Gooding Owen W, Vo Lanchi, Bhattacharyya Sukanta, Labadie Jeff W
Argonaut Technologies, 1101 Chess Drive, Foster City, California 94404, USA.
J Comb Chem. 2002 Nov-Dec;4(6):576-83. doi: 10.1021/cc0200282.
Two fields that routinely perform reaction optimization studies are chemical development (prior to scale-up) and medicinal or combinatorial chemistry (prior to analogue synthesis or library production). To date, the use of statistical design of experiments (DoE) in conjunction with automated synthesizers has been applied in process research to a greater extent than in the medicinal or combinatorial laboratories. We have applied DoE in conjunction with an automated synthesizer to optimize the synthesis of amides employing resin-bound N-hydroxybenzotriazole (PS-HOBt) active esters as intermediates. This methodology allowed the rapid development of an improved protocol for the parallel synthesis of amides by conversion of carboxylic acids to PS-HOBt esters followed by treatment with appropriate amines. Product isolation involved only simple filtration and evaporation.
两个经常进行反应优化研究的领域是化学开发（在放大生产之前）和药物化学或组合化学（在类似物合成或文库制备之前）。迄今为止，实验设计（DoE）与自动合成仪结合使用在工艺研究中的应用程度比在药物或组合化学实验室中更高。我们将DoE与自动合成仪结合应用，以树脂结合的N-羟基苯并三唑（PS-HOBt）活性酯为中间体优化酰胺的合成。该方法能够快速开发出一种改进的方案，通过将羧酸转化为PS-HOBt酯，然后用适当的胺处理，并行合成酰胺。产物分离仅涉及简单的过滤和蒸发。
