案例一
反应机理和工艺操作信息
反应机理
参数研究
实验操作
NaOt Bu (5.93 g, 61.7 mmol) and DME (15 mL) were added to a reactor previously inerted with nitrogen. TEPA (15.9 g, 70.9 mmol) was added at a rate such that the temperature was maintained at <30 °C (ca. 1 h). The reaction mixture was stirred until complete dissolution was observed (ca. 30 min). A solution of 3 in DME (5 g, 30.8 mmol and 10 g of DME) was added while maintaining the temperature between 20 and 30 °C. The reaction mixture was concentrated by distilling DME under vacuum at <60 °C until a concentration of ca. 1 M in 3 was achieved (distillate volume ca. 19 mL).10 The reaction mixture was stirred at ca. 60 °C (12-15 h) until the HPLC area percent of 3 was <2 relative to the product 2a. The temperature of the reaction mixture was increased to ca. 70 °C and maintained at this temperature (8-10 h) until the combined HPLC area percent of 3 and intermediate 7 was <2 relative to that of the product. The reaction mixture was cooled to <40 °C, and water (60 mL) was added. For the hydrolysis of 2a, sodium hydroxide (50 wt %, 14.8 g, 185 mmol) was added, and the reaction mixture was heated to 50-60 °C for ca. 2 h. The reaction mixture was cooled to 0-10 °C, and 85% phosphoric acid (4 mL) was added to lower the pH from ca. 14 to ca. 7. EtOAc (90 mL) was added, and the pH of the biphasic mixture was further lowered to ca. 4 with 85% phosphoric acid (7 mL). The phases were separated, and the upper rich EtOAc phase containing 2b (5.6 g, yield 88%, HPLC purity 99% (R,R)-isomer) was concentrated at 80 °C and atmospheric pressure until the moisture content of the solution was <0.1% (w/v). This solution was suitable for subsequent reactions leading to 1. An analytical sample of 2b was prepared by evaporating the EtOAc solution to an oil and then crystallizing from MTBE-heptane:
参考文献
Organic Process Research & Development 2002, 6, 618−620
案例二
化合物11和化合物12，在碱性条件下构建环丙烷，可得化合物13
HWE反应的扩展
实验操作
To a reactor under nitrogen was charged sodium tert-butoxide (239.3 mol,23.0 kg, 2.1 equiv.) and 1,2-dimethoxyethane (800 L). The reaction mixture was warmed up to 25 °C and ethyl 1-(diethoxyphosphoryl)acetate (240.9mol, 54.0 kg, 2.10 equiv.) was dosed over 1 h, followed by the addition of (R)-2-(4-bromo-3-fluorophenyl)oxirane 11 (21.9 wt%, 115.5 mol, 115 kg, 1.00 equiv.) as 1,2-dimethoxyethane solution over 1.5 h, then the mixture was warmed up to 80 °C.
Upon reaction completion, the reaction mixture was cooled to 25 °C and quenched by the slow addition of acetic acid (100 mol, 6.0 kg, 0.90 equiv.). Water (206 L) was added and the reaction mixture was extracted with heptane (250 L). The phases were separated then the aqueous layer was extracted with ethyl acetate (250 L). The organic layers were combined, concentrated under vacuum and solvent was switched to THF (84 L) to afford ethyl (1S,2S)-2-(4-bromo-3-fluorophenyl)cyclopropane-1-carboxylate 13 (29.7 wt%, 106 kg, 95 % yield) as a solution in THF.
参考文献
acs.oprd.1c00313
