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Method for synthesizing intermediate of benproperine phosphate through eco-friendly processes

A technology of benproperine phosphate and green synthesis, which is applied in the direction of organic chemistry to achieve the effects of improving selectivity, saving energy, and simplifying treatment

Active Publication Date: 2018-11-06
大连万福制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In order to solve the problems existing in the prior art, the present invention provides a method for the green synthesis of benproperine phosphate intermediate, using traditional raw material phenol and benzyl alcohol substrates, introducing 1,1, 3,3-Tetrafluoromethanesulfonylpropene (TTP) / hexafluoroisopropanol (HFIP) catalytic system to reduce operating procedures and increase reaction yield; in (2-benzylphenoxy)-2 -Propanol is chlorinated into (2-benzylphenyl) 2-chloropropyl ether one step, has adopted and introduced methyl dichlorosilane, anhydrous iron trichloride, ethylene glycol dimethyl ether reaction system, and productive rate is as high as More than 90%, successfully avoiding the environmental pollution caused by the reaction conditions of sulfur dioxide, hydrogen chloride, benzene and pyridine, the difficulty of post-processing and the danger of operation.

Method used

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  • Method for synthesizing intermediate of benproperine phosphate through eco-friendly processes
  • Method for synthesizing intermediate of benproperine phosphate through eco-friendly processes
  • Method for synthesizing intermediate of benproperine phosphate through eco-friendly processes

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] Embodiment 1: the synthesis of o-benzylphenol

[0017]

[0018] In a 500ml three-necked flask, sequentially add 1,1,3,3-tetrafluoromethanesulfonylpropene (TTP) (90.63g, 159mmol), phenol (10g, 106mmol), benzyl alcohol (13.78g, 127.2mmol) , add 200ml hexafluoroisopropanol (HFIP) as reaction solvent. Heating to 100°C for 24 hours of reaction, after the reaction, the solvent, phenol, and benzyl alcohol were distilled under reduced pressure. Drying; to obtain the target product A, 18.9 g of a white solid was obtained, and the yield was 97.0%. MS(EI):m / z:184.0888([M] + ).

Embodiment 2

[0019] Embodiment 2: the synthesis of (2-benzylphenoxy)-2-propanol

[0020]

[0021] In a 500ml three-necked flask, sequentially add 36g of compound A (18.9g, 103mmol) 50% NaOH aqueous solution (500g sodium hydroxide + 500g purified water), stir and heat up to 65°C, slowly add propylene oxide (7.160g, 123.6mmol) , reacted for 1 h, then slowly raised the temperature to 100 °C, reacted for 3 h, and the reaction was completed, adding acid to adjust the pH of the solution to 7, repeated extraction with toluene, combined the extraction phases, spin-dried the solvent under reduced pressure, and recrystallized with ethanol to obtain a light yellow solid B ( 23.5g, yield 100%). ;

Embodiment 3

[0022] Example 3: (2-benzylphenyl) 2-chloropropyl ether

[0023]

[0024] In a 500ml three-necked flask, add compound B (23.5g, 103mmol), methyl dichlorosilane (14.22g, 123.6mmol), anhydrous ferric chloride (1.67g, 10.3mmol), ethylene glycol dimethyl ether 200ml as The reaction solvent was heated to 84° C. for reflux reaction for 4 hours. After the reaction, the solvent was removed under reduced pressure and dried. Recrystallization from ethyl acetate afforded white solid C (23.8 g) with a yield of 88.59%. MS(EI):m / z:260.0968([M] + ).

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Abstract

The invention relates to a method for synthesizing an intermediate of benproperine phosphate through eco-friendly processes and belongs to the technical field of pharmaceutical intermediates. The method utilizes a 1, 1, 3, 3-tetratrifluoromethanesulfonylpropene (TTP) / hexafluoroisopropanol (HFIP) catalytic system in the benzylation reaction of phenol and benzyl alcohol so that the reaction yield isimproved to 95-100%. Through a series of reactions, the target product benproperine phosphate can be obtained so that it is avoided that the activation of Al2O3 is anterior to re-reaction and thus the production processes are greatly simplified, the selectivity is improved and the yield is greatly improved. In the step of change of a substituted hydroxyl group into substituted chlorine, methyldichlorosilane, anhydrous ferric chloride and ethylene glycol dimethyl ether are used to replace thionyl chloride, benzene and pyridine. The method does not produce corrosive pollutants such as sulfur dioxide and hydrogen chloride, reduces the difficulty of environmental pollution and post-processing, is easy to operate and handle, greatly improves the yield, reduces the cost, improves the safety, saves the energy and meets the modern industrial production requirements on the eco-friendly reaction.

Description

technical field [0001] The invention relates to a green method for synthesizing a benproperine phosphate intermediate, which belongs to the technical field of pharmaceutical intermediates. Background technique [0002] Phenproperine phosphate is a strong non-narcotic antitussive. It has the characteristics of double antitussive effect and is suitable for dry cough caused by various reasons. It not only acts on the cough center, but also directly acts on the tracheal mucosa and alveolar membrane conduction nerves, and has no side effects such as constipation and respiratory inhibition of general anesthetic antitussives, and no drug resistance and causative addiction have been found. The medicine is one of the antitussives widely used in the world at present. [0003] But there are some problems in this method, the yield of benzylation and chlorination steps is low, and in the process of benzylation reaction, Al must be activated first 2 o 3 , and then it can be carried ou...

Claims

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Application Information

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IPC IPC(8): C07D295/088
CPCC07D295/088
Inventor 钟良伟吴宜艳姜云功倪妮方典军孙庆发
Owner 大连万福制药有限公司
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