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【结 构 式】 
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【药物名称】Bisaramil hydrochloride, RGH-2957, YUTAC 【化学名称】3-Ethyl-7-methyl-9alpha-(4'-chlorobenzoyloxy)-3,7-diazabicyclo[3.3.1]nonane monohydrochloride 【CA登记号】96480-44-3, 89367-99-7 (diHCl), 89194-77-4 (free base) 【 分 子 式 】C17H24Cl2N2O2 【 分 子 量 】359.29903 |
【开发单位】Gedeon Richter (Originator), Taiho (Licensee) 【药理作用】Antiarrhythmic Drugs, CARDIOVASCULAR DRUGS |
合成路线1
The synthesis of [14C]- and deuterium-labeled bisaramil hydrochloride has been reported: 1) The reduction of (14)CO2 with LiAlH4 in THF gives labeled formaldehyde (II), which by a Mannich reaction is condensed with ethylamine (IV) and N-methylpiperidin-4-one (III) by means of acetic acid in refluxing methanol to yield labeled 3-ethyl-7-methyl-3,7-diazabicyclo[3.3.1]nonan-9-one (V). The reduction of (V) with NaBH4 in methanol/NaOH affords a mixture of the alpha- and beta-isomers of the labeled 9-hydroxy derivative (VI + VII). After separation by its different solubility in isopropanol, the alpha-isomer is condensed with 4-chlorobenzoyl chloride (VIII) in hot pyridine to give [2,4-14C]-labeled bisaramil.
| 【1】 Mlinko, S.; Simon Trompler, E.; Szammer, J.; Synthesis of bisaramil labelled with carbon-14 and deuterium. J Label Compd Radiopharm 1994, 34, 4, 313. |
| 【2】 Lapis, E.; YUTAC. Drugs Fut 1985, 10, 10, 837. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 10919 | 1-Methyl-4-piperidone; 1-Methyltetrahydro-4(1H)-pyridinone; N-Methyl-4-piperidone;1-methylpiperidin-4-one | 1445-73-4 | C6H11NO | 详情 | 详情 |
| (V) | 10920 | 3-Ethyl-7-methyl-3,7-diazabicyclo[3.3.1]nonan-9-one | C10H18N2O | 详情 | 详情 | |
| (V) | 44684 | 3-ethyl-7-methyl-3,7-diazabicyclo[3.3.1]nonan-9-one | C10H18N2O | 详情 | 详情 | |
| (VI) | 10921 | 3-Ethyl-7-methyl-3,7-diazabicyclo[3.3.1]nonan-9-ol | C10H20N2O | 详情 | 详情 | |
| (VI) | 44685 | 3-ethyl-7-methyl-3,7-diazabicyclo[3.3.1]nonan-9-ol | C10H20N2O | 详情 | 详情 | |
| (VII) | 10922 | 3-Ethyl-7-methyl-3,7-diazabicyclo[3.3.1]nonan-9-ol | C10H20N2O | 详情 | 详情 | |
| (VII) | 44686 | 3-ethyl-7-methyl-3,7-diazabicyclo[3.3.1]nonan-9-ol | C10H20N2O | 详情 | 详情 | |
| (VIII) | 10295 | p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride | 122-01-0 | C7H4Cl2O | 详情 | 详情 |
合成路线2
2) Hexadeuteroethyl alcohol (IX) is treated with red phosphorus and I2 at reflux temperature to give pentadeuteroethyl iodide (X), which is condensed with potassium phthalimide (XI) in DMF, yielding N-(pentadeuteroethyl)phthalimide (XII). The hydrolysis of (XII) with hydrazine and HCl affords pentadeuteroethylamine (XIII), which is condensed with 1-methylpiperidin-4-one (III) and formaldehyde (XIV) in a Mannich reaction to give 3-methyl-7-(pentadeuteroethyl)-3,7-diazabicyclo[3.3.1]nonan-9-one (XV). The reduction of (XV) with NaBH4 as before yields the diastereomeric mixture (XVI + XVII). Finally, the alpha-isomer (XVI) is condensed with 4-chlorobenzoyl chloride (VIII) as before to give the pentadeuterium-labeled bisaramil.
| 【1】 Mlinko, S.; Simon Trompler, E.; Szammer, J.; Synthesis of bisaramil labelled with carbon-14 and deuterium. J Label Compd Radiopharm 1994, 34, 4, 313. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 10919 | 1-Methyl-4-piperidone; 1-Methyltetrahydro-4(1H)-pyridinone; N-Methyl-4-piperidone;1-methylpiperidin-4-one | 1445-73-4 | C6H11NO | 详情 | 详情 |
| (VIII) | 10295 | p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride | 122-01-0 | C7H4Cl2O | 详情 | 详情 |
| (IX) | 10924 | Ethyl alcohol; Ethanol | 1516-08-1 | C2H6O | 详情 | 详情 |
| (IX) | 44687 | Ethanol-d6 | C2H6O | 详情 | 详情 | |
| (X) | 10925 | Iodoethane;ethyl iod | 75-03-6 | C2H5I | 详情 | 详情 |
| (X) | 44688 | 1-iodoethane-d5 | C2H5I | 详情 | 详情 | |
| (XI) | 10926 | (1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)potassium | C8H4KNO2 | 详情 | 详情 | |
| (XII) | 10927 | 2-Ethyl-1H-isoindole-1,3(2H)-dione | 5022-29-7 | C10H9NO2 | 详情 | 详情 |
| (XII) | 44689 | 2-ethyl-1H-isoindole-1,3(2H)-dione | C10H9NO2 | 详情 | 详情 | |
| (XIII) | 10928 | Ethanamine | 75-04-7 | C2H7N | 详情 | 详情 |
| (XIII) | 44690 | ethylamine; 1-ethanamine | C2H7N | 详情 | 详情 | |
| (XV) | 10929 | 3-Ethyl-7-methyl-3,7-diazabicyclo[3.3.1]nonan-9-one | C10H18N2O | 详情 | 详情 | |
| (XV) | 44691 | 3-ethyl-7-methyl-3,7-diazabicyclo[3.3.1]nonan-9-one | C10H18N2O | 详情 | 详情 | |
| (XVI) | 10921 | 3-Ethyl-7-methyl-3,7-diazabicyclo[3.3.1]nonan-9-ol | C10H20N2O | 详情 | 详情 | |
| (XVI) | 44692 | 3-ethyl-7-methyl-3,7-diazabicyclo[3.3.1]nonan-9-ol | C10H20N2O | 详情 | 详情 | |
| (XVII) | 10922 | 3-Ethyl-7-methyl-3,7-diazabicyclo[3.3.1]nonan-9-ol | C10H20N2O | 详情 | 详情 | |
| (XVII) | 44693 | 3-ethyl-7-methyl-3,7-diazabicyclo[3.3.1]nonan-9-ol | C10H20N2O | 详情 | 详情 |