Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907, USA.
Chemical Engineering, Purdue University, 480 W Stadium Ave., West Lafayette, IN 47907, USA.
Analyst. 2017 Jul 24;142(15):2836-2845. doi: 10.1039/c7an00622e.
Preparative electrospray (ES) exploits the acceleration of reactions in charged microdroplets to perform a small scale chemical synthesis. In combination with on-line mass spectrometric (MS) analysis, it constitutes a rapid screening tool to select reagents to generate specific products. A successful reaction in preparative ES triggers a refined microfluidic reaction screening procedure which includes the optimization for stoichiometry, temperature and residence time. We apply this combined approach for refining a flow synthesis of atropine. A successful preparative ES pathway for the synthesis of the phenylacetyl ester intermediate, using tropine/HCl/phenylacetyl chloride, was optimized for solvent in both the preparative ES and microfluidics flow systems and a base screening was conducted by both methods to increase atropine yield, increase percentage conversion and reduce byproducts. In preparative ES, the first step yielded 55% conversion (judged using MS) to intermediate and the second step yielded 47% conversion to atropine. When combined in two discrete steps in continuous-flow microfluidics, a 44% conversion of the starting material and a 30% actual yield of atropine were achieved. When the reactions were continuously telescoped in a new form of preparative reactive extractive electrospray (EES), atropine was synthesized with a 24% conversion. The corresponding continuous-flow microfluidics experiment gave a 55% conversion with an average of 34% yield in 8 min residence time. This is the first in depth study to utilize telescoped preparative ES and the first use of dual ESI emitters for multistep synthesis.
制备电喷雾（ES）利用带电微滴中反应的加速来进行小规模化学合成。与在线质谱（MS）分析相结合，它构成了一种快速筛选工具，可用于选择试剂以生成特定产物。在制备 ES 中成功的反应触发了精细的微流控反应筛选程序，其中包括对化学计量、温度和停留时间进行优化。我们应用这种组合方法来改进阿托品的流动合成。使用莨菪碱/HCl/苯乙酰氯，成功优化了制备 ES 和微流控流动系统中溶剂的苯乙酰酯中间体的合成途径，并通过两种方法进行了碱筛选，以提高阿托品收率、增加转化率和减少副产物。在制备 ES 中，第一步得到 55%的中间体转化率（通过 MS 判定），第二步得到 47%的阿托品转化率。当在连续流微流控中以两个离散步骤组合时，起始原料的转化率为 44%，实际收率为 30%的阿托品。当反应在新形式的制备反应性萃取电喷雾（EES）中连续缩合时，阿托品的合成转化率为 24%。相应的连续流微流控实验在 8 分钟的停留时间内转化率为 55%，平均收率为 34%。这是首次深入研究利用伸缩式制备 ES 以及首次使用双 ESI 发射器进行多步合成。
