実用的かつユニークな光学分割法を利用したPTDSS1阻害剤の効率的製造法の開発

抄録

DS55980254 (1) is a potent and selective PTDSS1 inhibitor discovered by Daiichi Sankyo. This study addresses the significant challenge of efficiently synthesizing the active pharmaceutical ingredient (API) with high enantiomeric excess by developing a practical and unique optical resolution method. Utilizing a diastereomeric salt crystallization of 2,3-pyrrolidinedione and chiral amine facilitates the large-scale production of the API. 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. This new process demonstrated a remarkable enhancement in productivity compared to the original synthesis route, resulting in an overall yield that increased approximately threefold. This method consistently yielded high-quality products at each step, enabling efficient and robust synthesis of the PTDSS1 inhibitor. Additionally, efforts to minimize impurities in each intermediate ensured the quality of the API throughout the entire manufacturing process, allowing for timely delivery on multi-kilogram scale. Notably, the quality of all intermediates was greater than 99.7% in all cases, indicating that this synthetic strategy was appropriate. In fact, the synthesis of 18.7 kg of the PTDSS1 inhibitor was successfully achieved using the developed method and the product quality met all specification requirements.

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