42% |
Stage #1: N-tert-butyloxycarbonylpiperidin-4-one; 3-bromophenylhydrazine With hydrogenchloride In ethanol; water for 18h; Reflux;
Stage #2: di-<i>tert</i>-butyl dicarbonate With dmap; triethylamine In dichloromethane at 20℃; for 18h; |
1.a
3-Bromophenylhydrazine (40.0 g, 0.179 mol) and JV-Boc-4-oxo-piperidine (35.4 g, 0.179 mol) were dissolved in ethanol (368 mL), and cone. HCl (72 mL) was added. The reaction mixture was then heated to reflux for 18 h, concentrated and basifed using 10% NH4OH in methanol (10%, 100 mL). The solvent was removed, and the residue was suspended in CH2Cl2 (1.2 L). BoC2O (39.2 g, 0.179 mol) followed by DMAP (195 mg, 1.6 mmol) and Attorney's Docket 2882.023B triethylamine (46.4 niL, 0.358 mol) were then added, and the reaction progressed at room temperature for 18 h. The mixture was washed with 0.5 N HCl, and the organic phase was removed, dried over Na2SO4, filtered and concentrated to dryness. The resulting mixture of regioisomers was purified by flash column chromatography (silica gel, hexanes/EtOAc, 100:0 to 80:20 to 50:50 then 25:75) to give the more polar title compound (26.2 g, 42%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.16 (br s, IH), 7.42 (s, IH), 7.28 (d, J= 8.1 Hz, IH, partially masked by solvent), 7.18 (d, J= 8.1 Hz, IH), 4.60 (s, 2H), 3.80 (t, J= 5.5 Hz, 2H), 2.79 (t, J= 5.6 Hz, 2H), 1.51 (s, 9H). |