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【结 构 式】 
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【药物名称】Avatrombopag 【化学名称】1-[3-Chloro-5-[N-[4-(4-chlorothien-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]carbamoyl]pyridin-2-yl]piperidine-4-carboxylic acid maleate 【CA登记号】677007-74-8;570406-98-3 (free base) 【 分 子 式 】C33H38Cl2N6O7S2 【 分 子 量 】765.727 |
【开发单位】Eisai Co., Ltd. (JP). 【药理作用】Thrombopoietin Receptor Agonist;Treatment of Thrombocytopenia |
合成路线1
Bromination of 1-(4-chloro-2-thienyl)ethanone (I) with Br2 in Et2O gives 2-bromo-1-(4-chloro-2-thienyl)ethanone (II), which by cyclocondensation with thiourea (III) in EtOH at 80 °C provides 2-amino-4-(4-chloro-2-thienyl)thiazole (IV). Treatment of thiazole (IV) with NBS in DMF and subsequent condensation with 1-cyclohexylpiperazine (V) by means of Et3N at 70 °C affords the 5-piperazinyl-thiazole derivative (VI). Coupling of the 2-aminothiazole (VI) with 5,6-dichloronicotinic acid (VII) in the presence of POCl3 in pyridine yields amide (VIII), which is then condensed with ethyl isonipecotate (IX) in THF at 50 °C to obtain the ethyl 1-(pyridyl)piperidine-4-carboxylate derivative (X). Finally, ethyl ester (X) is hydrolyzed by means of NaOH in MeOH .
| 【1】 Watanuki, S., Nagata, H., Wakayama, R. et al. 2-Acylaminothiazole derivative or salt thereof. EP 1466912, EP 2314586, JP 2009111001, US 2005153977, US 7638536, US 2010222329, US 2010222361, WO 2003062233. |
| 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) | 68277 | 1-(4-chloro-2-thienyl)ethanone;4-Chloro-2-acetylthiophene | 34730-20-6 | C6H5ClOS | 详情 | 详情 |
| (II) | 68278 | 2-bromo-1-(4-chloro-2-thienyl)ethanone | C6H4BrClOS | 详情 | 详情 | |
| (III) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (IV) | 68279 | 2-amino-4-(4-chloro-2-thienyl)thiazole | C7H5ClN2S2 | 详情 | 详情 | |
| (V) | 23174 | 1-cyclohexylpiperazine | 17766-28-8 | C10H20N2 | 详情 | 详情 |
| (VI) | 68280 | 4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-amine | C17H23ClN4S2 | 详情 | 详情 | |
| (VII) | 68282 | 5,6-dichloronicotinic acid | 41667-95-2 | C6H3Cl2NO2 | 详情 | 详情 |
| (VIII) | 68281 | 5,6-dichloro-N-(4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl)nicotinamide | C23H24Cl3N5OS2 | 详情 | 详情 | |
| (IX) | 17410 | Ethyl isonipecotate; ethyl 4-piperidinecarboxylate | 1126-09-6 | C8H15NO2 | 详情 | 详情 |
| (X) | 68283 | ethyl 1-(3-chloro-5-((4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl)carbamoyl)pyridin-2-yl)piperidine-4-carboxylate | C31H38Cl2N6O3S2 | 详情 | 详情 |