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Method for preparing Moxifloxacin impurity E

A moxifloxacin and impurity technology, applied in the field of medicinal chemistry, can solve the problems of easy tar generation, long reaction time, degradation and damage, and achieve the effects of mild reaction conditions, shortened reaction time, and increased reaction yield

Active Publication Date: 2015-09-30
NANJING YOUKE BIOLOGICAL MEDICAL RES +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The hydrobromic acid method is the most classic method of hydrolyzing methyl aryl ether to remove the methyl group. Generally, it is refluxed and heated in the presence of acetic acid. The reaction time is long and requires severe conditions. The substrate is required to be stable to strong acids. For some amides , esters and other sensitive groups that can cause degradation and destroy
The aluminum trichloride method is also relatively common, but only with aluminum trichloride, the yield is not high, and the product is complex
Pyridine hydrochloride melting method should be a more violent reaction of demethylation, almost all methyl ethers can be cracked, but it is very easy to cause changes in structure and stereochemistry, easy to produce tar, and the yield is low
In comparison, the boron tribromide method is a mild and excellent demethylation reagent; this reaction does not affect the ester groups and double bonds in the molecule, and generally uses dichloromethane as a solvent at -78°C to room temperature , its biggest disadvantage is that it is sensitive to air, a lot of mist will come out when it is used, and a lot of complexes will often appear when it is processed after adding water
In summary, no mild and simple synthetic method for the preparation of moxifloxacin impurity E has been found in the existing literature

Method used

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  • Method for preparing Moxifloxacin impurity E
  • Method for preparing Moxifloxacin impurity E
  • Method for preparing Moxifloxacin impurity E

Examples

Experimental program
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Effect test

Embodiment 1

[0034] Take moxifloxacin hydrochloride (30g, 0.068mol), dissolve it in 600mL of water, adjust the pH=7~8 with saturated sodium bicarbonate solution, then add dichloromethane (300ml×2) to extract the aqueous phase, and dichloromethane layer with anhydrous Dry over sodium sulfate for 1 h, filter, concentrate the filtrate to dryness, and dissolve the residue in 250 mL of acetonitrile.

[0035] Under the protection of nitrogen, hexamethyldisiloxane (17.8g, 0.11mol) and aluminum powder (3.8g, 0.14mol) were heated and stirred at a temperature of 60°C, solid iodine (28g, 0.11mol) was slowly added, and the temperature was raised to 140°C, reflux for 2 hours, slowly lower to room temperature, remove insoluble matter by filtration, and obtain about 42 g of freshly prepared crude iodotrimethylsilane oil. Under the protection of nitrogen, the obtained iodotrimethylsilane oil (42g, 0.21mol) was added to the moxifloxacin free base solution, sodium iodide (3g, 0.02mol) was added, and the rea...

Embodiment 2

[0038] Take moxifloxacin hydrochloride (20g, 0.05mol), dissolve it in 400mL of water, adjust the pH=7~8 with saturated sodium bicarbonate solution, then add ethyl acetate (300ml×2) to extract the aqueous phase, and wash the ethyl acetate layer with anhydrous Dry over sodium sulfate for 1 h, filter, concentrate the filtrate to dryness, and dissolve the residue in 200 mL of N,N-dimethylformamide DMF.

[0039] Under nitrogen protection, hexamethyldisiloxane (21.1g, 0.13mol) and aluminum powder (4.3g, 0.16mol) were heated and stirred at a temperature of 65°C, solid iodine (33g, 0.13mol) was slowly added, and the temperature was raised to Reflux reaction at 150°C for 2 hours, slowly lower to room temperature, remove insoluble matter by filtration, and obtain about 50 g of freshly prepared crude iodotrimethylsilane oil. Under the protection of nitrogen, the obtained iodotrimethylsilane oil (50g, 0.25mol) was added to the moxifloxacin free base solution, sodium iodide (4.5g, 0.03mol)...

Embodiment 3

[0042] Take moxifloxacin hydrochloride (50g, 0.12mol), dissolve it in 1000mL of water, adjust the pH=7~8 with saturated sodium bicarbonate solution, then add dichloromethane (300ml×2) to extract the aqueous phase, and dichloromethane layer with anhydrous Dry over sodium sulfate for 1 h, filter, concentrate the filtrate to dryness, and dissolve the residue in 300 mL of acetonitrile.

[0043] Under the protection of nitrogen, hexamethyldisiloxane (38.9g, 0.24mol) and aluminum powder (7.8g, 0.29mol) were heated and stirred at a temperature of 62°C, and solid iodine (60.9g, 0.24mol) was slowly added, and the temperature was raised To 145°C, reflux for 2 hours, slowly lower to room temperature, remove insoluble matter by filtration, and obtain about 96 g of freshly prepared crude iodotrimethylsilane oil. Under the protection of nitrogen, the obtained iodotrimethylsilane oil (96g, 0.48mol) was added to the moxifloxacin free base solution, sodium iodide (9g, 0.06mol) was added, and t...

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Abstract

The invention discloses a method for preparing Moxifloxacin impurity E. The method specifically comprises the steps of alkalizing Moxifloxacin hydrochloride with a sodium bicarbonate solution so as to obtain Moxifloxacin free alkali, carrying out demethylation reaction on the Moxifloxacin free alkali, and finally carrying out recrystallization refining, thereby obtaining the high-purity Moxifloxacin impurity E. The method has the characteristics that the synthesis route is short, the operation is simple, the obtained impurity product is relatively high in purity and can be applied to reference research, and the like.

Description

[0001] technical field [0002] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of moxifloxacin impurity E. Background technique [0003] 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. [0004] [0005] 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. Moxifloxacin hydrochloride has broad-spectrum antibacterial activity, especially the activity against Gram-positive, mycoplasma, chlamydia, Legionella, etc. is much better than ciprofloxacin, and is effective against anaerobic bacteria....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 闵涛陆晨光车晓明张峰薛峪泉
Owner NANJING YOUKE BIOLOGICAL MEDICAL RES
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