CN102229537A - Method for synthesizing citric acid diphenhydramine - Google Patents
Method for synthesizing citric acid diphenhydramine Download PDFInfo
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- CN102229537A CN102229537A CN2011101167817A CN201110116781A CN102229537A CN 102229537 A CN102229537 A CN 102229537A CN 2011101167817 A CN2011101167817 A CN 2011101167817A CN 201110116781 A CN201110116781 A CN 201110116781A CN 102229537 A CN102229537 A CN 102229537A
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- diphenhydramine
- citric acid
- diphenhydramine citrate
- phenylcarbinol
- synthetic method
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Abstract
The invention relates to a method for synthesizing citric acid diphenhydramine by a 'one boiler method'. The method comprises the following steps of: reacting diphenyl methanol-beta-chloroethylether with dimethylamine to generate diphenhydramine hydrochloride; adding sodium hydroxide to treat, so that the diphenhydramine is freed; and directly adding citric acid into the same reactor to perform acid-base reaction to prepare the citric acid diphenhydramine. By the method, an intermediate is not required to be separated and purified, so the operating steps can be simplified, yield of the products can be increased, production cycle can be shortened, and production cost can be reduced; the starting raw material diphenyl methanol-beta-chloroethylether can be obtained from a commercial channel or can be prepared by reacting diphenyl methanol with 2-chlorohydrin in the presence of concentrated sulfuric acid without using a toxic organic solvent, so the subsequent purification step is simplified and safety of personnel operation and products is improved; and a method for synthesizing the diphenyl methanol-beta-chloroethylether is combined with the method for synthesizing the citric acid diphenhydramine, remarkable effects of simplifying the operating steps, increasing the yield of the products and reducing the production cost are achieved.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, relate to a kind of synthetic method of bulk drug, particularly the synthetic method of diphenhydramine citrate.
Background technology
Diphenhydramine citrate (structural formula is as follows) has antihistamine, calmness, local anaesthesia, the anti-M-choline-like effect of Tuhe, town, be usually used in skin mucosa allergy, acute allergic reaction, the preceding administration of carsick seasick control, hypnosis and art, dentistry local anaesthesia, antibechic etc. clinically, Antiparkinsonian be can also be used for, also can Parkinson's disease and extrapyramidal symptoms be treated in conjunction with other drug.Compare with Vena, diphenhydramine citrate stability strengthens, and bitter taste alleviates, and pungency reduces, and fat-soluble increase easily absorbs.
U.S. Pat 4401665 and US4505862 disclose a kind of method of synthetic diphenhydramine citrate, are Vena and sodium hydroxide reaction are made diphenhydramine, make diphenhydramine citrate with the Citric Acid reaction again.But this method is starting raw material with the Vena, the cost height.U.S. Pat 2421714 discloses the method for two kinds of synthetic diphenhydramines: the one, ditane and reaction of hydrogen bromide are made the phenylbenzene monobromethane, again benzene-phenylbenzene monobromethane mixture is reacted with dimethylaminoethanol in the presence of anhydrous sodium carbonate, reactant adds water makes salt dissolving back extracted with diethyl ether, ether extraction liquid extracts with hydrochloric acid soln again, hcl as extraction agent liquid makes diphenhydramine dissociate out with sodium-hydroxide treatment, with volatilizing solvent after the ether extraction, add the benzene dissolving again, volatilize solvent, the residue underpressure distillation, collect 150 ~ 165 ℃/2mm cut, promptly get diphenhydramine; The 2nd, dimethylaminoethanol and sodium are reacted generation dimethylaminoethanol sodium in dimethylbenzene, react with the phenylbenzene monobromethane again after removing excessive sodium, reaction solution wash with water remove desalt and excessive dimethylaminoethanol sodium after, underpressure distillation, collect 199 ~ 202 ℃/11mm cut, promptly get diphenhydramine.But the equal complex operation complexity of above-mentioned two kinds of methods, product yield is lower.
Summary of the invention
In view of this, the object of the present invention is to provide a kind of synthetic method of diphenhydramine citrate, simple to operate, the product yield height, with short production cycle, cost is low, is applicable to suitability for industrialized production.
For achieving the above object, the invention provides following technical scheme:
Aqueous solution stirring reaction (this reaction generation Vena under 110 ~ 150 ℃ of temperature, pressure 0.5 ~ 2.5MPa condition with two phenylcarbinol-β-chloroethyl ether and excessive dimethylamine, chemical equation is suc as formula shown in the I), after reaction finishes, reaction solution is cooled to 60 ~ 100 ℃, in temperature-fall period, progressively remove pressure, the dimethylamine gas that the recovery part unreacted is intact, under condition of normal pressure, add an amount of NaOH aqueous solution then, (this reaction generates diphenhydramine to stirring reaction, and chemical equation is suc as formula shown in the II; Except as the reaction substrate, NaOH reduces the effect of the solubleness of dimethylamine in water in addition), (speed that generates diphenhydramine because of adding NaOH afterreaction is very fast to be warming up to 100 ~ 150 ℃, therefore, stirring reaction and intensification can be carried out simultaneously, directly stir intensification after promptly adding NaOH), reclaim the intact dimethylamine gas of remaining unreacted, at last reaction solution is cooled to room temperature (room temperature among the present invention means 10 ~ 30 ℃), adds citric acid soln, (this reaction generates diphenhydramine citrate to stirring reaction, chemical equation is shown in formula III), filter filter cake washing, drying promptly makes diphenhydramine citrate.
Further, the mol ratio of the described pair of phenylcarbinol-β-chloroethyl ether and dimethylamine is 1: 3 ~ 8.
Further, the massfraction of described dimethylamine agueous solution is 10% ~ 50%.
Further, the mol ratio of the described pair of phenylcarbinol-β-chloroethyl ether and NaOH is 1: 1.5 ~ 3.
Further, the massfraction of the described NaOH aqueous solution is 15% ~ 50%.
Further, the mol ratio of the described pair of phenylcarbinol-β-chloroethyl ether and Citric Acid is 1: 2 ~ 5.
Further, described citric acid soln is citron aqueous acid, ethanolic soln, propanol solution, aqueous isopropanol or acetone soln, and wherein the concentration of Citric Acid is 0.1 ~ 0.5g/ml.
Further, described pair of phenylcarbinol-β-chloroethyl ether adopts following method synthetic: benzhydrol and ethylene chlorhydrin are carried out etherification reaction for 70 ~ 130 ℃ in temperature in the presence of the vitriol oil (being the sulphuric acid soln of massfraction 〉=70%), after reaction finishes, cooling, standing demix, collect the upper strata oily liquids, use inorganic salt solution and hot wash successively, promptly make two phenylcarbinol-β-chloroethyl ether.
Further, described benzhydrol, chloroethanol and vitriolic mol ratio are 1: 1 ~ 1.5: 0.4 ~ 0.8.
Further, the described vitriol oil is that massfraction is 98% sulphuric acid soln.The effect of the vitriol oil in above-mentioned reaction is dehydration, the high more sulphuric acid soln of concentration then, and dehydrating effect is good more, but when the concentration of sulphuric acid soln surpassed 98% (w/w), the solution instability was decomposed generation SO easily in air
3Gas and and water vapour in conjunction with the generation smog, therefore, preferred mass mark of the present invention is 98% sulphuric acid soln.
Further, described upper strata oily liquids is the hot wash of 60 ~ 100 ℃ of 5 ~ 25% sodium carbonate solution and temperature successively with massfraction.
Beneficial effect of the present invention is: the method that the invention provides a kind of " one kettle way " synthetic diphenhydramine citrate, two phenylcarbinol-β-chloroethyl ether and dimethylamine reaction are generated Vena, adding the NaOH processing makes diphenhydramine dissociate out, directly adding Citric Acid again in same reactor carries out acid-base reaction and makes diphenhydramine citrate, this method does not need intermediate Vena and diphenhydramine are carried out separation and purification, step greatly can simplify the operation, reduce the intermediate loss, improve product yield, shorten the production cycle, reduce production costs, be applicable to large-scale industrialization production.Two phenylcarbinol-the β of starting raw material-chloroethyl ether can obtain or preparation voluntarily by the commercial channel, the present invention reacts benzhydrol and ethylene chlorhydrin and makes two phenylcarbinol-β-chloroethyl ether in the presence of the vitriol oil, do not use toxic organic solvent, not only simplify subsequent purification step, and improved personnel operation and security of products.With the synthetic method of above-mentioned pair of phenylcarbinol-β-chloroethyl ether and the synthetic method coupling of diphenhydramine citrate, in the step that simplifies the operation, improve product yield, have unusual effect especially aspect reducing production costs.
Embodiment
In order to make the purpose, technical solutions and advantages of the present invention clearer, below the preferred embodiments of the present invention are described in detail.
Synthesizing of embodiment 1, two phenylcarbinol-β-chloroethyl ether
With benzhydrol 92g, chloroethanol 40g, massfraction is that 98% sulfuric acid 21.8ml adds in the there-necked flask (benzhydrol, chloroethanol and vitriolic mol ratio are 1: 1: 0.8), be warming up to 70 ℃ of insulation reaction, with tlc monitoring reaction process, reaction in 6 hours finishes, and standing demix is collected the upper strata oily liquids, with massfraction is 25% sodium carbonate solution washing 3 times, use the hot wash 3 times of 60 ℃ of temperature again, promptly make two phenylcarbinol-β-chloroethyl ether, yield 78.5%.
Synthesizing of embodiment 2, two phenylcarbinol-β-chloroethyl ether
With benzhydrol 92g, chloroethanol 52.3g, massfraction is that 98% sulfuric acid 16.3ml adds in the there-necked flask (benzhydrol, chloroethanol and vitriolic mol ratio are 1: 1.3: 0.6), be warming up to 100 ℃ of insulation reaction, with tlc monitoring reaction process, reaction in 4 hours finishes, and standing demix is collected the upper strata oily liquids, with massfraction is 15% sodium carbonate solution washing 3 times, use the hot wash 3 times of 80 ℃ of temperature again, promptly make two phenylcarbinol-β-chloroethyl ether, yield 84.3%.
Synthesizing of embodiment 3, two phenylcarbinol-β-chloroethyl ether
With benzhydrol 92g, chloroethanol 60.4g, massfraction is that 98% sulfuric acid 10.9ml adds in the there-necked flask (benzhydrol, chloroethanol and vitriolic mol ratio are 1: 1.5: 0.4), be warming up to 130 ℃ of insulation reaction, with tlc monitoring reaction process, reaction in 3 hours finishes, and standing demix is collected the upper strata oily liquids, with massfraction is 5% sodium carbonate solution washing 3 times, use the hot wash 3 times of 100 ℃ of temperature again, promptly make two phenylcarbinol-β-chloroethyl ether, yield 73.6%.
Synthesizing of embodiment 4, diphenhydramine citrate
With two phenylcarbinol-β-chloroethyl ether 24.7g, massfraction is that 10% dimethylamine agueous solution 135g adds in the autoclave (mol ratio of two phenylcarbinol-β-chloroethyl ether and dimethylamine is 1: 3), 110 ℃ of temperature, stirring reaction under the pressure 0.5MPa condition, reaction in 6 hours finishes, reaction solution is cooled to 60 ℃, in temperature-fall period, progressively remove pressure, the dimethylamine gas that the recovery part unreacted is intact, adding massfraction again and be 15% the two phenylcarbinol-β of NaOH solution 40g(-chloroethyl ether and the mol ratio of NaOH under condition of normal pressure is 1: 1.5), stirring is warming up to 100 ℃, reclaim the intact dimethylamine gas of remaining unreacted, after recovery finishes, reaction solution is cooled to room temperature, dripping concentration under agitation condition is that the two phenylcarbinol-β of the aqueous solution of citric acid 385ml(-chloroethyl ether of 0.1g/ml and the mol ratio of Citric Acid are 1: 2), stirring reaction 30 minutes, the adularescent precipitation is separated out, suction filtration, filter cake washs 3 times with ethyl acetate, wash with water again 3 times, oven dry, promptly make diphenhydramine citrate, yield 56.5%.After measured, the fusing point of products obtained therefrom is 146 ~ 148 ℃, and is consistent with the fusing point of the disclosed diphenhydramine citrate of document; The UV spectrum of products obtained therefrom, infrared spectra, nuclear magnetic resonance spectrum and mass spectrum are consistent with the corresponding spectrogram of diphenhydramine citrate American Pharmacopeia reference substance.
Synthesizing of embodiment 5, diphenhydramine citrate
With two phenylcarbinol-β-chloroethyl ether 24.7g, massfraction is that 30% dimethylamine agueous solution 75g adds in the autoclave (mol ratio of two phenylcarbinol-β-chloroethyl ether and dimethylamine is 1: 5), 130 ℃ of temperature, stirring reaction under the pressure 0.75MPa condition, reaction in 4 hours finishes, reaction solution is cooled to 80 ℃, in temperature-fall period, progressively remove pressure, the dimethylamine gas that the recovery part unreacted is intact, adding massfraction again and be 30% the two phenylcarbinol-β of NaOH solution 26.7g(-chloroethyl ether and the mol ratio of NaOH under condition of normal pressure is 1: 2), stirring is warming up to 130 ℃, reclaim the intact dimethylamine gas of remaining unreacted, after recovery finishes, reaction solution is cooled to room temperature, dripping concentration under agitation condition is that the two phenylcarbinol-β of the Citric Acid ethanolic soln 192ml(-chloroethyl ether of 0.3g/ml and the mol ratio of Citric Acid are 1: 3), stirring reaction 30 minutes, the adularescent precipitation is separated out, suction filtration, filter cake washing with alcohol 3 times, wash with water again 3 times, oven dry, promptly make diphenhydramine citrate, yield 65.8%.After measured, the fusing point of products obtained therefrom is 146 ~ 148 ℃, and is consistent with the fusing point of the disclosed diphenhydramine citrate of document; The UV spectrum of products obtained therefrom, infrared spectra, nuclear magnetic resonance spectrum and mass spectrum are consistent with the corresponding spectrogram of diphenhydramine citrate American Pharmacopeia reference substance.
Synthesizing of embodiment 6, diphenhydramine citrate
With two phenylcarbinol-β-chloroethyl ether 24.7g, massfraction is that 50% dimethylamine agueous solution 72g adds in the autoclave (mol ratio of two phenylcarbinol-β-chloroethyl ether and dimethylamine is 1: 8), 150 ℃ of temperature, stirring reaction under the pressure 2.5MPa condition, reaction in 3 hours finishes, reaction solution is cooled to 100 ℃, in temperature-fall period, progressively remove pressure, the dimethylamine gas that the recovery part unreacted is intact, adding massfraction again and be 50% the two phenylcarbinol-β of NaOH solution 24g(-chloroethyl ether and the mol ratio of NaOH under condition of normal pressure is 1: 3), stirring is warming up to 150 ℃, reclaim the intact dimethylamine gas of remaining unreacted, after recovery finishes, reaction solution is cooled to room temperature, dripping concentration under agitation condition is that the two phenylcarbinol-β of the Citric Acid acetone soln 192ml(-chloroethyl ether of 0.5g/ml and the mol ratio of Citric Acid are 1: 5), stirring reaction 30 minutes, the adularescent precipitation is separated out, suction filtration, filter cake washing with acetone 3 times, wash with water again 3 times, oven dry, promptly make diphenhydramine citrate, yield 60.5%.After measured, the fusing point of products obtained therefrom is 146 ~ 148 ℃, and is consistent with the fusing point of the disclosed diphenhydramine citrate of document; The UV spectrum of products obtained therefrom, infrared spectra, nuclear magnetic resonance spectrum and mass spectrum are consistent with the corresponding spectrogram of diphenhydramine citrate American Pharmacopeia reference substance.
Explanation is at last, above embodiment is only unrestricted in order to technical scheme of the present invention to be described, although by invention has been described with reference to the preferred embodiments of the present invention, but those of ordinary skill in the art is to be understood that, can make various changes to it in the form and details, and the spirit and scope of the present invention that do not depart from appended claims and limited.
Claims (10)
1. the synthetic method of diphenhydramine citrate, it is characterized in that: with the aqueous solution of two phenylcarbinol-β-chloroethyl ether and excessive dimethylamine 110 ~ 150 ℃ of temperature, stirring reaction under pressure 0.5 ~ 2.5MPa condition, after reaction finishes, reaction solution is cooled to 60 ~ 100 ℃, in temperature-fall period, progressively remove pressure, the dimethylamine gas that the recovery part unreacted is intact, under condition of normal pressure, add the NaOH aqueous solution then, stir and be warming up to 100 ~ 150 ℃, reclaim the intact dimethylamine gas of remaining unreacted, at last reaction solution is cooled to room temperature, add citric acid soln, stirring reaction filters, filter cake washing, drying makes diphenhydramine citrate.
2. the synthetic method of diphenhydramine citrate according to claim 1 is characterized in that: the mol ratio of the described pair of phenylcarbinol-β-chloroethyl ether and dimethylamine is 1: 3 ~ 8.
3. the synthetic method of diphenhydramine citrate according to claim 1, it is characterized in that: the massfraction of described dimethylamine agueous solution is 10% ~ 50%.
4. the synthetic method of diphenhydramine citrate according to claim 1 is characterized in that: the mol ratio of the described pair of phenylcarbinol-β-chloroethyl ether and NaOH is 1: 1.5 ~ 3.
5. the synthetic method of diphenhydramine citrate according to claim 1, it is characterized in that: the massfraction of the described NaOH aqueous solution is 15% ~ 50%.
6. the synthetic method of diphenhydramine citrate according to claim 1 is characterized in that: the mol ratio of the described pair of phenylcarbinol-β-chloroethyl ether and Citric Acid is 1: 2 ~ 5.
7. the synthetic method of diphenhydramine citrate according to claim 1, it is characterized in that: described citric acid soln is citron aqueous acid, ethanolic soln, propanol solution, aqueous isopropanol or acetone soln, and wherein the concentration of Citric Acid is 0.1 ~ 0.5g/ml.
8. the synthetic method of diphenhydramine citrate according to claim 1, it is characterized in that: described pair of phenylcarbinol-β-chloroethyl ether adopts following method synthetic: benzhydrol and ethylene chlorhydrin are carried out etherification reaction for 70 ~ 130 ℃ in temperature in the presence of the vitriol oil, after reaction finishes, cooling, standing demix, collect the upper strata oily liquids, use inorganic salt solution and hot wash successively, promptly make two phenylcarbinol-β-chloroethyl ether.
9. the synthetic method of diphenhydramine citrate according to claim 8, it is characterized in that: described benzhydrol, chloroethanol and vitriolic mol ratio are 1: 1 ~ 1.5: 0.4 ~ 0.8.
10. the synthetic method of diphenhydramine citrate according to claim 8, it is characterized in that: the described vitriol oil is that massfraction is 98% sulphuric acid soln; Described upper strata oily liquids is the hot wash that 5 ~ 25% sodium carbonate solution and temperature are 60 ~ 100 ℃ with massfraction successively.
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| CN 201110116781 CN102229537B (en) | 2011-05-06 | 2011-05-06 | Method for synthesizing citric acid diphenhydramine |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103265439A (en) * | 2013-06-07 | 2013-08-28 | 启东东岳药业有限公司 | Preparation method of diphenhydramine |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4401665A (en) * | 1981-04-14 | 1983-08-30 | Bristol-Myers Company | Sleep-aid composition containing an analgesic and diphenhydramine dihydrogencitrate, and method of use |
| CN1050763C (en) * | 1991-10-16 | 2000-03-29 | 理查森-维克斯有限公司 | Enhanced skin penetration system for improved topical delivery of drugs |
| WO2006022966A1 (en) * | 2004-08-10 | 2006-03-02 | Allergan, Inc. | 2-heteroarylalkenylcyclopentane heptan- (ene) -oic acid derivatives as therapeutic agents |
-
2011
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4401665A (en) * | 1981-04-14 | 1983-08-30 | Bristol-Myers Company | Sleep-aid composition containing an analgesic and diphenhydramine dihydrogencitrate, and method of use |
| CN1050763C (en) * | 1991-10-16 | 2000-03-29 | 理查森-维克斯有限公司 | Enhanced skin penetration system for improved topical delivery of drugs |
| WO2006022966A1 (en) * | 2004-08-10 | 2006-03-02 | Allergan, Inc. | 2-heteroarylalkenylcyclopentane heptan- (ene) -oic acid derivatives as therapeutic agents |
Non-Patent Citations (2)
| Title |
|---|
| KUBO, HIDEO等: "Synthesis of antihistamic agents", 《NAGOYA IND.SCI.RESEARCH INST》 * |
| M.HANITI S.A.HAMID等: "Ruthenium-Catalyzed N-Alkylation of Amines and Sulfonamides Using Borrowing Hydrogen Methodology", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103265439A (en) * | 2013-06-07 | 2013-08-28 | 启东东岳药业有限公司 | Preparation method of diphenhydramine |
| CN103265439B (en) * | 2013-06-07 | 2014-07-16 | 启东东岳药业有限公司 | Preparation method of diphenhydramine |
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