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【结 构 式】 
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【分子编号】16395 【品名】(1R,2R,4S)-2-(6-methoxy-3-pyridinyl)-7-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]heptane; methyl 5-[(1R,2R,4S)-7-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]hept-2-yl]-2-pyridinyl ether 【CA登记号】 |
【 分 子 式 】C19H22N2O3S 【 分 子 量 】358.46136 【元素组成】C 63.66% H 6.19% N 7.81% O 13.39% S 8.95% |
合成路线1
该中间体在本合成路线中的序号：rac-(XXVIII)7) Sestanj and his coworkers succeeded in synthesizing epibatidine by a conjugate addition intramolecular displacement strategy.Conjugate addition of higher order cyanocuprate (XXIV) to alpha,beta-unsaturated ketone (XXV) obtained the ketone (XXVI), which was converted to (XXVII) in 60% overall yield. Under Mitsunobu conditions with DEAD and PPh3 as reagents, only the beta-amino-tosylate cyclized to give the epibatidine ring system.
| 【1】 Sestanj, K.; Melenski, E.; Jirkovsky, I.; Synthesis of epibatidine. Tetrahedron Lett 1994, 35, 5417-20. |
| 【2】 Bai, D.; Xu, R.; Zhu, X.; Epibatidine. Drugs Fut 1997, 22, 11, 1210. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (rac-I) | 16385 | (+)-Epibatidine hydrochloride; (1R,2R,4S)-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]heptane | 140111-52-0 | C11H13ClN2 | 详情 | 详情 |
| (rac-XVIII) | 16385 | (+)-Epibatidine hydrochloride; (1R,2R,4S)-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]heptane | 140111-52-0 | C11H13ClN2 | 详情 | 详情 |
| rac-(XXVI) | 16393 | (3S,4S)-3-(6-methoxy-3-pyridinyl)-4-[(trimethylsilyl)methyl]cyclohexanone | C16H25NO2Si | 详情 | 详情 | |
| rac-(XXVII) | 16394 | N-[(3R,4S)-4-hydroxy-3-(6-methoxy-3-pyridinyl)cyclohexyl]-4-methylbenzenesulfonamide | C19H24N2O4S | 详情 | 详情 | |
| rac-(XXVIII) | 16395 | (1R,2R,4S)-2-(6-methoxy-3-pyridinyl)-7-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]heptane; methyl 5-[(1R,2R,4S)-7-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]hept-2-yl]-2-pyridinyl ether | C19H22N2O3S | 详情 | 详情 | |
| (XXIV) | 16391 | (6-Methoxypyridin-3-yl)(2-thienyl)copper dilithium cyanide complex | C10H9CuNOS | 详情 | 详情 | |
| (XXV) | 16392 | 4-[(trimethylsilyl)methyl]-2-cyclohexen-1-one | C10H18OSi | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：rac(LXIV)15) Natsume's approach to epibatidine was to construct the basic skeleton of (I) by condensation of N-protected 7-azabicyclo[2.2.1]heptan-2-one with 5-lithio-2-chloropyridine, which was similar to Fletcher's synthesis. However, the azabicycloheptanone (LX) was derived from the Diels-Alder adduct (LIX) of 1-(p-toluenesulfonyl)pyrrole and dimethyl acetylenedicarboxylate through a standard sequence of reactions. Reaction of (LX) with 5-lithio-2-methoxypyridine gave (LXI), which was dehydrated to (LXII) with Burgess reagent. Catalytic hydrogenation of (LXII) over palladium-on-charcoal in 2-propanol/water (12:1) containing 1% HCl afforded (LXIII) and (LXIV) in 22% and 72% yields, respectively. Treatment of (LXIV) with POCl3/DMF obtained (LXV) in 70% yield.
| 【1】 Bai, D.; Xu, R.; Zhu, X.; Epibatidine. Drugs Fut 1997, 22, 11, 1210. |
| 【2】 Okabe, K.; Natsume, M.; Total synthesis of a frog poison, (±)-epibatidine, a potent non-opioid analgesic. Chem Pharm Bull 1994, 42, 7, 1432-6. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| rac(LXIV) | 16395 | (1R,2R,4S)-2-(6-methoxy-3-pyridinyl)-7-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]heptane; methyl 5-[(1R,2R,4S)-7-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]hept-2-yl]-2-pyridinyl ether | C19H22N2O3S | 详情 | 详情 | |
| rac-(LIX) | 16425 | dimethyl (1R,4S)-7-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]hept-2-ene-2,3-dicarboxylate | C17H19NO6S | 详情 | 详情 | |
| rac-(LX) | 16426 | (1R,4S)-7-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]heptan-2-one | C13H15NO3S | 详情 | 详情 | |
| rac-(LXI) | 16427 | (1R,2S,4S)-2-(6-methoxy-3-pyridinyl)-7-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]heptan-2-ol | C19H22N2O4S | 详情 | 详情 | |
| rac-(LXII) | 16428 | methyl 5-[(1R,4S)-7-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]hept-2-en-2-yl]-2-pyridinyl ether; (1R,4S)-2-(6-methoxy-3-pyridinyl)-7-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]hept-2-ene | C19H20N2O3S | 详情 | 详情 | |
| rac-(LXIII) | 16429 | (1R,2S,4S)-2-(6-methoxy-3-pyridinyl)-7-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]heptane; methyl 5-[(1R,2S,4S)-7-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]hept-2-yl]-2-pyridinyl ether | C19H22N2O3S | 详情 | 详情 | |
| rac-(LXV) | 16431 | (1R,2R,4S)-2-(6-chloro-3-pyridinyl)-7-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]heptane | C18H19ClN2O2S | 详情 | 详情 |