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Preparation method of N-(4-fluorophenyl)-4-benzyloxy benzylidene amine

A technology of benzyloxybenzylidene and fluorophenyl, which is applied in the field of preparation of ezetimibe intermediate N--4-benzyloxybenzylidene, can solve the problem of high irritation and difficult operation of benzyl bromide , high price of benzyl bromide and other problems, to achieve the effect of simplifying the reaction operation steps, reducing the reaction cost, and reducing the cost

Inactive Publication Date: 2012-02-22
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, benzyl bromide is more expensive, about ten times that of benzyl chloride. At the same time, benzyl bromide is more irritating and difficult to operate during application.

Method used

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  • Preparation method of N-(4-fluorophenyl)-4-benzyloxy benzylidene amine
  • Preparation method of N-(4-fluorophenyl)-4-benzyloxy benzylidene amine
  • Preparation method of N-(4-fluorophenyl)-4-benzyloxy benzylidene amine

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Experimental program
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Effect test

Embodiment 1

[0030] Add 4-hydroxybenzaldehyde (6g, 49.2mmol), 40ml of ethanol, potassium carbonate (7.5g, 54.3mmol), iodine (0.5g, 2mmol) and benzyl chloride (6.2ml, 54mmol) into a 100ml three-necked flask successively at room temperature ), heated to 80°C and refluxed for 3 hours, TLC detection (developing solvent: ethyl acetate / petroleum ether=2 / 5 (V / V)) was cooled to 45°C after the reaction was complete, and 4-fluoroaniline (5.6ml , 59mmol), while keeping the temperature below 55°C, solids precipitated out during the period, after dropping, continue to stir at 50°C for 2 hours, cool to room temperature, add 50ml of dichloromethane and 50ml of water to stir to dissolve the solids, separate layers, and reuse the water layer 20ml of dichloromethane was extracted once, the combined organic layers were washed with saturated Na 2 CO 3 Wash with 50ml×2 solution, 50ml×3 purified water, dry and concentrate to obtain a light yellow solid, add 20ml isopropanol and heat up to 45°C for slurry washi...

Embodiment 2

[0036]Add 4-hydroxybenzaldehyde (6g, 49.2mmol), ethanol 40ml, sodium carbonate (5.2g, 49.1mmol), sodium iodide (0.6g, 3.9mmol) and benzyl chloride (6.1 ml, 53mmol), heated to 60°C for 8 hours, TLC detection (developing solvent: ethyl acetate / petroleum ether = 2 / 5 (V / V)) after the reaction was complete, cooled to 45°C, slowly added dropwise 4-fluoroaniline (7.1ml, 74mmol), while keeping the temperature below 55°C, solids precipitated during the period, and continued to stir at 60°C for 4 hours after dropping, cooled to room temperature, added 50ml of dichloromethane and 50ml of water and stirred to dissolve the solids, layered, water layer was extracted once more with 20ml of dichloromethane, the combined organic layers were washed with saturated Na 2 CO 3 Wash with 50ml×2 solution, 50ml×3 purified water, dry and concentrate to obtain a light yellow solid, add 20ml isopropanol and heat up to 45°C for slurry washing for 1 hour, then cool to room temperature and filter, wash the...

Embodiment 3

[0038] Add 4-hydroxybenzaldehyde (6g, 49.2mmol), ethanol 60ml, potassium carbonate (10g, 73mmol), iodine (1g, 3.9mmol) and benzyl chloride (6.8ml, 59mmol) successively into a 100ml three-necked flask at room temperature, Heat up to 75°C for 7 hours, TLC detection (developing solvent: ethyl acetate / petroleum ether=2 / 5 (V / V)) After the reaction is complete, cool to 45°C, slowly add 4-fluoroaniline (7.1ml, 74mmol ), while keeping the temperature below 42°C, solids precipitated out during the period, and continued to stir at 42°C for 5 hours after dropping, cooled to room temperature and added 50ml of dichloromethane and 50ml of water to stir to dissolve the solids. Chloromethane was extracted once, the combined organic layers were washed with saturated Na 2 CO 3 Wash with 50ml×2 solution, 50ml×3 purified water, dry and concentrate to obtain a light yellow solid, add 20ml isopropanol and heat up to 45°C for slurry washing for 1 hour, then cool to room temperature and filter, wash...

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Abstract

The invention discloses a preparation method of N-(4-fluorophenyl)-4-benzyloxy benzylidene amine. The method comprises steps of: adding 4-hydroxybenzaldehyde, alkali carbonate, catalyst and benzyl chloride into a reaction solvent; stirring and reacting completely; adding 4-fluoroaniline and reacting completely; and carrying out a post-treatment to obtain the N-(4-fluorophenyl)-4-benzyloxy benzylidene amine. Beneficial effect of the invention lays in that the method of the invention employs cheap benzyl bromide to substitute expensive benzyl bromide for benzyl protection in order to substantially reduce reaction costs; meanwhile introduction of the protective group and a condensation reaction are integrated into a ''one kettle way'' reaction, which simplifies operating steps of the reaction, further reduces reaction costs and is suitable for industrialization.

Description

technical field [0001] The invention belongs to the field of synthesis of organic compound intermediates, in particular to a preparation method of N-(4-fluorophenyl)-4-benzyloxybenzylidene, an ezetimibe intermediate. Background technique [0002] Ezetimibe (Ezetimble, chemical name: 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl](4S)-(4- Phenyl)-2-azetidinone) is a new type of cholesterol absorption inhibitor developed by Schering-Plough, which was first listed in the United States in 2002. It is the first cholesterol absorption inhibitor approved by the FDA, ezetimibe Unlike bile acid sequestrants, it can selectively inhibit the absorption of cholesterol, and it has been proven to be more effective when combined with simvastatin. In addition, the therapeutic effect of ezetimibe on Alzheimer's disease is in clinical trials. [0003] In 1995, Schering-Plough Company disclosed the synthetic route of ezetimibe for the first time: [0004] [0005] In this r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C251/24C07C249/02
CPCY02P20/55
Inventor 杨健余长泉
Owner ZHEJIANG UNIV
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