KB-R7785
丁二酰胺,N1-羟基-2-甲基-N4-[(1S)-2-(甲基氨基)-2-氧基-1-苯乙基]-3-(2-甲基丙基)-,(2S,3R)-Chemical Name: N-[4-(Hydroxyamino)-2(R)-isobutyl-3(S)-methylsuccinyl]-L-2-phenylglycine methylamide
CAS No. 168158-16-5, 168393-60-0 (stereoisomer), 168393-52-0 (undefined isomer), 168393-53-1 (undefined isomer, monosodium salt)
项目整合开发状态: Preclinical
项目研究机构: Kanebo (Originator)
合成路线:Esterification of (S)-2-bromo-4-methylpentanoic acid (I) with isobutylene in the presence of H2SO4 affords the corresponding tert-butyl ester (II).Subsequent alkylation of dibenzyl malonate with bromoester (II) gives triester (III).After acidic tert-butyl group cleavage in (III),the resultant acid (IV) is coupled with L-phenylglycine-N-methylamide (V),yielding diamide (VI).Transfer hydrogenolysis of the dibenzyl ester (VI) with ammonium formate and Pd/C produces diacid (VII).Mannich reaction of malonic acid (VII) with formaldehyde and piperidine,with concomitant decarboxylation,leads to the alpha-methylene carboxylic acid (VIII),which is further coupled to O-benzyl hydroxylamine giving hydroxamate (IX).Simultaneous double bond hydrogenation and O-debenzylation of (IX) then produces a diastereomeric mixture of alpha-methyl hydroxamic acids,from which the desired diastereoisomer is isolated by preparative HPLC.
📌 参考资料/链接：
参考文献标题:Acylphenylglycine deriv.and preventive and remedy for diseases caused by increased collagenase activity containing said cpd.as active ingredient
文献作者:Hirayama,R.; Tsukida,T.; Yamamoto,M.; Ikeda,S.; Sakamoto,F.; Obata,Y.; Matsuo,K.(Kanebo Pharmaceuticals,Ltd.)
参考来源:EP 0712838; JP 1995101925; US 5795891; WO 9504715
📄 详细内容
合成路线:Esterification of (S)-2-bromo-4-methylpentanoic acid (I) with isobutylene in the presence of H2SO4 affords the corresponding tert-butyl ester (II).Subsequent alkylation of dibenzyl malonate with bromoester (II) gives triester (III).After acidic tert-butyl group cleavage in (III),the resultant acid (IV) is coupled with L-phenylglycine-N-methylamide (V),yielding diamide (VI).Transfer hydrogenolysis of the dibenzyl ester (VI) with ammonium formate and Pd/C produces diacid (VII).Mannich reaction of malonic acid (VII) with formaldehyde and piperidine,with concomitant decarboxylation,leads to the alpha-methylene carboxylic acid (VIII),which is further coupled to O-benzyl hydroxylamine giving hydroxamate (IX).Simultaneous double bond hydrogenation and O-debenzylation of (IX) then produces a diastereomeric mixture of alpha-methyl hydroxamic acids,from which the desired diastereoisomer is isolated by preparative HPLC.
合成路线:An alternative,stereoselective synthesis has been reported.The alkylation of the chiral N-acyl oxazolidinone (I) with benzyl L-2-[(trifluoromethylsulfonyl)oxy]propionate (II) leads to the succinic acid derivative (III).After hydrogenolysis of the benzyl ester group of (III),the resultant carboxylic acid (IV) is esterified with isobutylene and H2SO4 to afford the tert-butyl ester (V).Removal of the chiral auxiliary group of (V) is then effected by hydrolysis with lithium peroxide,yielding acid (VI).Subsequent coupling of (VI) with L-phenylglycine-N-methylamide (VII) provides diamide (VIII).Acidic tert-butyl ester cleavage in (VIII) gives acid (IX),which is condensed with O-benzyl hydroxylamine to furnish hydroxamate (X).The O-benzyl group of (X) is finally removed by catalytic hydrogenolysis over Pd/C.
参考文献标题:Synthesis and biological evaluation of orally active matrix metalloproteinase inhibitors
文献作者:Hirayama,R.; Yamamoto,M.; Tsukida,T.; Matsuo,K.; Obata,Y.; Sakamoto,F.; Ikeda,S.
参考来源:Bioorg Med Chem 1997,5(4),765
产品链接: CAS No. 168158-16-5››