1-Boc-(2S,4S)-2-cyano-4-fluoropyrrolidine

Step 2; (2S, 4S)-N-BOC-4-fluoropyrrolidine-2-carbonitrile; To a stirred and cooled (0 °C) solution of (2S, 47)-N-BOC-4-fluoropyrrolidine-2-carboxamide (10 g, 43.10 mmol) in dry THF (50 ml) was added triethylamine (13.93 g, 138 mmol) and trifluoroacetic anhydride (14.5 g, 69.05 mmol). The resulting clear solution was stirred at the same temperature for 1 h. The reaction was quenched with water (100 ml) and extracted with chloroform (2 x 100 ml). The combined organic extracts were washed with water (2 x 100 ml), brine (50 ml) and dried (Na2SO4). The solvent was evaporated under reduced pressure to give 9.0 g (97.6 percent) of the product as an off- white solid. IR (KBr) 2979, 2243, 1387, 1240, 1168, 1123, 1072, 960 cm-1 ;'H NMR (CDC13, 300 MHz) 8 1.49-1. 53 (d, rotomer, 9H), 2.25-2. 47 (m, 1H), 2.64 (t, J= 14.7 Hz, 1H), 3.52 (dd, J = 9.6, 3.6 Hz, 0. 5H, rotomer), 3.64 (dd, J = 9.3, 3.3 Hz, 0. 5H, rotomer), 3.73-3. 94 (m, 1H), 4.64 (d, J= 8.7 Hz, 0.6H, rotomer), 4.76 (d, J= 8.7 Hz, 0.4 H, rotomer), 5.31 (brd, J= 51.3 Hz, 1H).Step 2: (2To a stirred and cooled (0 Step 2: (2.S', 45)-N-BOC-4-Fluoropyrrolidine-2-carbonitrile: To a stirred and cooled (0 Step 2: (25To a solution of the title compound of Step 2 (550 mg, 2.37 mmol) and dry pyridine (0.4 mL, 2 equiv.) in anhydrous methylene chloride (15 mL) at 0° C. was added a solution of TFAA in 2 mL of methylene chloride under nitrogen. The solution was stirred at 0° C. for two hr and then at RT for one hr. The reaction mixture was washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel to give 458 mg (90percent yield) of an oil that solidified on standing. MS m/z 215.3 (MHA mixture of compound 14 (13g, 56.0mmol) and cyanuric chloride (6.19g, 33.6mmol) in DMF (10mL) was stirred at room temperature for 2h (monitored by TLC). After the reaction completed, the solution was extracted with EtOAc, washed, dried, concentrated, and purified by flash chromatography on silica gel, eluted with a mixture of PE/EA (1/1, v/v), to afford 15 (9.7g, 76percent) as a white solid. Step 4 Preparation of (2S, 4S)-tert-butyl 2-cyano-4-fluoropyrrolidine-1-carboxylate (2S, 4R)-tert-Butyl 2-cyano-4-hydroxypyrrolidine-1-carboxylate 13d (49.7 g, 0.2344 mol) was dissolved in 1130 mL of dichloromethane with stirring under argon atmosphere. The mixture was cooled to -30 °C followed by addition of diethylaminosulfur trifluoride (56.7 g, 0.3516 mol). After stirred for 45 minutes, the reaction mixture was warmed up to -5 °C. Then the mixture was reacted overnight at room temperature. The reaction was monitored by TLC until the disappearance of the starting materials. The reaction mixture was neutralized with saturated aqueous sodium carbonate solution to pH > 7 at such a rate that the reaction temperature was kept below 20 °C. Then ice water and 500 mL of dichloromethane were added. The separated organic phase was washed with 500 mL of saturated aqueous sodium hydrogen sulfate and 500 mL of saturated brine successively, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure in which the concentration temperature was kept below 38 °C to obtain the title compound (2S, 4S)-tert-butyl 2-cyano-4-fluoropyrrolidine-1-carboxylate 13e (50 g, yield 100percent) as a light yellow solid.Preparation of tert-Butyl (2S, 4S)-2-cyano-4-flouro-l-pyrrolidine-l-carboxylateIn a 3L 4-necked RB flask, fitted with a mechanical stirrer and condenser, MDC (880.0ml) was added and stirring begun. tert-Butyl (2S, 4R)-2-cyano-4-hydroxy-pyrrolidine-l- carboxylate (86.25g, 0.406M) was added and the reaction mass was maintained at 20-25

Molecular Weight:214.24
XLogP3:1.5
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:2
Exact Mass:214.11175589
Monoisotopic Mass:214.11175589
Topological Polar Surface Area:53.3
Heavy Atom Count:15
Complexity:302
Defined Atom Stereocenter Count:2
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes