L-375052

合成路线:The cyclization of acetyl cyclopropane (I) with 2-nitroacetamide (II) and formamide dimethylacetal (III) by means of p-tolulenesulfonic acid gives the nitro-pyridinone (IV) (1),which is reduced with H2 over Pd/C affording 3-amino-6-propylpyridin-2(1H)-one (V).The protection of the amino group of (V) with benzyl chloroformate affords the carbamate (VI),which is condensed with tert-butyl bromoacetate (VII) by means of NaH in THF giving substituted acetate ester (VIII).The deprotection of (VIII) by hydrogenolysis with H2 over Pd/C in ethyl acetate yields intermediate (IX) with a free amino group,which is treated with benzylsulfonyl chloride (X) and pyridine to afford the sulfonamide (XI).Hydrolysis of the ester group of (XI) with HCl in ethyl acetate gives the carboxylic acid (XII),which is condensed with the pyridylmethylamine (XIII) by means of EDC and HOBT to afford the carboxamide (XIV).Finally,this compound is deprotected with HCl as usual.

参考文献标题:Pyridinone thrombin inhibitors
文献作者:Dorsey,B.D.; Isaacs,R.C.A.; Sanderson,P.E.; Dyer,D.L.; Naylor-Olsen,A.M.; Fraley,M.E.; Vacca,J.P.(Merck & Co.,Inc.)
参考来源:US 5668289


合成路线:The cyclization of acetyl cyclopropane (I) with 2-nitroacetamide (II) and formamide dimethylacetal (III) by means of p-tolulenesulfonic acid gives the nitro-pyridinone (IV) (1),which is reduced with H2 over Pd/C affording 3-amino-6-propylpyridin-2(1H)-one (V).The protection of the amino group of (V) with benzyl chloroformate affords the carbamate (VI),which is condensed with tert-butyl bromoacetate (VII) by means of NaH in THF giving substituted acetate ester (VIII).The deprotection of (VIII) by hydrogenolysis with H2 over Pd/C in ethyl acetate yields intermediate (IX) with a free amino group,which is treated with benzylsulfonyl chloride (X) and pyridine to afford the sulfonamide (XI).Hydrolysis of the ester group of (XI) with HCl in ethyl acetate gives the carboxylic acid (XII),which is condensed with the pyridylmethylamine (XIII) by means of EDC and HOBT to afford the carboxamide (XIV).Finally,this compound is deprotected with HCl as usual.
参考文献标题:C6 modification of the pyridinone core of thrombin inhibitor L-374,087 as a means of enhancing its oral absorption
文献作者:Isaacs,R.C.A.; Cutrona,K.J.; Newton,C.L.; Sanderson,P.E.; Solinsky,M.G.; Baskin,E.P.; Chen,I.W.; Cooper,C.M.; Cook,J.J.; Gardell,S.J.; Lewis,S.D.; Lucas,R.J.Jr.; Lyle,E.A.; Lynch,J.J.Jr.; Naylor-Olsen,A.M.; Stranieri,M.T.; et al.
参考来源:Bioorg Med Chem Lett 1998,8(13),1719


产品链接: CAS No. 187162-97-6››