[Synthesis]
1. The crude products (3S,4R)-1-(tert-butyl)-4-(2,4-difluorophenyl)pyrrolidine-3-carbonitrile and (3R,4R)-1-(tert-butyl)-4-(2,4-difluorophenyl)pyrrolidine-3-carbonitrile (4.88 kg, 18.46 mol) were dissolved in n-heptane (ca. 65 L) and concentrated by reduced-pressure distillation (50-60 torr, 25 °C) to ca. 6 L. Ethanol (15 L) was added and concentration was continued to 6 L. The solution was then diluted with ethanol (14.6 L) to give a total volume of 20.6 L. The solution was then diluted with ethanol (14.6 L).
2. 50% aqueous NaOH solution (2.7L, 51.15mol) was slowly added to the above solution under stirring for 2 minutes. The mixture was heated to reflux (78-80°C) under nitrogen protection for 5 to 6 h. The reaction progress was monitored by HPLC.
3. After completion of the reaction, the solution was cooled to 20 °C and diluted with ethanol (25.4 L) and methanol (40.6 L) to obtain a 1:1 MeOH:EtOH mixture in a total volume of 88 L. The reaction was carried out by HPLC. The solution was cooled to 12°C and 96% H2SO4 (1.42L, 25.6 mol) was slowly added, maintaining the temperature at about 20°C.
4. The slurry was filtered through a Solka-Floc bed (5 kg) and anhydrous Na2SO4 (4 kg) and washed with 1:1 EtOH:MeOH (60 L). The filtrate was filtered again and the solvent was converted to 2-propanol solution (about 15 L) by distillation under reduced pressure, during which the product crystallized.
5. The slurry was heated to reflux (about 80°C) for 2 hours to partially dissolve the product. The mixture was then cooled to 16°C and MTBE (30.4L, 3 volumes relative to IPA) was added over 5 hours to form a mixture with a 1:3 IPA:MTBE ratio.
6. After stirring at 16-17°C for 3 days, the slurry was filtered and the solids were washed with 12 L of 1:3 IPA:MTBE. The solid was dried under vacuum at 50 °C (150 Torr) and purged with nitrogen for 3 days to give a white crystalline solid amphoteric 1-9. 7.
7. Product identification: HPLC purity 99.97%; enantiomeric excess >99.99%. 1H-NMR (400.25 MHz, D2O) δ 7.30 (m, 1H), 6.92-6.85 (m, 2H), 4.68 (OH), 3.75-3.66 (m, 3H), 3.45 (bm, 1H), 3.30-3.14 (m , 2H), 1.32-3.14 (m, 2H). , 2H), 1.32 (s, 9H).13C-NMR (100.65MHz, D2O) δ 176.5, 162.8 (dd, J=123.7,12.6), 160.3 (dd, J=124.5,12.7), 129.9 (dd, J=10.1,5.9), 119.7, 111.7 (dd, J=21.5,3.6), 2.5 (bm, 3.6), 3.30-3.14 (m, 2H), 3.30-3.14 (m), 1.32 (s, 9H). 21.5,3.6), 104.1 (t, J=26.2), 62.0, 51.9, 51.0, 50.6, 41.3, 23.7 (3C). Melting point (DSC): 215°C onset, 217°C peak. Elemental analysis (C15H19F2NO2): calculated values C, 63.59; H, 6.76; F, 13.41; N, 4.94; measured values C, 63.50; H, 6.81; F, 13.11; N, 4.91. |