Process development for a multi-kilogram-scale synthesis of GDC-0022, an inhibitor of retinoic acid receptor-related orphan receptor γ (RORc), is described. Delivery of the active pharmaceutical ingredient (API) relied on diastereoselective preparation of a six-membered sultam building block, as well as execution of its benzylation under heterogeneous conditions. Investigation and optimization of a challenging late-stage palladium-catalyzed C–N coupling of a bicyclic amine were likewise central to synthetic efforts. Understanding of this key reaction, as well as the development of API salt forms and isolations, ultimately enabled a successful reaction at 8.0 kg scale, utilizing 1.0 mol % XantPhos–Pd–G2 as precatalyst and, in turn, preparation of >5.0 kg of GDC-0022 tosylate salt for preclinical needs.

中文翻译：

---

工艺开发克服了具有挑战性的Pd催化的C-N偶联，用于合成RORc抑制剂GDC-0022

描述了以公斤级合成GDC-0022（视黄酸受体相关孤儿受体γ（RORc）的抑制剂）的工艺开发。活性药物成分（API）的输送依赖于六元sultam结构单元的非对映选择性制备，以及在异质条件下进行苄基化。研究和优化具有挑战性的后期钯催化的双环胺的C–N偶联也是合成努力的核心。对这一关键反应的理解以及API盐形式和分离物的开发，最终使8.0 kg规模的反应得以成功进行，利用1.0 mol％XantPhos–Pd–G2作为前催化剂，进而制备了> 5.0 kg GDC-0022 将甲苯磺酸盐用于临床前需求。