反应详情

A slurry of noroxymorphone (Example 5, 220 mg; 0.766 mmol), sodium hydrogen carbonate (77 mg; 0.92 mmol), cyclobutylmethyl bromide (160 mg; 1.07 mmol) and NMP (1 mL) was stirred under a nitrogen atmosphere at 90° C. for 19 h. Then the reaction mixture was cooled and quenched with water (10 mL). After adjusting the pH to 9, the product was extracted with DCM (3×5 mL). The combined organic layers were washed with water, brine and dried over MgSO4. Column chromatography afforded 180 mg (66%) of nalbuphone as a white solid; mp 170-172° C. (acetone), [lit. 173-174° C. (chloroform)]xxii; Rf 0.64 (ethyl acetate+20% methanol); [α]20D=−180.44 (c=1.0, MeOH); IR(CHCl3) v 3561, 3454, 2966, 2931, 2830, 1720, 1616, 1457, 1318, 1142, 1057, 944 cm−1; 1H NMR (600 MHz, CDCl3) δ 6.74 (d, J=8.0 Hz, 1H), 6.61 (d, J=8.0 Hz, 1H), 5.64 (bs, 1H, OH), 4.72 (s, 1H), 3.11 (d, J=18.4 Hz, 1H), 3.04 (ddd, J=14.4, 14.4, 3.6 Hz, 1H), 2.92 (d, J=4.9 Hz, 1H), 2.57 (m, 5H), 2.42 (ddd, J=12.4, 12.4, 4.4 Hz, 1H), 2.33 (d, J=14.4 Hz, 1H), 2.20 (ddd, J=12.0, 12.0, 2.2 Hz, 1H), 2.11 (m, 2H), 1.95 (m, 1H), 1.90 (m, 2H), 1.87 (m, 2H), 1.66 (ddd, J=13.6, 13.6, 2.2 Hz, 1H), 1.56 (d, J=12.6 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 209.68, 143.45, 138.69, 129.02, 124.34, 119.87, 117.71, 90.58, 70.31, 62.74, 60.48, 50.93, 43.74, 36.18, 33.73, 31.32, 30.69, 27.00, 26.79, 22.96, 18.76; MS (FAB+) m/z (%): 41 (27), 69 (9), 98 (5), 300 (88), 355 (38), 356 (100); HRMS calcd for C21H26NO4 356.1856. found 356.18552.

1. temperatureThen the reaction mixture was cooled
2. customquenched with water (10 mL)
3. extractionthe product was extracted with DCM (3×5 mL)
4. washThe combined organic layers were washed with water, brine
5. dry with materialdried over MgSO4