The p38α MAP kinase has been a heavily investigated target in the last two decades. The structural class of dibenzosuberone-based p38 inhibitors, exemplified by the promising candidate skepinone-L, was already successfully validated in several in vivo models of inflammatory as well as oncologic indications. The increasing demand of key intermediates and final compounds caused by the ongoing development of this inhibitor class urged the conception of an optimized route for the preparation of the core dibenzosuberone scaffold in multigram quantities. Rerouting of the initial discovery route resulted in an almost 4-fold increase of overall yield to 46%, the elimination of chromatographic purification, and the substitution of two critical reaction steps, which hindered a feasible scale-up. The key modification was the introduction and optimization of an early-stage Heck coupling based on Buchwald precatalysts allowing consistently high yields (ca. 90%) at multigram scales with a favorably low Pd loading of 0.1 mol %. This newly developed synthetic access to the dibenzosuberone intermediate 2-chloro-7-hydroxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one is capable of ensuring the supply of skepinone-L and other candidates during further development.

中文翻译：

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通过优化的早期 Heck 偶联改进基于二苯并芴酮的 p38 抑制剂的三环关键中间体的多克路线

在过去的二十年中，p38α MAP 激酶一直是一个深入研究的目标。基于二苯并芴酮的 p38 抑制剂的结构类别，以有希望的候选 skepinone-L 为例，已经在多个炎症和肿瘤适应症的体内模型中得到成功验证。由于此类抑制剂的持续开发，对关键中间体和最终化合物的需求不断增加，促使人们构思出用于制备数克数量的核心二苯并芴酮支架的优化路线。最初发现路线的改道导致总产率提高了近 4 倍，达到 46%，消除了色谱纯化，并取代了两个关键反应步骤，这阻碍了可行的放大。关键的改进是基于 Buchwald 预催化剂的早期 Heck 偶联的引入和优化，允许在多克规模下始终保持高产率（约 90%），并具有 0.1 mol% 的低 Pd 负载。这种新开发的合成获得了二苯并芴酮中间体 2-chloro-7-hydroxy-10,11-dihydro-5H -dibenzo[ a , d ][7] annulen-5-one 能够确保在进一步开发过程中提供 skepinone-L 和其他候选物。