反应详情

To a solution of 1-(2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (380 mg, 1.12 mmol) in toluene (10 mL) under nitrogen was added trans 2,6-dimethylmorpholine (155 mg, 1.34 mmol, 1.23 eq). The trans 2,6-dimethylmorpholine isomer was obtained by spinning band distillation of the commercially available mixture of 2,6-dimethylmorpholines. The solution was heated to reflux passing the solvent through 3 A molecular sieves in a modified Dean Stark arrangement. After 2 h, the solvent was removed, replaced with tetrahydrofuran (1.0 mL), and cooled to 0° C. Excess hydrogen chloride gas was bubbled into the solution and then purged with nitrogen. The reaction was warmed to room temperature and a solution of sodium cyanoborohydride (210 mg, 3.35 mmol, 9 eq) in methanol (0.50 mL) was added. A significant amount of gas was evolved. The reaction was stirred for 18 h and quenched with 2.5N NaOH (10 mL). The aqueous phase was extracted with ethyl acetate (3×10 mL). Combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The reaction product was purified by flash chromatography over silica gel (40 mL, eluent: 30% ethyl acetate in hexane) to yield the title compound as a white solid (371 mg, 76%), mp 237° C. (dec); NMR (CDCl3, 300 MHz) 7.23 (dd, J=5.9, 1.6 Hz, 1H), 7.12 (m, 4H), 6.92 (m, 3H), 4.22 (s, 1H), 3.97 (m, 2H), 3.67 (t, J=6.3 Hz, 1H), 3.58 (t, J=6.2 Hz, 1H), 3.32 (s, 2H), 2.52 (dd, J=11.0, 3.1 Hz, 2H), 2.19 (m, 4H), 1.71 (m, 3H), 1.20 (d, J=6.4 Hz, 6H) MS (CI, CH4) m/z 437 (M+1,100), 439 (34), 465 (M+29,15) The free base was dissolved in diethyl ether and acidified with ethereal HCl. The hydrochloride salt was filtered, rinsed with fresh ether and dried in vacuo (50° C., 13 pascal, 18 h) to yield a white solid, mp 237°-240° C. (dec).