合成路线:Similarly,combretastatin A4 (I) is phosphorylated employing bis (2,2,2-trichloroethyl) phosphorochloridate (II) to afford phosphate (III).Reductive cleavage of the trichloroethyl ester groups of (III) by means of Zn/AcOH,followed by passage through a cation exchange resin furnishes the target sodium phosphate salt.
参考文献标题:Combretastatin A-4 prodrug
文献作者:Pettit,G.R.(Arizona State University)
参考来源:US 5561122
合成路线:Reaction of 3,4,5-trimethoxybenzyl alcohol (I) with LiBr/Me3SiCl gives the benzylic bromide (II),which is further condensed with triphenylphosphine to provide the phosphonium salt (III).Wittig reaction of (III) with 4-methoxy-3-(thexyldimethylsilyloxy)benzaldehyde (thexyl is the acronym of 1,1,2-trimethylpropyl) derivative (IV) produces the cis-stilbene (V).Subsequent desilylation of (V) by means of tetrabutylammonium fluoride leads to combretastatin A4 (VI) (1).Phosphitylation of the phenolic hydroxyl group of (VI) with di-tert-butyl N,N-diethylphosphoramidite in the presence of tetrazol provides phosphite ester (VII),which is oxidized by means of m-CPBA to yield phosphate (VIII).The tert-butyl phosphate ester groups of (VIII) are finally cleaved employing trifluoroacetic acid to furnish the desired combretastatin A4 phosphate (1-3).
合成路线:A related phosphorylation of combretastatin A4 (I) is carried out by coupling with dibenzyl phosphite (A) in the presence of CCl4 and DMAP to furnish phosphate (II).The benzyl phosphate esters of (II) are removed by treatment with NaI/Me3SiCl to afford combretastatin A4 phosphate (III),which is finally converted to the corresponding disodium salt with sodium methoxide in MeOH (2-4).Alternatively,phosphitylation of combretastatin A4 (I) with bis(trimethylsilylethoxy) N,N-diisopropyl phosphoramidite (B),followed by oxidation with m-CPBA affords phosphate (IV).The silylethoxy ester groups of (IV) are then removed with tetrabutylammonium fluoride to yield combretastatin A4 phosphate (III) (2,3).
参考文献标题:Synthesis of combretastatin A-4 prodrugs and trans-isomers thereof
文献作者:Pettit,G.R.; Rhodes,M.R.(Arizona State University)
参考来源:WO 9935150
合成路线:A related phosphorylation of combretastatin A4 (I) is carried out by coupling with dibenzyl phosphite (A) in the presence of CCl4 and DMAP to furnish phosphate (II).The benzyl phosphate esters of (II) are removed by treatment with NaI/Me3SiCl to afford combretastatin A4 phosphate (III),which is finally converted to the corresponding disodium salt with sodium methoxide in MeOH (2-4).Alternatively,phosphitylation of combretastatin A4 (I) with bis(trimethylsilylethoxy) N,N-diisopropyl phosphoramidite (B),followed by oxidation with m-CPBA affords phosphate (IV).The silylethoxy ester groups of (IV) are then removed with tetrabutylammonium fluoride to yield combretastatin A4 phosphate (III) (2,3).
参考文献标题:Efficient method of synthesizing combretastatin A-4 prodrugs
文献作者:Seyedi,F.; Gale,J.; Haider,R.; Hoare,J.(OxiGene,Inc.)
参考来源:US 2002119951; WO 0206279
合成路线:Similarly,combretastatin A4 (I) is phosphorylated employing bis (2,2,2-trichloroethyl) phosphorochloridate (II) to afford phosphate (III).Reductive cleavage of the trichloroethyl ester groups of (III) by means of Zn/AcOH,followed by passage through a cation exchange resin furnishes the target sodium phosphate salt.
参考文献标题:Antineoplastic agents 322.Synthesis of combretastatin A-4 prodrugs
文献作者:Bansal,N.; Boyd,M.R.; Narayanan,V.L.; Pettit,G.R.; Rener,G.A.; Simpson,M.J.; Temple,C.Jr.; Varma,R.
参考来源:Anti-Cancer Drug Des 1995,10(4),299
合成路线:Reaction of 3,4,5-trimethoxybenzyl alcohol (I) with LiBr/Me3SiCl gives the benzylic bromide (II),which is further condensed with triphenylphosphine to provide the phosphonium salt (III).Wittig reaction of (III) with 4-methoxy-3-(thexyldimethylsilyloxy)benzaldehyde (thexyl is the acronym of 1,1,2-trimethylpropyl) derivative (IV) produces the cis-stilbene (V).Subsequent desilylation of (V) by means of tetrabutylammonium fluoride leads to combretastatin A4 (VI) (1).Phosphitylation of the phenolic hydroxyl group of (VI) with di-tert-butyl N,N-diethylphosphoramidite in the presence of tetrazol provides phosphite ester (VII),which is oxidized by means of m-CPBA to yield phosphate (VIII).The tert-butyl phosphate ester groups of (VIII) are finally cleaved employing trifluoroacetic acid to furnish the desired combretastatin A4 phosphate (1-3).
合成路线:A related phosphorylation of combretastatin A4 (I) is carried out by coupling with dibenzyl phosphite (A) in the presence of CCl4 and DMAP to furnish phosphate (II).The benzyl phosphate esters of (II) are removed by treatment with NaI/Me3SiCl to afford combretastatin A4 phosphate (III),which is finally converted to the corresponding disodium salt with sodium methoxide in MeOH (2-4).Alternatively,phosphitylation of combretastatin A4 (I) with bis(trimethylsilylethoxy) N,N-diisopropyl phosphoramidite (B),followed by oxidation with m-CPBA affords phosphate (IV).The silylethoxy ester groups of (IV) are then removed with tetrabutylammonium fluoride to yield combretastatin A4 phosphate (III) (2,3).
参考文献标题:Antineoplastic agents 389.New syntheses of combretastatin A-4 prodrug
文献作者:Pettit,G.R.; Rhodes,M.R.
参考来源:Anti-Cancer Drug Des 1998,13(3),183
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