反应详情

温度

50 °C

A mixture of methyl 2-(2-(1-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethyl)cyclopropanecarboxylate (61A; 8.8 g, 21.2 mmol), and PPTS (1.07 g, 4.25 mmol) in MeOH (50 mL) was stirred at 50° C. for 3 h, then was cooled to rt and concentrated in vacuo. The residual crude oil was chromatographed (SiO2; gradient with 0% to 30% EtOAc/hexane over 20 min to give methyl 2-(2-(1-(3-hydroxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethyl)cyclopropanecarboxylate (racemate; 7.0 g, 21.2 mmol, 100% yield) as a white solid. LCMS [M+H]+=331.1; 1H NMR (CDCl3) δ: 7.18 (t, J=7.9 Hz, 1H), 6.99-6.86 (m, 2H), 6.69 (ddd, J=8.0, 2.6, 1.0 Hz, 1H), 5.32 (s, 1H), 3.82 (d, J=1.1 Hz, 2H), 3.69 (s, 3H), 2.07-1.95 (m, 4H), 1.71-1.57 (m, 4H), 1.45-1.14 (m, 7H), 0.73 (ddd, J=8.1, 6.3, 4.2 Hz, 1H). This racemate was separated by chiral preparative HPLC (Instrument=Berger Multigram II SFC; Column: CHIRALPAK® AD-H, 30×250 mm, 5μ; Mobile Phase: 20% MeOH/80% CO2; Flow Conditions: 85 mL/min, 150 Bar, 40° C.; Detector Wavelength: 220 nm; Injection Details: 1.0 mL of ˜150 mg/mL) to give Example 65A (2.35 g, 7.11 mmol, 45% yield; [α]=+60.6° (1.8% in DCM) @589 nm) and Example 65B (2.34 g, 7.08 mmol, 45% yield; [α]=−72.2° (1.0% in DCM) @589 nm) as oils.

1. temperaturewas cooled to rt
2. concentrationconcentrated in vacuo
3. customThe residual crude oil was chromatographed (SiO2