|
【结 构 式】 
|
【药物名称】Combretastatin A-4 Phosphate, CA4DP，CA4P，Zybrestat 【化学名称】2-Methoxy-5-[2(Z)-(3,4,5-trimethoxyphenyl)vinyl]phenoxyphosphoric acid disodium salt 【CA登记号】168555-66-6, 222030-63-9 (free acid) 【 分 子 式 】C18H19Na2O8P 【 分 子 量 】440.2920 |
【开发单位】OXiGENE, Inc. (US) (licensed from Arizona State University). 【药理作用】Vascular disrupting agent, Oncolytic, Treatment of age-related macular degeneration. |
合成路线1
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
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
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. |