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【结 构 式】 
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【分子编号】26799 【品名】5-Aminoquinoline; 5-quinolinamine 【CA登记号】611-34-7 |
【 分 子 式 】C9H8N2 【 分 子 量 】144.176 【元素组成】C 74.98% H 5.59% N 19.43% |
合成路线1
该中间体在本合成路线中的序号：(VII)Alkylation of 3-chloro-4-methylaniline (I) with bromoacetaldehyde diethyl acetal (II) afforded secondary amine (III). Subsequent cyclization of (III) in boiling trifluoroacetic acid/trifluoroacetic anhydride provided a (3:2) mixture of indoles (IV) and (V), from which the desired 6-chloro isomer (IV) was isolated by column chromatography, and then reduced to indoline (VI) using NaBH3CN in AcOH. 5-Aminoquinoline (VII) was treated with carbonyl diimidazole to give intermediate (VIII). This was finally coupled with indoline (VI) in DMF at 100 C to yield the corresponding urea.
| 【1】 Ham, P.; Jones, G.E.; Forbes, I.T. (SmithKline Beecham plc); Indoline derivs. as 5HT2C antagonists. EP 0707581; JP 1996512299; US 5834494; WO 9501976 . |
| 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) | 26794 | 3-Chloro-4-methylaniline; 4-Amino-2-chlorotoluene | 95-74-9 | C7H8ClN | 详情 | 详情 |
| (II) | 12113 | 2-Bromo-1-ethoxyethyl ethyl ether; 2-Bromo-1,1-diethoxyethane; Bromoacetaldehyde diethylacetal | 2032-35-1 | C6H13BrO2 | 详情 | 详情 |
| (III) | 26795 | 3-chloro-N-(2,2-diethoxyethyl)-4-methylaniline | C13H20ClNO2 | 详情 | 详情 | |
| (IV) | 26796 | 6-chloro-5-methyl-1H-indole | C9H8ClN | 详情 | 详情 | |
| (V) | 26797 | 4-chloro-5-methyl-1H-indole | C9H8ClN | 详情 | 详情 | |
| (VI) | 26798 | 6-chloro-5-methylindoline | C9H10ClN | 详情 | 详情 | |
| (VII) | 26799 | 5-Aminoquinoline; 5-quinolinamine | 611-34-7 | C9H8N2 | 详情 | 详情 |
| (VIII) | 26800 | N-(5-quinolinyl)-1H-imidazole-1-carboxamide | C13H10N4O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)Malonic acid monoethyl ester (I) is converted into beta-ketoester (III) by formation of the corresponding trimethylsilyl ester with TMSCl and pyridine in ether followed by deprotonation with n-BuLi and acylation with cyclopropanecarbonyl chloride (II) in DME. Treatment of (III) with refluxing N,N-dimethylformamide dimethyl acetal (IV) affords enamine (V). Quinoline-5-amine (VI) is first subjected to diazotation by treatment with NaNO2 in H2O/HCl, reduced with SnCl2.2H2O in HCl and isolated as the corresponding dihydrochloride salt (VII) by treatment with HCl. Condensation of enamine (V) with hydrazine (VII) in the presence of Et3N in refluxing EtOH yields pyrazole ester (VIII), which is converted into acylguanidine (X) either by direct heating with guanidine (IX) in EtOH or by first transformation into the corresponding carboxylic acid (XI) by saponification with NaOH in refluxing MeOH, followed by treatment with refluxing thionyl chloride and reaction with guanidine hydrochloride (XII) under Schotten-Baumann conditions in refluxing THF/NaOH. Finally, treatment of the free base (X) with HCl in THF allows isolation of the corresponding monohydrochloride-monohydrate salt .
| 【1】 Wester, R.T.; Allen, M.C.; Guzman-Perez, A.; et al.; Discovery of zoniporide: A potent and selective sodium-hydrogen exchanger type 1 (NHE-1) inhibitor with high aqueous solubility. Bioorg Med Chem Lett 2001, 11, 6, 803. |
| 【2】 Guzman-Perez, A.; Ruggeri, R.B.; Wester, R.T.; Hamanaka, E.S.; Mularski, C.J. (Pfizer Inc.); N-[(Substd. five-membered di- or triaza diunsaturated ring)carbonyl] guanidine derivs. for the treatment of ischemia. EP 1056729; WO 9943663 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX),(XII) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |
| (I) | 15086 | 3-ethoxy-3-oxopropionic acid | 1071-46-1 | C5H8O4 | 详情 | 详情 |
| (II) | 14061 | Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride | 4023-34-1 | C4H5ClO | 详情 | 详情 |
| (III) | 15949 | 3-Cyclopropyl-3-oxo-propionic acid ethyl ester; ethyl 3-cyclopropyl-3-oxopropanoate | 24922-02-9 | C8H12O3 | 详情 | 详情 |
| (IV) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (V) | 48913 | ethyl (Z)-3-amino-2-(cyclopropylcarbonyl)-2-propenoate | C9H13NO3 | 详情 | 详情 | |
| (VI) | 26799 | 5-Aminoquinoline; 5-quinolinamine | 611-34-7 | C9H8N2 | 详情 | 详情 |
| (VII) | 48914 | 5-hydrazinoquinoline | C9H9N3 | 详情 | 详情 | |
| (VIII) | 48915 | ethyl 5-cyclopropyl-1-(5-quinolinyl)-1H-pyrazole-4-carboxylate | C18H17N3O2 | 详情 | 详情 | |
| (X) | 48917 | N''-[[5-cyclopropyl-1-(5-quinolinyl)-1H-pyrazol-4-yl]carbonyl]guanidine | C17H16N6O | 详情 | 详情 | |
| (XI) | 48916 | 5-cyclopropyl-1-(5-quinolinyl)-1H-pyrazole-4-carboxylic acid | C16H13N3O2 | 详情 | 详情 |