Reaction Steps
To a solution of (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (0.03 g, 0.078 mmol, example 1) in DCM (5 mL) was added (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (0.077 g, 0.408 mmol) followed by DCC (0.049 g, 0.235 mmol) and DMAP (9.58 mg, 0.078 mmol). The reaction mixture was stirred at rt for 18 h. Water (15 mL) was then added, and the layers were separated. The aqueous layer was extracted with DCM (3×15 mL) and the organic layers were combined, dried over Na2SO4, and concentrated to a crude product. The crude product was purified by preparative TLC eluting with 20% ethyl acetate in petroleum ether to provide the purified product (S)-4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl 2-((tert-butoxycarbonyl)amino)propanoate (0.032 g, 0.058 mmol, 74% yield) as off-white semi solid. LC-MS (Method A) RT=2.40 min, (M+H)+=554.2. 1H NMR (400 MHz, DMSO-d6) δ 7.51 (d, J=7.0 Hz, 1H), 7.44-7.32 (m, J=8.5 Hz, 2H), 7.21-7.09 (m, 4H), 7.07-6.98 (m, J=8.5 Hz, 2H), 4.62 (d, J=4.5 Hz, 1H), 4.39 (d, J=15.1 Hz, 1H), 4.30 (d, J=15.1 Hz, 1H), 4.27-4.17 (m, 1H), 3.58 (t, J=8.5 Hz, 1H), 3.50-3.40 (m, 1H), 3.22-3.07 (m, 2H), 2.81-2.64 (m, 3H), 2.39-2.31 (m, 1H), 2.29 (s, 3H), 2.17-2.04 (m, 1H), 1.93 (dd, J=12.8, 8.3 Hz, 1H), 1.78 (br. s., 1H), 1.74-1.59 (m, 1H), 1.41 (s, 9H), 1.39 (d, J=2.5 Hz, 3H). 19F NMR (376 MHz, DMSO-d6) δ −180.172.
