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【结 构 式】 
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【药物名称】Loperamide oxide, JKD-584, R-58425, Arestal 【化学名称】trans-4-(4-Chlorophenyl)-4-hydroxy-N,N-dimethyl-alpha,alpha-diphenyl-1-piperidinebutanamide N-oxide 【CA登记号】106900-12-3 【 分 子 式 】C29H33ClN2O3 【 分 子 量 】493.05096 |
【开发单位】Janssen (Originator), Janssen-Kyowa (Originator), Dainippon Pharmaceutical (Licensee) 【药理作用】Antidiarrheal Agents, GASTROINTESTINAL DRUGS |
合成路线1
Treatment of 2-oxo-3,3-diphenyl-tetrahydrofuran (I) with HBr(g) yields bromo derivative (II), which is then converted into butyryl chloride derivative (III) by means of thionyl chloride in refluxing chloroform. Reaction of derivative (III) with dimethylamine (IV) in toluene affords dimethyl (tetrahydro-3,3-diphenyl-2-furylidene)ammonium bromide (V), which is then condensed with 4-(4-chlorophenyl)-4-piperidinol (VI) by means of Na2CO3 and KI in refluxing 4-methyl-2-pentanone to provide N,N-dimethyl butyramide derivative (VII). Finally, the target product is obtained by N-oxidation of the piperidine ring in (VII) by heating with H2O2 in MeOH/methylbenzene or in 4-methyl-2-pentanone.
| 【1】 Cooymans, L.P.; Wals, L. (Janssen Pharmaceutica NV); Novel alpha,alpha-diaryl-4-aryl-4-hydroxy-1-piperidinebutanamide, N-oxides. EP 0219898; JP 1987087569; US 4824853; US 4898873 . |
| 【2】 Niemegeers, C.J.E.J.; Janssen, P.A.J.; Stokbroekx, R.A.; Vandenberk, J. (Janssen Pharmaceutica NV); 2,2-Diaryl-4-(4'-aryl-4'-hydroxy-piperidino)-butyramides. US 3714159 . |
| 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) | 48324 | alpha,alpha-Diphenyl-gamma-butyrolactone; 4-Methoxychalcone; (4-Methoxybenzylidene)acetophenone; Dihydro-3,3-diphenyl-2(3H)-furanone; 4-Hydroxy-2,2-diphenylbutyric acid gamma-lactone; alpha,alpha-Diphenylbutyrolactone | 959-33-1 | C16H14O2 | 详情 | 详情 |
| (II) | 48325 | 4-bromo-2,2-diphenylbutyric acid | C16H15BrO2 | 详情 | 详情 | |
| (III) | 48326 | 4-bromo-2,2-diphenylbutanoyl chloride | C16H14BrClO | 详情 | 详情 | |
| (IV) | 19443 | N-methylmethanamine; N,N-dimethylamine | 124-40-3 | C2H7N | 详情 | 详情 |
| (V) | 48327 | N-[3,3-diphenyldihydro-2(3H)-furanylidene]-N-methylmethanaminium bromide | C18H20BrNO | 详情 | 详情 | |
| (VI) | 35870 | 4-(4-chlorophenyl)-4-piperidinol; 4-(4-Chlorophenyl)-4-hydroxypiperidine | 39512-49-7 | C11H14ClNO | 详情 | 详情 |
| (VII) | 48328 | 4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-N,N-dimethyl-2,2-diphenylbutanamide | C29H33ClN2O2 | 详情 | 详情 |