015, 19, 576−581- 加料顺序很重要，否则杂质38不容易控制，相当于原位产生原位消耗。
(e) CDI, MeCN 70 then NEt3, NH2OH· HCl, MeCN, 0 °C, 89% yield, (f) TsCl, DIPEA, DCM, 20 to 40 °C, 79% yield, https://doi.org/10.1021/acs.oprd.4c00369
