反应详情

温度

22.5 °C

(S)-5-Chloro-α-(cyclopropylethynyl)-2-amino-α-(trifluoromethyl)benzenemethanol (15.7 kg, 54.3 mol) was dissolved in a mixture of heptanes (32 kg) and THF (52 kg) below -10° C. Phosgene (~8.0 kg, 80 mol) was directly fed below the surface over about 1 h, keeping the temperature below 0° C. The resulting slurry was warmed to 20-25° C. and held 1 hour. Methanol (6.5 kg, 203 mol) was added and the solution stirred about 30 min. Heptanes (97 kg) was added and ~140 L of solvent was distilled under reduced pressure. Heptanes (97 kg) and THF (22 kg) were added and the solution washed with 5% aqueous sodium bicarbonate (15 L), followed by water (15 L). The solution was warmed to 50° C. and filtered into a clean reactor, followed by a 40 kg heptanes rinse. The solution was concentrated under reduced pressure, diluted with heptanes (22 kg) and cooled below -10° C. The product was filtered, washed with heptanes (37 kg) and dried in vacuo at 90-100° C. to give 16.0 kg (95%) as an off-white to slightly pinkish solid. HPLC: 99.8 area %: mp 139-141° C.; [a]25D -94.1° (c 0.300, MeOH); 1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 7.54 (dd, J 32 2.5, 7 Hz, 1H), 7.43 (d, J=2.5 Hz, 1H), 6.99 (d, J=7 Hz, 1H), 1.58 (m, 1H), 0.92 (m, 2H), 0.77 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 146.23, 134.71, 132.04, 126.93, 126.57, 122.24, 116.83, 114.08, 95.63, 77.62, 65.85, 8.48, 8.44, -1.32; 19F NMR (282 MHz, DMSO-d6) δ -81.1.

1. customthe temperature below 0° C
2. distillation~140 L of solvent was distilled under reduced pressure
3. additionHeptanes (97 kg) and THF (22 kg) were added
4. washthe solution washed with 5% aqueous sodium bicarbonate (15 L)
5. temperatureThe solution was warmed to 50° C.
6. filtrationfiltered into a clean reactor
7. washrinse
8. concentrationThe solution was concentrated under reduced pressure
9. additiondiluted with heptanes (22 kg)
10. temperaturecooled below -10° C
11. filtrationThe product was filtered
12. washwashed with heptanes (37 kg)
13. customdried in vacuo at 90-100° C.
14. customto give 16.0 kg (95%) as an off-white to slightly pinkish solid