Synthesis of deuterium-labeled moxifloxacin
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Synthesis of deuterium-labeled moxifloxacin Lei Tian1 · Bo Shao2 · Jian Li3 · Mei He2 Received: 7 May 2020 © Akadémiai Kiadó, Budapest, Hungary 2020
Abstract The stable isotope-labeled moxifloxacin was required in the clinical pharmacokinetic studies. Starting from furo[3,4-b] pyridine-5, 7-dione, a seven-step synthesis for deuterium-labeled moxifloxacin was described, and deuteriums were incorporated in positions 14, 20 of pyrrolo ring of moxifloxacin. The stable labeled moxifloxacin provided an outstanding internal standard for metabolism process studies. Keywords Deuterium-labeled · Moxifloxacin · Tuberculosis · Resolution
Introduction Tuberculosis (TB) has been the leading cause of death from a single infectious agent, ranking above HIV/AIDS in the past 5 years [1]. With the increasing resistance of Mycobacterium tuberculosis to the existing anti-TB drugs, the development of new candidate has raised higher requirement. Moxifloxacin is more effective against rifampicinresistant bacteria than other fluoroquinolones such as levofloxicin and ofloxacin [2]. Compared with isoniazid, a first-line TB drug, moxifloxacin shows excellent oral bioavailability, long half-life and elimination half-life of 12 h [3]. Because of these advantages, moxiflaxacin has arisen as a new latent candidate in combination with other anti-TB drugs [4]. Moxiflaxacin in monotherapy may easily cause drug resistance [5, 6]. TB-resistant patients who receive treatment with long-term application of moxifloxacin result in adverse effects, including gastrointestinal, general and central nervous system disorder, and so on [7, 8]. Most of the adverse effects are directly and indirectly related to the * Mei He hemei‑[email protected] 1
School of Petroleum Engineering, Yangtze University, 1 Daxue Road, Caidian District, Wuhan 430100, Hubei, People’s Republic of China
2
School of Resources and Environment, Yangtze University, 1 Daxue Road, Caidian District, Wuhan 430100, Hubei, People’s Republic of China
3
School of Biochemical and Environmental Engineering, Nanjing Xiaozhuang University, 3601 Hongjing Road, Nanjing 211171, Jiangsu, People’s Republic of China
metabolism of moxifloxacin, and representative of the two metabolites are sulfo conjugate and acyl-glucuronate [9, 10]. The pharmacokinetics of moxifloxacin and its metabolites are analyzed by conventional noncompartmental approaches or identified and characterized by hydrogen/deuterium (H/D) exchange method combined with LC/ESI-MS/MS technique in previous reports [11, 12]. It can be obtained higher specificity and sensitivity to use stable isotope-labeled analogs for determining drugs and metabolites in biological samples by liquid chromatographymass spectrometry (LC–MS) [13]. The stable labeled moxifloxacin was requested for clinical pharmacokinetic studies. Although 14C-moxifloxacin has been prepared for pharamacological studies [14, 15], no literature has reported the synthesis of stable labeled moxifloxacin in detail [16]. Herein, a facile synthesis for [ 2H4] moxifloxacin was de
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