案例一
实验操作
To a stirred suspension of piperazinyl quinazoline 13 (48.9 kg, 99.0mol) in DMSO (270 kg) was added potassium fluoride (7.50kg, 129 mol, 1.30 equiv), DABCO (0.444 kg, 3.96 mol, 4 mol%), and methanesulfonic acid (0.381 kg, 3.96 mol, 4 mol %) at 25 °C. The mixture was heated to 65 °C and stirred for 3 h.
After reaching full conversion (IPC limit: 13 < 0.1 area %), the mixture was cooled to 50 °C and aged at this temperature for 1 h to initiate product crystallization. The resulting suspension was then cooled to 22 °C over 3 h, followed by slow addition of acetonitrile/water (1:2, v/v, 89 kg) over 2 h. The mixture was aged for 30 min, and the product was isolated by filtration and washed with acetonitrile/water (1:1, v/v, 43 kg). The crude wet cake was then suspended in acetonitrile/water (1:2, v/v, 136 kg) and aged for 30 min before it was filtered and washed with acetonitrile/water (1:2, v/v, 45 kg). The wet cake was dried at 60 °C under reduced pressure to afford quinazoline fluoride 2 (43.5 kg) in 92% yield and 99.5 area % HPLC purity.
杂质谱
参考文献
https://doi.org/10.1021/acs.oprd.3c00351
案例二
实验操作
A solution of 25 (632.5 g, 2.75 mol) in tetrahydrofuran (ca. 1500 mL) was concentrated to low volumes at <40 °C at reduced pressure and diluted with anhydrous dimethyl sulfoxide (2.5 vols). Anhydrous cesium fluoride (953.8 g, 6.28 mol) was added, and the reaction was heated at 100 °C for 18 h.
After full conversion, most of the DMSO was distilled off at 100 °C (<10 mbar) and the mixture was then cooled to 25 °C. Ethyl acetate (5 vols) was added and stirred until a homogeneous suspension formed. The suspension was filtered through Celite and washed with ethyl acetate (2 vols). The filtrate was stirred with aqueous potassium carbonate solution (5% w/w, 2 vols) and activated carbon (Norit A Supra, 75.4 g) for 30 min. The mixture was filtered again through Celite washing with ethyl acetate (1 vol) before the phases were separated, and the organic phase was concentrated to ca. 780 g at atmospheric pressure. The solution was cooled to 20 ± 5 °C and seeded, and after crystallization started, the fine suspension was cooled to −55 to −60 °C and then filtered. The filter cake was washed with methylcyclohexane: ethyl acetate (4:1, 350 mL). After drying, 36 (318.4 g, 59% yield over 2 steps, qNMR assay 99.8% m/m, HPLC (210 nm) purity 99.8% and chiral purity 99.7%) was obtained as a white solid.
参考文献
https://doi.org/10.1021/acs.oprd.4c00049
