- Preparation method for garenoxacin and intermediate thereof
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The invention provides a preparation method for garenoxacin and an intermediate thereof. The preparation method comprises the following steps: with a compound 5 as a raw material, reacting the compound 5 with bis(pinacolato)diboron or triisopropyl borate so as to obtain a compound 4; separately adding 7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-ethyl carboxylate, a palladium catalyst and inorganic aqueous alkali and carrying out a reaction so as to obtain a compound 3; and subjecting the compound 3 to hydrolysis and a reduction reaction so as to obtain a compound 2 and garenoxacin (a compound 1). The compound 3 has excellent stability; raw materials for preparation of garenoxacin are cheap and easily available; reaction operation is simple; yield is high; litter waste gas, waste water and industrial residue are produced; and thus, the preparation method has good industrial prospects.
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Paragraph 0043; 0044; 0045; 0046; 0047; 0048
(2017/07/20)
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- Synthesis, antibacterial activity, and toxicity of 7-(isoindolin-5-yl)-4-oxoquinoline-3-carboxylic acids: Discovery of the novel Des-F(6)-quinolone antibacterial agent garenoxacin (T-3811 or BMS-284756)
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The palladium-catalyzed cross-coupling reaction of 5-(tributylstannyl)isoindoline and its 1- and 3-methyl derivatives with 6-fluoro or 6-unsubstituted 7-bromo-1-cyclopropyl-8-methoxy (or difluoromethoxy)-4-oxoquinoline-3-carboxylate afforded the corresponding 1-cyclopropyl-7-(5-isoindolinyl)-4-oxoquinoline-3-carboxylic acids: 6-fluoro, 1a-7a and 6-nonfluoro, 1b-7b. The in vitro antibacterial spectra of the newly synthesized quinolones were mostly characterized by excellent Gram-positive activity against Staphylococcus aureus and Streptococcus pneumoniae including quinolone-resistant strains, and also by significant Gram-negative activity comparable to 7-(1-piperazinyl)fluoroquinolones. Comparative examinations of the in vitro antibacterial profiles and the in vivo toxicity in terms of intravenous lethality, micronuclei-inducing potential and convulsive activity provided 6-nonfluorinated 1-cyclopropyl-8-(difluoromethoxy)-7-(1-methylisoindolin-5-yl)-4- oxoquinoline-3-carboxylic acid [(±)-5b] as the candidate for evaluation of the stereoisomers. The enantiomers (R)-5b and (S)-5b were synthesized via the Suzuki coupling reaction of (R)- and (S)-1-methyl derivatives of 2-(triphenylmethyl)isoindolin-5-boronic acid with the corresponding 7-bromo-8-(difluoromethoxy)-4-oxoquinoline-3-carboxylate. The (R)-5b stereoisomer proved to be 2- to 4-fold more active than the (S)-5b stereoisomer against the organisms tested, with the exception of an equal potency observed with S. pneumoniae IID553 and Haemophilus influenzae ATCC49247. A noticeable in vitro antibacterial profile of (R)-5b was that it is 16- and 64-fold more active than levofloxacin (CAS 100986-85-4) and ciprofloxacin (CAS 86393-32-0), respectively, against Mycoplasma pneumoniae IID813 (MIC of 0.0313 μg/ml), and 4-fold more active than ciprofloxacin and levofloxacin against Mycobacterium tuberculosis M-4 (MIC of 0.0313 μg/ml). Additional studies indicate that (R)-5b (T-3811, CAS 194804-75-6) exhibits excellent antibacterial activity against a wide range of organisms including anaerobes and common respiratory pathogens, while demonstrating a high selectivity against the mammalian homolog topoisomerases. The methane-sulfonate of (R)-5b (T-3811ME, CAS 223652-90-2) is now undergoing clinical testings.
- Hayashi, Kazuya,Takahata, Masahiro,Kawamura, Yasuhito,Todo, Yozo
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p. 903 - 913
(2007/10/03)
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