化合物15的制备To a solution of 14 (50.4kg, 254.3 mol, 1.0 equiv) in THF (250 L, 5 vol) was charged N-phenylbis(trifluoromethanesulfonimide) (128 kg, 356.3 mol, 1.4 equiv). The resulting mixture was cooled to 0−5 °C, at which point lithium bis(trimethylsilyl)amide (LiHMDS) (1.0 M in THF, 330 L, 330.9 mol, 1.3 equiv) was charged over 1 h while maintaining the batch temperature below 5 °C. Upon addition completion, the batch was warmed to ambient temperature, and agitation continued for an additional 2 h. The batch was quenched with H2O (150 L, 3 vol) slowly followed by addition of 3 M NaOH (90 L) with agitation. To the resulting mixture was charged heptane (250 L, 5 vol), and the layers were separated. The bottom aqueous layer was discarded, and the top organic layer was washed with 5 wt % NaCl solution twice. The combined organic phases were concentrated by distillation under reduced pressure to afford 65.4 kg of crude 15 that was directly used in the next step. 化合物16的制备A reactor under N2 flow was charged with DMF (60 L, 2vol) and lithium chloride (14.4 kg, 269.7 mol, 3.0 equiv). The resulting mixture was agitated until most of the solids were dissolved. (Note: a mild exotherm was observed). The batch was cooled to ambient temperature, at which point 15 (29.7 kg, 89.9 mol, 1.0 equiv) was charged. The resulting mixture was agitated for 12−14 h at ambient temperature. The batch was charged with H2O (60 L, 2 vol) and continued to agitate for an additional 20−30 min, at which point heptane (80 L) was charged. The layers were settled and separated, and the bottom aqueous layer was discarded. The top organic layer was washed with 5 wt % NaCl solution twice, followed by concentration by distillation under reduced pressure to yield 16.2 kg of crude 16 that was directly used in the next step. 参考文献https://doi.org/10.1021/acs.oprd.3c00362
