反应详情

Under a nitrogen atmosphere, (2S)-1-(4-benzyloxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanone dibenzoyl D-tartrate salt (150.0 g, 0.19 mol) was suspended in ethyl acetate (0.45 L, 3.0 mL/g of tartrate salt) and water (0.75 L, 50 mL/g of tartrate salt) containing NaHCO3 (51.0 g, 0.61 mol). The mixture was stirred for 2 hours at 20 to 25° C. while CO2 was liberated (pHf=8.1). Stirring was stopped and the clear layers were allowed to separate. The lower aqueous layer was separated and then the ethyl acetate layer was concentrated to 0.1 L at 25 to 30° C. under reduced pressure. The concentrate was slowly added over 2 hours to hexanes (0.5 L) cooled to 15 to 20° C., The slurry was concentrated to 0.4 L, the solids were granulated for 1 hour at 15 to 20° C., filtered, and then washed with additional hexanes (80 mL). (2S)-1-(4-benzyloxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanone was dried in vacuo for 12 hours at 40 to 45° C. to give 77.8 g of white free base in 96.7% yield. M.p. 102.5-103.8; [α]D25+18.9 (c 8.9, CH3OH). 1H NMR (CDCl3) δ 8.13 (d, J=8.7 Hz, 2H) 7.2-7.4 (m, 10H), 7.00 (d, J=8.7 Hz, 2H), 5.13 (s, 2H), 4.11 (g, J=6.8 Hz, 1H), 2.6-2.9 (m, 4H), 2.0-2.2 (m, 2H), 1.7-1.8 (m, 2H), 1.31 (d, J=6.8 Hz, 3H). 13C NMR (CDCl3) δ 199.69, 162.75, 136.47, 131.49, 129.72, 128.96, 128.55, 128.50, 127.77, 127.23, 124.80, 114.58, 71.44, 70.34, 64.78, 47.83, 44.62, 39.14, 38.79, and 12.28. Chiral HPLC showed that the (−) enantiomer, (2R)-1-(4-benzyloxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanone was present at 1.2%.