反应详情

温度

25 °C

Charge 2 N NaOH (37 mL, 5.0 equivalents) and diethyl (1S,2S,5R,6S)-2-[[(2S)-2-(tert-butoxycarbonylamino)propanoyl]amino]spiro[bicyclo[3.1.0]hexane-4,1′-cyclopropane]-2,6-dicarboxylate (6.50 g, 14.81 mmol) to a reactor and allow to stir for at least 12 hours between 20-30° C. until the reaction is complete by HPLC. Transfer the reaction to a separatory funnel and allow it to settle for at least 10 minutes. Separate the phases and return the lower aqueous layer to the reactor. Add ethyl acetate (90 mL, 13.8 volumes) to the mixture, and then add 1 N NaHSO4 until pH reaches 2 to 2.5. Separate layers and wash the organic with water (45 mL, 6.9 volumes). Remove water in organic phase atmospheric distillation with ethyl acetate to remove residual water. Cool the resulting slurry between 20-30° C. over at least 2 hours and allowed to granulate at that temperature for at least 90 minutes. Filter the resulting solids and wash the wet cake with ethyl acetate (3×15 mL, 2.3 volumes). Dry under reduced pressure at 45° C. to provide the title compound as a white solid (4.45 g, 11.64 mmol, 78.6%) 1H NMR (DMSO-d6, 400 MHz, 50° C.): δ 12.01 (s, 2H), 8.22 (s, 1H), 6.49 (bs, 1H), 4.00 (bs, 1H), 2.43 (dd, J=6.5, 2.8, 1H), 1.83 (d, J=14.0, 1H), 1.68-1.62 (m, 2H), 1.42 (dd, J=6.5, 2.8, 1H), 1.36 (s, 9H), 1.15 (d, J=7.1, 3H), 0.67-0.61 (m, 1H), 0.56-0.51 (m, 1H), 0.46-0.36 (m, 2H).

1. customTransfer the reaction to a separatory funnel
2. waitto settle for at least 10 minutes
3. customSeparate the phases
4. additionAdd ethyl acetate (90 mL, 13.8 volumes) to the mixture, and then add 1 N NaHSO4 until pH
5. washSeparate layers and wash the organic with water (45 mL, 6.9 volumes)
6. distillationRemove water in organic phase atmospheric distillation with ethyl acetate
7. customto remove residual water
8. temperatureCool the resulting slurry between 20-30° C. over at least 2 hours
9. waitto granulate at that temperature for at least 90 minutes
10. filtrationFilter the resulting solids
11. washwash the wet cake with ethyl acetate (3×15 mL, 2.3 volumes)
12. customDry under reduced pressure at 45° C.