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Method for synthesizing moxifloxacin degradation impurity

A synthesis method and impurity technology are applied in the field of synthesis of moxifloxacin degrading impurities, which can solve the problems of complex reaction product components, unsuitable for directional preparation, and no mention of synthesis methods, so as to meet the requirements of quality research and the starting materials Inexpensive and easy to obtain, easy to control the effect of process operation

Active Publication Date: 2020-01-14
YANGTZE RIVER PHARM GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The compound shown in formula 7 is an impurity degraded by moxifloxacin, which was first mentioned in the literature (Photochem.Photobiol.Sci., 2012,11,351), but did not mention the synthesis method; the literature (Research on Chemical Intermediates 2015,41,10 , 7827–7845) mentioned that the impurity was found during the oxidative degradation of moxifloxacin with potassium permanganate, but the reaction product components of this method are complex and difficult to separate and purify, so it is not suitable for the directional preparation of the impurity

Method used

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  • Method for synthesizing moxifloxacin degradation impurity
  • Method for synthesizing moxifloxacin degradation impurity
  • Method for synthesizing moxifloxacin degradation impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] The preparation of embodiment 1 compound 2

[0056] Add 12.6g of (S,S)-2,8-diazabicyclo[4.3.0]nonane (moxifloxacin intermediate, 1.0 equivalent) into 126ml of acetonitrile, then lower the temperature to 0°C~10°C, Add 9.8g (0.5 equivalents) p-toluenesulfonyl chloride in batches, add and keep warm for 2 hours, take a sample, and monitor by thin-layer chromatography (ethyl acetate:petroleum ether=1:3, volume ratio) shows that the raw materials have been reacted, Add 100 mL of water to quench, and extract with 100 mL of dichloromethane, wash the organic layer with water, wash with saturated brine, and concentrate to obtain a residual solid. 60 milliliters (ethyl acetate:petroleum ether=1:1, volume ratio) of mixed solvent was stirred and heated to 50-60°C to dissolve, then cooled and crystallized, suction filtered, and the filter cake was washed with 20mL petroleum ether to obtain 10.7 grams of white Solid, yield 75.3%. 1 H NMR (CDCl 3 )δ=7.75-7.73(d,2H,Ph-H),7.33-7.32(d,...

Embodiment 2

[0057] The preparation of embodiment 2 compound 3

[0058] Add 7g of compound 2 to 700mL of tetrahydrofuran, then add 350mL of purified water, add 21g of sodium bicarbonate, stir to dissolve, slowly add 47.4g of iodine, continue to stir at 25°C for 6 hours, then take a sample, add ethyl acetate and sodium thiosulfate Aqueous solution, organic phase thin-layer chromatography (ethyl acetate) to monitor the reaction, the raw materials disappeared, the reaction solution was concentrated at 40 ° C to remove the solvent, added 1.0 liter of ethyl acetate for extraction and 500 mL of sodium thiosulfate aqueous solution, separated, and the organic layer was washed with water , washed with saturated brine, and concentrated to obtain a residue that was pulped in a mixed solvent of 30 ml (ethyl acetate:petroleum ether=1:1, volume ratio) for 30 minutes to obtain 6.1 g of off-white solid with a yield of 72.2%. 1 H NMR (CDCl 3 )δ=7.73-7.71(d,2H,Ph-H),7.35-7.37(d,2H,Ph-H),6.38(s,1H,NH),3.93-...

Embodiment 3

[0059] The preparation of embodiment 3 compound 4

[0060] Add 6g of compound 3 (6.0g, 0.042mol) to 40% hydrobromic acid (60ml), add acetic acid (15ml) and phenol (6.0g) under stirring, heat to 90°C and reflux for 8h, TLC [developer: chloroform -methanol (1:2, volume ratio), iodine color] shows that the reaction is completed and then cooled, followed by extraction with ethyl acetate (50ml×2). Add 40% sodium hydroxide solution to the water phase to adjust the pH to about 7, concentrate under reduced pressure to remove the solvent, and the residue is beaten with 60 mL of a mixed solvent of chloroform-methanol (1:2, volume ratio) for 30 minutes, then suction filtered and washed. After the filtrate was concentrated, the residue obtained was purified by silica gel column chromatography, methanol:dichloromethane=1:15 to 1:5 (volume ratio) was rinsed, and the target components were collected and concentrated to obtain 1.43g of a light yellow oil, which was collected. rate 50%.

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Abstract

The invention discloses a method for synthesizing a moxifloxacin degradation impurity. The method comprises the following steps: (1) enabling a compound of a formula 1 shown in the description to contact with p-methyl benzene sulfonic chloride so as to otbain a compound of a formula 2 shown in the description; (2) performing an oxidation on the compound of the formula 2 shown in the descrption soas to obtain a compound of a formula 3 shown in the description; (3) removing p-methyl benzene sulfonic chloride from the compound of the formula 3 shown in the description so as to obtain a compoundof a formula 4 shown in the description; (4) performing a substitution reaction on the compound of the formula 4 shown in the description and a compound of a formula 5 shown in the description so as to obtain a compound of a formula 6 shown in the description; and (5) performing acidic hydrolysis on the compound of the formula 6 shown in the description, so as to obtain a compound of a formula 7 shown in the description. The invention provides a method for orientated synthesis of the compound of the formula 7 shown in the description, by using the method, the compound of the formula 7 shown inthe description can be prepared, and meanwhile, the compound of the formula 7 shown in the description can be used as an impurity reference product for detecting related substances of the moxifloxacin degradation impurity.

Description

technical field [0001] The application relates to the field of drug synthesis, in particular, to a synthesis method for moxifloxacin to degrade impurities. Background technique [0002] Moxifloxacin is a fluoroquinolone antibacterial drug and a DNA topoisomerase inhibitor, which can be used to treat community-acquired pneumonia, acute exacerbation of chronic bronchitis, acute sinusitis, etc. caused by Staphylococcus aureus, influenza bacillus, pneumococcus, etc.; The fourth generation of quinolone antibacterial drugs is a new generation of antibiotics with a broad antibacterial spectrum. This product has strong antibacterial activity against common respiratory bacteria, such as Streptococcus pneumoniae, Haemophilus influenzae, Morahan catarrhalis and some Staphylococcus aureus, especially against Streptococcus pneumoniae. Clinically used for the treatment of acute sinus adenitis, acute exacerbation of chronic bronchitis) community-acquired pneumonia, as well as uncomplicate...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 徐助雄罗宏军徐浩宇张启英张海波吕慧敏蔡伟胡涛尹必喜
Owner YANGTZE RIVER PHARM GRP CO LTD
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