The development of an expedient synthesis to GDC-0852 (1), a reversible BTK inhibitor drug candidate, is described. The key starting material tricyclic lactam 5 was prepared by an annulation reaction of unprotected piperidine-2-carbaldehyde HCl salt (20) and N-Boc piperidine-2,4-dione 21 in a safe and scalable manner. A highly selective Pd-catalyzed CN coupling of lactam 5 and linker 2a, followed by Suzuki−Miyaura coupling to fragment 8 subsequently provided a direct and convergent access to the penultimate 17. A simple NaBH₄ aldehyde reduction completed the synthesis to GDC-0852 (1) in high yield (54% over 3 steps from 5) and purity (99.0 A% HPLC).

描述了向可逆的BTK抑制剂候选药物GDC-0852（1）的合成方法的开发。通过未保护的哌啶-2-甲醛甲醛盐酸盐（20）与N -Boc哌啶-2,4-二酮21的环合反应，以安全且可扩展的方式制备关键起始原料三环内酰胺5。内酰胺5和接头2a的高选择性Pd催化的C N偶联，然后是Suzuki-Miyaura偶联至片段8，随后直接并会聚地进入倒数第二个17。一个简单的NaBH ₄乙醛的还原以高收率（从5开始的3个步骤为54％）和纯度（99.0A％HPLC）完成了向GDC-0852（1）的合成。