Dalvastatin, RG-12561
达伐他汀 (4R,6S)-6-[(E)-2-[2-(4-氟-3-甲基苯基)-4,4,6,6-四甲基-1-环己烯基]乙烯基]-4-羟基四氢吡喃-2-酮 Chemical Name: (?-(4R*,6S*)-6-[(E)-2-[2-(4-Fluoro-3-methylphenyl)-4,4,6,6-tetramethyl-1-cyclohexenyl]vinyl]-4-hydroxytetrahydropyran-2-one
CAS No. 132100-55-1, 135910-20-2 ((4R,6S)-isomer)
项目整合开发状态: Phase III
项目研究机构: Aventis Pharma (Originator)
合成路线:The 2-chloro-4,4,6,6-tetramethylcyclohexene aldehyde (II),prepared by a Vilsmeier reaction on commercially available 3,3,5,5-tetramethylcyclohexanone (I),underwent a copper catalyzed 1,4 addition of the Grignard reagent derived from 5-bromo-2-fluorotoluene(III) to yield the 2-aryl substituted 4,4,6,6-tetramethylcyclohexene aldehyde (IV).Treatment of the aldehyde (IV) with the anion of ethylidenecyclohexylamine (V),followed by hydrolysis of the intermediate beta-hydroxyimine by silica gel chromatography,gave the extended aldehyde (VI).Addition of the dianion of methyl acetoacetate (VII) to aldehyde (VI) and stereospecific reduction of the resulting delta-hydroxy-beta-ketoester (VIII) with triethylborane and sodium borohydride yielded the erythro 3,5-dihydroxy methyl ester (IX).Hydrolysis of the methyl ester,followed by lactonization with triethylamine and methyl chloroformate produced dalvastatin).
📌 参考资料/链接：
参考文献标题:Novel HMG-CoA reductase inhibitors
文献作者:Neuenschwander,K.W.; Regan,J.R.; Kosmider,B.J.; Scotese,A.C.(Aventis Pharma SA)
参考来源:EP 0403487; JP 1991503280; US 4863957; WO 8905639
📄 详细内容
合成路线:The 2-chloro-4,4,6,6-tetramethylcyclohexene aldehyde (II),prepared by a Vilsmeier reaction on commercially available 3,3,5,5-tetramethylcyclohexanone (I),underwent a copper catalyzed 1,4 addition of the Grignard reagent derived from 5-bromo-2-fluorotoluene(III) to yield the 2-aryl substituted 4,4,6,6-tetramethylcyclohexene aldehyde (IV).Treatment of the aldehyde (IV) with the anion of ethylidenecyclohexylamine (V),followed by hydrolysis of the intermediate beta-hydroxyimine by silica gel chromatography,gave the extended aldehyde (VI).Addition of the dianion of methyl acetoacetate (VII) to aldehyde (VI) and stereospecific reduction of the resulting delta-hydroxy-beta-ketoester (VIII) with triethylborane and sodium borohydride yielded the erythro 3,5-dihydroxy methyl ester (IX).Hydrolysis of the methyl ester,followed by lactonization with triethylamine and methyl chloroformate produced dalvastatin).
参考文献标题:Dalvastatin
文献作者:Amin,D.; Neuenschwander,K.
参考来源:Drugs Fut 1992,17(5),377
产品链接: CAS No. 132100-55-1›› 产品链接: CAS No.135910-20-2››