The development of an in situ formed (Xantphos)Pd oxidative addition complex made possible a robust, scalable C–S coupling of a functionalized aryl bromide with 2-mercaptoethanol that ultimately enabled the synthesis of Janus Kinase inhibitor GDC-9918 on a kilogram scale. An insoluble, catalytically inactive, [12]metallacrown-6 palladium(II) complex, [Pd₆(μ₂-SCH₂CH₂OH)₁₂], was found to form quickly under most reaction conditions in the presence of 2-mercaptoethanol and a Pd catalyst and required up to 12 mol % Pd for full conversion in our generation route. A second-generation process was developed to minimize the formation of the [12]metallacrown-6 palladium(II) complex and enabled the decrease in catalyst loading to 2 mol % Pd. A soluble Pd scavenger, PIX, effectively removed Pd to <5 ppm. Catalytic sodium tungstate oxidation of the resulting thioether smoothly provided crude GDC-9918 that was recrystallized to the desired polymorph and micronized to a particle size distribution suitable for development as an inhalable treatment for asthma.

中文翻译：

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开发用于合成 Janus 激酶抑制剂 GDC-9918 的稳健 pd 催化 C-S 偶联


原位形成的 （Xantphos）Pd 氧化加成复合物的开发使功能化芳基溴与 2-巯基乙醇的稳健、可扩展的 C-S 偶联成为可能，最终实现了千克级 Janus 激酶抑制剂 GDC-9918 的合成。发现一种不溶性、催化无活性的 [12]metallacrown-6 钯（II） 复合物，[Pd₆（μ 2-SCH₂CH₂OH）₁₂]]，在 2-巯基乙醇和 Pd 催化剂存在下，在大多数反应条件下迅速形成，并且需要高达 12 mol % 的 Pd 才能在我们的生成路线中完全转化。开发了第二代工艺，以最大限度地减少 [12]metallacrown-6 钯 （II） 络合物的形成，并使催化剂负载量降低至 2 mol % Pd。可溶性 Pd 清除剂 PIX 可有效去除 Pd 至 <5 ppm。所得硫醚的催化钨酸钠氧化顺利得到粗 GDC-9918，该粗 GDC-9918 被重结晶为所需的多晶型物，并微粉化为适合开发作为哮喘可吸入治疗药物的粒径分布。