新药Vesatolimod(维沙莫德)合成检索总结报告

新药Vesatolimod（维沙莫德）合成检索总结报告

一、Vesatolimod（维沙莫德）简介

2020年3月10日公布了HIV治愈研究项目中Toll样受体7（TLR7）激动剂Vesatolimod一项Ib期试验的结果。数据显示：与安慰剂相比，vesatolimod的TLR7刺激作用与延长的病毒反弹时间、增强的免疫功能、完整HIV DNA水平的降低相关。吉利德还公布了额外的临床前研究，评估在停止抗逆转录病毒治疗的情况下，Vesatolimod联合治疗方案实现病毒缓解的潜力。

Vesatolimod（维沙莫德）分子结构式如下:

英文名称：Vesatolimod 中文名称：维沙莫德

本文主要对Vesatolimod（维沙莫德）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、Vesatolimod（维沙莫德）合成路线

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三、Vesatolimod（维沙莫德）合成检索总结报告 (一) Vesatolimod（维沙莫德）中间体3的合成方法一

合成方法 操作方法一 操作方法二 实验步骤 To a stirred solution of of 3-cyanobenzaldehyde 1 (15 g, 114.4 mmol) in THF (150 ml) was added pyrrolidine 2 (9.76 g, 137.2 mmol, 1.2 eq.), acetic acid (8,24 g, 137.2 mmol, 1.2 eq.) and sodium triacetoxyborohydride (36.3 g, 171.6 mmol, 1.5 eq.). The resulting suspension was vigorously stirred at r.t. for 24 hrs. under Ar. 5% NaHCO3 was then added and the mixture stirred for a further 10-15 min. The mixture was then extracted with ethylacetate. The organic phase was washed with brine, then dried with Na2SO4. After removal of the solvent the yellow liquid was distilled over a Vigreux column to afford the title compound as a colorless liquid 3 (19 g, 102 mmol, 89% yield). Sodium borohydride (6.2 kg) and dichloromethane (285 kg) were combined. The content temperature was adjusted to about 0°C and acetic acid (29 kg) was slowly charged over about 2 hours. The mixture was agitated at about 0°C for 2 hours and then warmed to about 20°C. in a second reaction vessel was combined 3-cyanobenzaldehyde 1 (14 kg), dichloromethane (52 kg) and pyrrolidine 2 (7.8 kg) and the resulting mixture was agitated at about 20°C. To this mixture was slowly charged with the sodium borohydride/dichloro- methane mixture over about 2 hours at about 20°C. After the addition was complete, the mixture was agitated for about 12 hours at about 20°C. Once the reaction was deemed complete, an aqueous sodium hydroxide solution (105 kg, 10% w/w) was added. The phases were separated and the aqueous phase was extracted with dichloromethane (53 kg) three times. Water (71 kg) was added to the combined organic phases and the pH was adjusted to ~2 by adding an 2

参考文献 US2001/6265426; (2001); (B1) English WO2016/44183; (2016); (A1) English

aqueous HCl solution (71 kg, 2M). The phases were separated and the organic phase was extracted with an aqueous HCl solution (44 kg, 1 M). The pH of the combined aqueous phases was adjusted to 12 by adding an aqueous sodium hydroxide solution (62 kg, 10% w/w). The aqueous phase was extracted with dichloromethane (62 kg) three times. The organic phase was washed with water (14 kg) two times, dried over sodium sulfate, and concentrated. Tetrahydrofuran (20 kg) was charged and concentrated to provide 3-(pyrrolio-l-ymiemyl)benzonitrile 3. (二) Vesatolimod（维沙莫德）中间体3的合成方法二

合成方法 操作方法一 实验步骤 To a solution of 3-(bromomethyl)-benzonitrile 4 (30.0 g, 1.00 equiv) in absolute EtOH (600 mL) was added pyrrolidine 2 (13.3 mL, 1.00 equiv), followed by K2CO3 (anhydrous, 63.5 g, 3.00 equiv). The reaction was stirred vigorously at 65°C. until consumption of the bromide was complete (Reaction is monitored on Merck 254 nm silica-coated TLC plates using a combination of EtOAc/hexane as eluent). The reaction (which may be orange-colored) was cooled to 23°C. and filtered over coarse glass frits, and the filtrate was concentrated. The resulting residue was partitioned between H2O and EtOAc (300 mL each) and the organic phase collected. The aqueous layer was extracted (2×200 mL EtOAc). All of the resulting organic layers were combined, dried (Na2SO4), filtered, and concentrated in vacuo, giving the title nitrile 3 (21.1 g, 74% yield) as an orange residue 参考文献 US2010/143301; (2010); (A1) English (三) Vesatolimod（维沙莫德）中间体5的合成

合成方法

实验步骤 A 1 Liter round-bottom flask was charged with LiAlH4 (7.55 g) and anhydrous Et2O (230 mL). After cooling to 0°C., 3-(pyrrolidin-1-ylmethyl)-benzonitrile 3 (18.55 g) in THF (30 mL) was added slowly over a 5 min period. transitioned from orange to green. Once the reaction was complete (as 3

参考文献