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9-fluoro-6,7-dihydro-8-(4-hydroxy-1-piperidinyl)-5-methyl-1-oxo-1H, 5H-benzo-quinoline-2-carboxylic acid preparation method

A benzoquinazine, piperidinyl technology, applied in the direction of organic chemistry and the like, can solve the problems of inability to industrialize, low yield, long synthesis steps of nalfloxacin, etc., to shorten the length of synthesis steps and improve yield Effect

Inactive Publication Date: 2016-02-03
NANJING GRITPHARMA CO LTD
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  • Claims
  • Application Information

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Problems solved by technology

[0012] In order to solve the above-mentioned problems of long synthetic steps of nafloxacin, low yield and inability to industrialize in the prior art, the present invention provides a preparation method of nafloxacin, which can shorten the long synthetic steps of nafloxacin, increase Yield

Method used

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  • 9-fluoro-6,7-dihydro-8-(4-hydroxy-1-piperidinyl)-5-methyl-1-oxo-1H, 5H-benzo-quinoline-2-carboxylic acid preparation method

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Embodiment 1

[0040] 1. Synthesis of compound 5-bromo-6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline (II)

[0041] The compound 5-bromo-6-fluoro-2-methylquinoline (I) (50 g, 0.21 mol), acetic acid (200 ml) and catalyst 5% platinum on carbon (20 g) were added to the high pressure hydrogenation reactor. Control the hydrogenation pressure at 0.25MP and the temperature at 50-60°C to carry out the hydrogenation reaction until the reaction liquid no longer absorbs hydrogen to stop the reaction. The catalyst was suction filtered from the reaction solvent, the filtrate was concentrated under reduced pressure, the residue was mixed with 30% NaOH solution, and extracted with ether. The organic phase was washed with water, and then dried over anhydrous magnesium sulfate. After filtering off magnesium sulfate, diethyl ether was removed by rapid distillation to obtain 48.3 g of oily compound (II) with a yield of 95%.

[0042] 2. Synthesis of compound 8 bromo-9-fluoro-5-methyl-6,7-dihydro-1-oxo-1H,5H-be...

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Abstract

The present invention provides a 9-fluoro-6,7-dihydro-8-(4-hydroxy-1-piperidinyl)-5-methyl-1-oxo-1H, 5H-benzo-quinoline-2-carboxylic acid preparation method comprising the following steps: selective reduction of 5-bromo-6-fluoro-2-methyl-quinoline (I) as a starting material under acetic acid and platinum-carbon catalytic hydrogenation to obtain 5-bromo-6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline (II); Gould-Jacobs cyclization reaction under polyphosphoric acid (PPA) catalysis after condensation of the 5-bromo-6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline (II) and diethyl ethoxymethylenemalonate (EMME) to obtain a mother nuclear compound (III); condensation of mother nuclear compound (III) with 4-hydroxypiperidine after chelation, and final hydrolysis for dechelating to obtain nadifloxacin. The method solves the problems of long synthetic steps, not high yield and incapability of industrialization of nadifloxacin in the prior art, the nadifloxacin preparation method can shorten the nadifloxacin synthetic step, and improve yield.

Description

technical field [0001] The invention belongs to the field of medicine, in particular to the synthesis of pharmaceutical compounds, and more particularly to a kind of 9-fluoro-6,7-dihydro-8-(4-hydroxy-1-piperidinyl)-5-methyl-1- The preparation method of oxo-1H, 5H-benzoquinazine-2-carboxylic acid. Background technique [0002] Quinolones are antibacterial drugs that emerged in the 1970s. Since the discovery of the first quinolone antibacterial drug, nalidixic acid, in 1962 by researchers such as Lesher from the Sterling-Winthrop Institute in the United States, quinolones have developed into a large class of excellent commonly used anti-infective drugs in just 50 years. Because of its excellent anti-infective effect, it has become one of the most rapidly developing chemically synthesized antibacterial drugs in the past 10 years. Quinolone antibiotics are an important branch in the global anti-infective drug market, accounting for about 18% of the international anti-infective...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D455/04
CPCC07D455/04
Inventor 罗琦于涛陆滢炎刘二军陶金来张慧
Owner NANJING GRITPHARMA CO LTD