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【结 构 式】 
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【分子编号】32142 【品名】ethyl 4,6-dichloro-1H-indole-2-carboxylate 【CA登记号】 |
【 分 子 式 】C11H9Cl2NO2 【 分 子 量 】258.1034 【元素组成】C 51.19% H 3.51% Cl 27.47% N 5.43% O 12.4% |
合成路线1
该中间体在本合成路线中的序号：(IV)GW150526 was easily prepared starting from the known 3-unsubstituted indole derivative (IV) following the general synthetic route described in Scheme 20235901a. The known indole derivative (IV) was formylated at the C-3 position according to the well known Vilsmaier-Haack procedure obtaining the intermediate (VI) in high yield. The subsequent Wittig-type olefination reaction afforded the compound (VII) with high regio control in the formation of the olefinic moiety. The hydrolysis of the ethyl ester group afforded GV-150526 as sodium salt derivative.
| 【1】 Di Fabio, R.; Cugola, A.; Donati, D.; Ferinai, A.; Gaviraghi, G.; Ratti, E.; Trist, D.G.; Reggiani, A.; Identification and pharmacological characterization of GV150526, a novel glycine antagonist as potent neuroprotective agent. Drugs Fut 1998, 23, 1, 61. |
| 【2】 Salituro, F.G.; et al.; 3-(2-Carboxyindol-3-yl)propionic acid derivatives: Antagonists of the strychnine-insensitive glycine receptor associated with the N-methyl-D-aspartate receptor complex. J Med Chem 1990, 33, 11, 2946-8. |
| 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) | 28066 | 1-(3,5-dichlorophenyl)hydrazine | 39943-56-1 | C6H6Cl2N2 | 详情 | 详情 |
| (II) | 17491 | ethyl acetate | 141-78-6 | C4H8O2 | 详情 | 详情 |
| (III) | 32141 | ethyl 2-[(E)-2-(3,5-dichlorophenyl)hydrazono]propanoate | C11H12Cl2N2O2 | 详情 | 详情 | |
| (IV) | 32142 | ethyl 4,6-dichloro-1H-indole-2-carboxylate | C11H9Cl2NO2 | 详情 | 详情 | |
| (V) | 32143 | N-methyl-N-phenylacetamide | 579-10-2 | C9H11NO | 详情 | 详情 |
| (VI) | 32144 | ethyl 4,6-dichloro-3-formyl-1H-indole-2-carboxylate | C12H9Cl2NO3 | 详情 | 详情 | |
| (VII) | 32145 | N-phenyl-2-(triphenylphosphoranylidene)acetamide | C26H22NOP | 详情 | 详情 | |
| (VIII) | 32147 | ethyl 3-[(E)-3-anilino-3-oxo-1-propenyl]-4,6-dichloro-1H-indole-2-carboxylate | C20H16Cl2N2O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)Alternatively, for the synthesis of analogues of GV-150526 substituted at the terminal phenyl ring belonging to the C-3 side chain as shown in Scheme 20235902a, compound (I) was transformed int the intermediate (III) in high yield. Following chemoselective deprotection of the tert-butyl ester group, the free carboxylic acid derivative (IV) was submitted to amidation reaction using different synthetic methods. In particular, the activation of the carboxy group through the formation of the corresponding 2-pyridyl thioester, generated in situ by the mild oxidation-reduction condensation reaction in the presence of 2,2'-dipyridyl disulfide and PPh3, was found to be highly efficient, also in the case of poor nucleophilic aromatic amines, affording the desired amide derivatives (VI) in high yield (either from the isolated 2-pyridyl thioester intermediate (V) or from the acid (IV) using a one pot procedure). Finally, target compounds were easily prepared by basic hydrolysis of the 2-carboxyethyl ester protecting group.
| 【1】 Struys, M.M.R.F.; et al.; Tetrahedron 1993, 49, 10, 2239. |
| 【2】 Davison, S.C.; et al.; VCH Publichers: Stuttgart 1989, 147, 4, 972-6. |
| 【3】 Di Fabio, R.; Cugola, A.; Donati, D.; Ferinai, A.; Gaviraghi, G.; Ratti, E.; Trist, D.G.; Reggiani, A.; Identification and pharmacological characterization of GV150526, a novel glycine antagonist as potent neuroprotective agent. Drugs Fut 1998, 23, 1, 61. |
| 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) | 28066 | 1-(3,5-dichlorophenyl)hydrazine | 39943-56-1 | C6H6Cl2N2 | 详情 | 详情 |
| (II) | 17491 | ethyl acetate | 141-78-6 | C4H8O2 | 详情 | 详情 |
| (III) | 32141 | ethyl 2-[(E)-2-(3,5-dichlorophenyl)hydrazono]propanoate | C11H12Cl2N2O2 | 详情 | 详情 | |
| (IV) | 32142 | ethyl 4,6-dichloro-1H-indole-2-carboxylate | C11H9Cl2NO2 | 详情 | 详情 | |
| (V) | 32143 | N-methyl-N-phenylacetamide | 579-10-2 | C9H11NO | 详情 | 详情 |
| (VI) | 32144 | ethyl 4,6-dichloro-3-formyl-1H-indole-2-carboxylate | C12H9Cl2NO3 | 详情 | 详情 | |
| (VII) | 32145 | N-phenyl-2-(triphenylphosphoranylidene)acetamide | C26H22NOP | 详情 | 详情 | |
| (VIII) | 32147 | ethyl 3-[(E)-3-anilino-3-oxo-1-propenyl]-4,6-dichloro-1H-indole-2-carboxylate | C20H16Cl2N2O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)Diazotization of 3,5-dichloroaniline (I), followed by reduction of the resultant diazonium salt provides hydrazine (II). Subsequent reaction of 3,5-dichlorophenylhydrazine (II) with ethyl pyruvate (III) under Fischer reaction conditions gives rise to indole (IV). Vilsmeier formylation of (IV) using N-methylformanilide and phosphoryl chloride produces aldehyde (V). This is reductively aminated with methyl glycinate and NaBH(OAc)3 to afford aminoester (VI). Condensation of (VI) with phenyl isocyanate, followed by cyclization in the presence of Et3N leads to hydantoin (VII). Finally, ester (VII) is hydrolyzed employing LiOH to furnish the target indolecarboxylic acid.
| 【1】 Jansen, M.; Potschka, H.; Brandt, C.; Loscher, W.; Dannhardt, G.; Hydantoin-substituted 4,6-dichloroindole-2-carboxylic acids as ligands with high affinity for the glycine binding site of the NMDA receptor. J Med Chem 2003, 46, 1, 64. |
| 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) | 26542 | 3,5-dichloroaniline | 626-43-7 | C6H5Cl2N | 详情 | 详情 |
| (II) | 28066 | 1-(3,5-dichlorophenyl)hydrazine | 39943-56-1 | C6H6Cl2N2 | 详情 | 详情 |
| (III) | 12135 | ethyl 2-oxopropanoate; Ethyl pyruvate | 617-35-6 | C5H8O3 | 详情 | 详情 |
| (IV) | 32142 | ethyl 4,6-dichloro-1H-indole-2-carboxylate | C11H9Cl2NO2 | 详情 | 详情 | |
| (V) | 32144 | ethyl 4,6-dichloro-3-formyl-1H-indole-2-carboxylate | C12H9Cl2NO3 | 详情 | 详情 | |
| (VI) | 64389 | ethyl 4,6-dichloro-3-({[2-(methyloxy)-2-oxoethyl]amino}methyl)-1H-indole-2-carboxylate | C15H16Cl2N2O4 | 详情 | 详情 | |
| (VII) | 64390 | ethyl 4,6-dichloro-3-[(2,4-dioxo-3-phenyl-1-imidazolidinyl)methyl]-1H-indole-2-carboxylate | C21H17Cl2N3O4 | 详情 | 详情 |