Abstract
Based on a foregoing gram-scale laboratory process, an efficient scale-up preparation process of 5,2′-dibromo-2,4′,5′-trihydroxydiphenylmethanone (LM49-API), a new acute pyelonephritis candidate drug, was developed and validated aiming to reduce by-products and achieve better impurity profiles. Meanwhile, the polymorph of LM49-API 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 LM49-API. Its finalized preparation process was further validated at 329–410 g scale-up production in 53.4–57.1% overall yield with 99.95–99.98% high-performance liquid chromatography (HPLC) purity, and it is currently viable for commercial production. LM49-API-imC and LM49-API-imX were identified as the main single impurities in LM49-API, with the content controlled to be less than 0.03%.
Highlights
Acute pyelonephritis (APN) is a bacterial infection of the renal pelvis, accompanied by severe symptoms that range from mild discomfort to life-threatening illness or death [1]
The original gram-scale laboratory preparation process of LM49-active pharmaceutical ingredients (API) is as follows [5]: (i) 2-methoxybenzoic acid reacted with anhydrous thionyl chloride (SOCl2 ) in the presence of N,N-dimethyl formamide (DMF) to prepare corresponding acyl chloride, conducted the Friedel–Crafts acylation reaction with 1,2-dimethoxybenzene (SM01) in anhydrous dichloromethane (CH2 Cl2 ) under the catalysis of aluminum chloride (AlCl3 ) to obtain the intermediate LM49-01 by column chromatography separation. (ii) LM49-01 was brominated with liquid bromine in acetic acid (HOAc), neutralized with aqueous ammonia in the post-treatment, and separated by column chromatography to gain the key intermediate LM49-02. (iii) LM49-02 was demethylated with boron tribromide (BBr3 ) in anhydrous CH2 Cl2, and the crude product was recrystallized with methanol to obtain the target product LM49-API
The preparation process of LM49-API was shortened to three steps from the original four steps, achieving a high yield, available reagents, low cost, and simple separation and purification [5]
Summary
Acute pyelonephritis (APN) is a bacterial infection of the renal pelvis, accompanied by severe symptoms that range from mild discomfort to life-threatening illness or death [1]. It is interesting that LM49-API does not directly inhibit bacteria; rather, its therapeutic efficacy on APN is closely related to inhibiting inflammation and regulating immune responses of T lymphocytes [9,10] These continuous research results suggest its prospectively important clinical application in the treatment of APN. In order to explore the preclinical research and development of the new drug, it is necessary to develop an active pharmaceutical ingredients (API) scale-up preparation process suitable for commercial production, conduct the polymorphism analysis, investigate impurity profiling, and control impurity limits. To address these problems, we focused on the improvement of the LM49-API preparation process aiming to develop an efficient, practical, economic, scalable, and safely reproducible process with mild reacting conditions, controllable impurities, easy purification, and high yield for its commercial production. The impurity reference substances were obtained, and the related impurities in the test samples were analyzed, identified, and controlled by high-performance liquid chromatography (HPLC)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
