反应详情

To a stirred solution of methyl 3,5-dihydroxybenzoate (5.95 mol) in DMF (6 L) was added potassium carbonate (9 mol), and the suspension stirred at ambient temperature under argon. To this was added benzyl bromide (8.42 mol) slowly over 1 hour, with a slight exotherm, and the reaction mixture stirred overnight at ambient temperature. The reaction was quenched cautiously with ammonium chloride solution (5 L) followed by water (35 L). The aqueous suspension was extracted with DCM (1×3 L and 2×5 L). The combined extracts were washed with water (10 L) and dried overnight (MgSO4). The solution was evaporated in vacuo, and the crude product chromatographed in 3 batches (flash column, 3×2 kg silica, eluting with a gradient consisting of hexane containing 10% DCM, to neat DCM, to DCM containing 50% ethyl acetate) to eliminate starting material. The crude eluant was further chromatographed in 175 g batches (Amicon HPLC, 5 kg normal-phase silica, eluting with isohexane containing 20% v/v of ethyl acetate) to give the desired compound (21% yield); 1H 1H NMR δ (d6-DMSO): 3.8 (s, 3H), 5.1 (s, 2H), 6.65 (m, 1H), 7.0 (m, 1H), 7.05 (m, 1H), 7.3-7.5 (m, 5H), 9.85 (br s, 1H).

1. stirringwith a slight exotherm, and the reaction mixture stirred overnight at ambient temperature
2. customThe reaction was quenched cautiously with ammonium chloride solution (5 L)
3. extractionThe aqueous suspension was extracted with DCM (1×3 L and 2×5 L)
4. washThe combined extracts were washed with water (10 L)
5. dry with materialdried overnight (MgSO4)
6. customThe solution was evaporated in vacuo
7. customthe crude product chromatographed in 3 batches (flash column, 3×2 kg silica
8. washeluting with a gradient
9. customThe crude eluant was further chromatographed in 175 g batches (Amicon HPLC, 5 kg normal-phase silica
10. washeluting with isohexane containing 20% v/v of ethyl acetate)