新产品编号:826313
Chemical Name: 1-(3-Fluoronaphthalen-2-yl)-3-methyl-N-(2'-sulfamoylbiphenyl-4-yl)-1H-pyrazole-5-carboxamide
CAS No. 330801-94-0
项目整合开发状态: Preclinical
项目研究机构: Millennium (Originator)
合成路线:3-Amino-2-naphthoic acid (I) is diazotized with NaNO2/HCl,and the obtained diazonium salt is then isolated as the corresponding tetrafluoroborate (II).Subsequent thermal decomposition of the diazonium tetrafluoroborate (II) in refluxing xylene leads to 3-fluoro-2-naphthoic acid (III).After chlorination of (III) with oxalyl chloride,the resultant acid chloride (IV) is treated with NaN3 to produce the acyl azide (V),which undergoes Curtius rearrangement to the amine (VI) in refluxing aqueous DMF.Diazotization of (VI),followed by reduction with SnCl2 gives rise to hydrazine (VII).Treatment of ethyl 2,4-dioxovalerate (VIII) with O-methylhydroxylamine gives oxime (IX),which is then condensed with hydrazine (VII),yielding the intermediate pyrazole (X).
合成路线:Addition of triisopropyl borate to the ortho-lithiated derivative of N-tert-butyl benzenesulfonamide (XI),followed by acid aqueous work-up,gives rise to the boronic acid (XII).Subsequent Suzuki coupling between (XII) and 4-bromoaniline (XIII) affords the biphenyl sulfonamide (XIV).Then,trimethylaluminum-catalyzed condensation of the pyrazole ester (X) with the biphenyl amine (XIV) generates amide (XV).The N-tert-butyl protecting group of (XV) is finally cleaved with trifluoroacetic acid to furnish the title compound.
📌 参考资料/链接：
参考文献标题:Benzamides and related inhibitors of factor Xa
文献作者:Wang,L.; Zhu,B.-Y.; Li,W.; Zhang,P.; Huang,W.; Song,Y.; Goldman,E.; Zuckett,J.; Scarborough,R.(Millennium Pharmaceuticals,Inc.)
参考来源:EP 1216228; EP 1216231; WO 0119788; WO 0119798
📄 详细内容
合成路线:3-Amino-2-naphthoic acid (I) is diazotized with NaNO2/HCl,and the obtained diazonium salt is then isolated as the corresponding tetrafluoroborate (II).Subsequent thermal decomposition of the diazonium tetrafluoroborate (II) in refluxing xylene leads to 3-fluoro-2-naphthoic acid (III).After chlorination of (III) with oxalyl chloride,the resultant acid chloride (IV) is treated with NaN3 to produce the acyl azide (V),which undergoes Curtius rearrangement to the amine (VI) in refluxing aqueous DMF.Diazotization of (VI),followed by reduction with SnCl2 gives rise to hydrazine (VII).Treatment of ethyl 2,4-dioxovalerate (VIII) with O-methylhydroxylamine gives oxime (IX),which is then condensed with hydrazine (VII),yielding the intermediate pyrazole (X).
合成路线:Addition of triisopropyl borate to the ortho-lithiated derivative of N-tert-butyl benzenesulfonamide (XI),followed by acid aqueous work-up,gives rise to the boronic acid (XII).Subsequent Suzuki coupling between (XII) and 4-bromoaniline (XIII) affords the biphenyl sulfonamide (XIV).Then,trimethylaluminum-catalyzed condensation of the pyrazole ester (X) with the biphenyl amine (XIV) generates amide (XV).The N-tert-butyl protecting group of (XV) is finally cleaved with trifluoroacetic acid to furnish the title compound.
参考文献标题:Design,synthesis and biological activity of novel non-amidine factor Xa inhibitors: Part 1: Structure-activity relationships of the substituted 1-(2-naphthyl)-1H-pyrazole-5-carboxylamides
文献作者:Jia,Z.J.; Wu,Y.; Huang,W.; Goldman,E.A.; Zhang,P.; Woolfrey,J.; Wong,P.C.; Huang,B.; Sinha,U.; Park,G.; Reed,A.; Scarborough,R.M.; Zhu,B.Y.
参考来源:Bioorg Med Chem Lett 2002,12(12),1651