4-Methylmorpholine → Diethyl (1S,2S,5R,6S)-2-[[(2S)-2-(tert-butoxycarbonylamino)propanoyl]amino]spiro[bicyclo[3.1.0]hexane-4,1'-cyclopropane]-2,6-dicarboxylate

Participants

Reaction Conditions

Reaction Steps

Charge tetrahydrofuran (45 mL, 10 volumes) and (2S)-2-(tert-butoxycarbonylamino)propanoic acid (3.4 g, 1.2 equivalents) to a reactor followed by N-methylmorpholine (1.96 mL, 1.2 equivalents) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (3.12 g, 1.2 equivalents). Stir the resulting thin slurry between 20-25° C. for at least 3 hours until the reaction is complete by HPLC. Charge diethyl (1S,2S,5R,6S)-2-aminospiro[bicyclo[3.1.0]hexane-4,1′-cyclopropane]-2,6-dicarboxylate hydrochloride (4.55 g, 14.81 mmol) in one portion between 20-25° C. followed by N-methylmorpholine (1.63 mL, 1.0 equivalents) over at least 10 minutes keeping the temperature between 20-25° C. Stir the resulting slurry between 20-25° C. for at least 2 hours until the reaction is complete by HPLC. Filter the resulting solids and wash the wet cake with tetrahydrofuran (2×10 mL, 2.2 volumes) to provide the title compound assuming 100% yield. Use the pale amber tetrahydrofuran solution of the title compound without further purification assuming a 100% yield. 1H NMR (DMSO-d6, 400 MHz): δ 8.46 (s, 1H), 6.72 (d, J=7.9, 1H), 4.08-3.92 (m, 5H), 2.42-2.37 (m, 1H), 1.81-1.64 (m, 3H), 1.47 (dd, J=6.6, 3.1, 1H), 1.34 (s, 9H), 1.18-1.08 (m, 9H), 0.66-0.59 (m, 1H), 0.57-0.52 (m, 1H), 0.46-0.36 (m, 2H).

Provenance & Evidence