Synthesis
Step 2: Synthesis of (2S,4S)-1-Boc-2-cyano-4-fluoropyrrolidine
To a stirred and cooled to 0 °C solution of (2S,4S)-N-Boc-4-fluoropyrrolidine-2-carboxamide (10 g, 43.10 mmol) in anhydrous THF (50 ml) was sequentially added triethylamine (13.93 g, 138 mmol) and trifluoroacetic anhydride (14.5 g, 69.05 mmol). The reaction mixture was continued to be stirred at 0°C for 1 hour. After completion of the reaction, the reaction was quenched with 100 ml of water and extracted with chloroform (2 x 100 ml). The organic phases were combined, washed sequentially with water (2 x 100 ml) and brine (50 ml) and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to give 9.0 g of off-white solid product in 97.6% yield.
IR (KBr, cm-1): 2979, 2243, 1387, 1240, 1168, 1123, 1072, 960.
1H NMR (CDCl3, 300MHz) δ: 1.49-1.53(d, rotary isomer, 9H), 2.25-2.47(m, 1H), 2.64(t, J=14.7Hz, 1H), 3.52(dd, J=9.6,3.6Hz, 0.5H, rotary isomer), 3.64(dd, J=9.3,3.3Hz , 0.5H, rotary isomer), 3.73-3.94 (m, 1H), 4.64 (dd, J=8.7 Hz, 0.6H, rotary isomer), 4.76 (dd, J=8.7 Hz, 0.4H, rotary isomer), 5.31 (brd, J=51.3 Hz, 1H).
References
[1] Chemical and Pharmaceutical Bulletin, 2008, vol. 56, # 8, p. 1110 - 1117
[2] Patent: WO2005/75426, 2005, A1. Location in patent: Page/Page column 35-36
[3] Patent: WO2006/90244, 2006, A1. Location in patent: Page/Page column 29
[4] Patent: WO2006/40625, 2006, A1. Location in patent: Page/Page column 44
[5] Patent: WO2007/99385, 2007, A1. Location in patent: Page/Page column 26
