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【结 构 式】 
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【分子编号】13044 【品名】4-((5R,5aR,8aR,9S)-9-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-methylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-6-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl)-2,6-dimethoxyphenyl dihydrogen phosphate 【CA登记号】 |
【 分 子 式 】C29H33O16P 【 分 子 量 】668.545182 【元素组成】C 52.1% H 4.98% O 38.29% P 4.63% |
合成路线1
该中间体在本合成路线中的序号：(IV)Several new, related syntheses of etoposide phosphate disodium salt have been described: 1) The reaction of etoposide (I) with phosphoryl chloride by means of ethyl diisopropylamine gives the corresponding dichlorophosphoryl ester (II), which is then hydrolyzed with NaHCO3 in water. 2) The reaction of etoposide (I) with diphenyl chlorophosphate gives the diphenoxyphosphoryloxy derivative (III), which is hydrogenated with H2 over PtO2 to afford the free phosphoric acid (IV). Finally, this compound is treated with NaHCO3 as before.
| 【1】 Saulnier, M.G.; Tun, M.M.; Langley, D.R.; Knipe, J.O.; Doyle, T.W.; Senter, P.D.; Kadow, J.F.; Vyas, D.M.; Synthesis of etoposide phosphate, BMY-40481: A water-soluble clinically active prodrug of etoposide. Bioorg Med Chem Lett 1994, 4, 21, 2567. |
| 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) | 13041 | Etoposide; (5R,5aR,8aR,9S)-9-[[(2R,4aR,6R,7R,8R,8aS)-7,8-Dihydroxy-2-methylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-5-(4-hydroxy-3,5-dimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one | 33419-42-0 | C29H32O13 | 详情 | 详情 |
| (II) | 13042 | (5R,5aR,8aR,9S)-5-[4-(Dichlorophosphoryloxy)-3,5-dimethoxyphenyl]-9-(4-O,6-O-ethylidene-beta-D-glucopyranosyloxy)-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6-one | C29H31Cl2O14P | 详情 | 详情 | |
| (III) | 13043 | 4-((5R,5aR,8aR,9S)-9-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-methylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-6-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl)-2,6-dimethoxyphenyl diphenyl phosphate | C41H41O16P | 详情 | 详情 | |
| (IV) | 13044 | 4-((5R,5aR,8aR,9S)-9-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-methylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-6-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl)-2,6-dimethoxyphenyl dihydrogen phosphate | C29H33O16P | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)3) The reaction of podophyllotoxin (V) with diphenyl chlorophosphate by means of ethyl diisopropylamine and dimethylaminopyridine (DMAP) gives the diphenylphosphoryloxy derivative (VI), which is glycosylated with 4,6-O-ethylidene-2,3-O-bis(2,2,2-trichloroethoxycarbonyl)-beta-D-glycopyranose (VII) by means of BF3/ethyl ether, yielding the protected etoposide derivative (VIII). The cleavage of the protecting groups of the carbohydrate moiety with Zn/acetic acid affords the free etoposide phosphate diphenyl ester (IX), already obtained (compound (III) of scheme 14675903a). The reductive cleavage of (IX) as before gives the free acid (X) (compound (IV) of scheme 14675903a), which is finally treated with NaHCO3. 4) The preceding reaction pathway carried out with dibenzyl chlorophosphate instead of diphenyl chlorophosphate yields compounds (XI), (XII), and finally (XIII), which by hydrogenolysis with H2 over Pd/C affords the free acid (X), already obtained.
| 【1】 Saulnier, M.G.; Tun, M.M.; Langley, D.R.; Knipe, J.O.; Doyle, T.W.; Senter, P.D.; Kadow, J.F.; Vyas, D.M.; Synthesis of etoposide phosphate, BMY-40481: A water-soluble clinically active prodrug of etoposide. Bioorg Med Chem Lett 1994, 4, 21, 2567. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 13053 | (5R,5aR,8aR,9S)-9-Hydroxy-5-(4-hydroxy-3,5-dimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one | 6559-91-7 | C21H20O8 | 详情 | 详情 |
| (VI) | 13045 | 4-[(5R,5aR,8aR,9S)-9-hydroxy-6-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl]-2,6-dimethoxyphenyl diphenyl phosphate | C33H29O11P | 详情 | 详情 | |
| (VII) | 13046 | (2R,4aR,6R,7R,8S,8aR)-6-hydroxy-2-methyl-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]hexahydropyrano[3,2-d][1,3]dioxin-8-yl 2,2,2-trichloroethyl carbonate | C14H16Cl6O10 | 详情 | 详情 | |
| (VIII) | 13047 | (2R,4aR,6R,7R,8S,8aR)-6-[((5S,5aR,8aR,9R)-9-[4-[(diphenoxyphosphoryl)oxy]-3,5-dimethoxyphenyl]-8-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl)oxy]-2-methyl-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]hexahydropyrano[3,2-d][1,3]dioxin-8-yl 2,2,2-trichloroethyl carbonate | C47H43Cl6O20P | 详情 | 详情 | |
| (IX) | 13043 | 4-((5R,5aR,8aR,9S)-9-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-methylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-6-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl)-2,6-dimethoxyphenyl diphenyl phosphate | C41H41O16P | 详情 | 详情 | |
| (X) | 13044 | 4-((5R,5aR,8aR,9S)-9-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-methylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-6-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl)-2,6-dimethoxyphenyl dihydrogen phosphate | C29H33O16P | 详情 | 详情 | |
| (XI) | 13050 | 4-[(5R,5aR,8aR,9S)-9-hydroxy-6-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl]-2,6-dimethoxyphenyl dibenzyl phosphate | C35H33O11P | 详情 | 详情 | |
| (XII) | 13051 | (2R,4aR,6R,7R,8S,8aR)-6-[[(5S,5aR,8aR,9R)-9-(4-[[bis(benzyloxy)phosphoryl]oxy]-3,5-dimethoxyphenyl)-8-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl]oxy]-2-methyl-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]hexahydropyrano[3,2-d][1,3]dioxin-8-yl 2,2,2-trichloroethyl carbonate | C49H47Cl6O20P | 详情 | 详情 | |
| (XIII) | 13052 | 4-((5R,5aR,8aR,9S)-9-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-methylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-6-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl)-2,6-dimethoxyphenyl dibenzyl phosphate | C43H45O16P | 详情 | 详情 |