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【结 构 式】 
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【药物名称】Y-931 【化学名称】8-Fluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine maleate 【CA登记号】221058-55-5, 221058-53-3 (free base), 221058-56-6 (fumarate salt (2:1)), 221059-36-5 (monohydrochloride), 221059-00-3 (phosphate 【 分 子 式 】C24H23FN4O4S 【 分 子 量 】482.53771 |
【开发单位】Mitsubishi Pharma (Originator) 【药理作用】Antipsychotic Drugs, PSYCHOPHARMACOLOGIC DRUGS, Dopamine D2 Antagonists |
合成路线1
The condensation of ethyl 2-aminobenzo[b]thiophene-3-carboxylate (I) with 2,4-difluoronitrobenzene (II) afforded the diaryl amine (III). The nitro group of (III) was then reduced to amine (IV) by catalytic hydrogenation over Pd/C. Then, cyclization of amino ester (IV) with N-methylpiperazine (V) using TiCl4 in hot anisole produced the target benzothienobenzodiazepine, which was finally isolated as the corresponding maleate salt.
| 【1】 Fujimura, M.; Horiuchi, H.; Tanaka, H.; Kohara, T.; Hashimoto, K.; Kimura, K.; Seio, K.; Yasumatsu, H. (Welfide Corporation); Fused thiophene cpds. and medicinal use thereof. EP 1016664; JP 2001072684; WO 9911647 . |
| 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) | 46396 | ethyl 2-amino-1-benzothiophene-3-carboxylate | C11H11NO2S | 详情 | 详情 | |
| (II) | 32036 | 2,4-difluoro-1-nitrobenzene | 446-35-5 | C6H3F2NO2 | 详情 | 详情 |
| (III) | 46397 | ethyl 2-(5-fluoro-2-nitroanilino)-1-benzothiophene-3-carboxylate | C17H13FN2O4S | 详情 | 详情 | |
| (IV) | 46398 | ethyl 2-(2-amino-5-fluoroanilino)-1-benzothiophene-3-carboxylate | C17H15FN2O2S | 详情 | 详情 | |
| (V) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
合成路线2
In a related procedure, the condensation of 2-aminobenzo[b]thiophene-3-carbonitrile (VI) with 2,4-difluoronitrobenzene (II) produced the diaryl amine (VII). Reduction of the nitro group of (VII) using sodium hydrosulfite yielded diamine (VIII). Subsequent cyclization of amino nitrile (VIII) upon acidic treatment gave rise to the tetracyclic system (IX). This was then treated with refluxing N-methylpiperazine (V) to provide the title compound.
| 【2】 Fujimura, M.; Horiuchi, H.; Tanaka, H.; Kohara, T.; Hashimoto, K.; Kimura, K.; Seio, K.; Yasumatsu, H. (Welfide Corporation); Fused thiophene cpds. and medicinal use thereof. EP 1016664; JP 2001072684; WO 9911647 . |
| 【1】 Horiuchi, H.; Kimura, K.; Tanaka, H.; et al.; Y-931, a novel antipsychotic with potential anti-NRH (NMDA receptor-hypofunction) activity: Synthesis and structure-activity relationships of 6H-[1]benzothieno[2,3-b][1,5]benzodiazepines. 16th Int Symp Med Chem (Sept 18 2000, Bologna) 2000, Abst PB-128. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 32036 | 2,4-difluoro-1-nitrobenzene | 446-35-5 | C6H3F2NO2 | 详情 | 详情 |
| (V) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
| (VI) | 46399 | 2-amino-1-benzothiophene-3-carbonitrile | C9H6N2S | 详情 | 详情 | |
| (VII) | 46400 | 2-(5-fluoro-2-nitroanilino)-1-benzothiophene-3-carbonitrile | C15H8FN3O2S | 详情 | 详情 | |
| (VIII) | 46401 | 2-(2-amino-5-fluoroanilino)-1-benzothiophene-3-carbonitrile | C15H10FN3S | 详情 | 详情 | |
| (IX) | 46402 | 8-fluoro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12-ylamine; 8-fluoro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12-amine | C15H10FN3S | 详情 | 详情 |