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
The method for preparing diphenhydramine
Technical field
The present invention relates to a kind of method of synthetic diphenhydramine.
Background technology
Diphenhydramine be synthetic antihistaminic dimenhydrinate and Vena and key
intermediate.Structure is as follows:
The preparation method of diphenhydramine has report on document and patent, a kind
of method is that employing diphenyl-chloromethane or diphenyl-bromomethane are
starting raw material, prepare diphenhydramine (Khimicheskii zhurnal Armenii, 52 (1-
2) with dimethylaminoethanol through the N-alkylated reaction; Zhurnal Obshchei
Khimii, 21,570-574); Another kind method is to be that starting raw material and
ethylene glycol carry out carrying out the N-alkylated reaction with dimethylamine
again after the etherificate and prepares diphenhydramine (Journal of American
Chem.Soc.13 (5) 1766-1774 with the benzhydrol; 2009).Article one, the source rareness
of the starting raw material of route employing is expensive, is not suitable for
suitability for industrialized production; The second route need be used expensive
catalysts, is not suitable for suitability for industrialized production equally

Summary of the invention

The object of the present invention is to provide a kind of production cost, the
convenient method for preparing diphenhydramine of implementing suitability for
industrialized production.
Technical solution of the present invention is:
A kind of method for preparing diphenhydramine is characterized in that: comprise the
steps: to add benzhydrol in solvent toluene or dimethylbenzene, add catalyzer, till the
atmospheric pressure reflux dehydration is limpid to the toluene of deviating from or
dimethylbenzene, be cooled to 80 ℃ then; Then in above-mentioned reaction solution,
add dimethylaminoethanol, temperature rising reflux divides water, limpid to the
toluene of deviating from or dimethylbenzene till; Be cooled to below 40 ℃, add the
moisture phase, water adds aqueous sodium hydroxide solution and toluene or
dimethylbenzene and dissociates, and toluene or dimethylbenzene are washed mutually,
and toluene or dimethylbenzene concentrate mutually and sloughs toluene or
dimethylbenzene, obtain diphenhydramine.
Catalyzer is tosic acid or methylsulfonic acid.
Reaction principle is as follows:
Synthesizing of (1) two methyl-phenoxide
(2) diphenhydramine is synthetic
The present invention adopts benzhydrol as starting raw material, tosic acid or
methylsulfonic acid prepare intermediate two methyl-phenoxides as catalyzer, carry out
ether exchange reaction with dimethylaminoethanol again and prepare
diphenhydramine, reduced production cost, the convenient suitability for industrialized
production of implementing.
Embodiment
Embodiment 1:
Benzhydrol 92 gram (0.5mol) is added in the 1000ml there-necked flask, add 400ml
toluene, 105 gram tosic acid monohydrates (0.55mol) heat up, and atmospheric pressure
reflux is divided water, limpid to the toluene of telling till.Be cooled to 80-85 ℃, add
the dimethylaminoethanol atmospheric pressure reflux and divide water, limpid to the
toluene of telling till.Be cooled to below 40 ℃, add 400ml water, stir, phase-splitting,
water adds 30% aqueous sodium hydroxide solution 100ml and 200ml toluene
dissociates, and toluene is washed mutually, and toluene concentrates mutually and
sloughs toluene, obtains diphenhydramine 108 grams (yield 85%)
Embodiment 2:
Benzhydrol 92 gram (0.5mol) is added in the 1000ml there-necked flask, add 400ml
dimethylbenzene, 105 gram tosic acid monohydrates (0.55mol) heat up, and
atmospheric pressure reflux is divided water, limpid to the dimethylbenzene of telling
till.Be cooled to 80-85 ℃, add the dimethylaminoethanol atmospheric pressure reflux
and divide water, limpid to the dimethylbenzene of telling till.Be cooled to below 40 ℃,
add 400ml water, stir, phase-splitting, water adds 30% aqueous sodium hydroxide
solution 100ml and 200ml dimethylbenzene dissociates, and dimethylbenzene is washed
mutually, and dimethylbenzene concentrates mutually and sloughs toluene, obtains
diphenhydramine 108 grams (yield 83%).
Embodiment 3:
Benzhydrol 92 gram (0.5mol) is added in the 1000ml there-necked flask, add 400ml
dimethylbenzene, 52.8 gram methylsulfonic acids (0.55mol) heat up, and atmospheric
pressure reflux is divided water, limpid to the dimethylbenzene of telling till.Be cooled
to 80-85 ℃, add the dimethylaminoethanol atmospheric pressure reflux and divide
water, limpid to the dimethylbenzene of telling till.Be cooled to below 40 ℃, add
400ml water, stir, phase-splitting, water adds 30% aqueous sodium hydroxide solution
100ml and 200ml toluene dissociates, and toluene is washed mutually, and toluene
concentrates mutually and sloughs toluene, obtains diphenhydramine 106 grams (yield
83%).

Claims (2)

1. method for preparing diphenhydramine is characterized in that: comprise the steps: to

add benzhydrol in solvent toluene or dimethylbenzene, add catalyzer, till the
atmospheric pressure reflux dehydration is limpid to the toluene of deviating from or
dimethylbenzene, be cooled to 80 ℃ then; Then in above-mentioned reaction solution,
add dimethylaminoethanol, temperature rising reflux divides water, limpid to the
toluene of deviating from or dimethylbenzene till; Be cooled to below 40 ℃, add the
moisture phase, water adds aqueous sodium hydroxide solution and toluene or
dimethylbenzene and dissociates, and toluene or dimethylbenzene are washed mutually,
and toluene or dimethylbenzene concentrate mutually and sloughs toluene or
dimethylbenzene, obtain diphenhydramine.