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【结 构 式】 
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【分子编号】53835 【品名】1-Methoxy-4-methylbenzene; 4-Methylanisole; Methyl P-Tolyl Ether; p-Cresyl methyl ether; 4-Methoxytoluene 【CA登记号】104-93-8 |
【 分 子 式 】C8H10O 【 分 子 量 】122.1668 【元素组成】C 78.65% H 8.25% O 13.1% |
合成路线1
该中间体在本合成路线中的序号：(I)The partial reduction of 4-methylanisole (I) with sodium in liquid ammonia/THF/ethanol gives the enol ether (II), which is condensed with 2-chloro-6-fluoroaniline (III) by means of TiCl4 in chlorobenzene/THF to yield the imine (IV), which, without isolation, is aromatized with I2 in AcOH/THF to provide N-(2-chloro-6-fluorophenyl)-N-(4-methylphenyl)amine (V). The acylation of (V) with 2-chloroacetyl chloride (VI) at 90 C affords the 2-chloroacetamide (VII), which is cyclized by means of AlCl3 by heating at 160?C to afford 1-(2-chloro-6-fluorophenyl)-5-methylindolin-2-one (VIII). Finally, this compound is hydrolyzed with NaOH in refluxing ethanol/water and acidified with 1N HCl. Alternatively, the intermediate N-(2-chloro-6-fluorophenyl)-N-(4-methylphenyl)amine (V) can also be obtained by condensation of 2-chloro-N-(4-methylphenyl)acetamide (IX) with 2-chloro-6-fluorophenol (X) by means of K2CO3 in isopropanol to yield 2-(2-chloro-6-fluorophenoxy)-N-(4-methylphenyl)acetamide (XI), which is treated with MeONa in methanol to obtain the target secondary amine (V).
| 【1】 Bayes, M.; Silvestre, J.S.; Sorbera, L.A.; Castaner, J.; Lumiracoxib. Drugs Fut 2002, 27, 8, 740. |
| 【2】 Xu, D.; Allmendinger, T.; Acemoglu, M.; Calienni, J.V.; Cercus, J.; Loiseleur, O.; Sedelmeier, G. (Novartis AG; Novartis-Erfindungen VmbH); Process for phenylacetic acid derivs.. WO 0123346 . |
| 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) | 53835 | 1-Methoxy-4-methylbenzene; 4-Methylanisole; Methyl P-Tolyl Ether; p-Cresyl methyl ether; 4-Methoxytoluene | 104-93-8 | C8H10O | 详情 | 详情 |
| (II) | 53836 | 1-methoxy-4-methyl-1,4-cyclohexadiene; methyl 4-methyl-1,4-cyclohexadien-1-yl ether | n/a | C8H12O | 详情 | 详情 |
| (III) | 53837 | 2-Chloro-6-fluoroaniline | 363-51-9 | C6H5ClFN | 详情 | 详情 |
| (IV) | 53838 | N-(2-chloro-6-fluorophenyl)-N-(4-methyl-2-cyclohexen-1-ylidene)amine; 2-chloro-6-fluoro-N-(4-methyl-2-cyclohexen-1-ylidene)aniline | n/a | C13H13ClFN | 详情 | 详情 |
| (V) | 53839 | 2-chloro-6-fluoro-N-(4-methylphenyl)aniline; N-(2-chloro-6-fluorophenyl)-N-(4-methylphenyl)amine | n/a | C13H11ClFN | 详情 | 详情 |
| (VI) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (VII) | 53840 | 2-chloro-N-(2-chloro-6-fluorophenyl)-N-(4-methylphenyl)acetamide | n/a | C15H12Cl2FNO | 详情 | 详情 |
| (VIII) | 53841 | 1-(2-chloro-6-fluorophenyl)-5-methyl-1,3-dihydro-2H-indol-2-one | n/a | C15H11ClFNO | 详情 | 详情 |
| (IX) | 31229 | 2-chloro-N-(4-methylphenyl)acetamide | C9H10ClNO | 详情 | 详情 | |
| (X) | 53842 | 2-chloro-6-fluorophenol | 2040-90-6 | C6H4ClFO | 详情 | 详情 |
| (XI) | 53843 | 2-(2-chloro-6-fluorophenoxy)-N-(4-methylphenyl)acetamide | n/a | C15H13ClFNO2 | 详情 | 详情 |