已有路线信息介绍
化合物1先制备苯并呋喃环得到化合物4，水解后得到化合物5
脱羧需要使用碳酸银，不是很好
脱羧得到的化合物6，钯碳还原硝基和双键后，乙酰化得到化合物3
制备化合物8收率很低，仅为25%
再水解得到目标物
新路线信息如下
以化合物9为原料，先制备化合物10，再制备化合物12
然后钯催化偶联引入乙酰胺得到化合物3，再Gallium介质进行傅克酰基化得到化合物8，再水解得到目标物
新旧路线对比
没有对比就没有亮点
钯催化引入乙酰胺实验操作
N-(2,3-Dihydrobenzofuran-6-yl)acetamide (3) was prepared according to the following procedure: 12 (5.0 g, 1.0 equiv),Pd(OAc)2 (56 mg, 1.0 mol %), BrettPhos (0.27 g, 2.0 mol%), Acetamide (2.97 g, 2.0 equiv), and K2CO3 (100 mg, 1.5equiv) were added to an oven-dried vial with stir bar and placed under N2 atmosphere. The reaction was diluted with monoglyme (100 mL, 0.25 M in 12) and heated to 100 °C for 24 h before cooling and concentrating under vacuum. The product was then precipitated with heptane, filtered, and triturated with water and heptane. The resulting solid was dried with a vacuum oven for 48 h to provide the desired product (4.7 g, 99% yield, 99% LCAP purity, 97% potency).
傅克酰基化实验操作
One-pot synthesis of 5-(2-chloroacetyl)-2,3-dihydrobenzofuran-6-aminium chloride(2) was performed according to the following procedure: To a dry 800 mL jacketed glass overhead stirred vessel was charged anhydrous 1,2-dichloroethane (450 mL, 30.8 volumes), GaCl3 (45.0 g, 3.1 equiv), and CAC (12.0 mL, 1.5 equiv). The vessel was placed under a N2 atmosphere. The reaction was stirred until it became homogeneous, and then it was cooled to −10 °C via the jacket. 3 (14.6 g, 1.0 equiv) was then added. The reaction was stirred under a N2 atmosphere for 4 h, whereupon it formed a slurry at the end point. At the end point of the reaction, ethanol (200 mL, 13.7 volumes) was added, and the reaction stirred until clear and homogeneous. The vessel was heated to reflux and 5.0 N HCl in isopropanol (100 mL, 6.8 volumes) was added. The reaction was refluxed for 2 h and then cooled to 5 °C. The product was collected by filtration, washed with cold ethanol, and dried in vacuo (13.35 g, 65% yield, 97.4% LCAP purity
参考文献
https://doi.org/10.1021/acs.oprd.4c00375
