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【结 构 式】 
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【分子编号】25801 【品名】(4-methylphenyl)(oxo)vinyl-lambda(4)-sulfane; 4-methylphenyl vinyl sulfoxide 【CA登记号】 |
【 分 子 式 】C9H10OS 【 分 子 量 】166.2438 【元素组成】C 65.02% H 6.06% O 9.62% S 19.29% |
合成路线1
该中间体在本合成路线中的序号：(II)Dipolar cycloaddition of hydroxypyridinium betaine (I) with R-(+)-p-tolyl vinyl sulfoxide (II) furnished the chiral tropenone (III). Subsequent copper-catalyzed conjugate addition of phenyl-magnesium bromide on the beta-face of (III) provided the trans diaryltropanone (IV). Then, ketone reduction of (IV) with LiAlH4 gave alcohol (V), which was condensed with phenyl thionochloroformate (VI) to afford thiocarbonate (VII). This was reduced with tributyltin hydride and azobis(isobutyronitrile) to produce tropane (VIII). The sulfoxide group of (VIII) was further reduced to sulfide (IX) with PCl3 in DMF. Finally, Raney Nickel-promoted desulfurization in boiling EtOH yielded the title compound.
| 【1】 Kozikowski, A.P.; Araldi, G.L.; Prakash, K.R.; Zhang, M.; Johnson, K.M.; Synthesis and biological properties of new 2beta-alkyl- and 2beta-aryl-3-(substituted phenyl)tropane derivatives: Stereochemical effect of C-3 on affinity and selectivity for neuronal dopamine and serotonin transporters. J Med Chem 1998, 41, 25, 4973. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 17616 | bromo(phenyl)magnesium; Phenyl Magnesium Bromide | 100-58-3 | C6H5BrMg | 详情 | 详情 | |
| (I) | 25800 | 1-methyl-4-(4-methylphenyl)-3-pyridiniumolate | C13H13NO | 详情 | 详情 | |
| (II) | 25801 | (4-methylphenyl)(oxo)vinyl-lambda(4)-sulfane; 4-methylphenyl vinyl sulfoxide | C9H10OS | 详情 | 详情 | |
| (III) | 25802 | (1S,5S,6R)-8-methyl-3-(4-methylphenyl)-6-[(4-methylphenyl)sulfinyl]-8-azabicyclo[3.2.1]oct-3-en-2-one | C22H23NO2S | 详情 | 详情 | |
| (IV) | 25803 | (1S,3R,4R,5S,6R)-8-methyl-3-(4-methylphenyl)-6-[(4-methylphenyl)sulfinyl]-4-phenyl-8-azabicyclo[3.2.1]octan-2-one | C28H29NO2S | 详情 | 详情 | |
| (V) | 25804 | (1S,3R,4R,5S,6R)-8-methyl-3-(4-methylphenyl)-6-[(4-methylphenyl)sulfinyl]-4-phenyl-8-azabicyclo[3.2.1]octan-2-ol | C28H31NO2S | 详情 | 详情 | |
| (VI) | 25805 | 1-[(chlorocarbothioyl)oxy]benzene; Phenylchlorothioformate | 1005-56-7 | C7H5ClOS | 详情 | 详情 |
| (VII) | 25806 | O-[(1S,3R,4R,5S,6R)-8-methyl-3-(4-methylphenyl)-6-[(4-methylphenyl)sulfinyl]-4-phenyl-8-azabicyclo[3.2.1]oct-2-yl] O-phenyl carbonothioate | C35H35NO3S2 | 详情 | 详情 | |
| (VIII) | 25807 | (1R,3R,4R,5S,6R)-8-methyl-3-(4-methylphenyl)-4-phenyl-8-azabicyclo[3.2.1]oct-6-yl 4-methylphenyl sulfoxide; (1S,2R,3R,5R,7R)-8-methyl-3-(4-methylphenyl)-7-[(4-methylphenyl)sulfinyl]-2-phenyl-8-azabicyclo[3.2.1]octane | C28H31NOS | 详情 | 详情 | |
| (IX) | 25808 | (1R,3R,4R,5S,6R)-8-methyl-3-(4-methylphenyl)-4-phenyl-8-azabicyclo[3.2.1]oct-6-yl 4-methylphenyl sulfide; (1S,2R,3R,5R,7R)-8-methyl-3-(4-methylphenyl)-7-[(4-methylphenyl)sulfanyl]-2-phenyl-8-azabicyclo[3.2.1]octane | C28H31NS | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The cycloaddition of the oxidopyridinium (I) with p-tolyl(vinyl)sulfoxide (II) in refluxing dioxane gives the tropenone derivative (III), which is treated with phenylmagnesium bromide and CuBr in THF yielding the diaryl tropanone derivative (IV). The reduction of (IV) with LiAlH4 in THF affords the corresponding alcohol (V), which is deoxigenated by reaction first with O-phenyl chlorothioformate and then with tributyltin hydride and AIBN in hot toluene to provide the diaryltropane (VI). The elimination of the sulfoxide group of (VI) with PCl3 and Raney-Ni in refluxing ethanol gives the diaryl tropane (VII) (1), which is submitted to N-demethylation with alpha-chloroethyl chloroformate and proton sponge in refluxing dichloroethane yielding the intermediate (VIII), which is finally N-alkylated with 2-phenylethyl bromide (IX) and K2CO3 in DMF.
| 【1】 Kozikowski, A.P.; Araldi, G.L.; Prakash, K.R.; Zhang, M.; Johnson, K.M.; Synthesis and biological properties of new 2beta-alkyl- and 2beta-aryl-3-(substituted phenyl)tropane derivatives: Stereochemical effect of C-3 on affinity and selectivity for neuronal dopamine and serotonin transporters. J Med Chem 1998, 41, 25, 4973. |
| 【2】 Johnson, K.M.; Tamiz, A.P.; Zhang, M,; Araldi, G.L.; Kozikowski, A.P.; Prakash, K.R.C.; N-Phenylalkyl-substituted tropane analogs of boat conformation with high selectivity for the dopamine versus serotonin transporter. Bioorg Med Chem Lett 1999, 9, 23, 3325. |
| 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) | 41384 | 1-methyl-4-(4-methylphenyl)-2-pyridiniumolate | C13H13NO | 详情 | 详情 | |
| (II) | 25801 | (4-methylphenyl)(oxo)vinyl-lambda(4)-sulfane; 4-methylphenyl vinyl sulfoxide | C9H10OS | 详情 | 详情 | |
| (III) | 41385 | (1R,5R,6R)-8-methyl-3-(4-methylphenyl)-6-[(4-methylphenyl)sulfinyl]-8-azabicyclo[3.2.1]oct-3-en-2-one | C22H23NO2S | 详情 | 详情 | |
| (IV) | 41386 | (1R,3R,4R,5R,6R)-8-methyl-3-(4-methylphenyl)-6-[(4-methylphenyl)sulfinyl]-4-phenyl-8-azabicyclo[3.2.1]octan-2-one | C28H29NO2S | 详情 | 详情 | |
| (V) | 41387 | (1R,3R,4R,5R,6R)-8-methyl-3-(4-methylphenyl)-6-[(4-methylphenyl)sulfinyl]-4-phenyl-8-azabicyclo[3.2.1]octan-2-ol | C28H31NO2S | 详情 | 详情 | |
| (VI) | 41388 | (1R,2R,3R,5S,7R)-8-methyl-3-(4-methylphenyl)-7-[(4-methylphenyl)sulfinyl]-2-phenyl-8-azabicyclo[3.2.1]octane; (1S,3R,4R,5R,6R)-8-methyl-3-(4-methylphenyl)-4-phenyl-8-azabicyclo[3.2.1]oct-6-yl 4-methylphenyl sulfoxide | C28H31NOS | 详情 | 详情 | |
| (VII) | 41389 | (1S,2R,3R,5R)-8-methyl-3-(4-methylphenyl)-2-phenyl-8-azabicyclo[3.2.1]octane | C21H25N | 详情 | 详情 | |
| (VIII) | 41390 | (1S,2R,3R,5R)-3-(4-methylphenyl)-2-phenyl-8-azabicyclo[3.2.1]octane | C20H23N | 详情 | 详情 | |
| (IX) | 20730 | 1-(2-bromoethyl)benzene；1-Bromo-2-phenylethane;(2-Bromoethyl)benzene;Phenethyl bromide | 103-63-9 | C8H9Br | 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 dipolar cycloaddition of betaine (I) with (R)-p-tolyl vinyl sulfoxide (II) produced a mixture of exo and endo cycloadducts (III). Flash chromatography of the reaction mixture led to the separation of the exo tropenones as a diastereomeric mixture, and further crystallization from EtOAc provided the pure major isomer (IV). Copper-catalyzed conjugate addition of n-propylmagnesium bromide to the unsaturated ketone (IV) gave (V). The keto group was then reduced to alcohol (VI) using LiBH4. Tropane (VIII) was obtained by Barton deoxygenation of tropanol (VI) via conversion to thiono carbonate (VII) and subsequent reduction with Bu3SnH. Oxidation of the sulfoxide group to sulfone (IX) was carried out by means of oxone in aqueous MeOH. Fluorination with N-fluorobenzenesulfonimide gave the beta-fluoro compound (X). Finally, reductive desulfonation with sodium amalgam yielded the title compound.
| 【1】 Johnson, K.M.; Trzcinska, M.; Kozikowski, A.P.; Prakash, K.R.C.; An enantioselective synthesis and biobehavioral evaluation of 7-fluoro-3-(p-fluorophenyl)-2-propyltropanes. Bioorg Med Chem Lett 2000, 10, 13, 1443. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIIa),(IV) | 46917 | (1S,5S,6R)-3-(4-fluorophenyl)-8-methyl-6-[(4-methylphenyl)sulfinyl]-8-azabicyclo[3.2.1]oct-3-en-2-one | C21H20FNO2S | 详情 | 详情 | |
| (IIIb) | 46918 | (1S,5S,6S)-3-(4-fluorophenyl)-8-methyl-6-[(4-methylphenyl)sulfinyl]-8-azabicyclo[3.2.1]oct-3-en-2-one | C21H20FNO2S | 详情 | 详情 | |
| (I) | 46916 | 4-(4-fluorophenyl)-1-methyl-3-pyridiniumolate | C12H10FNO | 详情 | 详情 | |
| (II) | 25801 | (4-methylphenyl)(oxo)vinyl-lambda(4)-sulfane; 4-methylphenyl vinyl sulfoxide | C9H10OS | 详情 | 详情 | |
| (V) | 46919 | (1S,4S,5S,6R)-3-(4-fluorophenyl)-8-methyl-6-[(4-methylphenyl)sulfinyl]-4-propyl-8-azabicyclo[3.2.1]octan-2-one | C24H28FNO2S | 详情 | 详情 | |
| (VI) | 46920 | (1S,2S,3R,4S,5S,6R)-3-(4-fluorophenyl)-8-methyl-6-[(4-methylphenyl)sulfinyl]-4-propyl-8-azabicyclo[3.2.1]octan-2-ol | C24H30FNO2S | 详情 | 详情 | |
| (VII) | 46921 | O-[(1S,2S,3R,4S,5S,6R)-3-(4-fluorophenyl)-8-methyl-6-[(4-methylphenyl)sulfinyl]-4-propyl-8-azabicyclo[3.2.1]oct-2-yl] O-phenyl carbonothioate | C31H34FNO3S2 | 详情 | 详情 | |
| (VIII) | 46922 | (1R,3R,4S,5S,6R)-3-(4-fluorophenyl)-8-methyl-4-propyl-8-azabicyclo[3.2.1]oct-6-yl 4-methylphenyl sulfoxide; (1S,2S,3R,5R,7R)-3-(4-fluorophenyl)-8-methyl-7-[(4-methylphenyl)sulfinyl]-2-propyl-8-azabicyclo[3.2.1]octane | C24H30FNOS | 详情 | 详情 | |
| (IX) | 46923 | (1S,2S,3R,5R,7R)-3-(4-fluorophenyl)-8-methyl-7-[(4-methylphenyl)sulfonyl]-2-propyl-8-azabicyclo[3.2.1]octane; (1R,3R,4S,5S,6R)-3-(4-fluorophenyl)-8-methyl-4-propyl-8-azabicyclo[3.2.1]oct-6-yl 4-methylphenyl sulfone | C24H30FNO2S | 详情 | 详情 | |
| (X) | 46924 | (1R,3R,4S,5S,6R)-6-fluoro-3-(4-fluorophenyl)-8-methyl-4-propyl-8-azabicyclo[3.2.1]oct-6-yl 4-methylphenyl sulfone; (1S,2S,3R,5R,7R)-7-fluoro-3-(4-fluorophenyl)-8-methyl-7-[(4-methylphenyl)sulfonyl]-2-propyl-8-azabicyclo[3.2.1]octane | C24H29F2NO2S | 详情 | 详情 |