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One-step synthesizing method of levofloxacin and ofloxacin

A levofloxacin and synthetic method technology, applied in the direction of organic chemistry, can solve the problems of low yield, low efficiency, and reduced recovery of N-methylpiperazine, so as to reduce reagent consumption, simplify reaction, and improve reaction Yield and Purity Effects

Active Publication Date: 2013-01-02
ZHEJIANG UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are problems of low yield and low efficiency
[0011] 4. N-methylpiperazine substitution reaction (abbreviated as piperizine reaction in the text): S-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo- 7H-pyrido[1,2,3-Δ]-[1,4]-benzoxazine-6-carboxylic acid or 9,10-difluoro-2,3-dihydro-3-methyl-7 -Oxy-7H-pyrido[1,2,3-Δ]-[1,4]-benzoxazine-6-carboxylic acid as starting material, reacted with excess N-methylpiperazine, the disadvantage of this reaction It is the hydrofluoric acid and N-methylpiperazine that generate in the substitution reaction process to form a salt, which reduces the recovery rate of N-methylpiperazine. It is also reported that the free carboxylic acid is used as a raw material and a base or a catalyst is used such as the Chinese patent CN101514208 etc., but above-mentioned method all adopts the raw material that hydrolyzes into acid to carry out further shrinkage reaction

Method used

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  • One-step synthesizing method of levofloxacin and ofloxacin
  • One-step synthesizing method of levofloxacin and ofloxacin
  • One-step synthesizing method of levofloxacin and ofloxacin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Weigh 30 grams of raw material S-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-Δ]-[1,4] - Benzoxazine-6-carboxylate, 30 grams of tetrahydrofuran, 30 grams of water and 4.3 grams of sodium hydroxide were incubated at 60°C for reaction, and the alcohol generated by the reaction was removed during the reaction, and the reaction was carried out for about 5 hours. After the hydrolysis was complete, the remaining solvent was evaporated, and then 40 g of N-methylpiperazine and 70 g of DMSO were directly added into the three-necked reaction flask, and the reaction was carried out at 90°C for about 10 hours. After N-methylpiperazine is completely substituted, N-methylpiperazine and DMSO are recovered under reduced pressure, and the remaining crude product of levofloxacin is dissolved in chloroform and water. , washing, concentration and other steps. Finally, the concentrated solid was recrystallized with methanol, filtered with suction, and the mother liquor was conc...

Embodiment 2

[0033] Weigh 30 grams of raw material S-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-Δ]-[1,4] - Benzoxazine-6-carboxylate, 60 grams of acetonitrile and 6.5 grams of potassium hydroxide, heat preservation reaction at 50° C., and remove the alcohol generated by the reaction during the reaction. After the hydrolysis was complete, 50 g of N-methylpiperazine was directly added into the three-necked reaction flask, and the temperature was raised to reflux for about 16 hours. After the substitution of N-methylpiperazine is complete, N-methylpiperazine is recovered under reduced pressure. The residual levofloxacin crude product was dissolved in ethyl acetate and water and washed. After adjusting the pH value of acid and alkali, it goes through the steps of extraction, washing and concentration. Finally, the concentrated solid was recrystallized with methanol, filtered with suction, and the mother liquor was concentrated and crystallized again. The solid was combined and ...

Embodiment 3

[0035] Weigh 30 grams of raw material S-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-Δ]-[1,4] - Benzoxazine-6-carboxylate, 40 grams of acetonitrile, 20 grams of water and 4.7 grams of sodium hydroxide, heat preservation reaction at 80 ° C, and remove the alcohol generated by the reaction during the reaction, and the reaction is carried out for about 2 hours. After the hydrolysis was complete, 40 g of N-methylpiperazine was directly added into the three-necked reaction flask, and the temperature was raised to reflux for about 15 hours. After the substitution of N-methylpiperazine is complete, N-methylpiperazine is recovered under reduced pressure. Dissolve the residual levofloxacin crude product with chloroform and water, adjust the pH value of acid and alkali, and go through steps such as extraction, washing, and concentration. Finally, the concentrated solid was recrystallized with methanol, filtered with suction, the mother liquor was concentrated and then separ...

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PUM

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Abstract

The invention provides a one-step synthesizing method of levofloxacin and ofloxacin. According to the invention, S-9,10-difluoro-2,3-dihydro-3-methyl-7-oxygen-7H-pyrido[1,2,3-delta]-[1,4]-benzoxazine-6-carboxylic acid ester or 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-delta]-[1,4]-benzoxazine-6-carboxylic acid ester is adopted as a raw material; the raw material is subjected to a reaction with alkali in an organic solvent or water or a mixed solvent of an organic solvent and water, such that a corresponding carboxylic acid salt is formed; the solvent is directly removed by evaporation after a hydrolysis process; The product is directly added into N-methylpiperazine in a form of a carboxylic acid salt; and a piperazine concentration reaction is carried out, such that levofloxacin or ofloxacin is obtained. The method provided by the invention is simple to operate. With the method, a hydrolysis and then acid adjusting process is not needed, reaction cost is reduced, production period is short, pollution is low, raw material utilization rate is high, the method is economical and simple, and the yield and purity of obtained levofloxacin and ofloxacin are high.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and relates to a synthesis method of fluoroquinolones, in particular to a levofloxacin and a preparation method of ofloxacin. Background technique [0002] Levofloxacin (Levofloxacin), chemical name (S)-(-)-9-fluoro-2,3-dihydro-3-methyl-10-[4-methyl-1-piperazinyl] -7-oxo-7-hydropyrido[1,2,3-Δ]-[1,4]benzoxazine-6-carboxylic acid is a new generation of fluorine Quinolones antibacterial drugs, the structural formula is as follows: [0003] [0004] Levofloxacin is the levorotatory form of ofloxacin, a hemihydrate, and its solubility in water is ten times that of ofloxacin. Levofloxacin has excellent in vitro activity, less toxic and side effects than ofloxacin, greater safety and good pharmacokinetic properties, and is widely used in respiratory tract infections, gynecological disease infections, skin and soft tissue infections, surgical infections, biliary tract infections, sexual ...

Claims

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Application Information

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IPC IPC(8): C07D498/06
CPCC07D498/06
Inventor 俞永平俞玩玩吴政杰
Owner ZHEJIANG UNIV
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