氧氟沙星甲基化物的核磁共振波谱研究

doi:10.3964/j.issn.1000-0593.2008.06.010

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Abstract Ofloxacin ((±)-9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid) is a totally synthetic fluoroquinolone antimicrobial agent with a broad spectrum of activity against Gram-positive and Gram-negative bacteria and atypical pathogens such as Mycoplasma, Chlamydia and Legionella. Even though it is widely used for the treatment of gastrointestinal, pulmonary, urinary, and other infections, the comprehensive mechanism of action at molecular level has not been known so far. It is very important to understand the structural characteristics of the drug and the effects that are caused by the environments. With the purpose of deeply investigating the structure of Ofloxacin, an analog of Ofloxacin, Methyl-Ofloxacin (Me-OFL), was synthesized by methylation of 4’N in piperazine ring from Ofloxacin with CH₃I. Then appropriate Me-OFL was dissolved in DCl/D₂O and NaOH/D₂O to prepare corresponding acidic and alkaline solutions. Systematic NMR spectroscopic investigation on Me-OFL in both acidic and alkaline solution was conducted using quantitative ¹H and ¹³C spectra, DEPT, HSQC together with HMBC techniques. The spectra were recorded with Bruker AM-300 spectrometer and DRX500 spectrometer. Chemical shifts have been given in values referred to dioxane (δ_H=3.7, δ_C=67.8). Complete assignments on 1H and ¹³C signals of Me-OFL were obtained in different pH environments where the coupling constant between ¹³C and ¹⁹F was found to be very helpful for the assignment of aromatic ¹³C signals. A comprehensive comparison between the ¹H, ¹³C chemical shifts, together with the structural transformation in acidic and alkaline solutions was made and discussed in details. Due to the formation of hydrogen bond between COOH and CO, the COOH and aromatic ring are in the same plane. As a result, a weak O…H—C hydrogen bond forms between CO from the carboxyl group and 5-H from aromatic ring. In alkaline solution, the deprivation of H⁺ from COOH destroys not only the hydrogen bond between COOH and carbonyl group but also the weak hydrogen between the CO from COOH and 5H. As a result, the 5H exhibited remarkable shift toward high field (1.02). Meanwhile, the chemical shift of 6C, 13C, 7C, 15C also exhibited remarkable shift to low field at 12.04, 7.46, 4.33, 2.88 respectively. Such variations were related to the changes of p electrons from carboxyl group caused by the transformation between the carboxyl group and the carboxylate group in different pH environments. Comparison of δ_H，δ_C data between Me-OFL and OFL in acidic solution and OFL in alkaline was made. In Me-OFL acidic solution, the chemical shift of 3’C，5’C，7’C，8’C also exhibited remarkable shift to low field at 6.66-7.32 respectively, the chemical shift of 2’C and 6’C also exhibited remarkable shift to high field 6.04. In OFL acidic solution, the chemical shift of 2’C, 3’C, 5’C, 6’C, 7’C, 8’C also exhibited remarkable shift to high field within 2.39, Comparison between the protonation and the methylation on the 4’N atom from the piperazine ring was also made. The distribution of positive charge also showed difference. When protonation occurred on the piperazine ring, the positive charge was on the proton connected with 4’N. However, if methylation occurred, the positive charge is on the 4’-N atom.

Key words：Quinolone;Methyl-Ofloxacin;NMR;Piperazine ring

Received: 2007-02-06 Accepted: 2007-05-12

ZTFLH:

O657.6

Corresponding Authors: XU Yi-zhuang E-mail: xiuxianggao@sina.com

Cite this article:

GAO Xiu-xiang,QI Jian,ZHAO Mei-xian, et al. A Study on the NMR Spectrum of Methyl-Ofloxacin[J]. SPECTROSCOPY AND SPECTRAL ANALYSIS, 2008, 28(06): 1420-1425.

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https://www.gpxygpfx.com/EN/10.3964/j.issn.1000-0593.2008.06.010 OR https://www.gpxygpfx.com/EN/Y2008/V28/I06/1420

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