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Method for refining delafloxacin and intermediate thereof

A delafloxacin and body-style technology, which is applied in the field of refining delafloxacin and its intermediates, can solve the problems of being unsuitable for large-scale industrial production, and achieve the effects of reducing the generation of impurities, mild reaction temperature and high yield

Active Publication Date: 2022-02-11
HAINAN PULIN PHARMA +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this method can effectively control the amount of delafloxacin dimer impurities, it is still not suitable for large-scale industrial production. Therefore, it is necessary to seek a more optimized method to completely reduce the production of this dimer impurities, and further improve product purity

Method used

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  • Method for refining delafloxacin and intermediate thereof
  • Method for refining delafloxacin and intermediate thereof
  • Method for refining delafloxacin and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Embodiment 1, the preparation of delafloxacin

[0042] Add 50.0 g of the compound of formula A-6 and 150 ml of ethyl acetate into a 1 L reaction flask, and control the temperature at 10-35°C. Add NCS solution dropwise (completed by adding 15.6g NCS to the mixed solution of 0.13g sulfuric acid and 0.09g citric acid in 250ml methyl acetate), after the completion of the dropwise reaction for 6-10 hours, use 250g1.5% bicarbonate Sodium aqueous solution and 140 g of 10% sodium sulfite aqueous solution were washed and separated, and the solvent was evaporated in vacuo to obtain 51.0 g of the compound of formula A-7 with a yield of 95.7%. Add 30g formula A-7 compound, 240g isopropanol and potassium hydroxide aqueous solution (9.1g potassium hydroxide is dissolved in 225g water) in reaction bottle afterwards, after 3h of temperature control 10-35 ℃ react, add 12% acetic acid solution 143g , stirred for 1 h and then dried by suction to obtain 23.7 g of delafloxacin, with a yiel...

Embodiment 2

[0043] Embodiment 2, the preparation of delafloxacin

[0044]Add 50.0 g of the compound of formula A-6 and 150 ml of ethyl acetate into a 1 L reaction flask, and control the temperature at 10-35°C. Add NCS solution dropwise (completed by adding 15.6g NCS to the mixed solution of 0.04g sulfuric acid and 0.26g citric acid in 250ml methyl acetate), after the completion of the dropwise reaction for 6-10 hours, use 250g1.5% bicarbonate Sodium aqueous solution and 140 g of 10% sodium sulfite aqueous solution were washed and separated, and the solvent was evaporated in vacuo to obtain 49.6 g of the compound of formula A-7 with a yield of 93%. Add 30g formula A-7 compound, 240g isopropanol and potassium hydroxide aqueous solution (9.1g potassium hydroxide is dissolved in 225g water) in reaction bottle afterwards, after 3h of temperature control 10-35 ℃ react, add 12% acetic acid solution 143g , stirred for 1 h and then dried by suction to obtain 22.1 g of delafloxacin, with a yield o...

Embodiment 3

[0045] Embodiment 3, the preparation of delafloxacin

[0046] Add 50.0 g of the compound of formula A-6 and 150 ml of ethyl acetate into a 1 L reaction flask, and control the temperature at 10-35°C. Add dropwise NCS solution (by adding 15.6gNCS to the mixed solution of 250ml methyl acetate of 0.34g citric acid to complete), after the completion of the dropwise reaction for 6-10 hours, use 250g1.5% sodium bicarbonate aqueous solution, 140g10 % sodium sulfite aqueous solution was washed and separated, and the solvent was evaporated in vacuo to obtain 48.5 g of the compound of formula A-7, with a yield of 91.0%. Add 30g formula A-7 compound, 240g isopropanol and potassium hydroxide aqueous solution (9.1g potassium hydroxide is dissolved in 225g water) in reaction bottle afterwards, after 3h of temperature control 10-35 ℃ react, add 12% acetic acid solution 143g , stirred for 1 h and then dried by suction to obtain 20.0 g of delafloxacin with a yield of 81.1% and a purity of 92.1...

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Abstract

The invention belongs to the field of medicine synthesis, and particularly provides a method for refining delafloxacin and an intermediate thereof. The method is characterized in that a compound of a formula A-6 reacts with a mixed acid of a chlorination reagent and sulfuric acid to obtain an intermediate compound of a formula A-7. According to the technical scheme, generation of delafloxacin dimer impurities can be effectively avoided, and delafloxacin with ultra-high purity and high yield is obtained. The purity of delafloxacin can reach 99.6% or above, and the delafloxacin is more suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis. Specifically, the invention provides a method for refining delafloxacin and its intermediates, which includes using a mixed acid of sulfuric acid as a reaction reagent. Background technique [0002] Delafloxacin chemical name: 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidine-1- Base)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, the structural formula is as shown in 1, and its corresponding meglumine salt structure is as shown in formula 2: [0003] [0004] Delafloxacin is the latest generation of broad-spectrum fluoroquinolone antimicrobial drug. It was originally developed by Wakunaga Pharmaceutical Company of Japan, and then authorized to Melinta Pharmaceutical Company of the United States for development. It was approved for marketing by the US FDA on June 19, 2017. It is primarily indicated for the treatment of acute bacterial skin and skin structure i...

Claims

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Application Information

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IPC IPC(8): C07D401/14
CPCC07D401/14
Inventor 朱逸凡范敏华陶璐璐李新林周胜军郭卫革方静陆翠军
Owner HAINAN PULIN PHARMA
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