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【结 构 式】

【分子编号】48916

【品名】5-cyclopropyl-1-(5-quinolinyl)-1H-pyrazole-4-carboxylic acid

【CA登记号】

【 分 子 式 】C16H13N3O2

【 分 子 量 】279.29824

【元素组成】C 68.81% H 4.69% N 15.04% O 11.46%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(XI)

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
Extended Information