|
【结 构 式】 
|
【分子编号】60505 【品名】2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenol 【CA登记号】117048-60-9 |
【 分 子 式 】C18H20O5 【 分 子 量 】316.3538 【元素组成】C 68.34% H 6.37% O 25.29% |
合成路线1
该中间体在本合成路线中的序号：(I)Combretastatin A-4 phosphate can be synthesized by phosphorylation of combretastatin A-4 (I) following several related strategies. Direct phosphorylation of (I) employing either bis(2,2,2-trichloroethyl) phosphorochloridate in pyridine (1, 2) or dibenzyl phosphite in the presence of CCl4 and DMAP (3-5) furnishes the corresponding bis-trichloroethyl (IIa) and dibenzyl (IIb) phosphate esters, which are subsequently deprotected to combretastatin A-4 phosphate (III) by either reductive trichloroethyl group cleavage with zinc dust and acetic acid (1, 2) or by debenzylation with chlorotrimethylsilane/sodium iodide (3-5). Alternatively, phosphitylation of (I) using di-tert-butyl N,N-diethylphosphoramidite (3, 4, 6) or bis(trimethylsilylethyl) N,N-diisopropylphosphoramidite (3-5) in the presence of tetrazole yields the phosphite esters (IVa) and (IVb), respectively, which are further oxidized to the corresponding phosphates (Va) and (Vb) using m-chloroperbenzoic acid in CH2Cl2/THF (3-6). Combretastatin A-4 phosphate (III) is then obtained by acidic cleavage of the tert-butyl ester (Va) with trifluoroacetic acid (3, 4, 6) or trifluoromethanesulfonic acid (6), or by tetrabutylammonium fluoride-promoted cleavage of the trimethylsilylethyl ester (Vb) (3-5). In a shorter procedure, phosphorylation of combretastatin A-4 (I) with POCl3 in the presence of Et3N in CH2Cl2 provides directly combretastatin A-4 phosphate (III) (7). Conversion of (III) to the title disodium salt is accomplished by treatment with methanolic NaOMe (3-5,7) or by passage through a cation exchange resin (1, 2). Scheme 1.
| 【1】 Pettit, G.R., Temple, C. Jr., Narayanan, V.L. et al. Antineoplastic agents 322. Synthesis of combretastatin A-4 prodrugs. Anticancer Drug Des 1995, 10(4): 299-309. |
| 【2】 Pettit, G.R. (Arizona State University). Combretastatin A-4 prodrug. US 5561122. |
| 【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. |
| 【5】 Gale, J., Haider, R., Hoare, J., Seyedi, F. (OxiGene, Inc.). Efficient method of synthesizing combretastatin A-4 prodrugs. US 2002119951, WO 0206279. |
| 【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. |
| 【7】 Gill, G.S., Grobelny, D., Flynn, B. A practical method for phosphorylation of combretastatin A-4 with phosphorus oxychloride. Org Prep Proc Int 2006, 38(6): 604-8. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Iia) | 65523 | C22H23Cl6O8P | 详情 | 详情 | ||
| (Iib) | 65524 | C32H33O8P | 详情 | 详情 | ||
| (Iva) | 65526 | C26H37O7P | 详情 | 详情 | ||
| (Ivb) | 65527 | C28H45O7PSi | 详情 | 详情 | ||
| (Va) | 65528 | C26H37O8P | 详情 | 详情 | ||
| (Vb) | 65529 | C28H45O8PSi | 详情 | 详情 | ||
| (I) | 60505 | 2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenol | 117048-60-9 | C18H20O5 | 详情 | 详情 |
| (III) | 65525 | Combretastatin A4 phosphate; Fosbretabulin | 222030-63-9 | C18H21O8P | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)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3
该中间体在本合成路线中的序号：(I)The CH2Cl2/MeOH extracts of Combretum caffrum stem wood were fractionated using a solvent partition sequence, followed by gel filtration and column chromatography to provide a mixture of three substituted stilbenes: combretastatin A-4 (I), combretastatin A-5 (II) and combretastatin A-6 (III). Further separation of these compounds was achieved via derivatization with tert-butyldimethylsilyl chloride and separation of the respective silyl ethers (IV), (V) and (VI) by preparative TLC. The least polar component (IV) was then desilylated by treatment with tetrabutylammonium fluoride to yield pure combretastatin A-4 (I)
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 60505 | 2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenol | 117048-60-9 | C18H20O5 | 详情 | 详情 |
| (II) | 60506 | 5-[(Z)-2-(3,4-dimethoxyphenyl)ethenyl]-2,3-dimethoxyphenol | C18H20O5 | 详情 | 详情 | |
| (III) | 65172 | 5-[(E)-2-(3,4-dimethoxyphenyl)ethenyl]-2,3-dimethoxyphenol | C18H20O5 | 详情 | 详情 | |
| (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 | |
| (V) | 60507 | tert-butyl(dimethyl)silyl 5-[(Z)-2-(3,4-dimethoxyphenyl)ethenyl]-2,3-dimethoxyphenyl ether; tert-butyl{5-[(Z)-2-(3,4-dimethoxyphenyl)ethenyl]-2,3-dimethoxyphenoxy}dimethylsilane | C24H34O5Si | 详情 | 详情 | |
| (VI) | 65173 | tert-butyl{5-[(E)-2-(3,4-dimethoxyphenyl)ethenyl]-2,3-dimethoxyphenoxy}dimethylsilane; tert-butyl(dimethyl)silyl 5-[(E)-2-(3,4-dimethoxyphenyl)ethenyl]-2,3-dimethoxyphenyl ether | C24H34O5Si | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)In a different synthetic strategy, the required dibromostyrene (XIV) was prepared in low yield by Wittig-like condensation of 3-hydroxy-4-methoxybenzaldehyde (XII) with carbon tetrabromide in the presence of PPh-3. In an improved process, the phenolic hydroxyl of (XII) was first protected as the silyl ether (X), which was then condensed with CBr4/PPh3 to give (XIII). Subsequent desilylation of (XIII) with tetrabutylammonium fluoride provided (XIV). Stereoselective debromination of the dibromostyrene (XIV) with tributyltin hydride and tetrakis(triphenylphosphine)palladium(0) led to the Z-bromostyrene (XV). This was finally subjected to a palladium-catalyzed Suzuki coupling with 3,4,5-trimethoxybenzeneboronic acid (XVI) to furnish the title Z-olefin as the major isomer
| 【1】 Gaukroger, K.; Hadfield, J.A.; Hepworth, L.A.; Lawrence, N.J.; McGrown, A.T.; Novel synthesis of cis and trans isomers of combretastatin A-4. J Org Chem 2001, 66, 24, 8135. |
| 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 |
| (X) | 26114 | 3-[[tert-butyl(dimethyl)silyl]oxy]-4-methoxybenzaldehyde | C14H22O3Si | 详情 | 详情 | |
| (XII) | 18455 | 3-hydroxy-4-methoxybenzaldehyde; Isovanillin | 621-59-0 | C8H8O3 | 详情 | 详情 |
| (XIII) | 60509 | tert-butyl(dimethyl)silyl 5-(2,2-dibromovinyl)-2-methoxyphenyl ether; tert-butyl[5-(2,2-dibromovinyl)-2-methoxyphenoxy]dimethylsilane | C15H22Br2O2Si | 详情 | 详情 | |
| (XIV) | 60510 | 5-(2,2-dibromovinyl)-2-methoxyphenol | C9H8Br2O2 | 详情 | 详情 | |
| (XV) | 60511 | 5-[(Z)-2-bromoethenyl]-2-methoxyphenol | C9H9BrO2 | 详情 | 详情 | |
| (XVI) | 60512 | 3,4,5-trimethoxyphenylboronic acid | C9H13BO5 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)A further synthetic strategy was based on the Perkin condensation between 3,4,5-trimethoxyphenylacetic acid (XVII) and 3-hydroxy-4-methoxybenzaldehyde (XII). Decarboxylation of the resultant phenylcinnamic acid (XVIII) by heating with copper powder in quinoline furnished the desired stilbene, accompanied by only minor amounts of the corresponding E-isomer
| 【1】 Gaukroger, K.; Hadfield, J.A.; Hepworth, L.A.; Lawrence, N.J.; McGrown, A.T.; Novel synthesis of cis and trans isomers of combretastatin A-4. J Org Chem 2001, 66, 24, 8135. |
| 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 |
| (XII) | 18455 | 3-hydroxy-4-methoxybenzaldehyde; Isovanillin | 621-59-0 | C8H8O3 | 详情 | 详情 |
| (XVII) | 25349 | 2-(3,4,5-trimethoxyphenyl)acetic acid | 937-52-0 | C11H14O5 | 详情 | 详情 |
| (XVIII) | 60513 | (E)-3-(3-hydroxy-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-2-propenoic acid | C19H20O7 | 详情 | 详情 |