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【结 构 式】 
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【药物名称】Granisetron hydrochloride, BRL-43694, Kytril 【化学名称】endo-1-Methyl-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1H-indazole-3-carboxamide hydrochloride 【CA登记号】107007-99-8, 109889-09-0 (free base) 【 分 子 式 】C18H25ClN4O 【 分 子 量 】348.87915 |
【开发单位】Chugai (Proprietary), Roche (Proprietary), GlaxoSmithKline (Originator) 【药理作用】Nausea and Vomiting, Treatment of, NEUROLOGIC DRUGS, 5-HT3 Antagonists |
合成路线1
The synthesis of granisetron has been reported: The reaction of 1-methylindazole-3-carboxylic acid (I) with oxalyl chloride and DMF in dichloromethane gives 1-methylindazole-3-carbonyl chloride (II), which is then condensed with endo-9-methyl-9-azabicyclo[3.3.1]nonan-3-amine (III) by means of triethylamine in dichloromethane.
| 【1】 GB 2125398 . |
| 【2】 King, F.D. (SmithKline Beecham plc); Indazolyl carboxylic acid amides useful for treating migraine clusters headache, trigeminal neuralgia or emesis. AU 8656579; EP 0200444; EP 0223385; EP 0498466; ES 8707948; JP 1986275276; JP 1993194508; US 4886808; US 5034398 . |
| 【3】 King, F.D.; Sanger, G.J.; 5-HT3 RECEPTOR ANTAGONISTS. Drugs Fut 1989, 14, 9, 875. |
| 【4】 W.D.; Sanger, G.J.; 5-Hydroxytryptamine (5-HT3) receptor antagonists. 1. Indazole and indolizine-3-carboxylic acid derivatives. J Med Chem 1990, 33, 7, 1924-9. |
| 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) | 11885 | 1-Methyl-1H-indazole-3-carboxylic acid | 50890-83-0 | C9H8N2O2 | 详情 | 详情 |
| (II) | 11886 | 1-Methyl-1H-indazole-3-carbonyl chloride | 106649-02-9 | C9H7ClN2O | 详情 | 详情 |
| (III) | 11887 | (1R,5S)-1-Amino-9-methyl-9azabicyclo[3.3.1]nonane; (1R,5S)-9-Methyl-9-azabicyclo[3.3.1]non-3-ylamine; (1R,5S)-9-Methyl-9-azabicyclo[3.3.1]nonan-3-amine; 1-Amino-9-methyl-9-azabicyclo[3.3.1]nonane | 76272-56-5 | C9H18N2 | 详情 | 详情 |
合成路线2
A synthesis of [11C]-granisetron has been published: The desmethylation of granisetron (I) with vinyl chloroformate in refluxing dichloroethane gives the intermediate vinyl ester (II), which is decarboxylated with dry HCl in dichloromethane yielding the desmethylgranisetron (III). Finally, this compound is methylated with [11C]-methyl iodide and NaOH in DMF at 145 C.
| 【1】 Vandersteene, I.; Dierckx, R.A.; Slegers, G.; Audenaert, K.; Synthesis of [C-11]granisetron, a possible positron emission tomography ligand for 5-HT3 receptor studies. J Label Compd Radiopharm 1998, 41, 3, 171. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 28068 | 1-[(Chlorocarbonyl)oxy]ethylene; Vinyl chloroformate | 5130-24-5 | C3H3ClO2 | 详情 | 详情 |
| (I) | 28067 | Granisetron; 1-Methyl-N-[(1R,5S)-9-methyl-9-azabicyclo[3.3.1]non-3-yl]-1H-indazole-3-carboxamide | C18H24N4O | 详情 | 详情 | |
| (II) | 28069 | vinyl (1R,5S)-3-[[(1-methyl-1H-indazol-3-yl)carbonyl]amino]-9-azabicyclo[3.3.1]nonane-9-carboxylate | C20H24N4O3 | 详情 | 详情 | |
| (III) | 28070 | N-[(1R,5S)-9-azabicyclo[3.3.1]non-3-yl]-1-methyl-1H-indazole-3-carboxamide | C17H22N4O | 详情 | 详情 |