CN102050749A - Preparation and refining method of alpha-(N-benzyl-N-methyl amino)-m-hydroxyacetophenone hydrochloride - Google Patents
Preparation and refining method of alpha-(N-benzyl-N-methyl amino)-m-hydroxyacetophenone hydrochloride Download PDFInfo
- Publication number
- CN102050749A CN102050749A CN2010105509310A CN201010550931A CN102050749A CN 102050749 A CN102050749 A CN 102050749A CN 2010105509310 A CN2010105509310 A CN 2010105509310A CN 201010550931 A CN201010550931 A CN 201010550931A CN 102050749 A CN102050749 A CN 102050749A
- Authority
- CN
- China
- Prior art keywords
- benzyl
- methylamino
- hydroxy acetophenone
- preparation
- hydrochloride
- 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
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to preparation and a refining method of alpha-(N-benzyl-N-methyl amino)-m-hydroxyacetophenone hydrochloride. The alpha-(N-benzyl-N-methyl amino)-m-hydroxyacetophenone hydrochloride is prepared by performing catalytic bromination, amination condensation and a salifying reaction on m-hydroxyacetophenone, a bromizating agent and methyl benzyl amine which serve as main raw materials and single petroleum ether which serves as a solvent. The method has a simple and convenient process, uses readily available raw materials and avoids using chemical solvents such as inflammable solvents, explosive solvents, toxic solvents and the like in a preparation process. The alpha-(N-benzyl-N-methyl amino)-m-hydroxyacetophenone hydrochloride has the characteristics of high yield, high purity, low cost, environmental friendliness and the like.
Description
Technical field
The present invention relates to the preparation and the process for purification of α-(N-benzyl-N-methylamino)-m-hydroxy acetophenone hydrochloride, belong to chemosynthesis technical field.
Background technology
Phenylephrine hydrochloride (Phenylephedrine Hydrochloride) has another name called neophryn, Phenylephrine Hydrochloride, is α type adrenergic receptor stimulant.It mainly increases peripheral vascular resistance, and local vascular is had contraction, makes elevation of blood pressure; In the anesthesia process, compare with Xylotox, ask in the time of can shortening anesthesia induction that anaesthetic effect is good, consumption is few, and side effect just reduces relatively; Also be used for supraventricular tachycardia and mydriasis inspection etc., this product all has bigger market outlook in these treatment fields.
α-(N-benzyl-N-methylamino)-m-hydroxy acetophenone hydrochloride is the key intermediate of preparation phenylephrine hydrochloride, its synthetic method mainly contains at present: (1) is main raw material with 3-benzoyloxy methyl phenyl ketone, make through reactions such as bromination, amination, hydrolysis, but in this reaction process, used the bigger organic solvent of toxicity, as chloroform and benzene, and by product is difficult to remove clean, cause product purity not high (Sergievskaya, S.I.; Ravdel, G.A., Zhurnal Obshchei Khimii, 22,496-502.).(2) be main raw material with the 3-hydroxy acetophenone, make through reactions such as the benzoyl protection of bromination, hydroxyl, amination, hydrolysis deprotections that this method causes total recovery lower because reactions steps is long, cost is higher, and degree of purity of production is not high.(Hukki，Jaakko；Honkanen，Erkki.Acta?Chemica?Scandinavica)。(3) be main raw material with the 3-nitro-acetophenone, make through reactions such as bromination, amination, shortening, diazotization, hydrolysis, this method reactions steps is long, side reaction is many, the three wastes are many, and in reaction process, also use inflammable, explosive solvent, overall yield of reaction is low, deficiencies such as cost is high and of poor quality (Sergievskaya, S.I.).
Summary of the invention
The deficiency that exists at the method for prior art, as reactions steps is long, total recovery is low, cost is high, use the bigger organic solvent of toxicity, shortcomings such as post-processing difficulty is big, final product quality difference, first purpose of the present invention is to provide the preparation method of the α that a kind of technology is easy, cost is low, yield is high, the three wastes are few, environmental pollution is little-(N-benzyl-N-methylamino)-m-hydroxy acetophenone hydrochloride.
In order to realize purpose of the present invention, the contriver gropes by a large amount of tests, finally obtained the synthetic route of following a kind of α-(N-benzyl-N-methylamino)-m-hydroxy acetophenone hydrochloride: with m-hydroxy acetophenone, bromizating agent and methyl-benzyl amine is main raw material, with single sherwood oil is solvent, prepares α-(N-benzyl-N-methylamino)-m-hydroxy acetophenone hydrochloride crude product through catalytic bromination, amination condensation, salt-forming reaction.
Particularly, the chemical equation of said synthesis route is as follows:
(1) catalytic bromination reaction:
(2) amination condensation reaction:
(3) salt-forming reaction:
Preferably, the preparation method of above-mentioned α-(N-benzyl-N-methylamino)-m-hydroxy acetophenone hydrochloride, wherein said catalytic bromination reactions steps is: mix sherwood oil, m-hydroxy acetophenone and 4 bromide, stir after being warming up to room temperature, drip C
5H
5NHBrBr
2, dropwise back insulation 0.5-3h, promptly get the bromide reaction solution.In order to reduce environmental pollution, the hydrogen bromide waste gas that described catalytic bromination reaction produces can absorb with alkali lye to be handled.
Preferably, the preparation method of above-mentioned α-(N-benzyl-N-methylamino)-m-hydroxy acetophenone hydrochloride, wherein said amination step of condensation is: under the room temperature condition, in bromination reaction liquid, add entry and soda ash, stir the back and transfer pH to neutral, static layering is removed lower floor's brine layer, drip the N-methylbenzylamine then, temperature control is in 30 ℃, and dropping is warming up to 45-50 ℃ after finishing, insulation 0.5-3h, suction filtration, filtrate are condensation reaction solution.
Preferably, the preparation method of above-mentioned α-(N-benzyl-N-methylamino)-m-hydroxy acetophenone hydrochloride, wherein said salt-forming reaction step is: add hydrochloric acid in condensation reaction solution, temperature is controlled in 40 ℃, and adjust pH is to 2-3, heat temperature raising, normal pressure reclaims sherwood oil, cools to room temperature insulated and stirred 0.2-2h, through suction filtration, centrifugal, oven dry, get α-(N-benzyl-N-methylamino)-m-hydroxy acetophenone hydrochloride crude product.
Second purpose of the present invention is to provide the process for purification of a kind of α-(N-benzyl-N-methylamino)-m-hydroxy acetophenone hydrochloride crude product.Specific as follows:
In α-(N-benzyl-N-methylamino)-m-hydroxy acetophenone hydrochloride crude product, add the ethanol that 2-4 doubly measures, being warming up to backflow and crude product all dissolves, ethanol 25-35% is reclaimed in air distillation, cool again to room temperature, stir insulation 0.2-2h, through suction filtration, centrifugal, oven dry, get α-(N-benzyl-N-methylamino)-m-hydroxy acetophenone hydrochloride elaboration.
Compared with prior art, the preparation of α of the present invention-(N-benzyl-N-methylamino)-m-hydroxy acetophenone hydrochloride and process for purification have following beneficial technical effects and progressive significantly:
(1) in preparation process, bromination reaction adds the catalyzer 4 bromide, does directly bromination of solvent with sherwood oil, has saved the phenolic hydroxyl group of old technology and has protected and deprotection reaction, has reduced processing step greatly, the total recovery height, has reduced cost.
(2) in the bromination reaction process, adopt novel bromizating agent C
5H
5NHBrBr
2With the catalyzer 4 bromide, improved the yield of bromination reaction, and bromination liquid is directly used in the next step, simplified operation process.
(3) the hydrolysis deprotection reaction of old technology has been saved in salt-forming reaction, has reduced processing step.
(4) in preparation process, solvent for use is single sherwood oil, has avoided adopting multiple solvent, helps reclaiming solvent, reduce cost, and also environmentally friendly.
Generally speaking, the preparation of α of the present invention-(N-benzyl-N-methylamino)-m-hydroxy acetophenone hydrochloride is compared with the method for prior art with process for purification, have that technology is easy, raw material is easy to get, removed from preparing and used organic solvents such as inflammable, explosive, poisonous, yield exceeds 10 percentage points than prior art, have characteristics such as yield height, purity good (content 〉=99%, HPLC detects), cost are low, environmental friendliness.
Embodiment
Below be specific embodiments of the invention, technical scheme of the present invention is done further the description, but protection scope of the present invention is not limited to these embodiment.Every do not deviate from the change of the present invention design or be equal to substitute include within protection scope of the present invention.
Synthesizing of embodiment 1 α-(N-benzyl-N-methylamino)-m-hydroxy acetophenone hydrochloride with refining
Sherwood oil: 400kg
M-hydroxy acetophenone: 68kg
4 bromide: 0.7kg
C
5H
5N·HBr·Br
2：80kg
Yellow soda ash: 30kg
N-methylbenzylamine: 121kg
Hydrochloric acid: 100kg
Ethanol: 300kg
(1) catalytic bromination reaction:
In the 1500L reactor, drop into 400kg sherwood oil and 68kg m-hydroxy acetophenone, add catalyzer 4 bromide 0.7kg, stir 0.5h after being warming up to room temperature, add bromizating agent C
5H
5NHBrBr
280kg, about 1h, the hydrogen bromide waste gas of generation absorbs with alkali lye, dropwises back insulation 2h, promptly gets the bromide reaction solution.
(2) amination condensation reaction:
Above-mentioned bromination reaction liquid is transferred in the amination still, at ambient temperature, adds entry 50kg and soda ash 30kg, after the stirring, adjust pH is to neutral, and behind the static 0.5h, layering divides and falls down a layer brine layer, with the clear water washing once, divides to fall washing water again; After layering finished, beginning dripped N-methylbenzylamine 121kg in the amination still, and temperature control is in 30 ℃, and dropping is warming up to 45-50 ℃ after finishing, insulation 1h, and suction filtration, filtrate promptly gets the reaction solution of condensation.
(3) salt-forming reaction:
Above-mentioned condensation reaction solution is transferred in the salt oven, add hydrochloric acid 100kg, temperature in the kettle is controlled in 40 ℃, control the pH value to 2-3, heat temperature raising, normal pressure reclaims sherwood oil, cool to room temperature, insulated and stirred 0.5h through suction filtration, centrifugal, oven dry, gets α-(N-benzyl-N-methylamino)-m-hydroxy acetophenone hydrochloride crude product 100kg.
(4) crude product refining
α-(N-benzyl-N-methylamino)-m-hydroxy acetophenone hydrochloride crude product 100kg is transferred in the refining kettle, add 300kg ethanol, being warming up to backflow and crude product all dissolves, ethanol about 30% is reclaimed in air distillation, cool again to room temperature, stir insulation 0.5h, through suction filtration, centrifugal, oven dry, get α-(N-benzyl-N-methylamino)-m-hydroxy acetophenone hydrochloride elaboration 95kg, content is 99.2%.
Synthesizing of embodiment 2 α-(N-benzyl-N-methylamino)-m-hydroxy acetophenone hydrochloride with refining
Sherwood oil: 400kg
M-hydroxy acetophenone: 70kg
4 bromide: 1.1kg
C
5H
5N·HBr·Br
2：90kg
Yellow soda ash: 30kg
N-methylbenzylamine: 130kg
Hydrochloric acid: 120kg
Ethanol: 310kg
(1) catalytic bromination reaction:
In the 1500L reactor, drop into 400kg sherwood oil and 70kg m-hydroxy acetophenone, add catalyzer 4 bromide 1.1kg, stir 0.5h after being warming up to room temperature, add bromizating agent C
5H
5NHBrBr
290kg, about 1h, the hydrogen bromide waste gas of generation absorbs with alkali lye, dropwises back insulation 3h, promptly gets the bromide reaction solution.
(2) amination condensation reaction:
Above-mentioned bromination reaction liquid is transferred in the amination still, at ambient temperature, adds entry 50kg and soda ash 30kg, after the stirring, adjust pH is to neutral, and behind the static 0.5h, layering divides and falls down a layer brine layer, with the clear water washing once, divides to fall washing water again; After layering finished, beginning dripped N-methylbenzylamine 130kg in the amination still, and temperature control is in 30 ℃, and dropping is warming up to 45-50 ℃ after finishing, insulation 3h, and suction filtration, filtrate promptly gets the reaction solution of condensation.
(3) salt-forming reaction:
Above-mentioned condensation reaction solution is transferred in the salt oven, add hydrochloric acid 120kg, temperature in the kettle is controlled in 40 ℃, control the pH value to 2-3, heat temperature raising, normal pressure reclaims sherwood oil, cool to room temperature, insulated and stirred 2h through suction filtration, centrifugal, oven dry, gets α-(N-benzyl-N-methylamino)-m-hydroxy acetophenone hydrochloride crude product 105kg.
(4) crude product refining
α-(N-benzyl-N-methylamino)-m-hydroxy acetophenone hydrochloride crude product 105kg is transferred in the refining kettle, add 310kg ethanol, being warming up to backflow and crude product all dissolves, ethanol about 30% is reclaimed in air distillation, cool again to room temperature, stir insulation 2h, through suction filtration, centrifugal, oven dry, get α-(N-benzyl-N-methylamino)-m-hydroxy acetophenone hydrochloride elaboration 106kg, content is 99.3%.
Claims (6)
1. the preparation method of α-(N-benzyl-N-methylamino)-m-hydroxy acetophenone hydrochloride is characterized in that: with m-hydroxy acetophenone, bromizating agent C
5H
5NHBrBr
2, catalyzer 4 bromide and methyl-benzyl amine is raw material, is solvent with the sherwood oil, is prepared from through catalytic bromination, amination, salt-forming reaction, its chemical equation is as follows:
(1) catalytic bromination reaction:
(2) amination condensation reaction:
(3) salt-forming reaction:
2. the preparation method of α as claimed in claim 1-(N-benzyl-N-methylamino)-m-hydroxy acetophenone hydrochloride, it is characterized in that: described catalytic bromination reactions steps is: mix sherwood oil, m-hydroxy acetophenone and 4 bromide, stir after being warming up to room temperature, drip C
5H
5NHBrBr
2, dropwise back insulation 0.5-3h, promptly get the bromide reaction solution.
3. the preparation method of α as claimed in claim 2-(N-benzyl-N-methylamino)-m-hydroxy acetophenone hydrochloride is characterized in that: the hydrogen bromide waste gas that described catalytic bromination reaction produces absorbs with alkali lye.
4. the preparation method of α as claimed in claim 1-(N-benzyl-N-methylamino)-m-hydroxy acetophenone hydrochloride, it is characterized in that: described amination step of condensation is: under the room temperature condition, add entry and soda ash in bromination reaction liquid, stir the back and transfer pH to neutral, static layering, remove lower floor's brine layer, drip the N-methylbenzylamine then, temperature control is in 30 ℃, be warming up to 45-50 ℃ after dripping end, insulation 0.5-3h, suction filtration, filtrate is condensation reaction solution.
5. the preparation method of α as claimed in claim 1-(N-benzyl-N-methylamino)-m-hydroxy acetophenone hydrochloride, it is characterized in that: described salt-forming reaction step is: add hydrochloric acid in condensation reaction solution, temperature is controlled in 40 ℃, adjust pH is to 2-3, heat temperature raising, and normal pressure reclaims sherwood oil, cool to room temperature, insulated and stirred 0.2-2h through suction filtration, centrifugal, oven dry, gets α-(N-benzyl-N-methylamino)-m-hydroxy acetophenone hydrochloride crude product.
6. the process for purification of α-(N-benzyl-N-methylamino)-m-hydroxy acetophenone hydrochloride crude product, it is characterized in that: in described crude product, add the ethanol that 2-4 doubly measures, being warming up to backflow and crude product all dissolves, ethanol 25-35% is reclaimed in air distillation, cool again to room temperature, stir insulation 0.2-2h,, get α-(N-benzyl-N-methylamino)-m-hydroxy acetophenone hydrochloride elaboration through suction filtration, centrifugal, oven dry.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010550931 CN102050749B (en) | 2010-11-19 | 2010-11-19 | Preparation and refining method of alpha-(N-benzyl-N-methyl amino)-m-hydroxyacetophenone hydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010550931 CN102050749B (en) | 2010-11-19 | 2010-11-19 | Preparation and refining method of alpha-(N-benzyl-N-methyl amino)-m-hydroxyacetophenone hydrochloride |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102050749A true CN102050749A (en) | 2011-05-11 |
| CN102050749B CN102050749B (en) | 2013-11-06 |
Family
ID=43955603
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201010550931 Active CN102050749B (en) | 2010-11-19 | 2010-11-19 | Preparation and refining method of alpha-(N-benzyl-N-methyl amino)-m-hydroxyacetophenone hydrochloride |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102050749B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102776251A (en) * | 2012-08-21 | 2012-11-14 | 尚科生物医药（上海）有限公司 | Preparation method of phenylephrine |
| CN104356013A (en) * | 2014-11-18 | 2015-02-18 | 浙江海翔药业股份有限公司 | Preparation method of alpha-(N-methyl-N-benzylamino)-3-hydroxyacetophenone hydrochloride |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1884252A (en) * | 2006-06-02 | 2006-12-27 | 台州明翔化工有限公司 | Process for synthesizing alpha-(N-methyl-benzyl)-3-hydroxy acetophenone |
| CN101088984A (en) * | 2006-06-14 | 2007-12-19 | 台州明翔化工有限公司 | Process of synthesizing alpha-(N-methyl-N-benzylamin)-3-hydroxy acetophenone hydrochloride |
-
2010
- 2010-11-19 CN CN 201010550931 patent/CN102050749B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1884252A (en) * | 2006-06-02 | 2006-12-27 | 台州明翔化工有限公司 | Process for synthesizing alpha-(N-methyl-benzyl)-3-hydroxy acetophenone |
| CN101088984A (en) * | 2006-06-14 | 2007-12-19 | 台州明翔化工有限公司 | Process of synthesizing alpha-(N-methyl-N-benzylamin)-3-hydroxy acetophenone hydrochloride |
Non-Patent Citations (7)
| Title |
|---|
| 《化工进展》 20030330 胡伟武等 芳基丙酮类alpha-溴代反应新工艺的研究 第287-289页 1-5 第22卷, 第3期 * |
| 《广西轻工业》 20080815 张玉涛等 alpha- 溴代苯乙酮合成方法研究 第22页 1-5 , 第8期 * |
| 《江西化工》 20060930 宋夏辉等 alpha- 甲氨基间羟基苯乙酮合成 第63-65页 1-5 , 第3期 * |
| 宋夏辉等: "α- 甲氨基间羟基苯乙酮合成", 《江西化工》, no. 3, 30 September 2006 (2006-09-30), pages 63 - 65 * |
| 张玉涛等: "α- 溴代苯乙酮合成方法研究", 《广西轻工业》, no. 8, 15 August 2008 (2008-08-15), pages 22 * |
| 胡伟武等: "芳基丙酮类α-溴代反应新工艺的研究", 《化工进展》, vol. 22, no. 3, 30 March 2003 (2003-03-30), pages 287 - 289 * |
| 胡艾希等: "溴化铜对芳基烷基酮的选择性溴化反应研究", 《中国药物化学杂志》, vol. 12, no. 6, 31 December 2002 (2002-12-31), pages 340 - 343 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102776251A (en) * | 2012-08-21 | 2012-11-14 | 尚科生物医药（上海）有限公司 | Preparation method of phenylephrine |
| CN104356013A (en) * | 2014-11-18 | 2015-02-18 | 浙江海翔药业股份有限公司 | Preparation method of alpha-(N-methyl-N-benzylamino)-3-hydroxyacetophenone hydrochloride |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102050749B (en) | 2013-11-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102267887A (en) | Synthesis process for 1-hydroxycyclohexyl phenyl ketone | |
| CN103554003A (en) | Method for synthesizing silodosin | |
| CN104478736B (en) | A kind of preparation method of cinacalcet hydrochloride | |
| CN102050749B (en) | Preparation and refining method of alpha-(N-benzyl-N-methyl amino)-m-hydroxyacetophenone hydrochloride | |
| CN101323575A (en) | Synthetic method of nitrobenzene methyl aldehyde | |
| CN103435507A (en) | Preparation method of L-alpha-methyl-3,4-dihydroxyphenylalanine | |
| CN107098822A (en) | A kind of preparation method for preparing the hydroxy acetophenone of 3 amino of Pranlukast key intermediate 2 | |
| CN105601496B (en) | A kind of preparation method of 3,4 dimethoxy benzenpropanoic acid | |
| CN105646261B (en) | A kind of method for preparing totokaine | |
| CN105646285B (en) | One kind dimension Lactel sieve intermediate and its preparation method and application | |
| CN106866434B (en) | A kind of preparation method of VENLAFAXINE HCL intermediate | |
| CN102690166A (en) | Preparation methods of 2, 4, 5-trifluoro-benzyl chloride and 2, 4, 5-trifluoro-phenylacetic acid | |
| CN109867604A (en) | A kind of environment-friendly production process of Para Amino Benzamide | |
| CN100448842C (en) | Process for synthesizing alpha-(N-methyl-benzyl)-3-hydroxy acetophenone | |
| CN101723845A (en) | Method for producing m-acetamino-N,N-diethyl aniline | |
| CN101914069A (en) | Novel chlorination technique of 6- chlorine-2-hydroxy quinoxaline | |
| CN104130545B (en) | A kind of preparation method of Graphene modified furan resin | |
| CN108484488B (en) | Method for synthesizing 4- [2- (5-ethyl-2-pyridyl) ethoxy ] benzaldehyde by photo/nickel concerted catalysis | |
| CN103772157B (en) | Method for preparing 1-alkoxy-1,1,2,2-tetrafluoroethane | |
| CN106957235B (en) | A kind of preparation method of tamoxifen | |
| CN110483238A (en) | A kind of fluorination new process of p-chloro benzo trifluoride-99 | |
| CN100363331C (en) | Method for preparing p-hydroxy phenylethylamine hydrochloride | |
| CN104693020A (en) | Preparation method of 3-(3-trifluoromethylphenyl) propionic acid serving as cinacalcethdrochloride intermediate | |
| CN109970579A (en) | A method of preparing ambroxol hydrochloride | |
| CN105061231A (en) | Preparation method of 3-methoxy-4-hydroxybenzylamine hydrochloride |
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 | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20190425 Address after: 430000 Wuhan Donghu Development Zone High-tech Avenue 666 Wuhan National Biological Industry Base Project B, C, D Development Building B1 Patentee after: Azithromycin Pharmaceutical (Hubei) Co. Ltd. Address before: 430028 Beiheng Pioneer River, Dawu County Economic Development Zone, Xiaogan City, Hubei Province Patentee before: Hubei Xinruite Medical Technology Co., Ltd. |
|
| TR01 | Transfer of patent right |