反应详情

A solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (489 mg, 2.13 mmol) in dry DCM (10 mL) was stirred under nitrogen, and 4-dimethylaminopyridine (DMPA, 40 mg, 0.327 mmol), (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 1.116 g, 5.82 mmol) and triethylamine (0.3 mL) were added. The resulting mixture was stirred for 30 min under nitrogen and 2-(2,4-dichlorophenoxy)phenylamine (AMR01026, 491 mg, 1.93 mmol) in dry DCM (5 mL) was added. After stirring at room temperature for 72 h, the mixture was diluted with DCM, washed with HCl 1M (3×25 mL), water, saturated NaHCO3 (2×25 mL) and brine. The organic layer was dried (MgSO4), filtered and evaporated to give 4-[2-(2,4-Dichlorophenoxy)phenylcarbamoyl]piperidine-1-carboxylic acid tert-butyl ester (754 mg, 84%) as a white solid (mp 120-121° C. from hexane), which was used in the next step without further purification. Rf: 0.31 (Hexane/EtOAc 7:3) LC/MS (APCI) tr=1.39 min, m/z 464.96 (21), 462.94 (M−−H, 32), 253.90 (66), 251.89 (100). 1H NMR (270 MHz, CDCl3) δ 1.44 (9H, s, 3CH3), 1.70 (2H, m, CH2), 1.86 (2H, br d, CH2), 2.40 (1H, tt, J=11.3, 3.7 Hz, CH), 2.77 (2H, br t, CH2), 4.14 (2H, m, CH2), 6.71 (1H, dd, J=8.2, 1.7 Hz, ArH), 6.94 (1H, d, J=8.9 Hz, ArH), 7.01 (1H, td, J=8.2, 1.5, ArH), 7.12 (1H, td, J=8.2, 1.5 Hz, ArH), 7.21 (1H, dd, J=8.9, 2.5 Hz, ArH), 7.48 (1H, d, J=2.5 Hz, ArH), 7.76 (1H, br s, NH) and 8.40 (1H, dd, J=7.9, 1.5 Hz, ArH).

1. stirringAfter stirring at room temperature for 72 h
2. washwashed with HCl 1M (3×25 mL), water, saturated NaHCO3 (2×25 mL) and brine
3. dry with materialThe organic layer was dried (MgSO4)
4. filtrationfiltered
5. customevaporated