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Method for preparing ciprofloxacin by piperazine reaction

A technology of ciprofloxacin and piperazine, which is applied in the fields of organic chemistry and antibacterial drugs, can solve the problems such as the yield needs to be improved and the reaction time is long, so as to shorten the production cycle, improve the reaction efficiency and reduce environmental pollution Effect

Active Publication Date: 2009-07-15
NINGBO CHEMGOO PHAMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This technology is still an organic solvent system, the reaction time is long, and the yield needs to be improved

Method used

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  • Method for preparing ciprofloxacin by piperazine reaction
  • Method for preparing ciprofloxacin by piperazine reaction
  • Method for preparing ciprofloxacin by piperazine reaction

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] a) Put 100.0g of cyclopropanecarboxylic acid and 141.2g of hexapentapiperazine into a 1L four-necked bottle, heat slowly to 70-80°C, add 3g of catalyst anhydrous aluminum trichloride, heat to about 120°C, and reflux for 1~ 3h, TLC monitors that the reaction is complete. b) Add additive Na 2 HPO 4 15g, add 18.5g / 50ml of NaOH / water solution dropwise, adjust the pH value of the reaction system to 9~12; after the dropwise addition, continue to stir for 20min, add 3g of activated carbon, reflux for 0.5h for decolorization, and filter while hot (keep the filtration temperature above 80°C ). c) Adjust the pH value of the filtrate to 7-8 with hydrochloric acid, stir and crystallize at room temperature, raise the temperature to 70-80°C, stir for 0.5h, filter while hot, wash the filter cake with 150ml of hot purified water at about 50°C for 3 times; bake the filter cake After drying, the crude product of ciprofloxacin was obtained as light yellow solid, about 116g. The crude...

Embodiment 2

[0038] a) Put 100.0g of cyclopropanecarboxylic acid and 61.2g of anhydrous piperazine into a 1L four-necked bottle, slowly heat to 70-80°C, add 5g of catalyst crystallized aluminum trichloride, 100g of purified water, heat to about 115°C, and reflux The reaction was carried out for 3-4 hours, and the reaction was monitored by TLC to complete. b) Add 6g of potassium benzoate as an auxiliary agent, add 18.5g / 50ml of NaOH / water solution dropwise, adjust the pH value of the reaction system to 9-12; after the dropwise addition, continue to stir for 20min, add 3g of activated carbon, reflux for 0.5h for decolorization, and heat Filter (keep the filter temperature above 80°C). c) Adjust the pH value of the filtrate to 7-8 with hydrochloric acid, stir and crystallize at room temperature, raise the temperature to 70-80°C, stir for 0.5h, filter while hot, wash the filter cake with 150ml of hot purified water at about 50°C for 3 times; bake the filter cake After drying, the crude produc...

Embodiment 3

[0042] a) Put 100.0g of cyclopropanecarboxylic acid and 188.3g of hexapentapiperazine into a 1L four-neck bottle, heat slowly to 70-80°C, add 6g of catalyst aluminum sulfate, heat to about 120°C, reflux for 1-3h, monitor by TLC The reaction went to completion. b) Add 18.5g / 50ml of NaOH / water solution dropwise to adjust the pH value of the reaction system to 9-12; after the dropwise addition, continue to stir for 20min, add 3g of activated carbon, reflux for 0.5h for decolorization, and filter while it is hot (keep the filtration temperature above 80°C ). c) Adjust the pH value of the filtrate to 7-8 with hydrochloric acid, stir and crystallize at room temperature, raise the temperature to 70-80°C, stir for 0.5h, filter while hot, wash the filter cake with 150ml of hot purified water at about 50°C for 3 times; bake the filter cake After drying, the crude product of ciprofloxacin was obtained as light yellow solid, about 116g. The crude yield is 99%.

[0043] HPLC analysis an...

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Abstract

The invention relates to a method for preparing ciprofloxacin by piperazine reaction. The technical problems to be solved are as follows: (1) reducing amount of a solvent or using no solvent, (2) reducing consumption of the piperazine, and (3) shortening the reaction time, simplifying operation, and enhancing overall yield. The method is characterized by (a) mixing the piperazine as shown in formula (iii) with the cyclopropane carboxylic acid as shown formula (ii) at the mol ratio of 1-10:1, adding metal Lewis acid catalyst with the chemical equivalent of 1%-30% for thorough reaction in an aqueous system at the temperature of 80-150 DEG C to obtain reaction solution, wherein, the metal Lewis acid catalyst is selected from one or more of aluminum (III) Lewis acid and iron (III) Lewis acids; (b) adding inorganic base to the reaction solution at the temperature of 20 DEG C-100 DEG C to regulate pH value of the reaction system to 9-12, and filtering while the system is hot; and (c) regulating the pH value of the filtrate to 7-8 with the inorganic base for recrystallization to obtain the product.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and in particular relates to a method for preparing ciprofloxacin through a piperazinization reaction. Background technique [0002] Ciprofloxacin, namely 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid, is a third-generation quinolone One of the outstanding representatives of , successfully synthesized by Bayer Pharmaceuticals in Germany in 1981, its structure is as follows: [0003] [0004] Ciprofloxacin is mainly prepared by condensation of acceptor fluoroquinolone and nucleophile piperazine and its derivatives (hereinafter referred to as piperazine reaction), the reaction is as follows: [0005] [0006] in, [0007] X=F, Cl or Ms, [0008] R=H or C(O)OEt. [0009] The piperazinization reaction is a bimolecular nucleophilic substitution reaction, and the nature of the leaving group, the activity of the nucleophile, solvent conditions, reaction ...

Claims

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Application Information

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IPC IPC(8): C07D498/06A61P31/04
Inventor 张达楼科侠李昌龙韩斌
Owner NINGBO CHEMGOO PHAMA TECH
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