【结 构 式】 |
【药物名称】Timiperone, DD-3480, Tolopelon 【化学名称】1-(4-Fluorophenyl)-4-[4-(2-thioxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]butan-1-one 【CA登记号】57648-21-2 【 分 子 式 】C22H24FN3OS 【 分 子 量 】397.51848 |
【开发单位】Daiichi Pharmaceutical (Originator) 【药理作用】Antipsychotic Drugs, PSYCHOPHARMACOLOGIC DRUGS |
合成路线1
The reaction of 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane (I) with 4-aminopyridine (II) gives the corresponding pyridinium salt (III), which is reduced with NaBH4 to 2-[3-(4-aminopiperidyl)propyl]-2-(4-fluorophenyl)-1,3-dioxolane (IV). The condensation of (IV) with 2-chloronitrobenzene (V) yields 2-[3-[4-(2-nitroanilino)piperidyl]propyl]-2-(4-fluorophenyl)-1,3-dioxolane (VI), which is hydrogenated with H2 over Raney-Ni affording the corresponding amino compound (VII). Finally this compound is cyclized with carbon disulfide and KOH
【1】 JP 76095096 . |
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) | 28203 | 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane | 3308-94-9 | C12H14ClFO2 | 详情 | 详情 |
(II) | 25661 | 4-pyridinamine; 4-aminopyridine | 5044-74-5 | C5H6N2 | 详情 | 详情 |
(III) | 60701 | 4-amino-1-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}pyridinium chloride | C17H20ClFN2O2 | 详情 | 详情 | |
(IV) | 60702 | 1-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-4-piperidinamine; 1-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-4-piperidinylamine | C17H25FN2O2 | 详情 | 详情 | |
(V) | 15248 | 1-chloro-2-nitrobenzene | 88-73-3 | C6H4ClNO2 | 详情 | 详情 |
(VI) | 60703 | 1-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-N-(2-nitrophenyl)-4-piperidinamine; N-(1-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-4-piperidinyl)-N-(2-nitrophenyl)amine | C23H28FN3O4 | 详情 | 详情 | |
(VII) | 60704 | N-(2-aminophenyl)-N-(1-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-4-piperidinyl)amine; N~1~-(1-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-4-piperidinyl)-1,2-benzenediamine | C23H30FN3O2 | 详情 | 详情 |
合成路线2
The reaction of o-phenylenediamine (IX) with 4-chloropyridine (VIII) gives 2-(4-pyridylamino)aniline (X), which is condensed with 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane (I) to give the corresponding pyridinium salt (XI). The reduction of (XI) with NaBH4 yields amino compound (VII). Finally this compound is cyclized with carbon disulfide and KOH
【1】 JP 76095096 . |
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) | 28203 | 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane | 3308-94-9 | C12H14ClFO2 | 详情 | 详情 |
(VII) | 60704 | N-(2-aminophenyl)-N-(1-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-4-piperidinyl)amine; N~1~-(1-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-4-piperidinyl)-1,2-benzenediamine | C23H30FN3O2 | 详情 | 详情 | |
(VIII) | 32889 | 4-chloropyridine | 7379-35-3 | C5H4ClN | 详情 | 详情 |
(IX) | 12824 | 2-Aminophenylamine; o-Phenylenediamine; 1,2-Benzenediamine | 95-54-5 | C6H8N2 | 详情 | 详情 |
(X) | 60705 | N-(2-aminophenyl)-N-(4-pyridinyl)amine; N~1~-(4-pyridinyl)-1,2-benzenediamine | C11H11N3 | 详情 | 详情 | |
(XI) | 60706 | 4-(2-aminoanilino)-1-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}pyridinium chloride | C23H25ClFN3O2 | 详情 | 详情 |
合成路线3
By condesation of 4-chloro-1-(4-fluorophenyl)-1-butanone ethylene ketal (I) with 1-(4-piperidyl)-2-mercaptobenzimidazole (II) by means of KI in refluxing butanol
【1】 Katsujiro, U.; et al. (Daiichi Seiyaku Co., Ltd.); DE 2526393; GB 1467097; US 3963727 . |
【2】 Sato, A. (Daiichi Seiyaku Co., Ltd.); JP 7584578 . |
【3】 Castaner, J.; Blancafort, P.; DD-3480. Drugs Fut 1978, 3, 6, 451. |
合成路线4
The condensation of 4-chloro-1-(4-fluorophenyl)-1-butanone ethylene ketal (I) with 4-(2-nitroanilino)piperidine (III) by means of KI in refluxing butanol gives 1-[3-(4-fluorobenzoyl)propyl]-4-(2-nitroanilino)piperidine ethylene ketal (IV), which is reduced with H2 over Raney-Ni in methanol yielding the corresponding amino compound (V). Finally this compound is cyclized with CS2 by means of KOH in refluxing ethanol
【1】 Katsujiro, U.; et al. (Daiichi Seiyaku Co., Ltd.); DE 2526393; GB 1467097; US 3963727 . |
【2】 Katsujiro, U.; et al. (Daiichi Seiyaku Co., Ltd.); JP 7584579 . |
【3】 Katsujiro, U.; et al. (Daiichi Seiyaku Co.; Ltd.); BE 830171; ZA 7593577 . |
【4】 Castaner, J.; Blancafort, P.; DD-3480. Drugs Fut 1978, 3, 6, 451. |
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) | 28203 | 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane | 3308-94-9 | C12H14ClFO2 | 详情 | 详情 |
(III) | 60708 | N-(2-nitrophenyl)-4-piperidinamine; N-(2-nitrophenyl)-N-(4-piperidinyl)amine | C11H15N3O2 | 详情 | 详情 | |
(IV) | 60703 | 1-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-N-(2-nitrophenyl)-4-piperidinamine; N-(1-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-4-piperidinyl)-N-(2-nitrophenyl)amine | C23H28FN3O4 | 详情 | 详情 | |
(V) | 60704 | N-(2-aminophenyl)-N-(1-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-4-piperidinyl)amine; N~1~-(1-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-4-piperidinyl)-1,2-benzenediamine | C23H30FN3O2 | 详情 | 详情 |
合成路线5
By reaction of 1-[1-[3-(4-fluorobenzoyl)propyl]-4-piperidyl]benzimidazol-2-one (VI) refluxing POCl3 to give 1-[1-[3-(4-fluorobenzoyl)propyl]-4-piperidyl]-2-chlorobenzimidazole (VII), which is refluxed with aqueous NaSH
【1】 Sato, M.; et al. (Daiichi Seiyaku Co., Ltd.); JP 76128975 . |
【2】 Castaner, J.; Blancafort, P.; DD-3480. Drugs Fut 1978, 3, 6, 451. |
合成路线6
By heating a mixture of 1-[1-[3-(4-fluorobenzoyl)propyl]-4-piperidyl]benzimidazol-2-one (VI) and P2S5
【1】 Sato, M.; et al. (Daiichi Seiyaku Co., Ltd.); JP 76128974 . |
【2】 Castaner, J.; Blancafort, P.; DD-3480. Drugs Fut 1978, 3, 6, 451. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(VI) | 60709 | 1-{1-[4-(4-fluorophenyl)-4-oxobutyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one | C22H24FN3O2 | 详情 | 详情 |