新产品编号:261539
Chemical Name: 1-[2-[3-(Benzyloxycarbonyl)phenyl]acetyl]-3(S)-(4-hydroxybenzyl)-4-oxoazetidine-2(S)-carboxylic acid benzyl ester
CAS No. 193959-27-2, 193959-22-7 (racemic, cis-isomer)
项目整合开发状态: Biological Testing
项目研究机构: Lilly (Originator)
合成路线:The precursor acid chloride (VII) was synthesized from isophthalic acid (I) as follows: Treatment of the triethylammonium salt of (I) with benzyl bromide provided the mono-benzyl ester (II).Acid chloride (III) was then formed by reaction of (II) with oxalyl chloride in the presence of a catalytic amount of DMF.Arndt-Eistert homologation of (III) to produce (VI) was achieved via reaction with diazomethane to yield the intermediate diazo ketone (IV).Wolff rearrangement of diazo ketone (IV) in the presence of Ag2O in hot trichloroethanol furnished the trichloroethyl ester (V).Reductive cleavage of the trichloroethyl ester group of (V) with Zn and HOAc then gave the carboxylic acid (VI).This was subsequently activated as the acid chloride (VII) by using oxalyl chloride and DMF.
合成路线:The homochiral azetidinone (IX) was prepared from the known beta-lactam (VIII) by N-silylation with tert-butyldimethylsilyl chloride followed by catalytic hydrogenolysis of the benzyl ester.The 3-silylated azetidinone intermediate (X) was obtained by treatment of the lithium enolate of (IX) with trimethylsilyl chloride.Subsequent Peterson reaction of (X) with the 4-silyloxybenzaldehyde (XI) and LDA furnished olefin (XII) as a mixture of geometric isomers.After esterification of the carboxylate group of (XII) with benzyl alcohol in the presence of EDC to yield (XIII),the catalytic hydrogenation of the olefin double bond of (XIII) gave rise to the cis-azetidinone (XIV).The N-tert-butyldimethylsilyl group of (XIV) was selectively removed by treatment with HF in acetonitrile to afford (XV).Acylation of the lactam N of (XV) with acid chloride (VII) in the presence of sodium hexamethyldisilazide provided (XVI).The remaining silyl group of (XVI) was finally removed by treatment with ammonium hydrogen difluoride in NMP-DMF.
📌 参考资料/链接：
参考文献标题:Design,synthesis,and proposed active site binding analysis of monocyclic 2-azetidinone inhibitors of prostate specific antigen
文献作者:Adlington,R.M.; Baldwin,J.E.; Becker,G.W.; Chen,B.; Cheng,L.Y.; Cooper,S.L.; Hermann,R.B.; Howe,T.J.; McCoull,W.; McNulty,A.M.; Neubauer,B.L.; Pritchard,G.J.
参考来源:J Med Chem 2001,44(10),1491
📄 详细内容
合成路线:The homochiral azetidinone (IX) was prepared from the known beta-lactam (VIII) by N-silylation with tert-butyldimethylsilyl chloride followed by catalytic hydrogenolysis of the benzyl ester.The 3-silylated azetidinone intermediate (X) was obtained by treatment of the lithium enolate of (IX) with trimethylsilyl chloride.Subsequent Peterson reaction of (X) with the 4-silyloxybenzaldehyde (XI) and LDA furnished olefin (XII) as a mixture of geometric isomers.After esterification of the carboxylate group of (XII) with benzyl alcohol in the presence of EDC to yield (XIII),the catalytic hydrogenation of the olefin double bond of (XIII) gave rise to the cis-azetidinone (XIV).The N-tert-butyldimethylsilyl group of (XIV) was selectively removed by treatment with HF in acetonitrile to afford (XV).Acylation of the lactam N of (XV) with acid chloride (VII) in the presence of sodium hexamethyldisilazide provided (XVI).The remaining silyl group of (XVI) was finally removed by treatment with ammonium hydrogen difluoride in NMP-DMF.
参考文献标题:Design and synthesis of novel monocyclic beta-lactam inhibitors of prostate specific antigen
文献作者:Chen,B.; Adlington,R.M.; Baldwin,J.E.; et al.
参考来源:Bioorg Med Chem Lett 1997,7(13),1689