Combretastatin A-1 phosphate , OXI-4503, CA1P

3-甲氧基-6-[(Z)-2-(3,4,5-三甲氧基苯基)乙烯]-1,2-苯二酚二酚(二氢磷酸盐)四钠盐Chemical Name: 3-Methoxy-6-[(Z)-2-(3,4,5-trimethoxyphenyl)vinyl]-1,2-benzenediol bis(dihydrogen phosphate) tetrasodium salt
CAS No. 288847-34-7, 288847-35-8 (free acid)
项目整合开发状态: Preclinical
项目研究机构: Arizona State University (Originator), Cancer Research UK (Codevelopment), OxiGene (Codevelopment)
合成路线:Selective cleavage of the 2,3 methyl ether functionalities of 2,3,4-trimethoxybenzaldehyde (I) employing boron trichloride furnished diol (II),which was subsequently converted to the bis-silylated derivative (III).The phosphonium bromide (V),prepared from 3,4,5-trimethoxybenzyl bromide (IV) and triphenyl phosphine,was then subjected to a Wittig reaction with aldehyde (III) to provide the corresponding olefin (VIa-b) as a mixture of E/Z isomers.After chromatographic isolation of the desired Z-isomer,the silyl protecting groups were removed by treatment with either potassium fluoride in DMF or tetrabutylammonium fluoride in THF to furnish combretastatin A-1 (VII).Further condensation of diphenol (VII) with dibenzyl phosphite in the presence of DIEA and DMAP in CCl4 produced the 2',3'-O-di(bis-benzylphosphoryl)combretastatin A-1 (VIII).Alternatively,(VII) was reacted with dibenzyl N,N-diisopropylphosphoramidite to yield the bis-phosphite (IX),which was further oxidized to the corresponding phosphate (VIII) with m-chloroperbenzoic acid.Cleavage of the benzyl phosphate esters of (VIII) was achieved by treatment with in situ-generated iodotrimethylsilane,and the resulting phosphoric acid was converted to the tetrasodium salt by means of methanolic sodium methoxide.