RWJ-58259
Chemical Name: N1-[3-Amino-1(S)-(benzylcarbamoyl)propyl]-Nalpha-[N-[1-(2,6-dichlorobenzyl)-3-(1-pyrrolidinylmethyl)-1H-indazol-6-yl]carbamoyl]-3,4-difluoro-L-phenylalaninamide
CAS No. 315203-31-7, 315203-41-9 (diHCl)
项目整合开发状态: Preclinical
项目研究机构: Millennium (Originator), R.W. Johnson (Originator)
合成路线:Treatment of 6-nitroindole (I) with aqueous NaNO2 and HCl affords 3-indazolecarboxaldehyde (II),which is then subjected to reductive amination with pyrrolidine (III) by means of NaBH(OAc)3 in dichloroethane/DMF in the presence of acetic acid to provide compound (IV).Alkylation of (IV) with 2,6-dichlorobenzyl bromide (V) by means of KOH in THF yields compound (VI),whose nitro group is reduced with dimethyl hydrazine (Me2NNH2),FeCl3 and charcoal in refluxing MeOH to furnish aminoindazole intermediate (VII).The synthesis of intermediate (XIII) is performed as follows: Coupling of protected diaminobutyric acid (VIII) with benzylamine (IX) by means of DCC and HOBt in acetonitrile,followed by Fmoc removal after treatment with diethylamine,gives derivative (X),which is then condensed with protected difluorophenylalanine (XI) by means of DIC and HOBt in acetonitrile to afford protected dipeptide (XII).Finally,intermediate (XIII) is obtained by Fmoc removal of (XII) by treatment with ethylamine.The desired product is finally obtained by condensation of intermediates (VII) and (XIII) by means of 4-nitrophenyl chloroformate and DIEA in dichloromethane,followed by Boc removal with TFA in dichloromethane.
📌 参考资料/链接：
参考文献标题:Novel indazole peptidomimetics as thrombin receptor antagonists
文献作者:Zhang,H.-C.; Pandey,A.; Scarborough,R.M.; Maryanoff,B.E.(COR Therapeutics,Inc.; Ortho-McNeil Pharmaceutical,Inc.)
参考来源:WO 0100656
📄 详细内容
合成路线:Treatment of 6-nitroindole (I) with aqueous NaNO2 and HCl affords 3-indazolecarboxaldehyde (II),which is then subjected to reductive amination with pyrrolidine (III) by means of NaBH(OAc)3 in dichloroethane/DMF in the presence of acetic acid to provide compound (IV).Alkylation of (IV) with 2,6-dichlorobenzyl bromide (V) by means of KOH in THF yields compound (VI),whose nitro group is reduced with dimethyl hydrazine (Me2NNH2),FeCl3 and charcoal in refluxing MeOH to furnish aminoindazole intermediate (VII).The synthesis of intermediate (XIII) is performed as follows: Coupling of protected diaminobutyric acid (VIII) with benzylamine (IX) by means of DCC and HOBt in acetonitrile,followed by Fmoc removal after treatment with diethylamine,gives derivative (X),which is then condensed with protected difluorophenylalanine (XI) by means of DIC and HOBt in acetonitrile to afford protected dipeptide (XII).Finally,intermediate (XIII) is obtained by Fmoc removal of (XII) by treatment with ethylamine.The desired product is finally obtained by condensation of intermediates (VII) and (XIII) by means of 4-nitrophenyl chloroformate and DIEA in dichloromethane,followed by Boc removal with TFA in dichloromethane.
参考文献标题:Discovery and optimization of a novel series of thrombin receptor (PAR-1) antagonists: Potent,selective peptide mimetics based on indole and indazole templates
文献作者:Zhang,H.-C.; Derian,C.K.; Andrade-Gordon,P.; Hoekstra,W.J.; McComsey,D.F.; White,K.B.; Poulter,B.L.; Addo,M.F.; Cheung,W.M.; Damiano,B.P.; Oksenberg,D.; Reynolds,E.E.; Pandey,A.; Scarborough,R.M.; Maryanoff,B.E.
参考来源:J Med Chem 2001,44(7),1021
产品链接: CAS No. 315203-31-7››