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【结 构 式】 
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【分子编号】43776 【品名】6-bromo-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene 【CA登记号】 |
【 分 子 式 】C14H19Br 【 分 子 量 】267.20886 【元素组成】C 62.93% H 7.17% Br 29.9% |
合成路线1
该中间体在本合成路线中的序号：(II)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：(I)Palladium-catalyzed coupling of 2-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (I) with 2-methyl-3-butyn-2-ol (II) provided adduct (III). Subsequent cleavage of the propargyl alcohol of (III) with KOH in toluene gave the free acetylene (IV). Lithiation of (IV), followed by quenching with ethyl chloroformate, yielded the aryl propiolic ester (V). Conjugate addition to (V) of the in situ-generated lithium dimethylcuprate gave the Z-crotonate (VI), which was further reduced to the allylic alcohol (VII) using DIBAL. Enantioselective Simmons-Smith cyclopropanation in the presence of (+)-diethyl tartrate produced the cyclopropyl alcohols (VIII) in 80% e.e. favoring the (-)-enantiomer. This mixture was converted to the diastereomeric camphenoate esters, which were separated by preparative chromatography. The desired major isomer (IX) was then hydrolyzed to give the enantiomerically pure alcohol (X), and then oxidized to aldehyde (XI) using N-methylmorpholine-N-oxide and tetrapropylammonium perruthenate.
| 【1】 Vuligonda, V.; et al.; Enantioselective syntheses of potent retinoid X receptor ligands: Differential biological activities of individuals antipodes. J Med Chem 2001, 44, 14, 2298. |
| 【2】 Vuligonda, V.; Chandraratna, R.A. (Allergan, Inc.); 2,4-Pentadienoic acid derivs. having retinoid-like biological activity. EP 0848696; JP 1999507053; US 5675033; WO 9639374 . |
| 【3】 Chandraratna, R.A.; Vuligonda, V. (Vision Pharmaceuticals, Inc.); 2,4-Pentadienoic acid derivs. having retinoid-like biological activity. WO 9908992 . |
| 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) | 43776 | 6-bromo-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene | C14H19Br | 详情 | 详情 | |
| (II) | 17922 | 2-methyl-3-butyn-2-ol; 3-Methyl butynol | 115-19-5 | C5H8O | 详情 | 详情 |
| (III) | 50525 | 2-methyl-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-3-butyn-2-ol | C19H26O | 详情 | 详情 | |
| (IV) | 50526 | 6-ethynyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene | C16H20 | 详情 | 详情 | |
| (V) | 50527 | ethyl 3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-2-propynoate | C19H24O2 | 详情 | 详情 | |
| (VI) | 50528 | ethyl (Z)-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-2-butenoate | C20H28O2 | 详情 | 详情 | |
| (VII) | 50529 | (Z)-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-2-buten-1-ol | C18H26O | 详情 | 详情 | |
| (VIII) | 50530 | [2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)cyclopropyl]methanol | C19H28O | 详情 | 详情 | |
| (IX) | 50531 | [(1R,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)cyclopropyl]methyl (1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxylate | C29H40O4 | 详情 | 详情 | |
| (X) | 50532 | [(1R,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)cyclopropyl]methanol | C19H28O | 详情 | 详情 | |
| (XI) | 50533 | (1R,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)cyclopropanecarbaldehyde | C19H26O | 详情 | 详情 |