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【结 构 式】 
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【分子编号】48498 【品名】5-(bromomethyl)-1,2,3-trimethoxybenzene; 4-(bromomethyl)-2,6-dimethoxyphenyl methyl ether 【CA登记号】 |
【 分 子 式 】C10H13BrO3 【 分 子 量 】261.11542 【元素组成】C 46% H 5.02% Br 30.6% O 18.38% |
合成路线1
该中间体在本合成路线中的序号：(VII)The parent compound combretastatin A-4 (I) can be synthesized by bromination of 3,4,5-trimethoxybenzyl alcohol (VI) with lithium bromide and chlorotrimethylsilane, followed by condensation of the obtained benzylic bromide (VII) with triphenylphosphine to provide the phosphonium salt (VIII). Wittig reaction of (VIII) with 4-methoxy-3-(thexyldimethylsilyloxy)benzaldehyde (IX) affords the silyl-protected cis-stilbene (X), which is desilylated to (I) by treatment with tetrabutylammonium fluoride in THF (3, 4, 6). Scheme 2.
| 【3】 Pettit, G.R., Rhodes, M.R. Antineoplastic agents 389. New syntheses of the combretastatin A-4 prodrug. Anticancer Drug Des 1998, 13(3): 183-91. |
| 【4】 Pettit, G.R., Rhodes, M.R. (Arizona State University). Synthesis of combretastatin A-4 prodrugs and trans-isomers thereof. CA 2314238, EP 1045853, US 7018987, WO 9935150. |
| 【6】 Griffin, R.J., Quarterman, C.P., Rathbone, D.L., Slack, J.A. (Aston Molecules Ltd.). Substd. diphenylethylenes and analogues of derivs. thereof. WO 9216486. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 60505 | 2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenol | 117048-60-9 | C18H20O5 | 详情 | 详情 |
| (VI) | 23613 | (3,4,5-trimethoxyphenyl)methanol | 3840-31-1 | C10H14O4 | 详情 | 详情 |
| (VII) | 48498 | 5-(bromomethyl)-1,2,3-trimethoxybenzene; 4-(bromomethyl)-2,6-dimethoxyphenyl methyl ether | C10H13BrO3 | 详情 | 详情 | |
| (VIII) | 19866 | triphenyl(3,4,5-trimethoxybenzyl)phosphonium bromide | C28H28BrO3P | 详情 | 详情 | |
| (IX) | 65530 | 4-methoxy-3-(thexyldimethylsilyloxy)benzaldehyde | C16H26O3Si | 详情 | 详情 | |
| (X) | 65531 | C23H38O2Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)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.
| 【1】 Pettit, G.R.; Lippert, J.W. III; Antineoplastic agents 429. Syntheses of the combretastatin A-1 and combretastatin B-1 prodrugs. Anti-Cancer Drug Des 2000, 15, 3, 203. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIa) | 48499 | 4-[(Z)-2-(2,3-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxyphenyl)ethenyl]-2,6-dimethoxyphenyl methyl ether; tert-butyl[2-[[tert-butyl(dimethyl)silyl]oxy]-6-methoxy-3-[(Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenoxy]dimethylsilane | C30H48O6Si2 | 详情 | 详情 | |
| (VIb) | 48500 | tert-butyl[2-[[tert-butyl(dimethyl)silyl]oxy]-6-methoxy-3-[(E)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenoxy]dimethylsilane; 4-[(E)-2-(2,3-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxyphenyl)ethenyl]-2,6-dimethoxyphenyl methyl ether | C30H48O6Si2 | 详情 | 详情 | |
| (I) | 22119 | 2,3,4-trimethoxybenzaldehyde | 2103-57-3 | C10H12O4 | 详情 | 详情 |
| (II) | 48496 | 4-Methoxy-2,3-Dihydroxybenzaldehyde; 2,3-Dihydroxy-4-Methoxybenzaldehyde | 4055-69-0 | C8H8O4 | 详情 | 详情 |
| (III) | 48497 | 2,3-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxybenzaldehyde | C20H36O4Si2 | 详情 | 详情 | |
| (IV) | 48498 | 5-(bromomethyl)-1,2,3-trimethoxybenzene; 4-(bromomethyl)-2,6-dimethoxyphenyl methyl ether | C10H13BrO3 | 详情 | 详情 | |
| (V) | 19866 | triphenyl(3,4,5-trimethoxybenzyl)phosphonium bromide | C28H28BrO3P | 详情 | 详情 | |
| (VII) | 48501 | 3-methoxy-6-[(Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]-1,2-benzenediol | C18H20O6 | 详情 | 详情 | |
| (VIII) | 48502 | dibenzyl 2-[[bis(benzyloxy)phosphoryl]oxy]-3-methoxy-6-[(Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl phosphate | C46H46O12P2 | 详情 | 详情 | |
| (IX) | 48503 | dibenzyl 2-[[bis(benzyloxy)phosphino]oxy]-3-methoxy-6-[(Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl phosphite | C46H46O10P2 | 详情 | 详情 |