Efficient Multikilogram-Scale Synthesis of PTDSS1 Inhibitor: Development of a Practical and Scalable Optical Resolution Method for Chiral 2,3-Pyrrolidinedione

DS55980254 (1) is a potent and selective phosphatidylserine synthase 1 (PTDSS1) inhibitor discovered by Daiichi Sankyo. We have developed a practical and unique optical resolution method using a chiral amine for 2,3-pyrrolidinedione, enabling the large-scale synthesis of the active pharmaceutical ingredient with high enantiomeric excess. Through optimization of the entire synthesis method from the perspective of process chemistry, enhancement in yields, complete elimination of chromatographic purification, and reduction in the number of unit operations were achieved. The productivity was dramatically improved compared to the original synthesis route, and the overall yield was increased by approximately 3-fold. This newly developed process consistently provided high-quality and high-yield products in each step, resulting in the efficient and robust synthesis of the PTDSS1 inhibitor on a multikilogram scale.