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Preparation method of diphenhydramine

A technology for diphenhydramine and toluene, applied in the field of synthesizing diphenhydramine, can solve the problems of high price, scarce source of starting materials, unsuitable for industrialized production and the like, and achieves the effects of reducing production cost and facilitating industrialized production

Active Publication Date: 2014-07-16
启东东岳药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The source of the starting material used in the first route is scarce, expensive, and not suitable for industrial production; the second route requires expensive catalysts, which is also not suitable for industrial production

Method used

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  • Preparation method of diphenhydramine
  • Preparation method of diphenhydramine
  • Preparation method of diphenhydramine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] Add 92 grams (0.5 mol) of benzyl alcohol into a 1000 ml three-necked flask, add 400 ml toluene, 105 grams p-toluenesulfonic acid monohydrate (0.55 mol), heat up, reflux at normal pressure to separate water, until the separated toluene is clear . Cool to 80-85°C, add dimethylaminoethanol to reflux at normal pressure to separate water until the separated toluene is clear. Cool to below 40°C, add 400ml of water, stir, separate phases, add 100ml of 30% aqueous sodium hydroxide solution and 200ml of toluene to the water phase to free, wash the toluene phase with water, concentrate the toluene phase to remove toluene, and obtain 108 grams of diphenhydramine ( Yield 85%)

Embodiment 2

[0018] Add 92 grams (0.5mol) of diphenylmethanol to a 1000ml three-necked flask, add 400ml xylene, 105 grams p-toluenesulfonic acid monohydrate (0.55mol), heat up, reflux at normal pressure to separate water, until the separated xylene until clear. Cool to 80-85°C, add dimethylaminoethanol under normal pressure and reflux to separate water until the separated xylene is clear. Cool to below 40°C, add 400ml of water, stir, separate phases, add 100ml of 30% sodium hydroxide aqueous solution and 200ml of xylene to the water phase for freeing, wash the xylene phase with water, concentrate the xylene phase to remove toluene, and obtain diphenhydramine 108 grams (83% yield).

Embodiment 3

[0020] Add 92 grams (0.5 mol) of diphenylmethanol to a 1000 ml three-necked flask, add 400 ml xylene and 52.8 g methanesulfonic acid (0.55 mol), raise the temperature, reflux under normal pressure to separate water, until the separated xylene becomes clear. Cool to 80-85°C, add dimethylaminoethanol under normal pressure and reflux to separate water until the separated xylene is clear. Cool to below 40°C, add 400ml of water, stir, separate phases, add 100ml of 30% aqueous sodium hydroxide solution and 200ml of toluene to the water phase to free, wash the toluene phase with water, concentrate the toluene phase to remove toluene, and obtain 106 grams of diphenhydramine ( Yield 83%).

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Abstract

The invention discloses a preparation method of diphenhydramine. The preparation method of diphenhydramine comprises the following steps of: adding benzhydrol into a solvent methylbenzene or xylene, adding a catalyst, carrying out normal-pressure backflow dehydration until the dehydrated methylbenzene or xylene is clear, and then cooling to 80DEG C; adding dimethylaminoethanol in the reaction liquid, and carrying out warming backflow water distribution until the distributed methylbenzene or xylene is clear; cooling to 40 DEG C below, adding a water phase into sodium hydroxide aqueous solution and methylbenzene or xylene for ionization, washing on the methylbenzene or xylene phase, and carrying out concentration on the methylbenzene or xylene phase to remove methylbenzene or xylene to obtain the diphenhydramine. According to the preparation method, benzhydrol is used as an initial material, and toluenesulfonic acid or methanesulfonic acid are used as the catalyst to prepare a midbody of di-anisole, and ether exchange reaction is carried out on the dimethylaminoethanol to prepare the diphenhydramine, so that the production cost is lowered, and industrial production can be implemented conveniently.

Description

technical field [0001] The invention relates to a method for synthesizing diphenhydramine. Background technique [0002] Diphenhydramine is a key intermediate in the synthesis of antihistamines diphenhydramine and diphenhydramine hydrochloride. The structure is as follows: [0003] [0004] The preparation method of diphenhydramine has been reported in documents and patents, and a method is to adopt benzhydryl chloride or benzhydryl bromide as starting raw material, prepare through N-alkylation reaction with dimethylaminoethanol Diphenhydramine (Khimicheskii zhurnal Armenii, 52(1-2); Zhurnal Obshchei Khimii, 21, 570-574); another method is to use diphenylmethanol as the starting material, etherification with ethylene glycol and then diphenhydramine Diphenhydramine was prepared by N-alkylation of methylamine (Journal of American Chem. Soc. 13(5) 1766-1774; 2009). The source of the starting material used in the first route is scarce, expensive, and unsuitable for industr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C217/10C07C213/06
Inventor 龙中柱吴福忠李林旺蔡水洪
Owner 启东东岳药业有限公司
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