Reaction Steps
(2S,4S)-4-Hydroxy-1-(1-methyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (62.0 g, 224 mmol) and 4-(dimethylamino)pyridine (98%, 1.5 g, 12.0 mmol) were dissolved in dichloromethane (370 mL), benzenesulfonyl chloride (31.1 mL, 242 mmol), followed by triethylamine (49.8 mL, 358 mmol) were added at room temperature and the mixture was stirred for 16 h. After that, it was diluted with water (140 mL) and acidified by addition of hydrochloric acid (25% m/m, 21.4 mL). The phases were separated and the organic layer was washed with water (160 mL). The combined aqueous phases were extracted with dichloromethane (160 mL), the combined organic extracts were concentrated in vacuo to a volume of 430 mL. The solvent was exchanged via continuous distillation in vacuo (internal temperature 40° C., 670-170 mbar) to ethanol (670 mL added), the overall volume was kept constant (430 mL). The resulting solution was allowed to cool to room temperature and seed crystals (ca. 10 mg) were added to initiate crystallization. After crystallization had started, the suspension was stirred for 30 min at room temperature, heptane (430 mL) was added within 50 min and it was stirred for 12 h. The suspension was then filtered, the precipitate was washed with heptane/ethanol 2:1 (v/v, 321 mL) and heptane (107 mL) and dried in vacuo at 40° C. to yield the title compound as a white crystalline solid (80.0 g, 85%). MS (ESI & APCI): m/z=418.1 [M+H]+. 1H NMR (CDCl3, 600 MHz): δ 0.59-0.64 (m, 1H), 0.65-0.69 (m, 1H), 0.80-0.90 (m, 1H), 0.99-1.05 (m, 1H), 1.12-1.21 (m, 2H), 1.30 (s, 3H), 1.47-1.53 (m, 2H), 2.15 (ddd, J=5.8 Hz, 9.2 Hz, 14.6 Hz, 1H), 2.70 (br d, J=14.0 Hz, 1H), 3.83 (dd, J=3.8 Hz, 12.3 Hz, 1H), 4.08 (dd, J=5.3 Hz, 12.4 Hz, 1H), 4.55 (br s, 1H), 5.04-5.08 (m, 1H), 7.49 (br s, 1H), 7.61 (t, J=7.8 Hz, 2H), 7.70 (t, J=7.5 Hz, 1H), 7.96 (d, J=7.6 Hz, 2H).
