Sodium Hydroxide → (1S,2S,5R,6S)-2-[[(2S)-2-(tert-butoxy carbonylamino)propanoyl]amino]spiro[bicyclo[3.1.0]hexane-4,1'-cyclopropane]-2,6-dicarboxylic acid

Participants

Reaction Conditions

Reaction Steps

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).

Provenance & Evidence