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【结 构 式】 
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【分子编号】36016 【品名】(1R,9R,13R)-1,13-dimethyl-10-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6-trien-4-ol 【CA登记号】 |
【 分 子 式 】C14H19NO 【 分 子 量 】217.311 【元素组成】C 77.38% H 8.81% N 6.45% O 7.36% |
合成路线1
该中间体在本合成路线中的序号：(VIII)The condensation of 4-methoxybenzylmagnesium chloride (I) with 3,4-dimethylpyridine methiodide (II) gives N,3,4-trimethyl-2-(p-methoxybenzyl)-1,2-dihydropyridine (III), which by partial reduction with NaBH4 in methanol is converted into the corresponding 1,2,5,6-tetrahydro derivative (IV). The cyclization of (IV) by refluxing with AlBr3 in CS2 yields 2,5,9-trimethyl-2'-hydroxy-7-benzomorphane (V), which is acetylated with acetic anhydride to the acetoxy compound (VI) and treated with BrCN in refluxing CHCl3 to afford the N-cyano compound (VII). This compound is refluxed with 6% HCl yielding 5,9-dimethyl-2'-hydroxy-6,7-benzomorphane (VIII) , which is condensed with 4-(p-fluorophenyl)-4,4-ethylenedioxy-1-chlorobutane (XVI) by means of NaHCO3 in DMF at 140 C to afford the corresponding N-alkyl derivative (IX). Finally, this compound is hydrolyzed by refluxing with diluted aqueous HCl.
| 【1】 Atsumi, T.; et al.; JP 7319314 . |
| 【2】 Atsumi, T.; et al.; JP 7343352 . |
| 【3】 Yamamoto, H.; et al.; The synthesis and pharmacology of a new analgesic, ID-1229. Arzneim-Forsch Drug Res 1975, 25, 5, 795-801. |
| 【4】 Atsumi, T.; et al. (Sumitomo Chemical Co., Ltd.); Novel benzomorphan and their salts as analgesics. US 3873706 . |
| 【5】 Castaner, J.; Paton, D.M.; ID-1229. Drugs Fut 1978, 3, 4, 298. |
| 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) | 39855 | chloro(4-methoxybenzyl)magnesium | C8H9ClMgO | 详情 | 详情 | |
| (II) | 39856 | 1,3,4-trimethylpyridinium iodide | C8H12IN | 详情 | 详情 | |
| (III) | 39857 | methyl 4-[(1,3,4-trimethyl-1,2-dihydro-2-pyridinyl)methyl]phenyl ether; 2-(4-methoxybenzyl)-1,3,4-trimethyl-1,2-dihydropyridine | C16H21NO | 详情 | 详情 | |
| (IV) | 39858 | 6-(4-methoxybenzyl)-1,4,5-trimethyl-1,2,3,6-tetrahydropyridine; methyl 4-[(1,3,4-trimethyl-1,2,5,6-tetrahydro-2-pyridinyl)methyl]phenyl ether | C16H23NO | 详情 | 详情 | |
| (V) | 39859 | (1R,9R,13R)-1,10,13-trimethyl-10-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6-trien-4-ol | C15H21NO | 详情 | 详情 | |
| (VI) | 39860 | (1R,9R,13R)-1,10,13-trimethyl-10-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6-trien-4-yl acetate | C17H23NO2 | 详情 | 详情 | |
| (VII) | 39861 | (1R,9R,13R)-10-cyano-1,13-dimethyl-10-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6-trien-4-yl acetate | C17H20N2O2 | 详情 | 详情 | |
| (VIII) | 36016 | (1R,9R,13R)-1,13-dimethyl-10-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6-trien-4-ol | C14H19NO | 详情 | 详情 | |
| (IX) | 39862 | (1R,9R,13R)-10-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-4-methoxy-1,13-dimethyl-10-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6-triene; (1R,9R,13R)-10-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-1,13-dimethyl-10-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6-trien-4-yl methyl ether | C27H34FNO3 | 详情 | 详情 | |
| (XVI) | 28203 | 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane | 3308-94-9 | C12H14ClFO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)The condensation of (VIII) with 3-(p-fluorobenzoyl)propionic acid (A) by means of ethyl chloroformate (B) and triethylamine in CHCl3 gives the corresponding N,O-diacyl derivative (X), which is then reduced with LiAlH4 in refluxing THF yielding 5,9-dimethyl-2-[4''-(p-fluorophenyl)4''-hydroxy-1''-butyl]-2'-hydroxy-5,9-dimethyl-6,7-benzomorphane (XI). Finally, this compound is oxidized with Jones reagent (H2CrO4 in H2SO4).
| 【1】 Atsumi, T.; et al. (Sumitomo Chemical Co., Ltd.); Processes for producing 2-benzoylalkylbenzomorphan derivatives and their salts. DE 2114511; ES 389920; FR 2092005; GB 1311387 . |
| 【2】 Castaner, J.; Paton, D.M.; ID-1229. Drugs Fut 1978, 3, 4, 298. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 11229 | 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate | 541-41-3 | C3H5ClO2 | 详情 | 详情 |
| (A) | 39863 | 4-(4-fluorophenyl)-4-oxobutyric acid | 366-77-8 | C10H9FO3 | 详情 | 详情 |
| (VIII) | 36016 | (1R,9R,13R)-1,13-dimethyl-10-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6-trien-4-ol | C14H19NO | 详情 | 详情 | |
| (X) | 39864 | (1R,9R,13R)-10-[4-(4-fluorophenyl)-4-oxobutanoyl]-1,13-dimethyl-10-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6-trien-4-yl 4-(4-fluorophenyl)-4-oxobutanoate | C34H33F2NO5 | 详情 | 详情 | |
| (XI) | 39865 | (1R,9R,13R)-10-[4-(4-fluorophenyl)-4-hydroxybutyl]-1,13-dimethyl-10-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6-trien-4-ol | C24H30FNO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)By condensation of 2'-hydroxy-5,9-dimethyl-6,7-benzomorphan (I) with allyl bromide (II) by means of NaHCO3 in refluxing ethanol.
| 【1】 Gordon, M.; Lafferty, J.J. (SmithKline Beecham Corp.); Novel N-allyl and N-propargyl benzmorphan derivs.. US 4048178 . |
| 【2】 Serradell, M.N.; Castaner, J.; Paton, D.M.; Blancafort, P.; SKF-10,047. Drugs Fut 1983, 8, 5, 439. |