Process Development and Synthesis of Process-Related Impurities of an Efficient Scale-Up Preparation of 5,2′-Dibromo-2,4′,5′-Trihydroxy Diphenylmethanone as a New Acute Pyelonephritis Candidate Drug

• Main Authors: Xiu E Feng, Ke Meng Cui, Qing Shan Li, Zi Cheng Wu, Fei Lei
• Format: Article
• Language: English
• Published: MDPI AG 2020-01-01
• Series: Molecules
• Subjects: 5,2′-dibromo-2,4′,5′-trihydroxydiphenylmethanone; process development; process-related impurity; acute pyelonephritis; polymorph
• Online Access: https://www.mdpi.com/1420-3049/25/3/468
• ISSN: 1420-3049

Based on a foregoing gram-scale laboratory process, an efficient scale-up preparation process of 5,2&#8242;-dibromo-2,4&#8242;,5&#8242;-trihydroxydiphenylmethanone (<b>LM49-API</b>), a new acute pyelonephritis candidate drug, was developed and validated aiming to reduce by-products and achieve better impurity profiles. Meanwhile, the polymorph of <b>LM49-API</b> and process-related impurities were also investigated. Ultimately, the optimal reaction conditions were verified by evaluating the impurity profiles and their formation during the synthesis. Six process-related impurities were synthesized and identified, being useful for the quality control of <b>LM49-API</b>. Its finalized preparation process was further validated at 329&#8722;410 g scale-up production in 53.4&#8722;57.1% overall yield with 99.95&#8722;99.98% high-performance liquid chromatography (HPLC) purity, and it is currently viable for commercial production. <b>LM49-API-imC</b> and <b>LM49-API-imX</b> were identified as the main single impurities in <b>LM49-API</b>, with the content controlled to be less than 0.03%.