新产品编号:150799
Chemical Name: 5-(4-Aminophenyl)-8(R)-methyl-7-(2-pyridinyl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h]-2,3-benzodiazepine
CAS No. 178751-16-1
项目整合开发状态: Preclinical
项目研究机构: Lilly (Originator)
合成路线:The chiral intermediate (S)-alpha-methyl-1,3-benzodioxole-5-ethanol (IV) was prepared by microbiological reduction of 3,4-methylenedioxyphenyl acetone (I) or,alternatively,by lithiation of 4-bromo-1,2-(methylenedioxy)benzene (II) with sec-butyllithium,followed by addition to (S)-propylene oxide (III).Hydrochloric acid-promoted condensation of (IV) with p-nitrobenzaldehyde (V) in hot toluene gave rise to the dioxolobenzopyran system (VIa-b),which was hydroxylated to (VIIa-b) by air oxidation under alkaline conditions.Hydrazone (IXa-b) was obtained as a mixture of E,Z isomers upon treatment of (VIIa-b) with 2-hydrazinopyridine (VIII) in refluxing EtOH.After mesylation of the alcohol group of (IXa-b) with methanesulfonyl chloride and triethylamine,the resulting mesylate (Xa-b) was cyclized to the dioxolo benzodiazepine (XI) using lithium tert-butoxide in THF.The nitro group of (XI) was finally reduced to the target aniline by transfer hydrogenation with potassium formate in the presence of Pd/C.
📌 参考资料/链接：
参考文献标题:Physical form of dihydro-2,3-benzodiazepine deriv.
文献作者:Anderson,B.A.; Hansen,M.M.; Vicenzi,J.T.; Varie,D.L.; Zmijewski,M.J.Jr.; Harkness,A.R.(Eli Lilly and Company)
参考来源:EP 0699676; JP 1996081468; JP 1996081469; JP 1996092255; JP 1998505066; US 5795886
📄 详细内容
合成路线:The chiral intermediate (S)-alpha-methyl-1,3-benzodioxole-5-ethanol (IV) was prepared by microbiological reduction of 3,4-methylenedioxyphenyl acetone (I) or,alternatively,by lithiation of 4-bromo-1,2-(methylenedioxy)benzene (II) with sec-butyllithium,followed by addition to (S)-propylene oxide (III).Hydrochloric acid-promoted condensation of (IV) with p-nitrobenzaldehyde (V) in hot toluene gave rise to the dioxolobenzopyran system (VIa-b),which was hydroxylated to (VIIa-b) by air oxidation under alkaline conditions.Hydrazone (IXa-b) was obtained as a mixture of E,Z isomers upon treatment of (VIIa-b) with 2-hydrazinopyridine (VIII) in refluxing EtOH.After mesylation of the alcohol group of (IXa-b) with methanesulfonyl chloride and triethylamine,the resulting mesylate (Xa-b) was cyclized to the dioxolo benzodiazepine (XI) using lithium tert-butoxide in THF.The nitro group of (XI) was finally reduced to the target aniline by transfer hydrogenation with potassium formate in the presence of Pd/C.
参考文献标题:Synthesis and anticonvulsant activity of 3-aryl-5H-2,3-benzodiazepine AMPA antagonists
文献作者:Anderson,B.A.; Harn,N.K.; Hansen,M.V.; Harkness,A.R.; Lodge,D.; Leander,J.D.
参考来源:Bioorg Med Chem Lett 1999,9(14),1953