Process Development of a PI3Kδ Inhibitor: A Novel and Practical [1,2]-Boc Migration on Purine Rings

This study describes the process development for the synthesis of a phosphoinositide 3-kinase (PI3K) δ selective inhibitor 1. The most important challenge was to establish the optimal method for introducing the carbonyl group at the 8-position, which posed the greatest difficulties in the medicinal chemistry (Med-Chem) method, and to determine the most suitable timing for this step in the manufacturing process. To address the challenges encountered with the Med-Chem method, three alternative synthetic routes were explored, focusing especially on functionalization of the 8-position, a key transformation in the process. During this route exploration, we developed a novel, practical, and high-yield [1,2]-Boc migration reaction. In the final selected route, after introducing the morpholine group at the 6-position, the 9-position was protected by Boc. Subsequently, employing lithium bis(trimethylsilyl)amide (LHMDS) facilitated our [1,2]-Boc migration reaction, which successfully produced the desired t-butyl ester at the 8-position in high yield. Subsequent steps involved Suzuki coupling to introduce the pyrazole part, hydrolysis of the t-butyl ester, amidation, and final recrystallization, ultimately yielding PI3Kδ inhibitor 1 with excellent yield. Over 7 steps, including the final recrystallization, the overall yield of 69% was achieved, representing a significant improvement over the Med-Chem approach.