反应详情

温度

85 °C

A solution of (S)-1-(4-(difluoromethyl)benzyl)-2-oxopyrrolidin-3-yl methanesulfonate (500 mg, 1.57 mmol, intermediate M) in 5.0 mL of acetonitrile was added dropwise over 1.5 h to a stirred mixture of 4-((3S,4S)-3-fluoropiperidin-4-yl)phenol, hydrochloride (363 mg, 1.57 mmol, intermediate F) and N,N-diisopropylethylamine (1.09 mL, 6.26 mmol) in 5.0 mL of acetonitrile maintained at 85° C. After complete addition, the reaction mixture was stirred at 85° C. for 16 h. The reaction mixture was concentrated in vacuo. The residue was purified using silica gel column chromatography (0-100% EtOAc/hexanes) to afford a diasteromeric mixture (partial epimerization of the lactam stereocenter) of 1-(4-(difluoromethyl)benzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one (235 mg, 35% yield). A sample of the diastereomeric mixture (780 mg) was separated by preparative chiral SFC (column=Lux Cellulose-2 (21×250 mm, 5 μm); isocratic solvent=20% methanol (with 15 mM ammonia)/80% CO2; temp=35° C.; flow rate=60 mL/min; injection volumn=1.0 mL (˜20 mg/mL in MeOH) stacked @ 13 min intervals; λ=210 nM; Peak 1=19.6 min, Peak 2=24.5 min) to afford the titled compounds of example 6 (Peak-1, 389 mg) and (S)-1-(4-(difluoromethyl)benzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one (Peak 2, 242 mg). Data for Example 6: LC-MS m/z 419.3 (M+H); 1H NMR (500 MHz, chloroform-d) δ 7.50 (d, J=7.9 Hz, 2H), 7.34 (d, J=7.9 Hz, 2H), 7.15 (d, J=8.5 Hz, 2H), 6.91-6.80 (m, 2H), 6.65 (t, J=56.4 Hz, 1H), 4.96 (s, 1H), 4.77-4.43 (m, 3H), 3.68 (t, J=8.8 Hz, 1H), 3.42-3.33 (m, 1H), 3.29-3.14 (m, 2H), 2.85 (d, J=10.4 Hz, 1H), 2.78-2.69 (m, 1H), 2.69-2.57 (m, 1H), 2.48 (td, J=9.9, 4.9 Hz, 1H), 2.21-2.11 (m, 1H), 2.04 (dq, J=13.0, 8.6 Hz, 1H), 1.94-1.82 (m, 2H)). The relative and absolute configuration of Example 114, P-1 was confirmed by single crystal X-ray analysis.

1. additionAfter complete addition
2. concentrationThe reaction mixture was concentrated in vacuo
3. customThe residue was purified