【药物名称】Doramapimod, BIBR-796, BIRB-796 BS, BIRB-0796, BIRB-796
化学结构式(Chemical Structure):
参考文献No.44417
标题:Aromatic heterocyclic cpds. as antiinflammatory agents
作者:Regan, J.R.; Zhang, L.-H.; Cirillo, P.F.; Hickey, E.R.; Gilmore, T.A. (Boehringer Ingelheim Pharmaceuticals Inc.)
来源:EP 1147104; US 6319921; WO 0043384
合成路线图解说明:

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.

参考文献No.54390
标题:Novel process for synthesis of heteroaryl-substd. urea cpds.
作者:Zhang, L.-H.; Zhu, L. (Boehringer Ingelheim Pharmaceuticals Inc.)
来源:WO 0104115
合成路线图解说明:

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No.677952
标题:Pyrazole urea-based inhibtitors of p38 MAP kinase: From lead compound to clinical candidate
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.
来源:J Med Chem 2002,45(14),2994
合成路线图解说明:

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.

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