Li Xiaoyu, Golden Jennifer E
Department of Pharmaceutical Sciences School of Pharmacy University of Wisconsin-Madison Madison Wisconsin 53705-2222 USA.
Adv Synth Catal. 2021 Mar 16;363(6):1638-1645. doi: 10.1002/adsc.202001279. Epub 2021 Feb 3.
Chiral 2-alkylquinazolinones are key synthetic intermediates, but their preparation in high optical purity is challenging. Thus, a multicomponent procedure integrating anthranilic acids, -Boc-amino acids, and amines in the presence of methanesulfonyl chloride, -methylimidazole, and copper(II) chloride was developed to mildly afford -Boc-2-alkylaminoquinazolin-4(3)-ones with excellent preservation of enantiomeric purity (>99% ee). Copper(II) chloride was essential to retaining enantiopurity, and reaction component structural changes were well tolerated, resulting in an efficient, all-in-one procedure that promotes sequential coupling, lactonization, aminolysis, and cyclization in good yields. The method was applied to the rapid assembly of four key intermediates used in the synthesis of high profile quinazolinones, including several PI3K inhibitor drugs.
手性2-烷基喹唑啉酮是关键的合成中间体，但其高光学纯度的制备具有挑战性。因此，开发了一种多组分方法，该方法在甲磺酰氯、N-甲基咪唑和氯化铜（II）存在下，将邻氨基苯甲酸、N-Boc-氨基酸和胺整合在一起，以温和的方式得到N-Boc-2-烷基氨基喹唑啉-4(3)-酮，同时对映体纯度得到了很好的保留（>99% ee）。氯化铜（II）对于保持对映体纯度至关重要，并且反应组分的结构变化具有良好的耐受性，从而产生了一种高效的一体化方法，该方法以良好的产率促进了顺序偶联、内酯化、氨解和环化。该方法被应用于快速组装用于合成几种引人注目的喹唑啉酮（包括几种PI3K抑制剂药物）的四种关键中间体。
