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Research on the Synthesis of Leyofloxacin

Author: ZhaoAiJie
Tutor: ChenXinZhi
School: Zhejiang University
Course: Chemical Engineering
Keywords: levofloxacin antibacterial synthesis industrializatio
CLC: TQ463
Type: Master's thesis
Year: 2011
Downloads: 190
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Abstract


Levofloxacin is one of the most famous quinolone antibacterial ofloxacin (norfloxacin) levorotary isomers, with potent broad-spectrum antibacterial effect. Because of the good pharmacokinetics character, mild adverse reactions, clinical curative effect, wide application range, levofloxacin synthesis research is attracting more and more attention.This article summarized the synthesis methods of levofloxacin, based on which a new synthetic route was proposed and optimized.2,3,4,5-Tetrafluorobenzoic chloride was selected as starting material. Levofloxacin was obtained with yield of55.35%after condensation, hydrolysis, decarboxylation, amination, cyclization, hydrolysis, condensation and refinary. The specific reaction conditions are as follows:1. The ratio (W/W) of2,3,4,5-Tetrafluorobenzoic chloride:diethyl malonate:ethanol:toluene:magnesium:4-methylbenzoic acid:hydrogen chloride is1:0.80:0.23:5:0.12:0.026. The condensation was carried out at45℃for1hours, hydrolysis and decarboxylation at100℃for3hours and crystallization for8hours at8℃. Intermediate1was obtained with yield of77.21%.2. The ratio (W/W) of (DMF-DMA):S-(+)-2-amino alcohol:toluene:DMSO: potassium fluoride:Na2CO3(5%) is1:0.60:0.28:3.50:0.90:0.30(1.00+8.00). Intermediate1reacted with DMF-DMA and S-(+)-2-amino alcohol successively in toluene, then cyclization was performed in KF-DMF system at150℃for2.5h. After that, hydrolysis was carried out using Na2CO3aqueous(5%)-glacial acetic acid as agent, with which the reaction condition was facile and the yield was improved. Intermediate2was obtained in83.2%yield after adjusting the pH value to6.5.3. The ratio (W/W) of Intermediate2:N-methylpiperazine:triethylamine:ammonium:767#activated carbon:ethanol(95%purity):DMSO:trichoromethane is1:2:0.60:0.30:(0.02+0.02):(2.00+3.00+1.00):0.80:7. The condensation was carried out at85℃for6h, then neutralized the system with ammonium. Recrystallization was performed at5℃, and the final product was obtained in86.16%yield.The product structure was confirmed by elemental analysis, ultraviolet spectrum, infrared spectroscopy, nuclear magnetic resonance spectroscopy, mass spectrometry, thermal analysis and X-ray diffraction analysis.The amplification of synthesis of levofloxacin gave yield in49.9%-57.3%, and the product quality met the national drug standards. The preparation process is reproducible and stable, and is also advanced in high yield, simple operation and less three wastes. The new route is of greate value in pharmarceutical industry.

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