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【结 构 式】

【药物名称】ID-1229

【化学名称】2-[3-(4-Fluorobenzoyl)-1-propyl]-5alpha,9alpha-dimethyl-2'-hydroxy-6,7-benzomorphan
　　　　　　3-[3-(4-Fluorobenzoyl)-1-propyl]-1,2,3,4,5,6-hexahydro-8-hydroxy-6,11-dimethyl-2,6-methano-3-benzazocine
　　　　　　(2alpha,6alpha,11R*)-1-(4-Fluorophenyl)-4-(1,4,5,6-tetrahydro-8-hydroxy-6,11-dimethyl-2,6-methano-3-benzazocin-3(2H)-1-butanone
　　　　　　4'-Fluoro-4-[1,4,5,6-tetrahydro-8-hydroxy-6,11-dimethyl-2,6-methano-3-benzazocin-3(2H)-yl]-butyrophenone

【CA登记号】56390-16-0

【 分 子 式 】C24H28FNO2

【 分 子 量 】381.49466

【开发单位】Sumitomo Pharmaceuticals (Originator)

【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Non-Opioid Analgesics

合成路线1合成路线2合成路线3合成路线4

合成路线1

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.

参考文献 中间体
【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

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).

参考文献 中间体
【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

The nitration of 2,5,9-trimethyl-6,7-benzomorphane (XII) gives the 2'-nitro derivative (XIII), which by hydrogenation is converted into the corresponding 2'-amino compound (XIV). Finally, this compound is diazotized and converted into the hydroxy compound (V), already obtained.

参考文献 中间体
【1】 Atsumi, T.; et al.; JP 7343352 .
【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
(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
(XII) 39866 (1R,9R,13R)-1,10,13-trimethyl-10-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6-triene C15H21N 详情 详情
(XIII) 39867 (1R,9R,13R)-1,10,13-trimethyl-4-nitro-10-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6-triene C15H20N2O2 详情 详情
(XIV) 39868 (1R,9R,13R)-1,10,13-trimethyl-10-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6-trien-4-amine; (1R,9R,13R)-1,10,13-trimethyl-10-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6-trien-4-ylamine C15H22N2 详情 详情

合成路线4

The condensation of 3,4-dimethylpyridine (XV) with 4-(p-fluorophenyl)-4,4-ethylenedioxy-1-chlorobutane (XVI) gives the corresponding pyridinium salt (XVII), which by reaction with p-methoxybenzylmagnesium chloride (I) in ether yields the dihydropyridine (XVIII). The reduction of (XVIII) with NaBH4 in methanol affords the tetrahydropyridine (XIX), which is finally cyclized by refluxing with AlBr3 in CS2; this reaction can also be performed by heating (XIX) with 48% aqueous HBr at 130 C.

参考文献 中间体
【1】 Atsumi, T.; et al. (Sumitomo Chemical Co., Ltd.); Preparation of 2-benzoylalkylbenzomorphan. DE 2128525; FR 2100743; GB 1329504; US 3953441 .
【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
(I) 39855 chloro(4-methoxybenzyl)magnesium C8H9ClMgO 详情 详情
(XV) 39869 3,4-dimethylpyridine 583-58-4 C7H9N 详情 详情
(XVI) 28203 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane 3308-94-9 C12H14ClFO2 详情 详情
(XVII) 39870 1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-3,4-dimethylpyridinium chloride C19H23ClFNO2 详情 详情
(XVIII) 39871 1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-2-(4-methoxybenzyl)-3,4-dimethyl-1,2-dihydropyridine; 4-[(1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-3,4-dimethyl-1,2-dihydro-2-pyridinyl)methyl]phenyl methyl ether C27H32FNO3 详情 详情
(XIX) 39872 1-(4-fluorophenyl)-4-[6-(4-methoxybenzyl)-4,5-dimethyl-3,6-dihydro-1(2H)-pyridinyl]-1-butanone C25H30FNO2 详情 详情
Extended Information