實驗操作A 2 L reactor with gas scrubbing (bleach/25% aqueous KOH, 5:1 v/v) was charged with DMSO (600 g) and 12 (100 g, 0.3 mol). This solution was heated to ca. 45 °C. Then, K2CO3 (107.6 g, 0.77 mol, 2.6−3.0 equiv) powder was added, and the batch was warmed to 45 °C. At this temperature, 20 L/h 10% O2 in N2 was added to the subsurface with intensive stirring until full conversion was achieved. After cooling to 20−25 °C, water (600 g) was dosed in a way that the temperature did not rise above 40 °C.The suspension is stirred for 1 h and filtered. The solid cake is washed with water (425 g) and the crude product fed back into the vessel. The filter cake is dissolved in ethyl acetate (765 g), and the organic phase is washed with 10% brine (480 g). The phases are allowed to settle and then separated. The organic phase is then distilled down to ca. 1/3 of the volume at normal pressure and then swapped to isopropanol. Distillation is continued to a sump weight of roughly 276 g. Upon cooling, the product crystallizes. The suspension is stirred at 0−5 °C for ca. 1 h, then the suspension is filtered and the filter cake washed with 9:1 m/m mixture of cyclohexane and iso-propanol (58.5 g). The product is dried at 40 °C under a vacuum with a nitrogen bleed to yield PF- 07062297 (70.9 g, 98.7% assay, 73.4% assay corrected yield, 98.0% HPLC purity). These conditions were reproduced on an 80 kg scale to obtain 80% yield.
Caution! Cyanide is evolved from the reaction. Cyanide and hydrogen cyanide are highly toxic, and appropriate precautions should be taken. The following safety precautions were taken: Off-gas wash with 6% NaOCl/16% NaOH (ca. 5:1); waste streams disposed of into caustic soda; sampling minimized in the pilot plant; HCN detectors near the reaction vessel and with operators. The flash point of DMSO is 89 °C in air, which increases even further when using 10% O2 in N2. The reaction can be performed at the desired temperature of 45 °C. The DSC of the isolated product has an onset temperature of 130 °C.參考文獻https://doi.org/10.1021/acs.oprd.3c00477
