反应详情

温度

60 °C

Crude (S)-6-Chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2-(4'-methoxyphenyl) -3, 1-benzoxazine (71 kg calculated dry weight) was charged to a mixture of methanol (301 kg), 30% NaOH (121 kg) and water (61L). The mixture was heated to 60° C. to give a clear solution then cooled to 30° C. A solution of sodium borohydride (3.2 kg, 84.2 mol) in 0.2 N NaOH (29L) was added to the methanolic solution over 20 min, keeping the temperature below 35° C. After 30 min, excess borohydride was quenched with acetone (5.8 kg) and the solution diluted with water (175L) then neutralized to pH 8 to 9 with acetic acid. The resulting slurry was cooled to about 0° C., filtered and the product washed with water then dried in vacuo at 40° C. The crude product was reslurried with a mixture of toluene (133 kg) and heptanes (106 kg) initially at 25° C., then with cooling below -10° C. The product was filtered, washed with heptanes (41 kg) and dried in vacuo at 40° C. to give 44.5 kg (88%) as an off-white/pale yellow crystalline solid. An analytical sample was recrystallized from t-butyl methyl ether/heptane: mp 141-143° C.; [a]25D -28.3° (c 0.106, MeOH); 1H NMR (300 MHz, CDCl3) δ7.54 (d, J=2 Hz, 1H), 7.13 (dd, J=9, 2 Hz, 1H), 6.61 (d, J=9 Hz, 1H), 4.61 (brs, 1H), 4.40 (brs, 1H), 1.44-135 (m, 1H), 0.94-0.78 (m, 2H): 13C NMR (75 MHz, DMSO-d6) δ146.7, 129.4, 129.0, 124.3, 118.4, 118.07, 118.05, 92.3, 72.6, 71.0, 8.2, 8.1, -1.1; 19F NMR (282 MHz CDCl3) δ-80.5.

1. customto give a clear solution
2. temperaturethen cooled to 30° C
3. customthe temperature below 35° C
4. customexcess borohydride was quenched with acetone (5.8 kg)
5. additionthe solution diluted with water (175L)
6. temperatureThe resulting slurry was cooled to about 0° C.
7. filtrationfiltered
8. washthe product washed with water
9. customthen dried in vacuo at 40° C
10. additionThe crude product was reslurried with a mixture of toluene (133 kg) and heptanes (106 kg) initially at 25° C.
11. temperaturewith cooling below -10° C
12. filtrationThe product was filtered
13. washwashed with heptanes (41 kg)
14. customdried in vacuo at 40° C.
15. customto give 44.5 kg (88%) as an off-white/pale yellow crystalline solid
16. customAn analytical sample was recrystallized from t-butyl methyl ether/heptane