合成路线:The intermediate 2-(5-nitro-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)acetic acid (IV) has been obtained by several related ways:1.The cyclization of N-(tert-butoxycarbonylmethyl)benzamidine (I) with 3-methoxy-2-nitro-2-propenoic acid methyl ester (II) by means of Na2CO3 gives 2-(5-nitro-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)acetic acid tert-butyl ester (III),which is hydrolyzed by means of TFA to the target intermediate acid (IV).2.The direct cyclization of N-(carboxymethyl)benzamidine (V) with propenoic ester (II) by means of NaOH gives the target intermediate (IV).3.The cyclization of N-allylbenzamidine (VI) with propenoic ester (II) by means of HCl in methanol gives the allyl pyrimidinone (VII),which is oxidized with NaIO4 and RhCl3 to afford the target intermediate acid (IV).4.The cyclization of N-(2-furylmethyl)benzamidine (VIII) with propenoic ester (II) by means of HCl in toluene/methanol gives the furylmethyl pyrimidinone (IX),with is treated with ozone,NaIO4 and RhCl3 in acetonitrile to yield the target intermediate acid (IV).5.The cyclization of N-(2,2-dimethoxyethyl(benzamidine (X) with propenoic ester (II) in methanol gives the pyrimidinone acetaldehyde dimethylacetal (XI),which is hydrolyzed with TFA to the corresponding aldehyde (XII).Finally,this compound is oxidized with NaClO2 to afford the target intermediate acid (IV).
合成路线:The condensation of intermediate acetic acid (IV) with 2-tert-butyl-5-(DL-valyl)-1,3,4-oxadiazole (XIII) by means of methyl chloroformate and NMM gives the corresponding amide (XIV),which is finally reduced with H2 over Pd/C in MeOH.
参考文献标题:Pyrimidine derivs.,process for preparing the derivs.and drugs containing the same as the active ingredient
文献作者:Okada,T.; Hachiya,K.; Motoi,T.; Kojima,T.; Hashimoto,S.(Ono Pharmaceutical Co.,Ltd.)
参考来源:WO 0123361
合成路线:The reaction of methyl pivalate (I) with hydrazine gives the expected hydrazide (II),which is cyclized with methyl or ethyl orthoformate and Ts-OH,yielding the 2-tert-butyl-1,3,4-oxadiazole (III).The condensation of (III) with N-(tert-butoxycarbonyl)-L-valinal (IV) by means of BuLi and MgBr2 in THF affords the alcohol (V),which is treated with HCl in dioxane to provide the amino alcohol (VI).The condensation of (VI) with 2-[5-(benzyloxycarbonyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl]acetic acid (VII) by means of EDC,HOBT and NMM in DMF gives the corresponding amide (VIII),which is treated with DMP or (COCl)2 in order to oxidize the secondary OH group to the ketone (IX).Finally,this compound is deprotected by means of AlCl3 and anisole or HBr in HOAc to afford the target compound.
参考文献标题:Serine protease inhibitors
文献作者:Spruce,L.W.; Gyorkos,A.(Cortech,Inc.)
参考来源:JP 2001192398; JP 2001507679; WO 9824806
合成路线:The reaction of methyl pivalate (I) with hydrazine gives the expected hydrazide (II),which is cyclized with methyl or ethyl orthoformate and Ts-OH,yielding the 2-tert-butyl-1,3,4-oxadiazole (III).The condensation of (III) with N-(tert-butoxycarbonyl)-L-valinal (IV) by means of BuLi and MgBr2 in THF affords the alcohol (V),which is treated with HCl in dioxane to provide the amino alcohol (VI).The condensation of (VI) with 2-[5-(benzyloxycarbonyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl]acetic acid (VII) by means of EDC,HOBT and NMM in DMF gives the corresponding amide (VIII),which is treated with DMP or (COCl)2 in order to oxidize the secondary OH group to the ketone (IX).Finally,this compound is deprotected by means of AlCl3 and anisole or HBr in HOAc to afford the target compound.
参考文献标题:Design and synthesis of new orally active nonpeptide inhibitors of human neutrophil elastase
文献作者:Ohmoto,K.; Yamamoto,T.; Horiuchi,T.; Imanishi,H.; Odagaki,Y.; Kawabata,K.; Sekioka,T.; Hirota,Y.; Matsuoka,S.; Nakai,H.; Toda,M.; Cheronis,J.C.; Spruce,L.W.; Gyorkos,A.; Wieczorek,M.
参考来源:J Med Chem 2000,43(26),4927
合成路线:The reaction of methyl pivalate (I) with hydrazine gives the expected hydrazide (II),which is cyclized with methyl or ethyl orthoformate and Ts-OH,yielding the 2-tert-butyl-1,3,4-oxadiazole (III).The condensation of (III) with N-(tert-butoxycarbonyl)-L-valinal (IV) by means of BuLi and MgBr2 in THF affords the alcohol (V),which is treated with HCl in dioxane to provide the amino alcohol (VI).The condensation of (VI) with 2-[5-(benzyloxycarbonyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl]acetic acid (VII) by means of EDC,HOBT and NMM in DMF gives the corresponding amide (VIII),which is treated with DMP or (COCl)2 in order to oxidize the secondary OH group to the ketone (IX).Finally,this compound is deprotected by means of AlCl3 and anisole or HBr in HOAc to afford the target compound.
合成路线:The intermediate 2-(5-nitro-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)acetic acid (IV) has been obtained by several related ways:1.The cyclization of N-(tert-butoxycarbonylmethyl)benzamidine (I) with 3-methoxy-2-nitro-2-propenoic acid methyl ester (II) by means of Na2CO3 gives 2-(5-nitro-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)acetic acid tert-butyl ester (III),which is hydrolyzed by means of TFA to the target intermediate acid (IV).2.The direct cyclization of N-(carboxymethyl)benzamidine (V) with propenoic ester (II) by means of NaOH gives the target intermediate (IV).3.The cyclization of N-allylbenzamidine (VI) with propenoic ester (II) by means of HCl in methanol gives the allyl pyrimidinone (VII),which is oxidized with NaIO4 and RhCl3 to afford the target intermediate acid (IV).4.The cyclization of N-(2-furylmethyl)benzamidine (VIII) with propenoic ester (II) by means of HCl in toluene/methanol gives the furylmethyl pyrimidinone (IX),with is treated with ozone,NaIO4 and RhCl3 in acetonitrile to yield the target intermediate acid (IV).5.The cyclization of N-(2,2-dimethoxyethyl(benzamidine (X) with propenoic ester (II) in methanol gives the pyrimidinone acetaldehyde dimethylacetal (XI),which is hydrolyzed with TFA to the corresponding aldehyde (XII).Finally,this compound is oxidized with NaClO2 to afford the target intermediate acid (IV).
合成路线:The condensation of intermediate acetic acid (IV) with 2-tert-butyl-5-(DL-valyl)-1,3,4-oxadiazole (XIII) by means of methyl chloroformate and NMM gives the corresponding amide (XIV),which is finally reduced with H2 over Pd/C in MeOH.
参考文献标题:Development of orally active nonpeptidic inhibitors of human neutrophil elastase
文献作者:Ohmoto,K.; Yamamoto,T.; Okuma,M.; Horiuchi,T.; Imanishi,H.; Odagaki,Y.; Kawabata,K.; Sekioka,T.; Hirota,Y.; Matsuoka,S.; Nakai,H.; Toda,M.; Cheronis,J.C.; Spruce,L.W.; Gyorkos,A.; Wieczorek,M.
参考来源:J Med Chem 2001,44(8),1268
产品链接: CAS No. 208848-19-5››