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【结 构 式】 
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【药物名称】Ro-60-0869 【化学名称】cis-7-Ethyl-6-hydroxy-8-methoxy-2-methyl-1,2,3,3a,4,9b-hexahydro-5H-benzo[e]isoindol-5-one 【CA登记号】204650-27-1, 204650-28-2 (fumarate(1:1)) 【 分 子 式 】C16H21NO3 【 分 子 量 】275.35067 |
【开发单位】Roche (Originator) 【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Antimigraine Drugs, Anxiolytics, PSYCHOPHARMACOLOGIC DRUGS, Sleep Disorders, Treatment of, 5-HT2C (5-HT1C) Agonists, 5-HT2C (5-HT1C) Antagonists |
合成路线1
The reaction of 4-ethyl-3,5-dimethoxybenzaldehyde (I) with (ethoxycarbonylmethyl)triphenylphosphonium bromide (II) by means o butyllithium in THF gives the acrylate (III), which is allowed to react with nitromethane/triton B in hot methanol yielding the 4-nitrobutyrate (IV). The reduction of (IV) with H2 over RaNi in ethanol affords the 4-aminobutyrate (V), which is cyclized to the pyrrolidinone (VI) by means of p-toluenesulfonic acid in refluxing ethanol. The methylation of (VI) with NaH/methyl iodide in THF gives the corresponding N-methylpyrrolidinone (VII), which is condensed with tert-butyl bromoacetate (VIII) by means of butyllithium/diisopropylamine in THF yielding the intermediate (IX). The reduction of the ketonic grupof (IX) with the complex borane/THF in THF affords the pyrrolidineacetate ester (X), which is cyclized by means of polyphosphoric acid (PPA) at 120 C giving the benzisoindole (XI). Finally, this compound is selectively demethylate by menas of BBr3 in dichloromethane.
| 【1】 Stadler, H.; Bos, M.; Wichmann, J. (F. Hoffmann-La Roche AG); Tricyclic benzo[e]isoindoles and benzo[h]isoquinolines . EP 0958285; JP 2000507965; WO 9830546 . |
| 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) | 20754 | 4-ethyl-3,5-dimethoxybenzaldehyde | C11H14O3 | 详情 | 详情 | |
| (II) | 20755 | (2-ethoxy-2-oxoethyl)(triphenyl)phosphonium bromide | 1530-45-6 | C22H22BrO2P | 详情 | 详情 |
| (III) | 20756 | ethyl (E)-3-(4-ethyl-3,5-dimethoxyphenyl)-2-propenoate | C15H20O4 | 详情 | 详情 | |
| (IV) | 20757 | ethyl 3-(4-ethyl-3,5-dimethoxyphenyl)-4-nitrobutanoate | C16H23NO6 | 详情 | 详情 | |
| (V) | 20758 | ethyl 4-amino-3-(4-ethyl-3,5-dimethoxyphenyl)butanoate | C16H25NO4 | 详情 | 详情 | |
| (VI) | 20759 | 4-(4-ethyl-3,5-dimethoxyphenyl)-2-pyrrolidinone | C14H19NO3 | 详情 | 详情 | |
| (VII) | 20760 | 4-(4-ethyl-3,5-dimethoxyphenyl)-1-methyl-2-pyrrolidinone | C15H21NO3 | 详情 | 详情 | |
| (VIII) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (IX) | 20762 | tert-butyl 2-[4-(4-ethyl-3,5-dimethoxyphenyl)-1-methyl-2-oxo-3-pyrrolidinyl]acetate | C21H31NO5 | 详情 | 详情 | |
| (X) | 20763 | tert-butyl 2-[4-(4-ethyl-3,5-dimethoxyphenyl)-1-methyl-3-pyrrolidinyl]acetate | C21H33NO4 | 详情 | 详情 | |
| (XI) | 20764 | (3aS,9bS)-7-ethyl-6,8-dimethoxy-2-methyl-1,2,3,3a,4,9b-hexahydro-5H-benzo[e]isoindol-5-one | C17H23NO3 | 详情 | 详情 |