Preparation method of pazufloxacin intermediate

A technology of pazufloxacin and intermediates, which is applied in the field of drug synthesis, can solve the problems of low yield, high pressure on environmental protection, and high potential safety hazards, and achieve the effects of high yield, low pressure on environmental protection, and less waste

Active Publication Date: 2014-05-07
ZHEJIANG HAISEN PHARMACY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] Because the current synthesis route of pazufloxacin intermediates has defects such as low yield, high safety hazards, and high environmental protection pressure, people still have high safety, simple operation, low cost, and green and e

Method used

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  • Preparation method of pazufloxacin intermediate

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preparation Embodiment 1

[0035]In a 250mL three-necked flask, add lye made of 20g of sodium hydroxide and 100mL of water, lower the temperature of the reaction system to 0~5°C while stirring, add 3g of benzyltriethylammonium chloride, and stir for 1 hour; Add 10 g of raw material compound II ((s)-10-ethylcyano-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyridine[1,2 ,3-de][1,4]Benzoxazine-6-carboxylate ethyl ester, commercially available), stirred at about 5°C for 1 hour, added 50mL of acetone and 4.5g of 1,2-dichloroethyl After the addition, the reaction system was stirred and reacted at room temperature for 5 hours, then heated to reflux for 6 hours, and then cooled. When the temperature of the system was between 20 and 30°C, it was neutralized by adding half-concentration hydrochloric acid dropwise to pH After = 6, the reaction system becomes turbid, and a large amount of solids precipitate out. After stirring for 10 minutes, the pH value is re-measured to be stable. After cooling down to 10-20°C, conti...

preparation Embodiment 2

[0037] In a 250mL three-necked flask, add lye made of 20g of sodium hydroxide and 100mL of water, lower the temperature of the reaction system to 0~5°C while stirring, add 3g of benzyltriethylammonium chloride, and stir for 1 hour; Add 10g of raw material compound II at 0~5°C, stir at about 5°C for 1 hour, add 50mL of a mixed solution of 4-methyl-2-pentanone and 4.5g of 1,2-dichloroethane, and complete the addition , the reaction system was stirred and reacted at room temperature for 5 hours, then heated to reflux for 3 hours, and then lowered the temperature. When the temperature of the system was between 20 and 30°C, it was neutralized by adding half-concentration hydrochloric acid to pH=6 or so, and the reaction system became It was turbid and a large amount of solids were precipitated. After stirring for 10 minutes, the pH value was re-measured to be stable. After cooling down to 10-20°C, stirring was continued for 1 hour, and the white solid was filtered to obtain compound...

preparation Embodiment 3

[0039] In a 250mL three-necked flask, add lye made up of 15g of sodium hydroxide and 150mL of water, lower the temperature of the reaction system to 0~5°C while stirring, add 3g of benzyltriethylammonium chloride, and stir for 1 hour; Add 10g of raw material compound II at 0~5°C, stir at about 5°C for 1 hour, add 4.5g of a mixed solution composed of 1,2-dichloroethane, after the addition is complete, the reaction system is stirred at room temperature for 5 hours, and then heated After 2 hours of reflux reaction, lower the temperature. When the temperature of the system is between 20 and 30°C, add half-concentration hydrochloric acid to neutralize it dropwise. When the pH is about 6, the reaction system becomes turbid and a large amount of solids are precipitated. After stirring for 10 minutes, resume The pH value was measured to be stable, and the temperature was lowered to 10-20°C, and the stirring was continued for 1 hour, and the white solid was filtered to obtain compound I...

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Abstract

The invention relates to a preparation method of a pazufloxacin intermediate, the preparation method is as folows: in a suitable solvent and at a suitable temperature, under the effects of a phase transfer catalyst and an inorganic alkali, a compound II reacts with 1, 2 -dichloroethane for cyclopropanation, the reaction system is direct heated and refluxed for hydrolysis reaction, a pazufloxacin intermediate compound IV is obtained by postprocessing; the weight ratio of inorganic alkali to compound II is 1.5-2.5:1; the ratio of solvent to compound II is 14-16mL:1g. Compared with the prior art, according to the preparation method, a specified concentration and the specific amount of the alkali is used, a two-step method is performed by a 'one pot' method, the unit operation is simplified; and in the preparation process, the three wastes are less, the environmental protection pressure is low, the yield is high, and the method is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a preparation method of a pazufloxacin intermediate. Background technique [0002] Pazufloxacin (I) is a quinolone antibacterial drug developed and marketed by Japan Toyama Chemical Company in 2002. It can act on topoisomerase IV and DNA gyrase at the same time, and inhibit the replication of bacterial DNA to exert antibacterial effect. The clinical efficacy of Pazufloxacin is equal to or slightly better than that of the second-generation quinolones such as ofloxacin, ciprofloxacin and levofloxacin, and its efficacy is better than that of other quinolones. [0003] The main ingredient of Pazufloxacin in clinical application is the mesylate salt of Pazufloxacin, that is, Pazufloxacin mesylate (Pazutloxacin mesylate), chemical name: (S)-10-(1-amino-1 -cyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyridin[1,2,3-de][1,4]benzoxazine-6- Carboxylic acid methanesulfonate, the struct...

Claims

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Application Information

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IPC IPC(8): C07D498/06
CPCC07D498/06
Inventor 李宽伟楼岩军王式跃张丽潘仙华
Owner ZHEJIANG HAISEN PHARMACY CO LTD
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