|
【结 构 式】 
|
【分子编号】13041 【品名】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 【CA登记号】33419-42-0 |
【 分 子 式 】C29H32O13 【 分 子 量 】588.56528 【元素组成】C 59.18% H 5.48% O 35.34% |
合成路线1
该中间体在本合成路线中的序号：(I)By reaction of etoposide (I) with POCl3 and diisopropylethylamine in acetonitrile, followed by hydrolysis with aqueous NaHCO3.
| 【1】 Saulnier, M.G.; Senter, P.D.; Kadow, J.F. (Bristol-Myers Squibb Co.); Epipodophyllotoxinglucoside-4'phosphate derivs. AU 8820306; BE 1002982; CH 676716; DE 3826562; FR 2622193; GB 2207674; US 4904768 . |
| 【2】 Castaner, J.; Prous, J.; Etoposide Phosphate Disodium Salt. Drugs Fut 1992, 17, 9, 779. |
合成路线2
该中间体在本合成路线中的序号：(I)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3
该中间体在本合成路线中的序号：(II)The title prodrug has been obtained by condensation of the peptide (I) with etoposide (II) by means of PPh3 and DIAD in DMF.
| 【1】 Toki, B.E.; et al.; Protease-mediated fragmentation of p-amidobenzyl ethers: A new strategy for the activation of anticancer prodrugs. J Org Chem 2002, 67, 6, 1866. |
| 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) | 53571 | benzyl (1S)-1-{[((1S)-4-[(aminocarbonyl)amino]-1-{[4-(hydroxymethyl)anilino]carbonyl}butyl)amino]carbonyl}-2-methylpropylcarbamate | n/a | C26H35N5O6 | 详情 | 详情 |
| (II) | 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 |
合成路线4
该中间体在本合成路线中的序号：(I)Condensation of etoposide (I) with 2,2-dimethyl-1,3-dioxolan-4-ylmethyl chloroformate (II) provides the carbonate ester (III). Then, acidic hydrolysis of the acetonide group of (III) leads to the target compound.
| 【1】 Wrasidlo, W.; et al.; Synthesis, hydrolytic activation and cytotoxicity of etoposide prodrugs. Bioorg Med Chem Lett 2002, 12, 4, 557. |
| 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) | 56226 | 4-{[(chlorocarbonyl)oxy]methyl}-2,2-dimethyl-1,3-dioxolane | C7H11ClO4 | 详情 | 详情 | |
| (III) | 62776 | 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 (2,2-dimethyl-1,3-dioxolan-4-yl)methyl car | C36H42O17 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)Reaction of etoposide (VI) with acid chloride (V) produces the carbamate adduct (VII). The silyl protecting groups of (VII) are then removed by treatment with HF-pyridine yielding triol (VIII). Finally, the benzyl ester function of (VIII) is deprotected by transfer hydrogenolysis in the presence of cyclohexadiene and Pd/C. (1,2)
| 【1】 Schmidt, F.; Monneret, C.; Prodrug mono therapy: Synthesis and biological evaluation of an etoposide glucuronide-prodrug. Bioorg Med Chem 2003, 11, 10, 2277. |
| 【2】 Monneret, C.; Schmidt, F. (CNRS (Centre National de la Recherche Scientifique); Institut Curie); Derivs. of etoposide and analogs, and pharmaceutical compsns. containing them. WO 0335661 . |
| 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) | 64997 | phenylmethyl 6-({2-[(chlorocarbonyl)(methyl)amino]-4-nitrophenyl}oxy)-3,4,5-tris{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}tetrahydro-2H-pyran-2-carboxylate | C39H63ClN2O10Si3 | 详情 | 详情 | |
| (VI) | 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 |
| (VII) | 64998 | benzyl (2S,3R,4S,5R,6S)-6-{2-[{[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-dimethoxyphenoxy]carbonyl}(methyl)amino]-4-nitrophenoxy}-3,4,5-tris{[tert-butyl(dimethyl)silyl]oxy}tetrahydro-2H-pyran-2-carboxylate | C68H94N2O23Si3 | 详情 | 详情 | |
| (VIII) | 64999 | benzyl (2S,3S,4S,5R,6S)-6-{2-[{[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-dimethoxyphenoxy]carbonyl}(methyl)amino]-4-nitrophenoxy}-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate | C50H52N2O23 | 详情 | 详情 |