反应详情

温度

0 °C

To a solution of 2-(1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethanol (60 mg, 0.185 mmol) in toluene (5 mL) was added tetrabutylammonium chloride hydrate (16.4 mg, 0.055 mmol). The reaction mixture was cooled to 0° C. and added 35% NaOH (5 mL), followed by tert-butyl bromoacetate (0.041 mL, 0.277 mmol). The reaction was stirred at rt for 4 h. The organic layer was separated, washed with 1 N aqueous HCl (3×5 mL) and brine (5 mL), dried, and concentrated in vacuo to afford tert-butyl 2-(2-(1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethoxy)acetate. The above ester was stirred with 1 N aqueous NaOH (3 mL) and MeOH (5 mL) under reflux for 2 h. The mixture was concentrated in vacuo. The residue was dissolved in EtOAc (5 mL), washed with 1 N aqueous HCl (5 mL) and H2O (3×5 mL), and concentrated in vacuo. The crude product was purified by preparative HPLC (PHENOMENEX® Axia 5μ C18 30×100 mm column; detection at 220 nm; flow rate=40 mL/min; continuous gradient from 30% B to 100% B over 10 min+2 min hold time at 100% B, where A=90:10:0.1 H2O:MeOH:TFA and B=90:10:0.1 MeOH:H2O:TFA) to afford the title compound (50 mg, 67% yield) as a clear oil. LCMS, [M+H]+=383.2. 1H NMR (500 MHz, CDCl3) δ 9.59 (s, 1H), 7.35-7.21 (m, 3H), 7.17-7.02 (m, 3H), 7.02-6.92 (m, 2H), 6.85 (ddd, J=8.1, 2.4, 1.0 Hz, 1H), 4.10 (s, 2H), 3.87 (s, 2H), 3.59 (t, J=6.9 Hz, 2H), 2.16-1.92 (m, 4H), 1.72 (q, J=7.6 Hz, 4H), 1.53 (t, J=6.9 Hz, 2H). HPLC-1: RT=11.0 min, purity=92.1%; HPLC-2: RT=9.7 min, purity=91.1%.

1. customThe organic layer was separated
2. washwashed with 1 N aqueous HCl (3×5 mL) and brine (5 mL)
3. customdried
4. concentrationconcentrated in vacuo