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【结 构 式】 
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【药物名称】Tonazocine mesylate, Win-421562 【化学名称】(±)-(2alpha,6alpha,11S*)-1-(1,2,3,4,5,6-Hexahydro-8-hydroxy-3,6,11-trimethyl-2,6-methano-3-benzazocin-11-yl)-3-octanone methanesulfonate (salt) 【CA登记号】73789-00-1, 71461-18-2 (free base) 【 分 子 式 】C24H39NO5S 【 分 子 量 】453.64613 |
【开发单位】Sanofi-synthélabo (Originator) 【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Opioid Analgesics, Opioid Agonists-Antagonists |
合成路线1
The reaction of 4-methoxybenzylmagnesium bromide (I) with 1,3,4-trimethylpyridinium bromide (II) in ether, followed by a Diels-Alder condensation with ethyl acrylate (III) gives ethyl 3-(4-methoxybenzyl)-2,4,8-trimethyl-2-azabicyclo[2.2.2]oct-7-ene-6-carboxylate (IV), which is cyclized by means of HF yielding ethyl 1,2,3,4,4a,5,10,10a-octahydro-7-methoxy-1,4a,5-trimethyl-2,5-methanobenzo[g]quinoline-3-carboxylate (V). Acylation of (V) with hexanoyl chloride (VI) and butyllithium-diisopropylamine in THF affords the corresponding acyl derivative (VII), which is submitted to a reductive ring opening with formic acid in refluxing mesytilene giving 1,2,3,4,5,6-hexahydro-8-methoxy-3,6,11-trimethyl-11-(3-oxo-1-octyl)-2,6-methano-3-benzazocine (VIII). Finally, this compound is demethylated with 48% HBr and treated with methanesulfonic acid.
| 【1】 Michne, W.F.; 11-Substituted hexahydro-2,6-methano-3-benzazocines. US 4255579 . |
| 【2】 Lewis, T.R.; Rosenberg, F.J.; Michalec, S.J.; Pierson, A.K.; Michne, W.F.; 2,6-Methano-3-benzazocin-11beta-yl)alkalones. 1. Alkylalkalones: A new series of N-methyl derivatives with novel opiate activity profiles. J Med Chem 1979, 22, 10, 1158-63. |
| 【3】 Castaner, J.; Serradell, M.N.; Tonazocine mesylate. Drugs Fut 1984, 9, 11, 844. |
| 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) | 35917 | bromo(4-methoxybenzyl)magnesium | C8H9BrMgO | 详情 | 详情 | |
| (II) | 35918 | 1,3,4-trimethylpyridinium bromide | C8H12BrN | 详情 | 详情 | |
| (III) | 10164 | ethyl acrylate | 140-88-5 | C5H8O2 | 详情 | 详情 |
| (IV) | 35919 | methyl 3-(4-methoxybenzyl)-2,4,8-trimethyl-2-azabicyclo[2.2.2]oct-7-ene-6-carboxylate | C20H27NO3 | 详情 | 详情 | |
| (V) | 35920 | methyl (1S)-4-methoxy-1,10,14-trimethyl-10-azatetracyclo[9.3.1.0(2,7).0(9,14)]pentadeca-2,4,6-triene-12-carboxylate | C20H27NO3 | 详情 | 详情 | |
| (VI) | 35921 | hexanoyl chloride | 142-61-0 | C6H11ClO | 详情 | 详情 |
| (VII) | 35922 | methyl (1S)-12-hexanoyl-4-methoxy-1,10,14-trimethyl-10-azatetracyclo[9.3.1.0(2,7).0(9,14)]pentadeca-2,4,6-triene-12-carboxylate | C26H37NO4 | 详情 | 详情 | |
| (VIII) | 35923 | 1-[(1S,9R)-4-methoxy-1,10,13-trimethyl-10-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6-trien-13-yl]-3-octanone | C24H37NO2 | 详情 | 详情 |