Syeda Shameem Sultana, Jakkaraj Sudhakar, Georg Gunda I
Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota, Minneapolis, MN 55414, United States of America.
Tetrahedron Lett. 2015 Jun 3;56(23):3354-3457. doi: 10.1016/j.tetlet.2015.02.062.
We have developed methods involving the use of alternate, safer reagents for the scalable syntheses of the potent BET bromodomain inhibitor JQ1. A one-pot three step method, involving the conversion of a benzodiazepine to a thioamde using Lawesson's reagent, followed by amidrazone formation and installation of the triazole moiety furnished JQ1. This method provides good yields and a facile purification process. For the synthesis of enantiomerically enriched (+)-JQ1, the highly toxic reagent diethyl chlorophosphate, used in a previous synthesis, was replaced with the safer reagent diphenyl chlorophosphate in the three-step one-pot triazole formation without effecting yields and enantiomeric purity of (+)-JQ1.
我们已经开发出了一些方法，这些方法涉及使用替代性的、更安全的试剂来进行强效BET溴结构域抑制剂JQ1的可扩展合成。一种一锅三步骤的方法，包括使用劳森试剂将苯并二氮杂䓬转化为硫代酰胺，随后形成脒腙并安装三唑部分，从而得到JQ1。该方法提供了良好的产率和简便的纯化过程。对于对映体富集的(+)-JQ1的合成，在之前的合成中使用的剧毒试剂氯磷酸二乙酯，在三步一锅法三唑形成过程中被更安全的试剂氯磷酸二苯酯所取代，而不会影响(+)-JQ1的产率和对映体纯度。
