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【结 构 式】 
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【药物名称】Flumezapine, LY-120363 【化学名称】7-Fluoro-2-methyl-4-(4-methylpiperazin-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine 【CA登记号】61325-80-2 【 分 子 式 】C17H19FN4S 【 分 子 量 】330.43018 |
【开发单位】Lilly (Originator) 【药理作用】Antipsychotic Drugs, PSYCHOPHARMACOLOGIC DRUGS, Dopamine D1 Antagonists |
合成路线1
The condensation of 2,5-difluoronitrobenzene (I) with ethyl 2-amino-5-methylthiophene-3-carboxylate (II) by means of triethylamine in hot DMSO or 2-methoxyethanol giving ethyl 2-(4-fluoro-2-nitroanilino)-5-methylthiophene-3-carboxylate (III), which is reduced with H2 over Pd/C in ethanol to ethyl 2-(4-fluoro-2-aminoanilino)-5-methylthiophene-3-carboxylate (IV). The cyclization of (IV) by means of NaH in DMSO affords 9,10-dihydro-7-fluoro-2-methyl-4H-thieno[2,3b][1,5]benzodiazepin-2-one (V), which is finally condensed with N-methylpiperazine by means of TiCl4 in anisole at 120 C.
| 【1】 Chakrabarti, J.K.; Tupper, D.E.; Benzodiazepine derivatives. DE 2552403; FR 2292479; GB 1533235; JP 51076296 . |
| 【2】 Pullar, I.A.; Chakrabarti, J.K.; Horsman, L.; Wright, F.C.; Tupper, D.E.; Hotten, T.M.; Heterooarenobenzodiazepines. 3. 4-Piperazinyl-10H-thieno[2,3-b][1,5]benzodiazepines as potential neuroleptics. J Med Chem 1980, 23, 8, 878-884. |
| 【3】 Blancafort, P.; Castañer, J.; Serradell, M.N.; Flumezapine. Drugs Fut 1983, 8, 2, 110. |
| 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) | 32036 | 2,4-difluoro-1-nitrobenzene | 446-35-5 | C6H3F2NO2 | 详情 | 详情 |
| (II) | 35949 | ethyl 2-amino-5-methyl-3-thiophenecarboxylate | C8H11NO2S | 详情 | 详情 | |
| (III) | 35950 | ethyl 2-(5-fluoro-2-nitroanilino)-5-methyl-3-thiophenecarboxylate | C14H13FN2O4S | 详情 | 详情 | |
| (IV) | 35951 | ethyl 2-(2-amino-5-fluoroanilino)-5-methyl-3-thiophenecarboxylate | C14H15FN2O2S | 详情 | 详情 | |
| (V) | 35952 | 7-fluoro-2-methyl-5,10-dihydro-4H-thieno[2,3-b][1,5]benzodiazepin-4-one | C12H9FN2OS | 详情 | 详情 | |
| (VI) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |