吡啶环的构建：收率从10%提高到70%，是怎么做到的？
文摘
科学
2024-11-09 07:59
天津
- 化合物3化合物4先制备化合物5，再化合物6关环得到化合物1，最后进行氯代得到化合物2，总收率10%
- 杂质7，来源于化合物1的水解，也可能来源于化合物2的水解
- 化合物5和化合物6反应得到化合物10，关环方向不一样，可以得到杂质8
- 最初认为杂质9的来源是氰基水解，但是弱碱碳酸钾的使用，以及低温的反应，不可能产生含量很大的杂质9
- 氰基被进攻，还是酯基被酰胺进攻，是形成杂质9的关键，两者的影响因素是碱的强弱。
- 根据杂质9来源的可能机理，推测采用对称的丙二腈代替氰基乙酰胺，可以定向得到目标物。
- 推测如下，化合物14，就是原路线的化合物10，此时没有酰胺和氰基之分，都是氰基，选择性唯一，先得到化合物15，再开环、关环得到化合物1
To a clean dry reactor equipped with overheaded mechanical stirrer and condenser, ethyl acetoacetate(0.4 L, 1 equiv), ethanol (0.82 L, 2 vol) and DMFDMA(0.46 L, 1.03 equiv) were charged. The mixture was warmed to an internal temperature of 41−43 °C for 5 to 6 h until ≤2% of ethyl acetoacetate remained by GC. The reaction mixture was cooled to 20−25 °C and triethylamine (44.4 mL, 0.1 equiv) was added followed by slow addition of a solution of malononitrile (235 g in 1.77 L of ethanol, 1.1 equiv), cautiously maintaining the temperature between 25 and 36 °C. The mixture was stirred for 16 h at 20 °C until less than 5% area of enaminone 5 remained by HPLC (315 nm). Acetic acid (217 mL, 1.2 equiv) was added slowly at 20−25 °C to pH 4−5, and a dense precipitate was formed. The mixture was warmed to 70−75 °C, and water (5.6 L) was charged. The suspension was cooled down to 10 °C over 3 h and stirred for 15 min at 0 °C. The product was filtered, washed three times with water (3 × 1.25 L), and dried at 50 °C under vacuum to afford 539 g (82% yield) of the desired product 1 as an orange solid pure by HPLC at 99.5% and 100.8% w/w NMR assay
参考文献
Org. Process Res. Dev. 2012, 16, 819−823
