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【结 构 式】 
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【分子编号】52523 【品名】ethyl 2-(4-hydrazinophenyl)-2-methylpropanoate 【CA登记号】 |
【 分 子 式 】C12H18N2O2 【 分 子 量 】222.2872 【元素组成】C 64.84% H 8.16% N 12.6% O 14.4% |
合成路线1
该中间体在本合成路线中的序号：(XI)Ethyl 2-(4-nitrophenyl)propionate (VIII), obtained by acid-catalyzed esterification of carboxylic acid (VII), was alkylated by means of iodomethane and NaH to furnish the 2-methylpropionate (IX). Subsequent nitro group hydrogenation over Pd/C gave aniline (X). Diazotization of (X), followed by SnCl2 reduction of the intermediate diazonium salt, afforded the aryl hydrazine (XI). Cyclization between hydrazine (XI) and ketone (VI) under Fischer indolization conditions occurred with concomitant cyclopropyl group rearrangement to generate the racemic beta-methyl tryptamine derivative (XII), which was further separated into the enantiomers.
| 【1】 Chu, L.; Wyvratt, M.J.; Ponpipom, M.M.; Lin, P.; Ashton, W.T.; Goulet, M.; Young, J.; Girotra, N.N.; Fisher, M.H. (Merck & Co., Inc.); Antagonists of gonadotropin releasing hormone. EP 1095038; WO 0004013 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 52519 | (3,5-dimethylphenyl)(2-methylcyclopropyl)methanone | C13H16O | 详情 | 详情 | |
| (VII) | 52520 | 2-(4-nitrophenyl)propanoic acid | C9H9NO4 | 详情 | 详情 | |
| (VIII) | 33983 | ethyl 2-(4-nitrophenyl)propanoate | C11H13NO4 | 详情 | 详情 | |
| (IX) | 52521 | ethyl 2-methyl-2-(4-nitrophenyl)propanoate | C12H15NO4 | 详情 | 详情 | |
| (X) | 52522 | ethyl 2-(4-aminophenyl)-2-methylpropanoate | C12H17NO2 | 详情 | 详情 | |
| (XI) | 52523 | ethyl 2-(4-hydrazinophenyl)-2-methylpropanoate | C12H18N2O2 | 详情 | 详情 | |
| (XII) | 52524 | ethyl 2-[3-(2-amino-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropanoate | C25H32N2O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)The reaction of 2(R)-methylcyclopropanecarboxylic acid (I) with (COCl)2 gives the corresponding acyl chloride (II), which is treated with N,O-dimethylhydroxylamine (III) and TEA to yield the amide (IV). The condensation of (IV) with 3,5-dimethylphenyl bromide (V) by means of BuLi in THF affords the benzoylcyclopropane (VI), which is cyclized with 2-(4-hydrazinophenyl)-2-methylpropionic acid ethyl ester (VII) in refluxing ethanol to provide the indole derivative (VIII) (1). The reaction of the amino group of (VIII) with 2,4-dinitrophenylsulfonyl chloride (IX) and collidine in dichloromethane gives the corresponding sulfonamide (X), which is condensed with 2-(1,2,3-benzotriazol-5-yl)ethanol (XI) by means of PPh3, DEAD and propylamine in benzene to yield the secondary amine (XII). The hydrolysis of the ester group of (XII) by means of KOH in methanol/THF affords the propionic acid derivative (XIII), which is finally condensed with 2-azabicyclo[2,2,2]octane (XIV) by means of PyBOP and TEA in dichloromethane to provide the target indole derivative.
| 【1】 Young, J.R.; et al.; 2-Arylindoles as gonadotropin releasing hormone (GnRH) antagonists: Optimization of the tryptamine side chain. Bioorg Med Chem Lett 2002, 12, 5, 827. |
| 【2】 Chu, L.; Wyvratt, M.J.; Ponpipom, M.M.; Lin, P.; Ashton, W.T.; Goulet, M.; Young, J.; Girotra, N.N.; Fisher, M.H. (Merck & Co., Inc.); Antagonists of gonadotropin releasing hormone. EP 1095038; WO 0004013 . |
| 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) | 55763 | (2R)-2-methylcyclopropanecarboxylic acid | C5H8O2 | 详情 | 详情 | |
| (II) | 55764 | (2R)-2-methylcyclopropanecarbonyl chloride | C5H7ClO | 详情 | 详情 | |
| (III) | 13361 | (Methoxyamino)methane; N,O-Dimethylhydroxylamine | 1117-97-1 | C2H7NO | 详情 | 详情 |
| (IV) | 55765 | (2R)-N-methoxy-N,2-dimethylcyclopropanecarboxamide | C7H13NO2 | 详情 | 详情 | |
| (V) | 52517 | 5-Bromo-1,3-dimethylbenzene; 5-Bromo-m-xylene; 1-Bromo-3,5-dimethylbenzene; 3,5-Dimethylbromobenzene | 556-96-7 | C8H9Br | 详情 | 详情 |
| (VI) | 55766 | (3,5-dimethylphenyl)[(2R)-2-methylcyclopropyl]methanone | C13H16O | 详情 | 详情 | |
| (VII) | 52523 | ethyl 2-(4-hydrazinophenyl)-2-methylpropanoate | C12H18N2O2 | 详情 | 详情 | |
| (VIII) | 52525 | ethyl 2-[3-(2-amino-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropanoate | C25H32N2O2 | 详情 | 详情 | |
| (IX) | 52531 | 2,4-dinitrobenzenesulfonyl chloride | C6H3ClN2O6S | 详情 | 详情 | |
| (X) | 55767 | ethyl 2-[2-(3,5-dimethylphenyl)-3-((1S)-2-{[(2,4-dinitrophenyl)sulfonyl]amino}-1-methylethyl)-1H-indol-5-yl]-2-methylpropanoate | C31H34N4O8S | 详情 | 详情 | |
| (XI) | 55768 | 2-(1H-1,2,3-benzotriazol-5-yl)-1-ethanol | C8H9N3O | 详情 | 详情 | |
| (XII) | 55769 | ethyl 2-[3-((1S)-2-{[2-(1H-1,2,3-benzotriazol-5-yl)ethyl]amino}-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropanoate | C33H39N5O2 | 详情 | 详情 | |
| (XIII) | 55770 | 2-[3-((1S)-2-{[2-(1H-1,2,3-benzotriazol-5-yl)ethyl]amino}-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropanoic acid | C31H35N5O2 | 详情 | 详情 |