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【结 构 式】 
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【分子编号】27665 【品名】phenyl (1R,2S,3R,5S)-3-(4-methylphenyl)-2-phenyl-8-azabicyclo[3.2.1]octane-8-carboxylate 【CA登记号】 |
【 分 子 式 】C27H27NO2 【 分 子 量 】397.51692 【元素组成】C 81.58% H 6.85% N 3.52% O 8.05% |
合成路线1
该中间体在本合成路线中的序号：(XIV)The reaction of tropanone (I) with N,N-bis(trifluoromethylsulfonyl)aniline and sodium hexamethyldisilylazide in THF gives the enol triflate (II), which is condensed with 4-methylphenylboronic acid (III) by means of palladium tetrakis(triphenylphosphine) yielding the p-tolyltropane (IV). The hydrolysis of the methyl ester of (IV) with KOH affords the carboxylic acid (V), which is treated with diphenoxyphosphoryl azide in hot toluene to give the isocyanate (VI). The hydrolysis of (VI) in refluxing ethanol yields the tropanone (VII), which by reaction with phenylmagnesium bromide in ethyl ether affords the diphenyltropanol (VIII). The dehydration of (VIII) with refluxing conc. HBr gives the diphenyltropene (XI), which by reaction with phenyl chloroformate in dichloromethane yields the N-carboxylate (XII). The reduction of (XII) with H2 over Pd/C in methanol affords a mixture of the (exo, exo) (XIII) and (endo, endo) (XIV) compounds, which is reduced with LiAlH4 in ethyl ether providing a mixture of the target compound and its (endo, endo) isomer (XV) that is separated by chromatography.
| 【1】 Jiang, S.; Chang, A.-C.; Abraham, P.; Kuhar, M.J.; Carroll, F.I.; Synthesis and transporter binding properties of (R)-2beta,3beta- and (R)-2alpha,3alpha-diaryltropanes. Bioorg Med Chem Lett 1998, 8, 24, 3689. |
| 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) | 27655 | methyl (1R,5S)-8-methyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate | C10H15NO3 | 详情 | 详情 | |
| (II) | 27656 | methyl (1R,5S)-8-methyl-3-[[(trifluoromethyl)sulfonyl]oxy]-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate | C11H14F3NO5S | 详情 | 详情 | |
| (III) | 15540 | 4-methylphenylboronic acid; p-Tolylboronic acid | 5720-05-8 | C7H9BO2 | 详情 | 详情 |
| (IV) | 27657 | methyl (1R,5S)-8-methyl-3-(4-methylphenyl)-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate | C17H21NO2 | 详情 | 详情 | |
| (V) | 27658 | (1R,5S)-8-methyl-3-(4-methylphenyl)-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylic acid | C16H19NO2 | 详情 | 详情 | |
| (VI) | 27659 | (1R,5S)-8-methyl-3-(4-methylphenyl)-8-azabicyclo[3.2.1]oct-2-en-2-yl isocyanate | C16H18N2O | 详情 | 详情 | |
| (VII) | 27660 | (1R,5S)-8-methyl-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octan-2-one | C15H19NO | 详情 | 详情 | |
| (VIII) | 27661 | (1R,5S)-8-methyl-3-(4-methylphenyl)-2-phenyl-8-azabicyclo[3.2.1]octan-2-ol | C21H25NO | 详情 | 详情 | |
| (XI) | 27662 | (1R,5S)-8-methyl-3-(4-methylphenyl)-2-phenyl-8-azabicyclo[3.2.1]oct-2-ene | C21H23N | 详情 | 详情 | |
| (XII) | 27663 | phenyl (1R,5S)-3-(4-methylphenyl)-2-phenyl-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate | C27H25NO2 | 详情 | 详情 | |
| (XIII) | 27664 | phenyl (1R,2R,3S,5S)-3-(4-methylphenyl)-2-phenyl-8-azabicyclo[3.2.1]octane-8-carboxylate | C27H27NO2 | 详情 | 详情 | |
| (XIV) | 27665 | phenyl (1R,2S,3R,5S)-3-(4-methylphenyl)-2-phenyl-8-azabicyclo[3.2.1]octane-8-carboxylate | C27H27NO2 | 详情 | 详情 | |
| (XV) | 27666 | (1R,2S,3R,5S)-8-methyl-3-(4-methylphenyl)-2-phenyl-8-azabicyclo[3.2.1]octane | C21H25N | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIV)The reaction of tropanone (I) with N,N-bis(trifluoromethylsulfonyl)aniline and sodium hexamethyldisilylazide in THF gives the enol triflate (II), which is condensed with 4-methylphenylboronic acid (III) by means of palladium tetrakis(triphenylphosphine) yielding the p-tolyltropane (IV). The hydrolysis of the methyl ester of (IV) with KOH affords the carboxylic acid (V), which is treated with diphenoxyphosphoryl azide in hot toluene to give the isocyanate (VI). The hydrolysis of (VI) in refluxing ethanol yields the tropanone (VII). By reaction of the tropanone (VII) with N,N-bis(trifluoromethylsulfonyl)aniline to give the corresponding enol triflate (IX), which is then condensed with phenylboronic acid (X) by means of Pd(Ph3)4 to give (XI), which by reaction with phenyl chloroformate in dichloromethane yields the N-carboxylate (XII). The reduction of (XII) with H2 over Pd/C in methanol affords a mixture of the (exo, exo) (XIII) and (endo, endo) (XIV) compounds, which is reduced with LiAlH4 in ethyl ether providing a mixture of the target compound and its (endo, endo) isomer (XV) that is separated by chromatography.
| 【1】 Jiang, S.; Chang, A.-C.; Abraham, P.; Kuhar, M.J.; Carroll, F.I.; Synthesis and transporter binding properties of (R)-2beta,3beta- and (R)-2alpha,3alpha-diaryltropanes. Bioorg Med Chem Lett 1998, 8, 24, 3689. |
| 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) | 27655 | methyl (1R,5S)-8-methyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate | C10H15NO3 | 详情 | 详情 | |
| (II) | 27656 | methyl (1R,5S)-8-methyl-3-[[(trifluoromethyl)sulfonyl]oxy]-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate | C11H14F3NO5S | 详情 | 详情 | |
| (III) | 15540 | 4-methylphenylboronic acid; p-Tolylboronic acid | 5720-05-8 | C7H9BO2 | 详情 | 详情 |
| (IV) | 27657 | methyl (1R,5S)-8-methyl-3-(4-methylphenyl)-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate | C17H21NO2 | 详情 | 详情 | |
| (V) | 27658 | (1R,5S)-8-methyl-3-(4-methylphenyl)-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylic acid | C16H19NO2 | 详情 | 详情 | |
| (VI) | 27659 | (1R,5S)-8-methyl-3-(4-methylphenyl)-8-azabicyclo[3.2.1]oct-2-en-2-yl isocyanate | C16H18N2O | 详情 | 详情 | |
| (VII) | 27660 | (1R,5S)-8-methyl-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octan-2-one | C15H19NO | 详情 | 详情 | |
| (VIII) | 27661 | (1R,5S)-8-methyl-3-(4-methylphenyl)-2-phenyl-8-azabicyclo[3.2.1]octan-2-ol | C21H25NO | 详情 | 详情 | |
| (IX) | 27667 | (1R,5S)-8-methyl-3-(4-methylphenyl)-8-azabicyclo[3.2.1]oct-2-en-2-yl trifluoromethanesulfonate | C16H18F3NO3S | 详情 | 详情 | |
| (X) | 16593 | Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide | 98-80-6 | C6H7BO2 | 详情 | 详情 |
| (XI) | 27662 | (1R,5S)-8-methyl-3-(4-methylphenyl)-2-phenyl-8-azabicyclo[3.2.1]oct-2-ene | C21H23N | 详情 | 详情 | |
| (XII) | 27663 | phenyl (1R,5S)-3-(4-methylphenyl)-2-phenyl-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate | C27H25NO2 | 详情 | 详情 | |
| (XIII) | 27664 | phenyl (1R,2R,3S,5S)-3-(4-methylphenyl)-2-phenyl-8-azabicyclo[3.2.1]octane-8-carboxylate | C27H27NO2 | 详情 | 详情 | |
| (XIV) | 27665 | phenyl (1R,2S,3R,5S)-3-(4-methylphenyl)-2-phenyl-8-azabicyclo[3.2.1]octane-8-carboxylate | C27H27NO2 | 详情 | 详情 | |
| (XV) | 27666 | (1R,2S,3R,5S)-8-methyl-3-(4-methylphenyl)-2-phenyl-8-azabicyclo[3.2.1]octane | C21H25N | 详情 | 详情 |