|
【结 构 式】 
|
【分子编号】63601 【品名】methyl (3aR,4R,5S,5aR,10bR,13aR)-4-(acetyloxy)-3a-ethyl-9-[(13S,15S)-17-ethyl-13-(methoxycarbonyl)-1,11-diazatetracyclo[13.3.1.0~4,12~.0~5,10~]nonadeca-4(12),5,7,9,17-pentaen-13-yl]-5-hydroxy-8-methoxy-6-methyl-3a,4,5,5a,6,11,12,13a-octahydro-1H-indolizino[8,1-cd]carbazole-5-carboxylate 【CA登记号】 |
【 分 子 式 】C46H56N4O8 【 分 子 量 】792.9728 【元素组成】C 69.68% H 7.12% N 7.07% O 16.14% |
合成路线1
该中间体在本合成路线中的序号：(VIII)N-Oxide (VII) is subjected to a new Polonovski rearrangement, leading to enamine (VIII). Exposure of (VIII) to thallium triacetate gives rise to the iminium salt (IX), which undergoes further reduction and acetate ester hydrolysis in the presence of NaBH4 to yield the desired compound (3).
| 【1】 Mangeney, P.; Andriamialisoa, R.Z.; Langlois, N.; Langlois, Y.; Potier, P.; Preparation of vinblastine, vincristine, and leurosidine, antitumor alkaloids from Catharanthus spp. (Apocynaceae). J Am Chem Soc 1979, 101, 8, 2243. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 63600 | (13S,15S,17S)-13-[(3aR,4R,5S,5aR,10bR,13aR)-4-(acetyloxy)-3a-ethyl-5-hydroxy-8-methoxy-5-(methoxycarbonyl)-6-methyl-3a,4,5,5a,6,11,12,13a-octahydro-1H-indolizino[8,1-cd]carbazol-9-yl]-17-ethyl-13-(methoxycarbonyl)-11-aza-1-azoniatetracyclo[13.3.1.0~4,12~.0~5,10~]nonadeca-4(12),5,7,9-tetraen-1-olate | C46H58N4O9 | 详情 | 详情 | |
| (VIII) | 63601 | methyl (3aR,4R,5S,5aR,10bR,13aR)-4-(acetyloxy)-3a-ethyl-9-[(13S,15S)-17-ethyl-13-(methoxycarbonyl)-1,11-diazatetracyclo[13.3.1.0~4,12~.0~5,10~]nonadeca-4(12),5,7,9,17-pentaen-13-yl]-5-hydroxy-8-methoxy-6-methyl-3a,4,5,5a,6,11,12,13a-octahydro-1H-indolizino[8,1-cd]carbazole-5-carboxylate | C46H56N4O8 | 详情 | 详情 | |
| (IX) | 63602 | (13S,15R,17S)-13-[(3aR,4R,5S,5aR,10bR,13aR)-4-(acetyloxy)-3a-ethyl-5-hydroxy-8-methoxy-5-(methoxycarbonyl)-6-methyl-3a,4,5,5a,6,11,12,13a-octahydro-1H-indolizino[8,1-cd]carbazol-9-yl]-17-(acetyloxy)-17-ethyl-13-(methoxycarbonyl)-11-aza-1-azoniatetracyclo[13.3.1.0~4,12~.0~5,10~]nonadeca-1(18),4(12),5,7,9-pentaene | C50H62N4O12 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)In a similar procedure, coupling of catharanthine-N-oxide (I) with vindoline (II) under Polonovski reaction conditions leads to the iminium salt (III). This is subsequently converted into the desired enamine (IV) employing NADH as the reducing reagent. Aeration of enamine (IV) in the presence of FeCl3, followed by reductive work up leads to the title compound (4).
| 【1】 Kutney, J.P.; Choi, L.S.L.; Nakano, J.; Tsukamoto, H.; McHugh, M.; Boulet, C.A.; A highly efficient and commercially important synthesis of the antitumor Catharantus alkaloids vinblastine and leurosidine from catharanthine and vindoline. Heterocycles 1988, 27, 8, 1845. |
| 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) | 63595 | (1R,15R,18R)-17-ethyl-1-(methoxycarbonyl)-3-aza-13-azoniapentacyclo[13.3.1.0~2,10~.0~4,9~.0~13,18~]nonadeca-2(10),4,6,8,16-pentaen-13-olate | C21H24N2O3 | 详情 | 详情 | |
| (II) | 63596 | methyl 4-(acetyloxy)-3a-ethyl-5-hydroxy-6-methyl-8-(methyloxy)-3a,4,5,5a,6,11,12,13a-octahydro-1H-indolizino[8,1-cd]carbazole-5-carboxylate | C25H32N2O6 | 详情 | 详情 | |
| (III) | 63597 | (13S,15R)-13-[(3aR,4R,5S,5aR,10bR,13aR)-4-(acetyloxy)-3a-ethyl-5-hydroxy-8-methoxy-5-(methoxycarbonyl)-6-methyl-3a,4,5,5a,6,11,12,13a-octahydro-1H-indolizino[8,1-cd]carbazol-9-yl]-17-ethyl-13-(methoxycarbonyl)-11-aza-1-azoniatetracyclo[13.3.1.0~4,12~.0~5,10~]nonadeca-1(18),4(12),5,7,9,16-hexaene | C48H55F3N4O10 | 详情 | 详情 | |
| (IV) | 63601 | methyl (3aR,4R,5S,5aR,10bR,13aR)-4-(acetyloxy)-3a-ethyl-9-[(13S,15S)-17-ethyl-13-(methoxycarbonyl)-1,11-diazatetracyclo[13.3.1.0~4,12~.0~5,10~]nonadeca-4(12),5,7,9,17-pentaen-13-yl]-5-hydroxy-8-methoxy-6-methyl-3a,4,5,5a,6,11,12,13a-octahydro-1H-indolizino[8,1-cd]carbazole-5-carboxylate | C46H56N4O8 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(X)The Grignard reaction of ethyl heptanoate (I) with deuterated methylmagnesium iodide (II) in ether gives deuterated 2-methyl-2-octanol (III), which is treated with deuterium oxide to yield heptadeuterated 2-methyl-2-octanol (IV). The condensation of (IV) with monodeuterated 2,6-dimethoxyphenol (V) (obtained by treatment of 2,6-dimethoxyphenol (VI) with deuterium oxide) by means of deuterated trifluoromethylsulfonic acid affords the alkylated phenol (VII), which is phosphorylated with diethyl phosphite and triethylamine giving the phosphate (VIII). The reduction of (VIII) with Li/NH3 yields the deuterated dimethoxybenzene (IX), which is demethylated with boron tribromide in dichloromethane to afford the deuterated resorcinol (X). The condensation of (X) with alpha-pinene-3,10-diol 10-O-pivalic ester (XI) by means of boron trifluoride etherate in methylene chloride gives the deuterated target compound as its monopivalic ester (XII), which is finally treated with LiAlH4 in THF to eliminate the ester group.
| 【1】 Pop, E.; et al.; Synthesis of deuterated dexanabinol, a nonpsychotropic cannabinoid with neuroprotective properties. J Label Compd Radiopharm 1998, 41, 10, 885. |
| 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) | 20224 | ethyl heptanoate | 106-30-9 | C9H18O2 | 详情 | 详情 |
| (II) | 20225 | iodo(methyl)magnesium | 917-64-6 | CH3IMg | 详情 | 详情 |
| (II) | 63794 | iodo(methyl)magnesium | CH3IMg | 详情 | 详情 | |
| (III) | 20226 | 2-methyl-2-octanol | C9H20O | 详情 | 详情 | |
| (III) | 63795 | 2-methyl-2-octanol | C9H20O | 详情 | 详情 | |
| (IV) | 20226 | 2-methyl-2-octanol | C9H20O | 详情 | 详情 | |
| (IV) | 63796 | 2-methyl-2-octanol | C9H20O | 详情 | 详情 | |
| (V) | 20228 | 2,6-dimethoxyphenol | 91-10-1 | C8H10O3 | 详情 | 详情 |
| (V) | 63797 | 2,6-dimethoxyphenol | 91-10-1 | C8H10O3 | 详情 | 详情 |
| (VI) | 20228 | 2,6-dimethoxyphenol | 91-10-1 | C8H10O3 | 详情 | 详情 |
| (VII) | 20230 | 4-(1,1-dimethylheptyl)-2,6-dimethoxyphenol | C17H28O3 | 详情 | 详情 | |
| (VII) | 63798 | 4-(1,1-dimethylheptyl)-2,6-dimethoxyphenol | C17H28O3 | 详情 | 详情 | |
| (VIII) | 20231 | 4-(1,1-dimethylheptyl)-2,6-dimethoxyphenyl diethyl phosphate | C21H37O6P | 详情 | 详情 | |
| (VIII) | 63799 | 4-(1,1-dimethylheptyl)-2,6-dimethoxyphenyl diethyl phosphate | C21H37O6P | 详情 | 详情 | |
| (IX) | 20232 | 1-(1,1-dimethylheptyl)-3,5-dimethoxybenzene; 3-(1,1-dimethylheptyl)-5-methoxyphenyl methyl ether | C17H28O2 | 详情 | 详情 | |
| (IX) | 63800 | 3-(1,1-dimethylheptyl)-5-methoxyphenyl methyl ether; 1-(1,1-dimethylheptyl)-3,5-dimethoxybenzene | C17H28O2 | 详情 | 详情 | |
| (X) | 20233 | 5-(1,1-dimethylheptyl)-1,3-benzenediol | C15H24O2 | 详情 | 详情 | |
| (X) | 63601 | methyl (3aR,4R,5S,5aR,10bR,13aR)-4-(acetyloxy)-3a-ethyl-9-[(13S,15S)-17-ethyl-13-(methoxycarbonyl)-1,11-diazatetracyclo[13.3.1.0~4,12~.0~5,10~]nonadeca-4(12),5,7,9,17-pentaen-13-yl]-5-hydroxy-8-methoxy-6-methyl-3a,4,5,5a,6,11,12,13a-octahydro-1H-indolizino[8,1-cd]carbazole-5-carboxylate | C46H56N4O8 | 详情 | 详情 | |
| (XI) | 20234 | (4-hydroxy-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methyl pivalate | C15H24O3 | 详情 | 详情 | |
| (XII) | 20235 | [(6aS,10aS)-3-(1,1-dimethylheptyl)-1-hydroxy-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-9-yl]methyl pivalate | C30H46O4 | 详情 | 详情 | |
| (XII) | 63802 | [(6aS,10aS)-3-(1,1-dimethylheptyl)-1-hydroxy-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-9-yl]methyl pivalate | C30H46O4 | 详情 | 详情 |