反应详情

A mixture of ethyl 2-iodo-4-trifluoromethyl-benzoate (723 g, 2.1 mol), (3S, 4R)-(3-benzyl-4-hydroxy-chroman-7-yl)-boronic acid (627 g, 2.2 mol), potassium fluoride (366 g, 6.3 mol), 10% palladium on carbon (157 g, 50% water wet), and anhydrous ethanol (6.27 L) was heated at reflux for 3 hours at which point thin layer chromatography (toluene/acetic acid, 5:1) indicated the reaction to be complete. The reaction mixture was diluted with isopropyl ether (8 L), filtered through Celite® and washed with 10% aqueous sodium bicarbonate (1.5 L). The aqueous layer was separated and extracted with isopropyl ether (3 L). The combined organic layers were washed with water (6 L), dried over magnesium sulfate, and treated with Darco®G-60 (1.0 kg) and silica gel (1 kg, 70-230 mesh) at ambient temperature. This mixture was filtered-through a pad of silica gel (70-230 mesh) and concentrated in vacuo to 922 g of dark oil. This oil was diluted with ethyl acetate (1 L) and filtered through a column of silica gel (2 kg) eluting with ethyl acetate giving a light amber solution which was concentrated to afford 897 g (92%) of (3S, 4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoicacid ethyl ester as a light amber oil: 1H NMR (400 MHz, CDCl3) 67 7.89 (d, J=8.1 Hz, 1H), 7.63-7.67 (m, 2H), 7.18-7.38 (m, 6H), 6.91 (dd, J=1.8, 7.8 Hz, 1 H), 6.86 (d, J =1.7 Hz, 1H), 4.55 (bs, 1H), 4.25 (dd, J=2.7, 11.2 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H), 4.00 (ddd, J=1.0, 4.5, 11.2 Hz, 1 H), 2.75 (dd, J=6.4, 13.9 Hz, 1 H), 2.56 (dd, J=9.3, 13.8 Hz, 1 H), 2.26 (m, 1 H), 1.93 (d, J=4.3 Hz, 1 H), 1.09 (t, J=7.2 Hz, 3H); IR 3307 (br), 3216 (br), 1734, 1339, 1298, 1247, 1191, 1175, 1118, 1097, 1050 cm−1.

1. temperaturewas heated
2. customthe reaction
3. filtrationfiltered through Celite®
4. washwashed with 10% aqueous sodium bicarbonate (1.5 L)
5. customThe aqueous layer was separated
6. extractionextracted with isopropyl ether (3 L)
7. washThe combined organic layers were washed with water (6 L)
8. dry with materialdried over magnesium sulfate
9. additiontreated with Darco®G-60 (1.0 kg) and silica gel (1 kg, 70-230 mesh) at ambient temperature
10. filtrationThis mixture was filtered-through a pad of silica gel (70-230 mesh)
11. concentrationconcentrated in vacuo to 922 g of dark oil
12. additionThis oil was diluted with ethyl acetate (1 L)
13. filtrationfiltered through a column of silica gel (2 kg)
14. washeluting with ethyl acetate giving a light amber solution which
15. concentrationwas concentrated