Doramapimod, BIBR-796, BIRB-796 BS, BIRB-0796, BIRB-796
多马莫德Chemical Name: N-[3-tert-Butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-N'-[4-[2-(4-morpholinyl)ethoxy]naphthalen-1-yl]urea
CAS No. 285983-48-4
项目整合开发状态: Phase II
项目研究机构: Boehringer Ingelheim (Originator)
合成路线:The N-protection of 4-amino-1-naphthol (I) with Boc2O by means of BuLi in THF gives the carbamate (II),which is condensed with 4-(2-chloroethyl)morpholine (III) by means of K2CO3 in hot acetonitrile,yielding the corresponding aryl ether (IV).The deprotection of the amino group of (IV) with HCl in dioxane affords the naphthylamine (V),which is finally condensed with 3-(tert-butyl)-1-(4-methylphenyl)-1H-pyrazole-5-amine (VI) by means of COCl2 in toluene/dichloromethane and aq.NaHCO3 to provide the target urea.The intermediate 3-(tert-butyl)-1-(4-methylphenyl)-1H-pyrazole-5-amine (VI) is obtained by cyclization of 4-methylphenylhydrazine (VII) with 4,4-dimethyl-3-oxopentanenitrile (VIII) by means of HCl in refluxing ethanol.
📌 参考资料/链接：
参考文献标题:Aromatic heterocyclic cpds.as antiinflammatory agents
文献作者:Regan,J.R.; Zhang,L.-H.; Cirillo,P.F.; Hickey,E.R.; Gilmore,T.A.(Boehringer Ingelheim Pharmaceuticals Inc.)
参考来源:EP 1147104; US 6319921; WO 0043384
📄 详细内容
合成路线:The cyclization of 4-methylphenylhydrazine (I) with pivaloylacetonitrile (II) in refluxing methanol gives the aminopyrazole (III),which is treated with Troc-Cl and NaOH in water/ethyl acetate to yield the carbamate (IV).Finally,this compound is condensed with 4-[2-(4-morpholinyl)ethoxy]naphthalene-1-amine (V) by means of DIEA in hot DMSO to afford the target urea.The intermediate 4-[2-(4-morpholinyl)ethoxy]naphthalene-1-amine (V) is obtained by condensation of 2-(4-morpholinyl)ethanol (VI) with 4-nitro-1-naphthol (VII) by means of NaOH and K2CO3 in hot 1-methyl-2-pyrrolidone to yield the corresponding ether (VIII),which is finally reduced with H2 over Pd/C in methanol.
参考文献标题:Novel process for synthesis of heteroaryl-substd.urea cpds.
文献作者:Zhang,L.-H.; Zhu,L.(Boehringer Ingelheim Pharmaceuticals Inc.)
参考来源:WO 0104115
合成路线:The reaction of 4-amino-1-naphthol (I) with Boc2O in THF gives the carbamate (II),which is condensed with 4-(2-chloroethyl)morpholine (III) by means of K2CO3 in hot acetonitrile to yield ether (IV).The hydrolysis of the carbamate group of (IV) by means of HCl in dioxane affords the naphthylamine (V),which is finally condensed with 3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-amine (VI) and phosgene (VII) in THF to provide the target urea.The intermediates 3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-amine (VI) and phosgene (VII) are obtained by cyclization of 4-methylphenylhydrazine (VIII) with 4,4-dimethyl-3-oxopentanenitrile (IX) in refluxing toluene or by means of HCl in refluxing ethanol.
参考文献标题:Pyrazole urea-based inhibtitors of p38 MAP kinase: From lead compound to clinical candidate
文献作者:Regan,J.; Breitfelder,S.; Cirillo,P.; Gilmore,T.A.; Graham,A.G.; Hickey,E.R.; Klaus,B.; Madwed,J.; Moriak,M.; Moss,N.; Pargellis,C.; Pav,S.; Proto,A.; Swinamer,A.; Tong,L.; Torcellini,C.
参考来源:J Med Chem 2002,45(14),2994
产品链接: CAS No. 285983-48-4››