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【结 构 式】 
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【分子编号】43777 【品名】5,5,8,8-tetramethyl-N-(2-nitrophenyl)-5,6,7,8-tetrahydro-2-naphthalenamine; N-(2-nitrophenyl)-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)amine 【CA登记号】 |
【 分 子 式 】C20H24N2O2 【 分 子 量 】324.42284 【元素组成】C 74.05% H 7.46% N 8.63% O 9.86% |
合成路线1
该中间体在本合成路线中的序号：(III)Treatment of o-nitroaniline (I) with 6-bromo-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphtalene (II), K2CO3 and CuI in xylene yields diphenylamine derivative (III), which is then N-methylated by means of NaH and MeI in DMF to provide (IV). Reduction of the nitro group of (IV) by hydrogenation over Pd/C in ethanol or by treatment with Fe and HCl in H2O/EtOH affords the corresponding amine derivative (V), which is then condensed with terephthalic acid monomethyl ester chloride (VI) in benzene/pyridine to furnish compound (VII). Cyclization of (VII) by means of polyphosphoric acid (PPA) in CH2Cl2 gives diazepin derivative (VIII), which is finally converted in the target product by first nitration with KNO3 in H2SO4 followed by hydrolysis with NaOH in EtOH.
| 【1】 Ohta, K.; Ebisawa, M.; Umemiya, H.; et al.; Retinoid X receptor-antagonistic diazepinylbenzoic acids. Chem Pharm Bull 1999, 47, 12, 1778. |
| 【2】 Shudo, K. (Nikken Chemicals Co., Ltd.); Cpds. potentiating retinoid. JP 1998059951; US 5929069; US 6121256; WO 9711061 . |
| 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) | 11608 | o-Nitroaniline; 2-Nitroaniline; 2-Nitrophenylamine | 88-74-4 | C6H6N2O2 | 详情 | 详情 |
| (II) | 43776 | 6-bromo-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene | C14H19Br | 详情 | 详情 | |
| (III) | 43777 | 5,5,8,8-tetramethyl-N-(2-nitrophenyl)-5,6,7,8-tetrahydro-2-naphthalenamine; N-(2-nitrophenyl)-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)amine | C20H24N2O2 | 详情 | 详情 | |
| (IV) | 43778 | N-methyl-N-(2-nitrophenyl)-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)amine; N,5,5,8,8-pentamethyl-N-(2-nitrophenyl)-5,6,7,8-tetrahydro-2-naphthalenamine | C21H26N2O2 | 详情 | 详情 | |
| (V) | 43779 | N-(2-aminophenyl)-N-methyl-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)amine; N(1)-methyl-N(1)-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-1,2-benzenediamine | C21H28N2 | 详情 | 详情 | |
| (VI) | 25029 | p-Phthalic acid monomethyl ester chloride; Terephthalic acid monomethyl ester chloride; Methyl 4-chlorocarbonylbenzoate | 7377-26-6 | C9H7ClO3 | 详情 | 详情 |
| (VII) | 43780 | methyl 4-([2-[methyl(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)amino]anilino]carbonyl)benzoate | C30H34N2O3 | 详情 | 详情 | |
| (VIII) | 43781 | methyl 4-(5,7,7,10,10-pentamethyl-7,8,9,10-tetrahydro-5H-naphtho[2,3-b][1,5]benzodiazepin-12-yl)benzoate | C30H32N2O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)Catalytic hydrogenation of 3,5-di-tert-butyl-4-hydroxycinnamic acid (I) afforded the saturated carboxylic acid (II), which was converted into amide (IV) via the corresponding acid chloride (III). Reduction of the amide function of (IV) by means of LiAlH4 furnished the primary amine (V). This was condensed with O-benzyl maltol (VI) to produce the pyridone (VII). After hydrogenolysis of the benzyl protecting group of (VII), the title compound was isolated as the corresponding mesylate salt.
| 【1】 Malcolm, C.S.; Bebbington, D.; Monck, N.J.T.; Palmer, A.M.; Gaur, S.; Benwell, K.; Porter, R.H.P.; Harvey, V.; 3,5-Disubstituted-4-hydroxyphenyls linked to 3-hydroxy-2-methyl-4(1H)-pyridinone: Potent inhibitors of lipid peroxidation and cell toxicity. J Med Chem 2000, 43, 15, 2779. |
| 【2】 Malcolm, C.; Porter, R.; Bebbington, D.; Palmer, A.; Gaur, S.; Monck, N. (Vernalis Research Ltd.); Ortho-hydroxypyridinone derivs. as iron chelating and antioxidant agents. EP 1027335; WO 9923075 . |
| 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) | 43375 | (E)-3-[3,5-di(tert-butyl)-4-hydroxyphenyl]-2-propenoic acid | 22014-01-3 | C17H24O3 | 详情 | 详情 |
| (II) | 43376 | 3-[3,5-di(tert-butyl)-4-hydroxyphenyl]propionic acid | 20170-32-5 | C17H26O3 | 详情 | 详情 |
| (III) | 43777 | 5,5,8,8-tetramethyl-N-(2-nitrophenyl)-5,6,7,8-tetrahydro-2-naphthalenamine; N-(2-nitrophenyl)-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)amine | C20H24N2O2 | 详情 | 详情 | |
| (IV) | 43378 | 3-[3,5-di(tert-butyl)-4-hydroxyphenyl]propanamide | C17H27NO2 | 详情 | 详情 | |
| (V) | 43379 | 4-(3-aminopropyl)-2,6-di(tert-butyl)phenol | C17H29NO | 详情 | 详情 | |
| (VI) | 12074 | 3-(Benzyloxy)-2-methyl-4H-pyran-4-one；3-(benzyloxy)-2-methylpyran-4-one | 61049-69-2 | C13H12O3 | 详情 | 详情 |
| (VII) | 43380 | 3-(benzyloxy)-1-[3-[3,5-di(tert-butyl)-4-hydroxyphenyl]propyl]-2-methyl-4(1H)-pyridinone | C30H39NO3 | 详情 | 详情 |