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【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.
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) 60707 1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazole-2-thione 57648-17-6 C12H15N3S 详情 详情

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.
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
(VII) 65093 4-[4-(2-chloro-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone C22H25ClFN3O 详情 详情

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
Extended Information