CN104892435B - The preparation method of diphenhydramine - Google Patents
The preparation method of diphenhydramine Download PDFInfo
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- CN104892435B CN104892435B CN201510161376.5A CN201510161376A CN104892435B CN 104892435 B CN104892435 B CN 104892435B CN 201510161376 A CN201510161376 A CN 201510161376A CN 104892435 B CN104892435 B CN 104892435B
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- diphenhydramine
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- benzhydrol
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- dimethylaminoethanol
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- 0 **1ccccc1 Chemical compound **1ccccc1 0.000 description 2
- QILSFLSDHQAZET-UHFFFAOYSA-N OC(c1ccccc1)c1ccccc1 Chemical compound OC(c1ccccc1)c1ccccc1 QILSFLSDHQAZET-UHFFFAOYSA-N 0.000 description 1
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Abstract
The present invention relates to the preparation method of a kind of diphenhydramine, with benzhydrol and dimethylaminoethanol as raw material, in the presence of Dibutyltin oxide and ionic liquefaction compound, benzhydrol and dimethylaminoethanol carry out intermolecular dehydration, obtain diphenhydramine.This preparation technology simplicity, reaction condition gentleness, low cost, product yield height and purity are high.
Description
Technical field
The present invention relates to the preparation method of a kind of diphenhydramine, belong to the field of chemical synthesis.
Background technology
Diphenhydramine is synthesis antihistaminic dimenhydrinate, diphhydramine hydrochloride and Diphenhydramine citrate (citric acid benzene sea
Lamine) crucial medicine intermediate, domestic and international market demand is big, has good market prospect.
The synthetic route of the diphenhydramine reported at present is less, and following three synthetic routes of main employing synthesize:
(1) with diphenyl methyl chloride or diphenyl bromomethane as raw material, to carry out nucleophilic displacement of fluorine anti-with dimethylaminoethanol
Diphenhydramine should be prepared.This course of reaction can occur the quaternization of dimethylamino position, cause purge process complicated, product
Yield is low.
(2) with benzhydrol raw material, first it is etherified with ethylene chlorhydrin, then prepares diphenhydramine with dimethylamine reaction.
(3) with benzhydrol raw material, first carry out intermolecular etherificate generate two methyl phenyl ethers anisoles with p-methyl benzenesulfonic acid, then with diformazan ammonia
Base ethanol carries out ether exchange reaction and prepares diphenhydramine.This technique is used substantial amounts of p-methyl benzenesulfonic acid and can not recycle,
Cause production cost higher.
Accordingly, it would be desirable to continual exploitation product yield is high, purity is good, preparation technology is simple and the process route of low cost.
Summary of the invention
In view of this, it is an object of the invention to provide a kind of preparation technology simplicity, reaction condition gentleness, low cost, product
The preparation method of the diphenhydramine that product yield is high and purity is high, to overcome drawbacks described above present in prior art.
The present invention provides the non-solvent preparation of a kind of diphenhydramine, and the method includes: benzhydrol and dimethylamino
Ethanol is raw material, and in the presence of Dibutyltin oxide and ionic liquefaction compound, benzhydrol and dimethylaminoethanol carry out molecule
Between dehydration, obtain diphenhydramine.Reaction equation is as follows:
Below, the preparation method of the present invention is specifically described.
In the present invention, described ionic liquefaction compound (hereinafter referred ILs) is the ionic liquid represented selected from following structural formula
Among compound:
In described structural formula A and B, R is C1～C8Alkyl, X is Cl or Br.In the present invention, described ionic liquid chemical combination
Thing is preferably following compound, and wherein R is preferably C2～C5Alkyl, most preferably ethyl or propyl group base；X is Cl or Br, preferably
For Br.The concrete example of this ionic liquefaction compound can be bromination N-n-pro-pyl pyridine, bromination N-ethylpyridine, bromination 1-first
Base-3-n-pro-pyl base imidazole salts or bromination 1-methyl-3-butylimidazolium salt.
In the preparation process in accordance with the present invention, in the dehydration of benzhydrol and dimethylaminoethanol, dibutyl aoxidizes
Stannum is 1: 1～1: 10 with the mol ratio of benzhydrol, preferably 1: 1.2～1: 5, most preferably 1: 1.5；Dibutyltin oxide
Consumption is the 0.5～15% of benzhydrol, preferably 3～10%, most preferably 8%, by weight；Described ionic liquefaction compound
Consumption be so that this ionic liquid compound amount is benzhydrol consumption 0.2～10%, most preferably 3%, by weight.
In the dehydration of benzhydrol and dimethylaminoethanol, exist at Dibutyltin oxide and ionic liquefaction compound
Under, stirred under reflux temperature reaction 8～20h；Use gas chromatographic detection reaction process；When benzhydrol after completion of the reaction, first
Low-temperature reduced-pressure is evaporated off unnecessary dimethylaminoethanol (boiling point 134 DEG C), then rise high-temperature decompression distill products benzene sea is drawn
Bright (163-167 DEG C, 0.4Kpa).
Beneficial effect
Present invention have the advantage that
(1) in the present invention with benzhydrol and dimethylaminoethanol as raw material, at Dibutyltin oxide and ionic liquid chemical combination
In the presence of thing, benzhydrol and dimethylaminoethanol carry out intermolecular dehydration, obtain diphenhydramine.Due to for solvent-free instead
Should and Dibutyltin oxide and ionic liquid can recycle (recycling more than 10 times, yield is held essentially constant), this work
Skill has pollution-free and that productivity is high feature.
(2) preparation method of the diphenhydramine of the present invention, it is short, easy and simple to handle, pollution-free that this technology path has route, de-
Water preparation and catalyst can recycle, it is easy to the feature of industrialized production, are that a kind of very economical, easy benzene sea of preparing is drawn
Bright method.
(3) product yield of the present invention is high, can reach more than 95%, and purity can reach more than 99%, Ke Yiman
The sufficient requirement as pharmaceutical intermediate to purity.
Detailed description of the invention
Below by embodiment, the present invention is described in more detail further, but the invention is not limited in that these are implemented
Example.
Embodiment 1
250mL single port bottle adds 36.8 grams of (0.2mol) benzhydrols, dimethylaminoethanol 26.7 grams (0.3mol),
2.9 grams of (accounting for the 8% of benzhydrol quality) Dibutyltin oxides and ionic liquid bromination N-n-pro-pyl pyridine 1.1 grams (account for hexichol first
The 3% of alcohol quality), this reactant mixture reacts in being stirred at reflux.Reaction uses gas chromatographic detection reaction to carry out degree.?
After reaction 10h, reacting complete, first decompression is distilled off unnecessary dimethylaminoethanol (can be with recycling), then rises high temperature
Degree carries out decompression and distills to obtain diphenhydramine 49.0 grams, productivity 96.0%, gas phase analysis purity 99.5%.
Embodiment 2
250mL single port bottle adds 36.8 grams of (0.2mol) benzhydrols, dimethylaminoethanol 26.7 grams (0.3mol),
1.1 grams of (accounting for the 3% of benzhydrol quality) Dibutyltin oxides and ionic liquid bromination N-n-pro-pyl pyridine 1.1 grams (account for hexichol first
The 3% of alcohol quality), this reactant mixture reacts in being stirred at reflux.Reaction uses gas chromatographic detection reaction to carry out degree.?
After reaction 20h, reacting complete, first decompression is distilled off unnecessary dimethylaminoethanol (can be with recycling), then rises high temperature
Degree carries out decompression and distills to obtain diphenhydramine 48.6 grams, productivity 95.1%, gas phase analysis purity 99.0%.
Embodiment 3
250mL single port bottle adds 36.8 grams of (0.2mol) benzhydrols, dimethylaminoethanol 35.6 grams (0.4mol),
3.68 grams of (accounting for the 10% of benzhydrol quality) Dibutyltin oxides and ionic liquid 1-ethyl-3-methyl-imidazolium bromine salt 1.8 grams
(accounting for the 5% of benzhydrol quality), this reactant mixture reacts in being stirred at reflux.Reaction use gas chromatographic detection react into
Stroke degree.After reaction 8h, reacting complete, first decompression is distilled off unnecessary dimethylaminoethanol (can be with recycling),
Rise high-temperature again to carry out decompression and distill to obtain diphenhydramine 49.5 grams, productivity 97.0%, gas phase analysis purity 99.6%.
Embodiment 4
250mL single port bottle adds 36.8 grams of (0.2mol) benzhydrols, dimethylaminoethanol 35.6 grams (0.4mol),
3.68 grams of (accounting for the 10% of benzhydrol quality) Dibutyltin oxides and ionic liquid 1-ethyl-3-methyl-imidazolium chloride salt 1.8 grams
(accounting for the 5% of benzhydrol quality), this reactant mixture reacts in being stirred at reflux.Reaction use gas chromatographic detection react into
Stroke degree.After reaction 15h, reacting complete, first decompression is distilled off unnecessary dimethylaminoethanol (can be with recycling),
Rise high-temperature again to carry out decompression and distill to obtain diphenhydramine 49.3 grams, productivity 96.5%, gas phase analysis purity 99.2%.
Embodiment 5
250mL single port bottle adds 36.8 grams of (0.2mol) benzhydrols, dimethylaminoethanol 53.4 grams (0.6mol),
2.6 grams of (accounting for the 7% of benzhydrol quality) Dibutyltin oxides and ionic liquid bromination 1-methyl-3-n-pro-pyl imidazole salts 1.8 grams
(accounting for the 5% of benzhydrol quality), this reactant mixture reacts in being stirred at reflux.Reaction use gas chromatographic detection react into
Stroke degree.After reaction 8h, reacting complete, first decompression is distilled off unnecessary dimethylaminoethanol (can be with recycling),
Rise high-temperature again to carry out decompression and distill to obtain diphenhydramine 50.0 grams, productivity 98.0%, gas phase analysis purity 99.5%.
Embodiment 6
Embodiment 5 finally reduces pressure in the remaining Dibutyltin oxide distilled and ionic liquid, adds 36.8 grams (0.2mol)
Benzhydrol and dimethylaminoethanol 26.7 grams (0.3mol), this reactant mixture reacts in being stirred at reflux.Reaction uses gas
The detection reaction of phase chromatograph carries out degree.After reaction 10h, reacting complete, first decompression is distilled off unnecessary dimethylaminoethanol
(can be with recycling), then rise high-temperature and carry out decompression and distill to obtain diphenhydramine 49.5 grams, productivity 97.0%, gas phase is divided
Analysis purity 99.5%.
Claims (14)
1. the preparation method of a diphenhydramine, it is characterised in that the method comprises the following steps, with benzhydrol and diformazan ammonia
Base ethanol is raw material, and in the presence of Dibutyltin oxide and ionic liquefaction compound, benzhydrol and dimethylaminoethanol are carried out point
Dehydration between son, obtains diphenhydramine, and reaction equation is as follows, and wherein in reaction equation, ILs is ionic liquefaction compound,
Described ionic liquefaction compound is among the ionic liquefaction compound that following structural formula represents:
In described structural formula A and B, R is C1～C8Alkyl, X is Cl or Br.
The preparation method of diphenhydramine the most according to claim 1, it is characterised in that wherein R is C2～C5Alkyl；X is
For Br.
The preparation method of diphenhydramine the most according to claim 2, it is characterised in that this ionic liquefaction compound is bromination N-
N-pro-pyl pyridine, bromination N-ethylpyridine, bromination 1-methyl-3-n-pro-pyl base imidazole salts or bromination 1-methyl-3-normal-butyl miaow
Azoles salt.
4. according to the preparation method of the diphenhydramine described in any one of claim 1-3, it is characterised in that Dibutyltin oxide with
The mol ratio of benzhydrol is 1: 1～1: 10.
5. according to the preparation method of the diphenhydramine described in any one of claim 1-3, it is characterised in that Dibutyltin oxide with
The mol ratio of benzhydrol is 1: 1.2～1: 5.
6. according to the preparation method of the diphenhydramine described in any one of claim 1-3, it is characterised in that Dibutyltin oxide with
The mol ratio of benzhydrol is 1: 1.5.
7. according to the preparation method of the diphenhydramine described in any one of claim 1-3, it is characterised in that by weight；Two fourths
The consumption of base stannum oxide is the 0.5～15% of benzhydrol.
8. according to the preparation method of the diphenhydramine described in any one of claim 1-3, it is characterised in that by weight；Two fourths
The consumption of base stannum oxide is the 3～10% of benzhydrol.
9. according to the preparation method of the diphenhydramine described in any one of claim 1-3, it is characterised in that by weight；Two fourths
The consumption of base stannum oxide is the 8% of benzhydrol.
10. according to the preparation method of the diphenhydramine described in any one of claim 1-3, it is characterised in that by weight, described
The consumption of ionic liquefaction compound is the 0.2～10% of benzhydrol consumption.
11. according to the preparation method of the diphenhydramine described in any one of claim 1-3, it is characterised in that by weight, described
The consumption of ionic liquefaction compound is the 3% of benzhydrol consumption.
12. according to the preparation method of the diphenhydramine described in any one of claim 1-3, it is characterised in that at benzhydrol and
In the dehydration of dimethylaminoethanol, in the presence of Dibutyltin oxide and ionic liquefaction compound, stirred under reflux temperature is anti-
Answer 8～20h；Use gas chromatographic detection reaction process；When benzhydrol after completion of the reaction, it is unnecessary that first low-temperature reduced-pressure is evaporated off
Dimethylaminoethanol, then rise high-temperature decompression distill to obtain product diphenhydramine.
13. according to the preparation method of the diphenhydramine described in any one of claim 1-3, it is characterised in that at 250mL single port bottle
36.8 grams of (0.2mol) benzhydrols of middle addition, dimethylaminoethanol 53.4 grams (0.6mol), 2.6 grams of Dibutyltin oxides and from
Sub-bromine 1-methyl-3-n-pro-pyl imidazole salts 1.8 grams, this reactant mixture reacts in being stirred at reflux, and reaction uses gas phase
Chromatograph detection reaction carries out degree, after reaction 8h, reacts complete, and first decompression is distilled off unnecessary dimethylaminoethanol, then
Liter high-temperature carries out decompression and distills to obtain diphenhydramine 50.0 grams, productivity 98.0%, gas phase analysis purity 99.5%.
14. according to the preparation method of the diphenhydramine described in any one of claim 1-3, it is characterised in that at 250mL single port bottle
36.8 grams of (0.2mol) benzhydrols of middle addition, dimethylaminoethanol 35.6 grams (0.4mol), 3.68 grams of Dibutyltin oxides and
Ionic liquid 1-ethyl-3-methyl-imidazolium bromine salt 1.8 grams, this reactant mixture reacts in being stirred at reflux, and reaction uses gas phase
Chromatograph detection reaction carries out degree, after reaction 8h, reacts complete, and first decompression is distilled off unnecessary dimethylaminoethanol, then
Liter high-temperature carries out decompression and distills to obtain diphenhydramine 49.5 grams, productivity 97.0%, gas phase analysis purity 99.6%.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101440041A (en) * | 2007-11-23 | 2009-05-27 | 广东省石油化工研究院 | Process for synthesizing mephenamine citrate salt |
| CN102675148A (en) * | 2012-04-23 | 2012-09-19 | 嘉兴学院 | Preparation method of hydroxybenzyl cyanide |
| CN103265439A (en) * | 2013-06-07 | 2013-08-28 | 启东东岳药业有限公司 | Preparation method of diphenhydramine |
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- 2015-04-07 CN CN201510161376.5A patent/CN104892435B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101440041A (en) * | 2007-11-23 | 2009-05-27 | 广东省石油化工研究院 | Process for synthesizing mephenamine citrate salt |
| CN102675148A (en) * | 2012-04-23 | 2012-09-19 | 嘉兴学院 | Preparation method of hydroxybenzyl cyanide |
| CN103265439A (en) * | 2013-06-07 | 2013-08-28 | 启东东岳药业有限公司 | Preparation method of diphenhydramine |
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