Synthesis And Analysis Of Lomefloxacin Impurities

Lomefloxacin is a third-generation quinolone broad-spectrum antimicrobial drug.It was jointly produced by Hokriku Pharmaceutical Co.,Ltd.and Shionogi Pharmaceutical Co.,Ltd.of Japan in 1985 and first launched on the market.Subsequently,it quickly became one of the commonly used anti-infective chemotherapy drugs worldwide.Clinically,it is often used to treat the infection symptoms of respiratory tract,skin soft tissue,abdominal biliary tract and other parts caused by sensitive bacteria.With the continuous development of science and technology as well as the innovation and reform of the pharmaceutical industry,the reference substances of drug impurities are gradually brought into the category of drug standards.Lomefloxacin hydrochloride is one of the most reported fluoroquinolones in photosensitivity and phototoxicity.Therefore,it is particularly important to prepare the corresponding impurity standard and optimize the detection method of relevant substances for the corresponding preparation to control the quality of API and improve the reliability of the product.When lomefloxacin is hydrolyzed and anaerobic,F^-at C-8 will be replaced by OH^-to form 1-ethyl-6-fluoro-8-hydroxy-7-（3-methyl-1-piperazinyl）-4-oxo-1,4-dihydroquinoline-3-carboxylic acid that is lomefloxacin impurity 2.This thesis takes this impurity as the target compound,and 2,4,5-trifluoro-3-methoxybenzoic acid is designed as the starting material,after acylation with thionyl chloride,condensation with trans-N,N-dimethylamino ethyl acrylate,N-ethylation,condensation cyclization,hydrolysis,condensation with 2-methylpiperazine and acidification,seven-step synthesis reaction Route,and then use high performance liquid chromatography with C18 fast separation column to separate and purify the compound to obtain the pure product of lomefloxacin impurity 2.Its structure is confirmed by ¹H-NMR,¹³C-NMR,HRMS spectra,and the purity determined by HPLC is above 96%.It can be used for quality research and control of lomefloxacin API and process synthesis.Lomefloxacin hydrochloride capsules and lomefloxacin impurity 2,impurity 3,impurity 6 and impurity 8 were used to conduct methodological research on related substances by HPLC.The chromatographic conditions were optimized with reference to the Chinese Pharmacopoeia and related literature.The established chromatographic conditions for related substances are as follows:Chromatographic column is Elite Supersil ODS2（4.6×150mm,5μm）;mobile phase A is sodium pentane sulfonate solution（containing 1.5 g sodium pentane sulfonate and 3.5 g ammonium dihydrogen phosphate per 1000 m L solution,p H adjusted to 3.0 by phosphoric acid）,mobile phase B is mass spectrometric methanol;the gradient elution was carried out for 0～5 min,and the concentration of B phase was 33%;5～10min,B phase was 33%→35%;10～15 min,B phase was 35%;15～20min,B phase was 35%→45%;20～26 min,B phase was 45%;26～27min,B phase was 43%→35%;27～37 min,B phase was 35%;flow rate was 1.0 m L/min;column temperature was 35℃;detection Wavelength was287 nm;injection volume was 20μL.The system applicability,limit of quantification,limit of detection,specificity,linearity,precision,durability,accuracy,solution stability and membrane adsorption of the above detection methods were verified accordingly.The results showed that the relative substances had good precision,high specificity,high sensitivity,and the limits of detection and quantification were accurate and reliable.The durability is better when the chromatographic parameters vary within a small range.Lomefloxacin Hydrochloride Capsules can be completely separated from the impurities,and the system has good applicability.The four impurities and the tested products have good linear relationship in the corresponding concentration range,which is suitable for the determination of related substances in lomefloxacin hydrochloride preparation.