Prulifloxacin and its key intermediate NM441 preparing method

A compound and reaction technology, which is applied in the field of preparation of fluoroquinolone antibacterial drug prulifloxacin, can solve the problems of unsatisfactory pharmacokinetics and safety, and achieve the effect of large-scale production, high yield and low cost

Inactive Publication Date: 2007-11-14
亚邦化工集团有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Its development is divided into 4 stages: the first stage is the initial stage of development, the products are nalidixic acid and pipemidic acid, which

Method used

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  • Prulifloxacin and its key intermediate NM441 preparing method
  • Prulifloxacin and its key intermediate NM441 preparing method
  • Prulifloxacin and its key intermediate NM441 preparing method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Example 1: [[(3-Chloro-4-fluoro-phenyl)amino]methylene]diethylmercaptopotassium malonate (3)

[0052]Suspend 66g of finely ground KOH (90%) in 2000ml of 1,4-dioxane, and add 170g (1.06mol) of diethyl malonate dropwise at 20-30°C within 1 hour under stirring, continuously Precipitate a white milky solid, after the dropwise addition, keep stirring at 20-30°C for 1 hour, then pour 198g (1.06mol) of 3-fluoro-4-chlorophenyl isothiocyanate into it, and the reaction heats up to 35°C For about 3 hours at 45° C., the solid was collected by filtration, rinsed with a little ether, and dried to obtain 366 g of the target product (yield: 90%).

Embodiment 2

[0053] Example 2: Diethyl 1-((3-chloro-4-fluoro-phenyl)amino)-1-(ethylthio)-malonate (4)

[0054] Dissolve 308.4g (0.8mol) of compound 3 in 1000ml of DMF, add 185g (1.2mol) of diethyl sulfate dropwise at 20-30°C within 1 hour under stirring, and then keep stirring at 20-30°C for 1 After 2 hours, heat up to 45°C and keep stirring to react for 2 hours. Pour the reaction solution into 4L of ice water, extract with 1000ml*3 dichloromethane, combine the organic phases, wash with water, and dry over anhydrous magnesium sulfate for more than 3 hours. Concentrate to dryness under reduced pressure to obtain 258 g (yield: 85.2%) of light yellow oil, which is the target product.

Embodiment 3

[0055] Example 3: Diethyl 1-(3-chloro-4-fluoro-phenyl)amine-1-(ethylthio)-methylene-malonate (4)

[0056] Suspend 85.7g (1mol) of potassium ethylate (98%) in 1000ml of absolute ethanol, add 168g (1.05mol) of diethyl malonate dropwise at 20-30°C within 1 hour under stirring, during which white milky Solid, after the dropwise addition, keep stirring at 20-30°C for 1 hour, then pour 187.5g (1mol) of 3-fluoro-4-chlorophenyl isothiocyanate into it, the reaction is exothermic, and then keep it at 45°C for reaction For 3 hours, cool down to 25°C and add 200g (1.3mol) of diethyl sulfate dropwise. After the dropwise addition, keep stirring at 20-30°C for 1 hour, then raise the temperature to 45°C and keep stirring for 2 hours. Pour the reaction solution into Extract with 1000ml*3 dichloromethane in 4L of ice water, combine the organic phases, wash with water, dry over anhydrous magnesium sulfate for more than 3 hours, and concentrate to dryness under reduced pressure below 45°C to obta...

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Abstract

This invention relates to preparation method of a compound as formulae(1). The chart is the structure of R.

Description

Technical field: [0001] The invention relates to a new method for preparing fluoroquinolone antibacterial drug prulifloxacin and its key intermediate NM441 Background technique: [0002] Quinolones antibacterials are rapidly developing anti-infectives this year, accounting for 18.5% of the world's antibiotic market, with an average annual growth rate of 7%, and are one of the most active areas in the development of anti-infectives. Its development is divided into four stages: the first stage is the initial stage of development, and the products are nalidixic acid and pipemidic acid, which have only moderate antibacterial activity, and their pharmacokinetics and safety are not satisfactory. At present, they are basically eliminated. From the second stage, quinolones entered a period of rapid development, and their comprehensive clinical curative effect on Gram-negative bacteria has surpassed that of penicillins, reaching the effect of the first and second generation cephalosp...

Claims

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Application Information

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IPC IPC(8): C07D513/04
Inventor 刘定明吴宾王思清石卫兵颜文革
Owner 亚邦化工集团有限公司
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