CN103265439A - Preparation method of diphenhydramine - Google Patents
Preparation method of diphenhydramine Download PDFInfo
- Publication number
- CN103265439A CN103265439A CN2013102265549A CN201310226554A CN103265439A CN 103265439 A CN103265439 A CN 103265439A CN 2013102265549 A CN2013102265549 A CN 2013102265549A CN 201310226554 A CN201310226554 A CN 201310226554A CN 103265439 A CN103265439 A CN 103265439A
- Authority
- CN
- China
- Prior art keywords
- diphenhydramine
- toluene
- methylbenzene
- dimethylbenzene
- xylene
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 229960000520 diphenhydramine Drugs 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title abstract description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 90
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims abstract description 53
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 18
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229960002887 deanol Drugs 0.000 claims abstract description 9
- QILSFLSDHQAZET-UHFFFAOYSA-N diphenylmethanol Chemical compound C=1C=CC=CC=1C(O)C1=CC=CC=C1 QILSFLSDHQAZET-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims abstract description 6
- 230000018044 dehydration Effects 0.000 claims abstract description 3
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 3
- 239000002904 solvent Substances 0.000 claims abstract description 3
- 238000010992 reflux Methods 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 8
- 239000012141 concentrate Substances 0.000 claims description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical group CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 3
- 230000000630 rising effect Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 239000003054 catalyst Substances 0.000 abstract description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 2
- 125000001033 ether group Chemical group 0.000 abstract description 2
- 239000008096 xylene Substances 0.000 abstract 7
- 238000001816 cooling Methods 0.000 abstract 2
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 abstract 1
- 239000007864 aqueous solution Substances 0.000 abstract 1
- 239000012295 chemical reaction liquid Substances 0.000 abstract 1
- 238000009826 distribution Methods 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 229940098779 methanesulfonic acid Drugs 0.000 abstract 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 abstract 1
- 150000005172 methylbenzenes Chemical class 0.000 abstract 1
- 238000010792 warming Methods 0.000 abstract 1
- 238000005406 washing Methods 0.000 abstract 1
- 239000002994 raw material Substances 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 description 2
- -1 tosic acid monohydrates Chemical class 0.000 description 2
- ZDVDCDLBOLSVGM-UHFFFAOYSA-N [chloro(phenyl)methyl]benzene Chemical compound C=1C=CC=CC=1C(Cl)C1=CC=CC=C1 ZDVDCDLBOLSVGM-UHFFFAOYSA-N 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- OQROAIRCEOBYJA-UHFFFAOYSA-N bromodiphenylmethane Chemical compound C=1C=CC=CC=1C(Br)C1=CC=CC=C1 OQROAIRCEOBYJA-UHFFFAOYSA-N 0.000 description 1
- MZDOIJOUFRQXHC-UHFFFAOYSA-N dimenhydrinate Chemical compound O=C1N(C)C(=O)N(C)C2=NC(Cl)=N[C]21.C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 MZDOIJOUFRQXHC-UHFFFAOYSA-N 0.000 description 1
- 229960004993 dimenhydrinate Drugs 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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
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.
2. the method for preparing diphenhydramine according to claim 1.It is characterized in that: catalyzer is tosic acid or methylsulfonic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310226554.9A CN103265439B (en) | 2013-06-07 | 2013-06-07 | Preparation method of diphenhydramine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310226554.9A CN103265439B (en) | 2013-06-07 | 2013-06-07 | Preparation method of diphenhydramine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103265439A true CN103265439A (en) | 2013-08-28 |
| CN103265439B CN103265439B (en) | 2014-07-16 |
Family
ID=49009118
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310226554.9A Active CN103265439B (en) | 2013-06-07 | 2013-06-07 | Preparation method of diphenhydramine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103265439B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104892435A (en) * | 2015-04-07 | 2015-09-09 | 嘉兴学院 | Preparation method of diphenhydramine |
| CN112028780A (en) * | 2019-06-03 | 2020-12-04 | 北京益民药业有限公司 | Purification method of diphenhydramine |
| CN117603063A (en) * | 2023-11-22 | 2024-02-27 | 浙江大学 | A kind of synthesis method of N,N-dimethylaminoethyl diphenylmethyl ether |
Citations (2)
| 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 |
| CN102229537A (en) * | 2011-05-06 | 2011-11-02 | 西南大学 | Method for synthesizing citric acid diphenhydramine |
-
2013
- 2013-06-07 CN CN201310226554.9A patent/CN103265439B/en active Active
Patent Citations (2)
| 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 |
| CN102229537A (en) * | 2011-05-06 | 2011-11-02 | 西南大学 | Method for synthesizing citric acid diphenhydramine |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104892435A (en) * | 2015-04-07 | 2015-09-09 | 嘉兴学院 | Preparation method of diphenhydramine |
| CN104892435B (en) * | 2015-04-07 | 2016-08-24 | 嘉兴学院 | The preparation method of diphenhydramine |
| CN112028780A (en) * | 2019-06-03 | 2020-12-04 | 北京益民药业有限公司 | Purification method of diphenhydramine |
| CN117603063A (en) * | 2023-11-22 | 2024-02-27 | 浙江大学 | A kind of synthesis method of N,N-dimethylaminoethyl diphenylmethyl ether |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103265439B (en) | 2014-07-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103265439B (en) | Preparation method of diphenhydramine | |
| JP6690557B2 (en) | Method for producing carbon-based light emitting material | |
| CN103613672A (en) | Method for preparing cellulose acetate by employing ionic liquid as catalyst | |
| CN101591237A (en) | Anti-form-1, the synthetic method of 4-cyclohexane cyclohexanedimethanodibasic | |
| CN105384648A (en) | Preparation method for 2,2'-di(methoxy)-4,4'-diaminophenyl | |
| CN104262397B (en) | A kind of preparation method of high-purity tenofovir | |
| Zou et al. | Facile and efficient N-arylation of amino acid esters with (−)-methyl-3-dehydroshikimiate (3-MDHS): a bio-based and metal-free strategy leading to N-aryl amino acid derivatives | |
| Sedighi et al. | Synthesis of biscoumarin derivatives as biological compounds using cellulose sulfonic acid | |
| CN102757367A (en) | Splitting process of racemic ethyl benzene sulfonic acid | |
| CN103102272A (en) | Preparation method of 2,2-bis[(3-nitro-4-hydroxy)phenyl)-hexafluoropropane | |
| CN102351699B (en) | Gulonate and preparation method thereof | |
| CN109134258B (en) | Product separation process for preparing methyl glycolate by dimethyl oxalate hydrogenation | |
| CN101654422A (en) | 3, the preparation method of 3'-diaminodiphenyl sulfone | |
| JP5886113B2 (en) | Method for producing monocarboxylic anhydride | |
| CN108927220A (en) | A kind of synthetic method of Jie of synchronous immobilized phosphotungstic acid-micro-diplopore Cr-MIL-101 carrier | |
| CN108727200A (en) | The synthetic method of nonamethylene diamine | |
| CN103539660A (en) | Method of preparing trans-1,4-cyclohexane dicarboxylic acid from hybrid 1,4-cyclohexane dicarboxylic acid | |
| CN102746144A (en) | Preparation method of 1,4-cyclohexanedicarboxylic acid | |
| CN102627526A (en) | Preparation method of 1,2-pentanediol | |
| CN105439837A (en) | Synthetic method of 6-Bromoisovanillin | |
| CN102766051A (en) | Method for preparing benzyl benzoate by oxidizing dibenzyl ether | |
| CN103694285B (en) | A kind of preparation method of isopropyl-β-D-thiogalactoside(IPTG) | |
| CN110423205B (en) | Synthesis process of 2,3,4, 5-tetrafluoro-N-methylbenzamide suitable for continuous production | |
| CN106146393A (en) | Prepare 3,4,6-trichloropyridine-2-formic acid and the method for corresponding esters thereof | |
| CN105237432A (en) | Synthesis method of N,N-methylene-bis-benzamide compounds |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |