{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T19:46:03Z","timestamp":1778701563768,"version":"3.51.4"},"reference-count":23,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2020,1,22]],"date-time":"2020-01-22T00:00:00Z","timestamp":1579651200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Drug Innovation Major Project of China","award":["2018ZX09101003001-017"],"award-info":[{"award-number":["2018ZX09101003001-017"]}]},{"name":"Key Research and Development Plan (key project) of Shanxi Province","award":["201703D111033"],"award-info":[{"award-number":["201703D111033"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Based on a foregoing gram-scale laboratory process, an efficient scale-up preparation process of 5,2\u2032-dibromo-2,4\u2032,5\u2032-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\u2013410 g scale-up production in 53.4\u201357.1% overall yield with 99.95\u201399.98% 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%.<\/jats:p>","DOI":"10.3390\/molecules25030468","type":"journal-article","created":{"date-parts":[[2020,1,27]],"date-time":"2020-01-27T11:41:57Z","timestamp":1580125317000},"page":"468","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Process Development and Synthesis of Process-Related Impurities of an Efficient Scale-Up Preparation of 5,2\u2032-Dibromo-2,4\u2032,5\u2032-Trihydroxy Diphenylmethanone as a New Acute Pyelonephritis Candidate Drug"],"prefix":"10.3390","volume":"25","author":[{"given":"Xiu E","family":"Feng","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Science, Shanxi Medical University, 56 Xinjian South Road, Taiyuan 030001, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ke Meng","family":"Cui","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science, Shanxi Medical University, 56 Xinjian South Road, Taiyuan 030001, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qing Shan","family":"Li","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science, Shanxi Medical University, 56 Xinjian South Road, Taiyuan 030001, China"},{"name":"Shanxi Key laboratory of Chronic Inflammatory Targeted Drugs, School of Chinese Materia Medica, Shanxi University of Traditional Chinese Medicine, 121 University Street, Jinzhong 030602, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zi Cheng","family":"Wu","sequence":"additional","affiliation":[{"name":"Beijing Zhendong Guangming Pharmaceutical Research Institute, 18 Chuangye Road, Beijing 100089, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fei","family":"Lei","sequence":"additional","affiliation":[{"name":"Beijing Zhendong Guangming Pharmaceutical Research Institute, 18 Chuangye Road, Beijing 100089, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,1,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1086\/519268","article-title":"Population-Based Epidemiologic Analysis of Acute Pyelonephritis","volume":"45","author":"Czaja","year":"2007","journal-title":"Clin. Infect. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2311","DOI":"10.1007\/s10096-019-03679-9","article-title":"A Pharmacokinetic-pharmacodynamic Assessment of Oral Antibiotics for Pyelonephritis","volume":"38","author":"Cattrall","year":"2019","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1093\/cid\/ciw378","article-title":"Ceftazidime-avibactam Versus Doripenem for the Treatment of Complicated Urinary Tract Infections, Including Acute Pyelonephritis: RECAPTURE, a Phase 3 Randomized Trial Program","volume":"63","author":"Wagenlehner","year":"2016","journal-title":"Clin. Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1093\/cid\/ciq257","article-title":"International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases","volume":"52","author":"Gupta","year":"2011","journal-title":"Clin. Infect. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4132","DOI":"10.1016\/j.bmcl.2010.05.068","article-title":"Synthesis and Biological Activity of Halophenols as Potent Antioxidant and Cytoprotective Agents","volume":"20","author":"Zhao","year":"2010","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Feng, X.E., Liang, T.G., Gao, J., Kong, D.P., Ge, R., and Li, Q.S. (2017). Heme Oxygenase-1, a Key Enzyme for the Cytoprotective Actions of Halophenols by Upregulating Nrf2 Expression via Activating Erk1\/2 and PI3K\/Akt in EA.hy926 Cells. Oxid. Med. Cell. Longev., 7028478.","DOI":"10.1155\/2017\/7028478"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"14254","DOI":"10.3390\/molecules200814254","article-title":"Protective Effect of 2,4\u2032,5\u2032-Trihydroxyl-5,2\u2032-dibromo diphenylmethanone, a New Halophenol, Against Hydrogen Peroxide-Induced EA.hy926 Cells Injury","volume":"20","author":"Li","year":"2015","journal-title":"Molecules"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1111\/jcmm.13948","article-title":"5,2\u2032-Dibromo-2,4\u2032,5\u2032-trihydroxydiphenylmethanone Attenuates LPS-induced Inflammation and ROS Production in EA.hy926 Cells via HMBOX1 Induction","volume":"23","author":"Yuan","year":"2019","journal-title":"J. Cell. Mol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/j.intimp.2019.04.034","article-title":"5,2\u2032-Dibromo-2,4,5-trihydroxydiphenylmethanone, a Novel Immunomodulator of T lymphocytes by Regulating the CD4+ T Cell Subset Balance via Activating the Mitogen-activated Protein Kinase Pathway","volume":"72","author":"Yang","year":"2019","journal-title":"Int. Immunopharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.intimp.2018.07.001","article-title":"Therapeutic Effects of 5,2\u2032-Dibromo-2,4\u2032,5\u2032-trihydroxydiphenylmethanone (LM49) in an Experimental Rat Model of Acute Pyelonephritis by Immunomodulation and Anti-inflammation","volume":"62","author":"Zhang","year":"2018","journal-title":"Int. Immunopharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1021\/acs.oprd.9b00182","article-title":"Process Development of an Efficient Kilogram-Scale Preparation of a Preferential Dopamine D3 Versus D2 Receptor Antagonist SIPI 6398 as a New Antipsychotic Candidate","volume":"23","author":"Zhou","year":"2019","journal-title":"Org. Process. Res. Dev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"31654","DOI":"10.1039\/C9RA05532K","article-title":"Enantioselective Bromination of Axially Chiral Cyanoarenes in the Presence of Bifunctional Organocatalysts","volume":"9","author":"Wada","year":"2019","journal-title":"RSC Adv."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1007\/s40242-016-5233-4","article-title":"One-pot Synthesis of \u03b1,\u03b2-Dehydroamino Derivatives From \u03b2, \u03b2-Dicyanostyrene With 1,3-Dibromo-5,5-dimethylhydantoin Promoted by Mild Base","volume":"32","author":"Chen","year":"2016","journal-title":"Chem. Res. Chin. Univ."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1007\/s11426-017-9192-x","article-title":"Phosphine oxide-Sc(OTf)3 Catalyzed Enantioselective Bromoaminocyclization of Tri-substituted Allyl N-tosylcarbamates","volume":"61","author":"Tan","year":"2018","journal-title":"Sci. China Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5948","DOI":"10.1016\/j.tetlet.2012.08.111","article-title":"A Convenient Method for the Preparation of Mono- and Bis-substituted Photochromic Bis(benzothienyl)perfluorocyclopentenes via Regioselective Friedel\u2013Crafts Acylation","volume":"53","author":"Bogacheva","year":"2012","journal-title":"Tetrahedron. Lett."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/j.tetlet.2012.11.118","article-title":"Improved synthesis of 4-phenylphenalenones: The case of isoanigorufone and structural analogs","volume":"54","author":"Cano","year":"2013","journal-title":"Tetrahedron. Lett."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"19649","DOI":"10.1021\/acs.iecr.9b02780","article-title":"The Autoxidation of Alkenyl Succinimides-Mimics for Polyisobutenyl Succinimide Dispersants","volume":"58","author":"Ruffell","year":"2019","journal-title":"Ind. Eng. Chem. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1016\/j.jpba.2010.05.002","article-title":"Quantitative Analysis of Sulfathiazole Polymorphs in Ternary Mixtures by Attenuated Total Reflectance Infrared, Near-infrared and Raman spectroscopy","volume":"53","author":"Hu","year":"2010","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.ejps.2017.05.013","article-title":"Evaluation of a Biphasic in Vitro Dissolution Test for Estimating the Bioavailability of Carbamazepine Polymorphic Forms","volume":"105","author":"Deng","year":"2017","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_20","first-page":"981","article-title":"Polymorphic Properties and Dissolution Profile of Efavirenz due to Solvents Recrystallization","volume":"32","author":"Wardhana","year":"2019","journal-title":"Pak. J. Pharm. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1016\/j.molstruc.2019.07.024","article-title":"Synthesis, Growth, Crystal Structure, Thermal, Linear and Nonlinear Opticalanalysis of New Extended p-conjugated Organic Material Based on Methyl Pyridinium Compound of 4-(4-(4-(dimethylamino) phenyl) buta-1,3-dienyl)-1-methylpyridinium p-styrenesulfonate Hydrate","volume":"1196","author":"Antony","year":"2019","journal-title":"J. Mol. Struct."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1016\/j.polymdegradstab.2011.01.033","article-title":"Thermal Characterization of HCN Polymers by TG\u2013MS, TG, DTA and DSC Methods","volume":"96","year":"2011","journal-title":"Polym. Degrad. Stabil."},{"key":"ref_23","first-page":"1358","article-title":"Polymorphs of Clopidogrel Bisulfate","volume":"48","author":"Liu","year":"2013","journal-title":"Acta Pharm. Sin."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/3\/468\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:30:17Z","timestamp":1760362217000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/3\/468"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,22]]},"references-count":23,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2020,2]]}},"alternative-id":["molecules25030468"],"URL":"https:\/\/doi.org\/10.3390\/molecules25030468","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,22]]}}}