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Preparation method for removing aromatic methyl ether and methyl

A technique for removing aromatic methyl ether, applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of difficult recovery of methyl tertiary butyl ether, large amount of methyl tertiary butyl ether, average yield and purity, etc., and achieves the preparation method. Green, less by-products, high product yield and purity

Inactive Publication Date: 2021-02-23
UNIV OF JINAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] European patent WO2016035847 reports a method of removing methyl groups from aromatic methyl ethers using dichloromethane as a solvent and aluminum trichloride as a catalyst. Pyridine, anisole, tetrahydrofuran, etc. are used in the reaction process, and the operation process is complicated. , which is more harmful to the environment, and the yield and purity are average
[0007] European patent WO2010078511 reports a kind of dichloromethane as solvent, BBr 3 As a method of demethylation reagent, in the post-treatment process, methyl tert-butyl ether is used for purification, but the operation process is cumbersome
And the amount of methyl tert-butyl ether is large, the yield is low, and methyl tert-butyl ether is not easy to recycle

Method used

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  • Preparation method for removing aromatic methyl ether and methyl
  • Preparation method for removing aromatic methyl ether and methyl

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] Add 2g (0.011mol) 2-chloro-4-methoxy-3-hydroxybenzaldehyde to a 100ml three-necked flask, add 8ml of dichloromethane, stir until dissolved, and drop 5g (0.019mol) of BBr at -30°C 3 , after the dropwise addition was completed, the reaction solution was placed at room temperature and stirred for 4 hours. Under an ice-water bath environment (-10°C), 25ml of methanol was slowly added dropwise. ) adjust the pH of the reaction solution to 3~4, heat to reflux at a temperature of 50° C., and reflux for 1.5 h, and filter to obtain 1.63 g of a solid product with a yield of 85.9% and a purity of 97.1%.

Embodiment 2

[0018] Add 5g (0.027mol) of 2-chloro-4-methoxy-3-hydroxybenzaldehyde to a 250ml three-necked flask, add 25ml of dichloromethane, stir until dissolved, and dropwise add 12.5g (0.050mol) of BBr at -30°C 3 , after the dropwise addition, the reaction solution was placed at room temperature and stirred for 4.6h. Under an ice-water bath environment (-25°C), 65ml of methanol was slowly added dropwise. After 3h, the dropwise addition was completed. %) to adjust the pH of the reaction solution to 2~3, heated to reflux at a temperature of 55°C, and refluxed for 2.5 hours, and filtered to obtain 4.16 g of a solid product with a yield of 89.4% and a purity of 95.2%.

Embodiment 3

[0020] Add 5g (0.027mol) of 2-chloro-4-methoxy-3-hydroxybenzaldehyde to a 250ml three-necked flask, add 25ml of dichloromethane, stir until dissolved, and dropwise add 13.53g (0.054mol) of BBr at -20°C 3 , after the dropwise addition was completed, the reaction solution was placed at room temperature and stirred for 5 hours, and 85ml of methanol was slowly added dropwise in an ice-water bath environment (-20°C). ) adjust the pH of the reaction solution to 2~3, heat to reflux at a temperature of 60° C., and reflux for 2 hours, and filter to obtain 4.06 g of a solid product with a yield of 87.3% and a purity of 93.7%.

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Abstract

The invention discloses a method for removing aromatic methyl ether and methyl in synthesis of a key intermediate 2-chloro-3, 4-dihydroxybenzaldehyde of cefdinir, and belongs to the field of synthesisof medical intermediates. The method comprises the following steps: dissolving 2-chloro-4-methoxy-3-hydroxy benzaldehyde serving as a raw material, putting the dissolved 2-chloro-4-methoxy-3-hydroxybenzaldehyde into a low-temperature reactor, dropwise adding a boron tribromide solution, reacting for a certain time, quenching BBr3 by using methanol after the reaction is finished, adding hydrochloric acid to adjust the pH value, heating and refluxing, reducing the temperature of a reaction solution, cooling to obtain the aromatic methyl ether, separating out solid, filtering and collecting thesolid, namely the 2-chloro-3, 4-dihydroxybenzaldehyde. Compared with other methyl removal methods, the method has the advantages of mild reaction conditions, simpler operation, more efficient and faster reaction, and fewer impurities, byproducts and side reactions.

Description

technical field [0001] The invention belongs to the field of synthesis of pharmaceutical intermediates, and relates to a preparation method for demethylation of aromatic methyl ether. Background technique [0002] Cefiderole was developed by Shionogi, a Japanese pharmaceutical company. It is a new type of siderophore cephalosporin with a unique mechanism of action that penetrates the cell membrane of Gram-negative bacteria: Cefiderole binds to ferric iron , and is actively transported into bacterial cells through the outer membrane of the cell membrane by bacterial iron transporter. [0003] Ceftidil has strong antibacterial activity against polymyxin and carbapenem-resistant Pseudomonas aeruginosa, Acinetobacter baumannii and Enterobacter spp. Lambert-positive bacteria had no apparent activity. The U.S. Food and Drug Administration approved it on November 14, 2019, for the treatment of complicated urinary tract infections (including pyelonephritis) caused by the following...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C45/64C07C47/565
CPCC07C45/64C07C47/565
Inventor 亓志远高令峰郑庚修张启龙高禄丰邱宇
Owner UNIV OF JINAN
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