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【结 构 式】 
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【分子编号】52517 【品名】5-Bromo-1,3-dimethylbenzene; 5-Bromo-m-xylene; 1-Bromo-3,5-dimethylbenzene; 3,5-Dimethylbromobenzene 【CA登记号】556-96-7 |
【 分 子 式 】C8H9Br 【 分 子 量 】185.06346 【元素组成】C 51.92% H 4.9% Br 43.18% |
合成路线1
该中间体在本合成路线中的序号：(IV)The intermediate ketone (VI) was prepared as follows: 2-Methylcyclopropanecarboxylic acid (I) was converted to the Weinreb amide (III) via activation as the corresponding acid chloride (II) followed by reaction with N,O-dimethylhydroxylamine. The organolithium reagent (V), prepared by metalation of 5-bromo-m-xylene (IV) with n-BuLi, was then added to the methoxy amide (III), producing the target aryl cyclopropyl ketone (VI).
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 52514 | 2-Methylcyclopropanecarboxylic acid | 29555-02-0 | C5H8O2 | 详情 | 详情 |
| (II) | 52515 | 2-methylcyclopropanecarbonyl chloride | C5H7ClO | 详情 | 详情 | |
| (III) | 52516 | N,2-dimethyl-N-(methyloxy)cyclopropanecarboxamide | C7H13NO2 | 详情 | 详情 | |
| (IV) | 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 |
| (V) | 52518 | (3,5-dimethylphenyl)lithium | C8H9Li | 详情 | 详情 | |
| (VI) | 52519 | (3,5-dimethylphenyl)(2-methylcyclopropyl)methanone | C13H16O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)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 |