A 30 L doublejacketed glass-lined steel reactor was charged with 32 (2.06 kg, 5.67 mol, 1.00 equiv), 4-HCl (1.69 kg, 5.67 mmol, 1.00 equiv),HOBt hydrate (920 g, 6.80 mmol, 1.20 equiv), H2O (6.2 L, 3vol.), and THF (8.2 L, 4 vol.). The mixture was basified to pH 11 by the addition of 32% aqueous NaOH solution (1.6 L, 0.8vol.) at IT = 20−30 °C. A solution of EDC HCl (1.54 kg, 7.94mol, 1.40 equiv) in H2O (3.1 L, 1.5 vol.) was added to the resulting mixture over 10 min at IT = 20−30 °C, and the pH was checked to be 11 (expected range: pH 8−10). Accordingly, a 32% aqueous HCl solution (100 mL) was added to the mixture at IT = 20−30 °C. The reaction mixture was then stirred at IT = 20−30 °C for 18 h (91% conversion of 32). Another portion of EDC HCl (549 g, 2.84 mol, 0.500equiv) was added, and stirring was continued at IT = 20−30°C for 5 h (>98% conversion of 32). The reaction mixture was diluted with CH2Cl2 (10.3 L, 5 vol.) and acidified to pH 1 by the addition of 32% aqueous HCl solution (1 L, 0.5 vol.). The phases were separated, and the aqueous phase was discarded. The organic phase was washed two times with aqueous 1 M aq. NaOH solution (2 × 10.3 L, 2 × 5 vol.) before it was partially concentrated at ET = 60 °C under reduced pressure (700−500 mbar), resulting in the removal of 6 L (3 vol.) of solvent. Then, methylcyclohexane (20.6 L, 10 vol.) was added and the distillation was continued at ET = 60 °C under reduced pressure (300−200 mbar), resulting in the removal of 6 L (3 vol.) of solvent. The resulting suspension was cooled to IT =0−10 °C and aged at this temperature for 1 h. The solid was collected by filtration, washed with methylcyclohexane (5.2 L, 2.5 vol.), and dried at ET = 50 °C under vacuum to afford 35 (2.30 kg, 4.16 mol, 73% yield) as a white crystalline solid. 参考文献https://doi.org/10.1021/acs.oprd.3c00492
案例二
滴加CDI的DMSO溶液
10 L double-jacketed glass reactor was charged with 2 (250 g, 1.11 mol, 1.00 equiv) and DMSO (1.25 L, 5.0 vol). Under strong stirring, a solution of CDI (216 g, 1.33 mol, 1.20 equiv) in DMSO (1.0 L, 4.0 vol) was added dropwise over 30 min via peristaltic pump at IT = 20−25 °C (attention: CO2 release!). After complete addition, the resulting suspension was stirred at IT = 20−25 °C for 30 min (>98% conversion of 2 into activated acylimazolide). A solution of 36-TFA (455 g, 1.22 mol, 1.10 equiv) in DMSO (1.0 L, 4.0 vol) was added dropwise over 30 min via peristaltic pump at IT = 20−25 °C. Stirring of the resulting solution was continued at IT = 20−25 °C for 1 h (>98% conversion of activated acylimazolide into 29). The reaction mixture was quenched by slow addition of H2O (2.5 L, 10 vol) over 1 h at IT = 20−30 °C. The resulting suspension was aged at IT = washed with H2O (2 × 1.5 L) and heptane (1 × 1.0 L), and then dried at 65 °C under vacuum to give 29 (469 g, 1.01 mol, 91% yield) as a white solid.参考文献https://doi.org/10.1021/acs.oprd.3c00446
