|
【结 构 式】 
|
【分子编号】63182 【品名】2,6-dichlorophenyl isocyanate; 1,3-dichloro-2-isocyanatobenzene 【CA登记号】 |
【 分 子 式 】C7H3Cl2NO 【 分 子 量 】188.01236 【元素组成】C 44.72% H 1.61% Cl 37.71% N 7.45% O 8.51% |
合成路线1
该中间体在本合成路线中的序号：(V)Radical bromination of 2,6-dibromo-4-methoxytoluene (I) affords the benzylic bromide (II), which is subsequently condensed with p-methoxybenzylamine (III) to produce the bis-benzyl amine derivative (IV). Coupling of amine (IV) with 2,6-dichlorophenyl isocyanate (V) furnishes urea (VI). Intramolecular cyclization of (VI) in the presence of K2CO3 and CuI leads to quinazolinone (VII). The p-methoxybenzyl protecting group is then removed by refluxing in trifluoroacetic acid to provide (VIII). Transmetalation of 2-chloro-4-fluoro-1-iodobenzene (IX) with isopropylmagnesium chloride, followed by condensation with trimethyl borate results in the boronic acid (X). Then, Suzuki coupling of (X) with aryl bromide (VIII) furnishes (XI). The methyl ether group of (XI) is cleaved by means of BBr3 to yield phenol (XII), which is further converted into triflate (XIII) upon treatment with either N-phenyl trifluoromethanesulfonimide or with N-(5-chloro-2-pyridyl) trifluoromethanesulfonimide.
| 【1】 Stelmach, J.E.; Liu, L.; Patel, S.B.; Pivnichny, J.V.; Scapin, G.; Singh, S.; Hop, C.E.C.A.; Wang, Z.; Strauss, J.R.; Cameron, P.M.; Nichols, E.A.; O'Keefe, S.J.; O'Neill, E.A.; Schmatz, D.M.; Schwartz, C.D.; Thompson, C.M.; Zaller, D.M.; Doherty, J.B.; Design and synthesis of potent, orally bioavailable dihydroquinazolinone inhibitors of p38 MAP kinase. Bioorg Med Chem Lett 2003, 13, 2, 277. |
| 【2】 Doherty, J.B.; Rupprecht, K.M.; Goulet, J.L.; Chen, M.-H.; Bao, J.; Liu, L.; Miao, S.; Hunt, J.A.; Hong, X.; Stelmach, J.E.; Ruzek, R.D.; Wisnoski, D.D.; Natarajan, S.R. (Merck & Co., Inc.); (Halo-benzo carbonyl)heterocyclic fused phenyl p38 kinase inhibiting agents. EP 1345603; WO 0258695 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 63179 | 3,5-dibromo-4-methylphenyl methyl ether; 1,3-dibromo-5-methoxy-2-methylbenzene | C8H8Br2O | 详情 | 详情 | |
| (II) | 63180 | 1,3-dibromo-2-(bromomethyl)-5-methoxybenzene; 3,5-dibromo-4-(bromomethyl)phenyl methyl ether | C8H7Br3O | 详情 | 详情 | |
| (III) | 15098 | 4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine | 2393-23-9 | C8H11NO | 详情 | 详情 |
| (IV) | 63181 | N-(2,6-dibromo-4-methoxybenzyl)(4-methoxyphenyl)methanamine; N-(2,6-dibromo-4-methoxybenzyl)-N-(4-methoxybenzyl)amine | C16H17Br2NO2 | 详情 | 详情 | |
| (V) | 63182 | 2,6-dichlorophenyl isocyanate; 1,3-dichloro-2-isocyanatobenzene | C7H3Cl2NO | 详情 | 详情 | |
| (VI) | 63183 | N-(2,6-dibromo-4-methoxybenzyl)-N'-(2,6-dichlorophenyl)-N-(4-methoxybenzyl)urea | C23H20Br2Cl2N2O3 | 详情 | 详情 | |
| (VII) | 63184 | 5-bromo-1-(2,6-dichlorophenyl)-7-methoxy-3-(4-methoxybenzyl)-3,4-dihydro-2(1H)-quinazolinone | C23H19BrCl2N2O3 | 详情 | 详情 | |
| (VIII) | 63185 | 5-bromo-1-(2,6-dichlorophenyl)-7-methoxy-3,4-dihydro-2(1H)-quinazolinone | C15H11BrCl2N2O2 | 详情 | 详情 | |
| (IX) | 63186 | 2-chloro-4-fluoro-1-iodobenzene | C6H3ClFI | 详情 | 详情 | |
| (X) | 63187 | 2-chloro-4-fluorophenylboronic acid | C6H5BClFO2 | 详情 | 详情 | |
| (XI) | 63188 | 5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-7-methoxy-3,4-dihydro-2(1H)-quinazolinone | C21H14Cl3FN2O2 | 详情 | 详情 | |
| (XII) | 63189 | 5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-7-hydroxy-3,4-dihydro-2(1H)-quinazolinone | C20H12Cl3FN2O2 | 详情 | 详情 | |
| (XIII) | 63190 | 5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydro-7-quinazolinyl trifluoromethanesulfonate | C21H11Cl3F4N2O4S | 详情 | 详情 |