반응 #540211

반응 방정식

3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride

triethylamine

3-chloro-4-methyl-phenyl isocyanate

→

1-(3-chloro-4-methyl-phenyl)-3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-urea

수율 70.0%

용매

THF

반응 조건

후처리

1. 1
   기타The mixture was quenched with methanol (˜1 mL)
2. 2
   기타the solvent was evaporated
3. 3
   기타The residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%)

실험 절차

To a stirred suspension of 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.46 g, 1.4 mmol) and triethylamine (0.27 mL, 1.9 mmol) in THF (10 mL) at 5˜10° C., was added 3-chloro-4-methyl-phenyl isocyanate (0.24 mL, 1.8 mmol), and the mixture was stirred at room temperature overnight. The mixture was quenched with methanol (˜1 mL), and the solvent was evaporated. The residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 1-(3-chloro-4-methyl-phenyl)-3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-urea as an off-white solid (450 mg, 70% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.38 min (98.4%); mp, 186-188° C.; 1HNMR (DMSO-d6) 2.15-2.23 (m, 4H, CHH and CH3Ar), 2.56-2.86 (m, 6H, CHCH2, CH3), 4.40 (d, J=6 Hz, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 6.81 (t, J=5 Hz, 1H, CH2NH), 7.11-7.95 (m, 6H, Ar), 8.75 (s, 1H, NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 18.71, 20.93, 23.39, 30.61, 42.34, 56.53, 116.45, 117.66, 120.01, 123.67, 126.54, 127.39, 130.99, 132.96, 133.95, 139.05, 139.58, 145.76, 154.51, 155.08, 160.47, 169.47, 172.60. LCMS MH=468, 470; Anal Calcd For C23H22N5O4Cl+0.6H2O: C, 57.71; H, 4.88; N, 14.63; Cl, 7.41. Found: C, 57.63; H, 4.96; N, 14.50; Cl, 7.64.

출처