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【结 构 式】 
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【药物名称】E-4031 【化学名称】4'-[[1-[2-(6-Methyl-2-pyridyl)ethyl]-4-piperidinyl]carbonyl]methanesulfonanilide dihydrochloride dihydrate 【CA登记号】113559-13-0 (anhydrous), 113558-89-7 (free base, anhydrous) 【 分 子 式 】C21H33Cl2N3O5S 【 分 子 量 】510.48426 |
【开发单位】Eisai (Originator) 【药理作用】Antiarrhythmic Drugs, CARDIOVASCULAR DRUGS, Potassium Channel Blockers |
合成路线1
The mesylation of aniline (I) with methanesulfonyl chloride gives the sulfonamide (II), which is condensed with 1-acetylpiperidine-4-carbonyl chloride (III) by means of AlCl3 in dichloromethane to give N-[4-(1-acetylpiperidin-4-ylcarbonyl)phenyl]methanesulfonamide (IV). Deacetylation of (IV) with HCl in water yields the piperidine (V), which is finally condensed with 2-methyl-6-vinylpyridine by means of sodium acetate in methanol - water. The same procedure has been performed with [14C]-labeled aniline in order to obtain [14C]-labeled E-4031.
| 【1】 Oinuma, H.; Yamanaka, M.; Miyake, K.; Hoshiko, T.; Minami, N.; Shoji, T.; Daiku, Y.; Sawada, K.; Nomoto, K. (Eisai Co., Ltd.); Piperidine deriv., pharmaceutical compsn. containing the same and use. EP 0235752; US 4876262; US 4996215; US 5118689; US 5179095 . |
| 【2】 Miyake, K.; Yamanaka, M.; Katoh, H.; Shino, M.; Hamano, S.; Nomoto, K.-I.; Oinuma, H.; Sawada, K.; 4'-[(4-Piperidyl)carbonyl]methanesulfonanilides as potent, selective, bioavailable class III antiarrhythmic agents. J Med Chem 1990, 33, 3, 903. |
| 【3】 Shino, M.; Oinuma, H.; Hamano, S.; Miyake, K.; Yamanaka, M.; Synthesis of antiarrhythmic [phenyl-14C]4'-[(4-piperidyl)carbonyl]methanesulfonanilides. J Label Compd Radiopharm 1990, 28, 8, 921. |
| 【4】 Castaner, J.; Prous, J.; E-4031. Drugs Fut 1992, 17, 6, 455. |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (II) | 13699 | N-Phenylmethanesulfonamide; N-Phenyl methanesulfonamide | 1197-22-4 | C7H9NO2S | 详情 | 详情 |
| (III) | 13700 | 1-Acetyl-4-piperidinecarbonyl chloride | C8H12ClNO2 | 详情 | 详情 | |
| (IV) | 13701 | N-[4-[(1-Acetyl-4-piperidinyl)carbonyl]phenyl]methanesulfonamide | C15H20N2O4S | 详情 | 详情 | |
| (V) | 13702 | N-[4-(4-Piperidinylcarbonyl)phenyl]methanesulfonamide | C13H18N2O3S | 详情 | 详情 | |
| (VI) | 13703 | 2-Methyl-6-vinylpyridine | 1122-70-9 | C8H9N | 详情 | 详情 |