Preparation method of Marbofloxacin

A technology for marbofloxacin and compounds, applied in the field of preparing marbofloxacin, can solve the problems of unfavorable commercial production, long reaction time and high production cost, achieve good social and economic benefits, improve product purity and yield, and reduce The effect of production costs

Active Publication Date: 2011-05-18
NINGBO MENOVO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] It is obvious that the reaction time of the above-mentioned method is long, and an impurity shown in formula (E) will be produced in t

Method used

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  • Preparation method of Marbofloxacin
  • Preparation method of Marbofloxacin
  • Preparation method of Marbofloxacin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Embodiment 1: Preparation of the compound shown in the intermediate formula (IV) of marbofloxacin

[0032] Add 200 g of toluene, 21.5 g of N-methylpiperazine, and 17 g of triethylamine to the flask successively, and then drop into 50 g of 6,7,8-trifluoro-1,4-dihydro-1-(N-methyl Formamido)-4-oxo-3-quinolinecarboxylic acid ethyl ester, heat up to reflux, react for 12 hours, then cool down to room temperature (25°C), add 250g of purified water and 23.5g of potassium hydroxide, and then heat up to React at 90°C for 3 hours, cool down to 25°C, separate the aqueous phase, adjust the pH value to 7.0 with 6 mol equivalent hydrochloric acid, then extract with 250mL of dichloromethane, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 6 , 8-difluoro-1,4-dihydro-1-(N-methylamino)-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid 32.1 g.

[0033] (Molar yield: 74.41%, HPLC: 99.79%)

Embodiment 2

[0034] Embodiment 2: Preparation of the compound shown in the intermediate formula (IV) of marbofloxacin

[0035] Add 350 g of toluene, 30 g of N-methylpiperazine, and 30 g of triethylamine in sequence in the flask, and then drop in 50 g of 6,7,8-trifluoro-1,4-dihydro-1-(N-methyl formylamino)-4-oxo-3-quinolinecarboxylic acid ethyl ester, warming up to reflux, reacting for 8 hours, then cooling down to room temperature (25°C), adding 350g of purified water and 40g of potassium hydroxide, then warming up to React at 60°C for 5 hours, cool down to 25°C, separate the water phase, and adjust the pH value to 7.0 with 6 mol equivalent hydrochloric acid. It was then extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 6,8-difluoro-1,4-dihydro-1-(N-methylamino)-7-(4 -Methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid 32.1 g.

[0036] (Molar yield: 77.65%, HPLC: 99.85%)

Embodiment 3

[0037] Embodiment 3: the preparation of marbofloxacin

[0038] The 6,8-difluoro-1,4-dihydro-1-(N-methylamino)-7-(4-methyl-1-piperazinyl)-4-oxo Put 25g of substituted-3-quinolinecarboxylic acid into a 500mL stainless steel kettle, add 60mL of purified water and 28.6g of potassium hydroxide, the reaction temperature is 125°C, the internal pressure is 0.1Mpa, react for 12 hours; cool down to 50°C, add dropwise 45mL of 94% Formic acid and 10.8mL 37% formaldehyde, after dropping, heat up to 75°C and react for 6 hours, then cool down to 0°C, filter, wash with purified water, put the filter cake into a 500mL flask and add 150mL purified water, dissolve, and use the mass concentration Adjust the pH value to 8.5 with 24% ammonia water, extract with dichloromethane, dry the organic phase with anhydrous sodium sulfate, filter, and distill the filtrate under reduced pressure to obtain 17.97g of crude marbofloxacin, crystallize with 720mL of 50% ethanol solution 16.75 g of marbofloxacin w...

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Abstract

The invention discloses a preparation method of Marbofloxacin, which comprises the following steps: (1) mixing a compound disclosed as Formula (V) with phenylmethane, triethylamine and N-methylpiperazine, heating to react for 8-12 hours, cooling to room temperature, adding purified water and potassium hydroxide, reacting at 60-90 DEG C for 3-5 hours, cooling to 20-25 DEG C, separating out a waterphase, regulating the pH value of the water phase to 6.8-7.2 with hydrochloric acid, extracting with dichloromethane, and concentrating while depressurizing to obtain a compound disclosed as Formula (IV); and (2) reacting the compound disclosed as Formula (IV) with potassium hydroxide in medium water at 125-160 DEG C under the pressure of 0.1-0.4 Mpa for 5-12 hours to obtain a compound disclosed as Formula (II), dropwisely adding a formic acid water solution and a formaldehyde water solution when the temperature drops to 40-50 DEG C, carrying out cyclization reaction at 70-75 DEG C for 6-10 hours, and carrying out after-treatment on the reaction product to obtain the Marbofloxacin. The invention utilizes a new intermediate to prepare Marbofloxacin, has the advantages of short reaction time, low cost and high product purity, and is suitable for commercial production.

Description

(1) Technical field [0001] The invention relates to a preparation method of special antibacterial drugs for animals, in particular to a new method for preparing marbofloxacin. (2) Background technology [0002] Marbofloxacin (marbofloxacin) is a new type of fluoroquinolone antibacterial drug for animals. Its chemical name is: 9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl) )-7-oxo-7H-pyridine[3,2,1-i,j][4,1,2]benzoxadiazine-6-carboxylic acid, developed by Roche, the structural formula is as follows : [0003] [0004] Marbofloxacin intermediate: 6-fluoro-1,4-dihydro-8-hydroxy-1-(methylamino)-7-(4-methyl-1-piperazinyl)-4-oxo- 3-quinoline carboxylic acid alkali metal salt, its structural formula is as shown in formula (II): [0005] [0006] M is an alkali metal cation. [0007] Compound represented by formula (II): 6-fluoro-1,4-dihydro-8-hydroxyl-1-(methylamino)-7-(4-methyl-1-piperazinyl)-4-oxo -3-quinoline carboxylic acid alkali metal salt is an importan...

Claims

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Application Information

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IPC IPC(8): C07D498/06
Inventor 周广军裴仲魁
Owner NINGBO MENOVO PHARMA
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