Zoniporide hydrochloride, CP-597396
[1-(喹啉-5-基)-5-环丙基-1H-吡唑-4-甲酰基]胍 Chemical Name: N''-[5-Cyclopropyl-1-(5-quinolyl)-1H-pyrazol-4-ylcarbonyl]guanidine hydrochloride monohydrate
CAS No. 241800-97-5 (anhydrous), 241800-98-6 (free base, anhydrous), 249296-45-5 (mesylate)
项目整合开发状态: Preclinical
项目研究机构: Pfizer (Originator)
合成路线: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 .
📌 参考资料/链接：
参考文献标题:N-[(Substd.five-membered di- or triaza diunsaturated ring)carbonyl] guanidine derivs.for the treatment of ischemia
文献作者:Guzman-Perez,A.; Ruggeri,R.B.; Wester,R.T.; Hamanaka,E.S.; Mularski,C.J.(Pfizer Inc.)
参考来源:EP 1056729; WO 9943663
📄 详细内容
合成路线: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 .
参考文献标题:Discovery of zoniporide: A potent and selective sodium-hydrogen exchanger type 1 (NHE-1) inhibitor with high aqueous solubility
文献作者:Guzman-Perez,A.; Wester,R.T.; Allen,M.C.; Brown,J.A.; Buchholz,A.R.; Cook,E.R.; Day,W.W.; Hamanaka,E.S.; Kennedy,S.P.; Knight,D.R.; Kowalczyk,P.J.; Marala,R.B.; Mularski,C.J.; Novomisle,W.A.; Ruggeri,R.B.; Tracey,W.R.; Hill,R.J.
参考来源:Bioorg Med Chem Lett 2001,11(6),803
产品链接: CAS No. 241800-97-5›› 产品链接: CAS No.241800-98-6››