药物Simeprevir(西咪匹韦)合成检索总结报告

药物Simeprevir（西咪匹韦）合成检索总结报告

一、Simeprevir（西咪匹韦）简介

Simeprevir（西咪匹韦）于2013年11月22日在美国上市。Simeprevir（西咪匹韦）通过抑制HCV NS3/4A蛋白酶的活性，从而抑制病毒复制，适应于HCV感染及HCV/HIV-l共同感染。Simeprevir（西咪匹韦）不良反应：皮疹(包括光敏反应)、瘙痒、恶心。

Simeprevir（西咪匹韦）分子结构式如下:

英文名称：Simeprevir 中文名称：西咪匹韦

本文主要对Simeprevir（西咪匹韦）的合成路线、关键中间体的合成方法及实验操作方法进行了文献检索并作出了总结。

二、Simeprevir（西咪匹韦）合成路线 中间体19的合成路线一：

1

中间体19的合成路线二：

2

Simeprevir（西咪匹韦）的合成：

三、Simeprevir（西咪匹韦）合成检索总结报告 (一) Simeprevir（西咪匹韦）中间体2的合成方法一

合成方法

实验步骤 Sodium hydroxide (1M, 74 mL, 0.074 mol) was added to a stirred solution of 1 (3.73 g, 0.018 mol) in methanol (105 mL) at room temperature. After 4 h, the reaction mixture was neutralized with 3M HCl, evaporated and co-evaporated with 3

参考文献 US2009/23758; (2009); (A1) English; 操作方法一 操作方法二 toluene several times. Pyridine (75 mL) and Ac2O (53 mL) were added and the reaction mixture was allowed to shake overnight at room temperature. The mixture was then co-evaporated with toluene and purified by flash column chromatography (ethyl acetate+1% acetic acid) to give the title compound 2 (2.51 g, 88%) as a yellow oil. To a solution of 1 (3.0 g) in THF (60 mL)/acetone (60 mL) were added ethylchloroformate (1.77 mL, 18.6 mmol) and triethylamine (2.6 mL, 18.6 mmol) at 0oC. After 30 min, molecular sieve 4A (18 g) was added to the mixture. The resulting mixture was allowed to warm to room temperate for 16 h. The reaction mixture was filtered through celite and concentrated to give 2 (2.3 g). WO2008/95999; (2008); (A1) English. US2009/149491; (2009); (A1) English (二) Simeprevir（西咪匹韦）中间体2的合成方法二

合成方法 操作方法一 实验步骤 To a suspension of compound 3 (1 g, 5.74 mmol) in THF (50 mL) was added TEA (1.74 g, 17.23 mmol), followed by the addition of ethyl carbonochloridate (0.69 g, 6.32 mmol). The reaction mixture was stirred at room temperature overnight and then filtered. The precipitate was collected by filtration to give crude compound 2 (1 g, yield 85%) as a white solid. 参考文献 WO2017/35360; (2017); (A1) English (三) Simeprevir（西咪匹韦）中间体5的合成

合成方法 操作方法一 实验步骤 3-Oxo-2-oxa-bicyclo[2.2.1]heptane-5-carboxylic acid 2 (500 mg, 3.2 mmol) in 4 mL DMF was added at 0 oC to 2-(7-Aza- 1H-benzotriazole-l-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (ΗATU) (1.34 g, 3.52 mmol) and N-methylhex-5-enylamine 4 (435 mg, 3.84 mmol) in DMF (3 mL), followed by N,N-diisopropylethylamine (DIPEA). After stirring for 40 min at 0 oC, the mixture was stirred at room temperature for 5 h. Then, the solvent was evaporated, the residue dissolved in EtOAc ethyl acetate (70 mL) and washed with saturated NaHCO3 (10 mL). The aqueous layer 4

参考文献 WO2007/14921; (2007); (A1) English; WO2007/14925; (2007); (A1) English; WO2007/14926; (2007); (A1) English; WO2008/96002;