2MD
Chemical Name: (20S)-1alpha,25-Dihydroxy-2-methylene-19-norvitamin D3
项目整合开发状态: Preclinical
项目研究机构: Wisconsin Alumni Research Foundation (Originator), Pfizer (Licensee), Deltanoid (Codevelopment)
合成路线:The disilylated methyl quinicate (I) is oxidized to ketone (II) employing RuCl3 and NaIO4.Subsequent Wittig reaction of ketone (II) with methylenetriphenylphosphorane leads to olefin (III).Reduction of the ester function of (III) is performed by either treatment with DIBAL or,in an improved process,with LiAlH4.The resultant vicinal diol (IV) is then subjected to oxidative cleavage with NaIO4,producing ketone (V).Petrson olefination of (V) with methyl (trimethylsilyl)acetate affords the unsaturated ester (VI),which is further reduced with DIBAL to the allylic alcohol (VII).Tosylation of alcohol (VII),followed by displacement of tosylate (VIII) with the lithium salt of diphenylphosphine generates the allylic phosphine (IX).This is then oxidized by H2O2 to the phosphine oxide (X).
合成路线:Wittig-Horner coupling of phosphine oxide (X) with the protected 25-hydroxy Grudmann's ketone (XI) produces the target 19-norvitamin D derivative (XII).Finally,complete desilylation of (XII) with a cation-exchange resin in MeOH/benzene leads to the title compound.
📌 参考资料/链接：
参考文献标题:2-Alkylidene-19-nor-vitamin D cpds.
文献作者:DeLuca,H.F.; Sicinski,R.R.(Wisconsin Alumni Research Foundation)
参考来源:EP 0970047; JP 2001504135; US 5843928; WO 9841501
📄 详细内容
合成路线:The disilylated methyl quinicate (I) is oxidized to ketone (II) employing RuCl3 and NaIO4.Subsequent Wittig reaction of ketone (II) with methylenetriphenylphosphorane leads to olefin (III).Reduction of the ester function of (III) is performed by either treatment with DIBAL or,in an improved process,with LiAlH4.The resultant vicinal diol (IV) is then subjected to oxidative cleavage with NaIO4,producing ketone (V).Petrson olefination of (V) with methyl (trimethylsilyl)acetate affords the unsaturated ester (VI),which is further reduced with DIBAL to the allylic alcohol (VII).Tosylation of alcohol (VII),followed by displacement of tosylate (VIII) with the lithium salt of diphenylphosphine generates the allylic phosphine (IX).This is then oxidized by H2O2 to the phosphine oxide (X).
合成路线:Wittig-Horner coupling of phosphine oxide (X) with the protected 25-hydroxy Grudmann's ketone (XI) produces the target 19-norvitamin D derivative (XII).Finally,complete desilylation of (XII) with a cation-exchange resin in MeOH/benzene leads to the title compound.
参考文献标题:New 1alpha,25-dihydroxy-19-norvitamin D3 compounds of high biological activity: synthesis and biological evaluation of 2-hydroxymethyl,2-methyl,and 2-methylene analogues
文献作者:Sicinski,R.R.; Prahl,J.M.; Smith,C.M.; DeLuca,H.F.
参考来源:J Med Chem 1998,41(23),4662