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A kind of method of green synthetic benproperine phosphate intermediate

A technology of benproperine phosphate and green synthesis, applied in the direction of organic chemistry, etc., to achieve the effects of simplified production process, easy operation and improved safety

Active Publication Date: 2021-05-28
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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  • A kind of method of green synthetic benproperine phosphate intermediate
  • A kind of method of green synthetic benproperine phosphate intermediate
  • A kind of method of green synthetic benproperine phosphate intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0017] Embodiment 1: the synthesis of o-benzylphenol

[0018]

[0019] 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

[0020] Embodiment 2: the synthesis of (2-benzylphenoxy)-2-propanol

[0021]

[0022] 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

[0023] Example 3: (2-benzylphenyl) 2-chloropropyl ether

[0024]

[0025] 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

A green method for synthesizing a benproperine phosphate intermediate belongs to the technical field of pharmaceutical intermediates. In this process, 1,1,3,3-tetrafluoromethanesulfonylpropene (TTP) / hexafluoroisopropanol (HFIP) catalytic system is introduced into the benzylation reaction of phenol and benzyl alcohol, and the reaction of this step produces The rate is increased to 95%-100%; through a series of reactions, the target product benproperine phosphate can be obtained, avoiding the use of Al 2 o 3 First activate and then react, the production process is greatly simplified, the selectivity is improved, and the yield is greatly increased. In the step where the substituted hydroxyl group is changed to substituted chlorine, methyldichlorosilane, anhydrous ferric chloride, ethylene glycol dimethyl ether are introduced instead of thionyl chloride, benzene and pyridine. Does not produce sulfur dioxide, hydrogen chloride and other corrosive pollutants. The environmental pollution and post-processing difficulty are reduced; and the operation is easy and the processing is simple. The method greatly improves the yield, reduces the cost, improves the safety, saves energy, and meets the modern chemical production requirements of green 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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Patent Type & Authority Patents(China)
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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