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【结 构 式】 
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【分子编号】22119 【品名】2,3,4-trimethoxybenzaldehyde 【CA登记号】2103-57-3 |
【 分 子 式 】C10H12O4 【 分 子 量 】196.20288 【元素组成】C 61.22% H 6.16% O 32.62% |
合成路线1
该中间体在本合成路线中的序号：(II)By reductocondensation of 2,3,4-trimethoxybenzaldehyde (I) with l-[bis(4-fluorophenyl)methyl] piperazine (II) by means of formic acid at 100-120 C.
| 【1】 Stukamoto, G.; Kanazawa, T.; Ohtaka, H.; Ito, K.; Benzylpiperazine derivatives. IV. Synthesis and ce. Chem Pharm Bull 1987, 35, 8, 3270. |
| 【2】 Ito, K.; Kanazawa, T.; Ohtaka, H.; Tsukamoto, G. (Kanebo Pharmaceuticals, Ltd.); 1-(2,3,4-Tri-methoxybenzyl)-4[bis(4-fluorophenyl)m. EP 0159566; ES 8702393; ES 8801236; ES 8801237; JP 1985222472; US 4663325 . |
| 【3】 Prous, J.; Castaner, J.; KB-2796. Drugs Fut 1988, 13, 4, 312. |
合成路线2
该中间体在本合成路线中的序号：(I)The reductocondensation of 2,3,4-trimethoxybenzaldehyde (I) with ethyl piperazine-1-carboxylate (II) by means of NaBH3CN in AcOH gives the corresponding benzyl derivative (III), which is decarboxylated with aqueous KOH at 130 C yielding 1-(2,3,4-trimethoxybenzyl)piperazine (IV). The acylation of (IV) with chloroacetyl chloride in dichloromethane affords 1-(2-chloroacetyl)-4-(2,3,4-trimethoxybenzyl)piperazine (V)., which is finally condensed with diosmetin (VI) by means of KHCO3 in DMF.
| 【1】 Ferté, J.; Kühnel, J.-M.; Chapuis, G.; Rolland, Y.; Lewin, G.; Schwaller, M.A.; Flavonoid-related modulators of multidrug resistance: Synthesis, pharmacological activity, and structure-activity relationships. J Med Chem 1999, 42, 3, 478. |
| 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) | 22119 | 2,3,4-trimethoxybenzaldehyde | 2103-57-3 | C10H12O4 | 详情 | 详情 |
| (II) | 24694 | N-ethoxycarbonylpiperidine; Ethyl 1-piperazinecarboxylate; N-Ethoxycarbonyl piperazine; N-Carbethoxy piperazine | 120-43-4 | C7H14N2O2 | 详情 | 详情 |
| (III) | 30010 | ethyl 4-(2,3,4-trimethoxybenzyl)-1-piperazinecarboxylate | C17H26N2O5 | 详情 | 详情 | |
| (IV) | 24354 | 2,3-dimethoxy-4-(1-piperazinylmethyl)phenyl methyl ether | C14H22N2O3 | 详情 | 详情 | |
| (V) | 30011 | 2-chloro-1-[4-(2,3,4-trimethoxybenzyl)-1-piperazinyl]-1-ethanone | C16H23ClN2O4 | 详情 | 详情 | |
| (VI) | 30012 | 5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)-4H-chromen-4-one | 520-34-3 | C16H12O6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)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 |