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【结 构 式】 
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【分子编号】19866 【品名】triphenyl(3,4,5-trimethoxybenzyl)phosphonium bromide 【CA登记号】 |
【 分 子 式 】C28H28BrO3P 【 分 子 量 】523.406282 【元素组成】C 64.25% H 5.39% Br 15.27% O 9.17% P 5.92% |
合成路线1
该中间体在本合成路线中的序号：(IX)The O-silyl stilbene precursor (IV) was also synthesized by the Wittig reaction either between 3,4,5-trimethoxybenzaldehyde (VII) and the phosphonium salt (VIII) or between phosphonium bromide (IX) and 3-(tert-butyldimethylsilyloxy)-4-methoxybenzaldehyde (X), to furnish in both cases a mixture of the target Z-stilbene (IV) and its E-isomer (XI), which were separated by flash chromatography
| 【1】 Pettit, G.R.; Singh, S.B.; Boyd, M.R.; Hamel, E.; Pettit, R.K.; Schmidt, J.M.; Hogan, F.; Antineoplastic agents. 291. Isolation and synthesis of combretastatins A-4, A-5, and A-6. J Med Chem 1995, 38, 10, 1666. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 26118 | tert-butyl[2-methoxy-5-[(E)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenoxy]dimethylsilane; tert-butyl(dimethyl)silyl 2-methoxy-5-[(E)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl ether | C24H34O5Si | 详情 | 详情 | |
| (VII) | 11136 | 3,4,5-Trimethoxybenzaldehyde | 86-81-7 | C10H12O4 | 详情 | 详情 |
| (VIII) | 26117 | (3-[[tert-butyl(dimethyl)silyl]oxy]-4-methoxybenzyl)(triphenyl)phosphonium bromide | C32H38BrO2PSi | 详情 | 详情 | |
| (IX) | 19866 | triphenyl(3,4,5-trimethoxybenzyl)phosphonium bromide | C28H28BrO3P | 详情 | 详情 | |
| (X) | 26114 | 3-[[tert-butyl(dimethyl)silyl]oxy]-4-methoxybenzaldehyde | C14H22O3Si | 详情 | 详情 | |
| (XI) | 60508 | tert-butyl{2-methoxy-4-[(E)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenoxy}dimethylsilane; tert-butyl(dimethyl)silyl 2-methoxy-4-[(E)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl ether | C24H34O5Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Wittig reaction of phosphonium bromide (I) with 4-methoxy-3-nitrobenzaldehyde (II) in the presence of NaOMe provided an approximately equimolecular mixture of Z- and E-stilbenes (III) and (IV), from which the E-isomer was isolated by crystallization. Stilbene (IV) was converted to bromohydrin (V) by treatment with N-bromosuccinimide in aqueous DMSO. Further Swern oxidation of (V) with DMSO-trifluoroacetic anhydride (TFAA) yielded bromoketone (VI), which was then cyclized with thiourea (VII) in the presence of K2CO3 in DMF to give aminothiazole (VIII). Finally, the nitro of (VIII) group was reduced to the target amine by treatment with Zn in AcOH.
| 【1】 Ohsumi, K.; Hatanaka, T.; Fujita, K.; Nakagawa, R.; Fukuda, Y.; Nihei, Y.; Suga, Y.; Morinaga, Y.; Akiyama, Y.; Tsuji, T.; Syntheses and antitumor activity of cis-restricted combretastatins: 5-Membered heterocyclic analogues. Bioorg Med Chem Lett 1998, 8, 22, 3153. |
| 【2】 Suga, Y.; Ohsumi, K.; Fukuda, Y.; Nihei, Y.; Hatanaka, T.; Tsuji, T.; Nakagawa, R.; Morrinaga, Y.; Ohishi, K.; Akiyama, Y.; Novel combretastatin analogue effective against murine solid tumors: Design and structure-activity relationships. J Med Chem 1998, 41, 16, 3022. |
| 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) | 19866 | triphenyl(3,4,5-trimethoxybenzyl)phosphonium bromide | C28H28BrO3P | 详情 | 详情 | |
| (II) | 18225 | 4-METHOXY-3-NITROBENZALDEHYDE | 31680-08-7 | C8H7NO4 | 详情 | 详情 |
| (III) | 28720 | 2,3-dimethoxy-5-[(Z)-2-(4-methoxy-3-nitrophenyl)ethenyl]phenyl methyl ether; 1,2,3-trimethoxy-5-[(Z)-2-(4-methoxy-3-nitrophenyl)ethenyl]benzene | C18H19NO6 | 详情 | 详情 | |
| (IV) | 18226 | 2,3-dimethoxy-5-[(E)-2-(4-methoxy-3-nitrophenyl)ethenyl]phenyl methyl ether; 1,2,3-trimethoxy-5-[(E)-2-(4-methoxy-3-nitrophenyl)ethenyl]benzene | C18H19NO6 | 详情 | 详情 | |
| (V) | 18226 | 2,3-dimethoxy-5-[(E)-2-(4-methoxy-3-nitrophenyl)ethenyl]phenyl methyl ether; 1,2,3-trimethoxy-5-[(E)-2-(4-methoxy-3-nitrophenyl)ethenyl]benzene | C18H19NO6 | 详情 | 详情 | |
| (V) | 19870 | 2-bromo-2-(4-methoxy-3-nitrophenyl)-1-(3,4,5-trimethoxyphenyl)-1-ethanol | C18H20BrNO7 | 详情 | 详情 | |
| (VI) | 19871 | 2-bromo-2-(4-methoxy-3-nitrophenyl)-1-(3,4,5-trimethoxyphenyl)-1-ethanone | C18H18BrNO7 | 详情 | 详情 | |
| (VII) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (VIII) | 19873 | 5-(4-methoxy-3-nitrophenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-thiazol-2-amine; 5-(4-methoxy-3-nitrophenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-thiazol-2-ylamine | C19H19N3O6S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)Reduction of N-methyl-2-pyridone-4-carboxylic acid (I) with LiBH4 provided alcohol (II), which was further oxidized to aldehyde (III) with MnO2. Wittig reaction of (III) with trimethoxybenzylphosphonium salt (IV) in the presence of NaOMe provided a mixture of E and Z olefins, from which the target Z isomer was isolated by column chromatography.
| 【1】 Hatanaka, T.; Tanizawa, K.; Ohsumi, K.; Nakagawa, R.; Fukuda, Y.; Nihei, Y.; Suga, Y.; Akiyama, Y.; Tsuji, T.; Novel B-ring modified combretastatin analogues: Synthesis and antineoplastic activity. Bioorg Med Chem Lett 1998, 8, 23, 3371. |
| 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) | 26521 | 1-methyl-2-oxo-1,2-dihydro-4-pyridinecarboxylic acid | C7H7NO3 | 详情 | 详情 | |
| (II) | 26522 | 4-(hydroxymethyl)-1-methyl-2(1H)-pyridinone | C7H9NO2 | 详情 | 详情 | |
| (III) | 26523 | 1-methyl-2-oxo-1,2-dihydro-4-pyridinecarbaldehyde | C7H7NO2 | 详情 | 详情 | |
| (IV) | 19866 | triphenyl(3,4,5-trimethoxybenzyl)phosphonium bromide | C28H28BrO3P | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)Title compound was prepared by Wittig reaction of 2-methoxypyridine-5-carboxaldehyde (I) with trimethoxybenzylphosphonium salt (II) in the presence of NaOMe, followed by chromatographic separation of the mixture of E and Z isomers.
| 【1】 Hatanaka, T.; Tanizawa, K.; Ohsumi, K.; Nakagawa, R.; Fukuda, Y.; Nihei, Y.; Suga, Y.; Akiyama, Y.; Tsuji, T.; Novel B-ring modified combretastatin analogues: Synthesis and antineoplastic activity. Bioorg Med Chem Lett 1998, 8, 23, 3371. |
合成路线5
该中间体在本合成路线中的序号：(V)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 |
合成路线6
该中间体在本合成路线中的序号：(VIII)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7
该中间体在本合成路线中的序号：(VIII)In a related strategy, the precursor di-tert-butyl combretastatin A-4 phosphate (Va) is prepared by protection of isovanillin (XI) as the corresponding imine (XII) with butylamine and p-toluenesulfonic acid, followed by phosphitylation with di-tert-butyl N,N-diethylphosphoramidite in the presence of tetrazole, and oxidation to phosphate (XIII) with m-chloroperbenzoic acid. Subsequent Wittig reaction of aldehyde (XIII) with 3,4,5-trimethoxybenzyl triphenylphosphonium bromide (VIII) produces the target stilbene phosphate derivative (Va) (6). Scheme 3.
| 【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. |