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Preparation method of moxifloxacin impurity F

A technology of moxifloxacin and moxifloxacin hydrochloride, which is applied in the field of medicinal chemistry, can solve the problems of cumbersome preparation steps, lengthy reaction steps, monitoring the reaction process and difficulty in separating the required products, and achieves the effect of short synthetic route and easy operation

Active Publication Date: 2013-11-20
NANJING YOUKE BIOLOGICAL MEDICAL RES +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The preparation method has lengthy reaction steps (about 8 steps in total), and the preparation steps are cumbersome, which is reflected in the fact that two nitrogen atoms on (S,S)-2,8-diazabicyclo[4,3,0]nonane are connected to Boc The reaction selectivity of the protecting group is poor, and the second step involves difficult column chromatography purification
Moreover, nonane derivatives belong to cyclic alkanes and have no ultraviolet fluorescence absorption, which brings difficulties in monitoring the reaction process and separating the desired products, resulting in low overall yields
Moreover, the method described to obtain the form of moxifloxacin impurity F and its salts only outlines its preparation process and operation mode, no matter whether it is an intermediate or a final product, it does not provide sufficient physical and chemical data to confirm its structure

Method used

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  • Preparation method of moxifloxacin impurity F
  • Preparation method of moxifloxacin impurity F
  • Preparation method of moxifloxacin impurity F

Examples

Experimental program
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Embodiment 1

[0030] Take moxifloxacin hydrochloride (30g, 0.068mol), dissolve it in 600mL of water, adjust the pH=7-8 with saturated sodium bicarbonate solution, add dichloromethane (300ml×2) to extract the aqueous phase, and dichloromethane layer with anhydrous sodium sulfate Dry for 1 hour, add methyl iodide (18g, 0.126mol, twice the moxifloxacin hydrochloride moxifloxacin hydrochloride), anhydrous potassium carbonate (18g, 0.13mol, twice the moxifloxacin hydrochloride moxifloxacin hydrochloride), 32-35°C The reaction was stirred for 12 h, and the reaction was monitored by TLC. After the reaction is complete, remove the insoluble solids by suction filtration, add 400ml of sodium hydroxide solution (10%, weight to volume ratio) to the filtrate, reflux for 2 hours, cool to room temperature, then adjust pH=7 with glacial acetic acid, separate the organic phase, anhydrous sulfuric acid Dry over sodium and concentrate in vacuo to give about 18.5 g of crude solid. Suspend the above crude soli...

Embodiment 2

[0032]Take moxifloxacin hydrochloride (15g, 0.034mol), dissolve it in 300mL of water, adjust the pH to 7-8 with saturated sodium bicarbonate solution, then add dichloromethane (150ml×2) to extract the aqueous phase, and dichloromethane layer with anhydrous sulfuric acid Dry with sodium for 1 h, add iodomethane (9.7g, 0.068mol, 2 times the moxifloxacin hydrochloride moxifloxacin hydrochloride), potassium tert-butoxide (7.6g, 0.068mol, 2 times the moxifloxacin hydrochloride moxifloxacin hydrochloride), 30 Stir and react at -32°C for 10 hours, monitor the reaction by TLC, remove the insoluble solids by suction filtration, add 220ml of sodium hydroxide solution (10%, weight to volume ratio) to the filtrate, reflux for 2 hours, cool to room temperature, adjust the pH to 7 with glacial acetic acid, The organic phase was obtained by liquid separation, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain about 9.1 g of crude solid. Suspend the above crude solid in ...

Embodiment 3

[0034] Take moxifloxacin hydrochloride (20g, 0.045mol), dissolve it in 400mL of water, adjust the pH=7-8 with saturated sodium bicarbonate solution, then add dichloromethane (200ml×2) to extract the aqueous phase, and dichloromethane layer with anhydrous Dry over sodium sulfate for 1 h, add iodomethane (12.8g, 0.09mol, twice the moxifloxacin hydrochloride moxifloxacin hydrochloride), triethylamine (9.1g, 0.09mol, twice the moxifloxacin hydrochloride moxifloxacin hydrochloride), 30 Stir and react at -32°C for 10 hours, monitor the reaction by TLC, remove the insoluble solids by suction filtration, add 280ml of lithium hydroxide solution (10%, weight to volume ratio) to the filtrate, reflux for 2 hours, cool to room temperature, adjust the pH to 7 with glacial acetic acid, The organic phase was obtained by liquid separation, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain about 11.8 g of crude solid. Suspend the above crude solid in a mixed solvent of et...

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Abstract

The invention discloses a preparation method of moxifloxacin impurity F. The method comprises the following steps of: alkalifying moxifloxacin hydrochloride with sodium bicarbonate solution to get moxifloxacin free alkali, treating the moxifloxacin free alkali with methylation and alkaline hydrolysis reaction, and finally, obtaining high-purity moxifloxacin impurity F by recrystallization. The preparation method has the characteristics that the synthetic routes are simple and short, operations are simple and convenient, the obtained impurity product has higher purity, and the preparation method can be used for moxifloxacin impurity reference substance research, and so on.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of moxifloxacin impurity F. Background technique [0002] Moxifloxacin hydrochloride (Moxifloxacin hydrochloride) chemical name: 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[(4αS,7αS)-octahydro-6H-pyrrole [3,4-b]pyridin-6-yl]-4-oxo-3-quinoline carboxylic acid hydrochloride, Cas No.: 151096-09-2, has the chemical structure shown in the following formula. [0003] [0004] Moxifloxacin hydrochloride is an extended-spectrum quinolone antibiotic developed by Bayer Pharmaceutical Company of Germany. It was first launched in Germany in September 1999 and was approved by FDA in December of the same year. Available in China are tablets, capsules and injections. Moxifloxacin hydrochloride has broad-spectrum antibacterial activity, especially the activity against Gram-positive, mycoplasma, chlamydia, Legionella, etc. is much better than ciprofloxa...

Claims

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Application Information

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IPC IPC(8): C07D471/04
Inventor 叶海晁阳闵涛张峰薛峪泉
Owner NANJING YOUKE BIOLOGICAL MEDICAL RES
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