CN106831457B - A kind of preparation method of 3- amino -2- hydroxy acetophenone - Google Patents
A kind of preparation method of 3- amino -2- hydroxy acetophenone Download PDFInfo
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- CN106831457B CN106831457B CN201710110644.XA CN201710110644A CN106831457B CN 106831457 B CN106831457 B CN 106831457B CN 201710110644 A CN201710110644 A CN 201710110644A CN 106831457 B CN106831457 B CN 106831457B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
- C07C303/22—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof from sulfonic acids, by reactions not involving the formation of sulfo or halosulfonyl groups; from sulfonic halides by reactions not involving the formation of halosulfonyl groups
Abstract
It the invention discloses a kind of preparation method for preparing Pranlukast key intermediate 3- amino -2- hydroxy acetophenone, has main steps that using Ortho-Aminophenol -4- sulfonic acid as starting material, through acylation, Fries is reset, and hydrolysis, deprotection is made.Compared with prior art, the raw materials used in the present invention is cheap is easy to get, technique industrialization easy to accomplish, gained final products purity is high；Without dangerous technique, equipment is simple；Route is novel, and synthetic route is short.
Description
Technical field
The present invention relates to field of medicaments, the preparation method of specifically a kind of 3- amino -2- hydroxy acetophenone.
Background technique
Pranlukast (pranlukast, 1), entitled N- [4- oxo -2- (1H-TETRAZOLE -5- the base) -4H-1- benzopyrene of chemistry
Mutter -8- base] -4- (4- phenylbutoxy) benzamide is the leukotriene receptor antagonists of Japanese Ono company research and development, nineteen ninety-five
It is listed for the first time in Japan, clinic is mainly used as anti-asthma and antiallergic.To prevention and treatment Zhong Er Yan ﹑ dysmenorrhea and psoriasis etc.
There is good efficacy；Animal cerebral ischemia is significantly improved simultaneously, and Central nervous system adverse reaction is light.
Key intermediate of the 3- amino -2- hydroxy acetophenone as Pranlukast, there are mainly two types of for synthetic method:
A kind of scheme is using p bromophenol as raw material, and through acylation, Fries is reset, and nitrification, reduction is made.Such as: CN101450943.
Two kinds of schemes are using parachlorophenol as starting material, and through acylation, Fries is reset, and nitrification, reduction is made.Such as:
BioTechnology: An Indian Journal, 8(7),987-991; 2013.Both schemes are similar, and difference exists
It is bromo in raw materials used one, one is chloro.Synthetic schemes route is long, and reduction needs high-pressure hydrogenation, and yield is low.
Specific route is as follows:
Scheme one:
Scheme two:
Summary of the invention
The purpose of the present invention is to provide a kind of preparation methods of 3- amino -2- hydroxy acetophenone, to solve above-mentioned background
The problem of being proposed in technology.
Synthetic route of the invention is as follows:
The invention provides the following technical scheme:
A kind of preparation method of 3- amino -2- hydroxy acetophenone, including following synthesis steps:
Step 1: synthesizing 3- second under alkali or acid catalysis with Ortho-Aminophenol -4- sulfonic acid and acetic anhydride in polar solvent
Amide groups -4- acetyloxybenzenesulfonic acid.
Solvent selection therein, acetic acid, methanol, ethyl alcohol, pyridine, DMF, methylene chloride, chloroform etc..It is preferred that methanol, ethyl alcohol.
Alkali selects pyridine, 4-dimethylaminopyridine, triethylamine, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, diisopropylethylamine
Deng preferably pyridine, triethylamine.The acid selection concentrated sulfuric acid, p-methyl benzenesulfonic acid, polyphosphoric acids etc..It is preferred that the concentrated sulfuric acid.
Step 2: one pot process 3- amino -2- hydroxy acetophenone.3- acetamido -4- acetoxy acetophenone is non-
In proton solvent, Fries rearrangement is carried out through Catalyzed by Anhydrous Aluminium Chloride, dilute hydrochloric acid hydrolyzes one pot process 3- amino -2- hydroxyl
Acetophenone.
Solvent selection chloroform therein, ethyl acetate, nitrobenzene, methylene chloride, carbon tetrachloride, carbon disulfide.It is preferred that chlorine
Imitative, methylene chloride, ethyl acetate.
Compared with prior art, the beneficial effects of the present invention are: (one) it is raw materials used it is cheap be easy to get, technique is easy real
It now industrializes, gained final products purity is high.(2) without dangerous technique, equipment is simple.(3) route is novel, and synthetic route is short.
Specific embodiment
The technical scheme in the embodiments of the invention will be clearly and completely described below, it is clear that described implementation
Example is only a part of the embodiment of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, this field is common
Technical staff's every other embodiment obtained without making creative work belongs to the model that the present invention protects
It encloses.
The preparation (I) of embodiment 1:3- acetamido -4- acetyloxybenzenesulfonic acid
Take Ortho-Aminophenol -4- sulfonic acid (189g), acetic anhydride (224g), methanol 400g, 10 milliliters of the concentrated sulfuric acid, back flow reaction
After reaction, methanol is recovered under reduced pressure in 4h., is cooled to room temperature, and saturated sodium bicarbonate solution is added into reaction system and is adjusted to
PH9-10,400 milliliters of ethyl acetate extractions, is washed to neutrality, anhydrous sodium sulfate dries, filters, and solvent is recovered under reduced pressure, and obtains pale yellow
Color solid 264g, yield 97%.
The synthesis (II) of embodiment 2:3- amino -2- hydroxy acetophenone
3- acetamido -4- acetyloxybenzenesulfonic acid 136g is taken, is dissolved in 300 milliliters of chloroforms, aluminum trichloride (anhydrous) is added
133g is heated to reflux 5h, after reaction, most of solvent is recovered under reduced pressure, is cooled to room temperature, under ice bath, reaction solution slowly adds
Enter into 30% dilute hydrochloric acid, 2h is stirred at room temperature, be to slowly warm up to flow back, reacts 4h, after reaction, reaction solution is cooled to room
20% sodium hydroxide solution is added into reaction system and adjusts pH9-10 for temperature.300 milliliters of chloroform extractions are added, are washed to neutrality,
Anhydrous sodium sulfate dries, filters, filtrate decompression recycling, residue petroleum ether: ethyl acetate=1:3 recrystallization light yellow solid
65.7g, yield 87%.
It is obvious to a person skilled in the art that invention is not limited to the details of the above exemplary embodiments, Er Qie
In the case where without departing substantially from spirit or essential attributes of the invention, the present invention can be realized in other specific forms.Therefore, no matter
From the point of view of which point, the present embodiments are to be considered as illustrative and not restrictive, and the scope of the present invention is by appended power
Benefit requires rather than above description limits, it is intended that all by what is fallen within the meaning and scope of the equivalent elements of the claims
Variation is included within the present invention.Any reference signs in the claims should not be construed as limiting the involved claims.
In addition, it should be understood that although this specification is described in terms of embodiments, but not each embodiment is only wrapped
Containing an independent technical solution, this description of the specification is merely for the sake of clarity, and those skilled in the art should
It considers the specification as a whole, the technical solutions in the various embodiments may also be suitably combined, forms those skilled in the art
The other embodiments being understood that.
Claims (3)
1. a kind of preparation method of 3- amino -2- hydroxy acetophenone, which is characterized in that including following synthesis steps:
(1) preparation (I) of 3- acetamido -4- acetyloxybenzenesulfonic acid:
Using Ortho-Aminophenol -4- sulfonic acid and acetic anhydride as raw material, in polar solvent, reaction synthesis 3- second in the presence of alkali or acid
Amide groups -4- acetyloxybenzenesulfonic acid (I), reaction equation are as follows:
(I)
Wherein, polar solvent is acetic acid, methanol, ethyl alcohol, pyridine, DMF, methylene chloride or chloroform, and alkali is pyridine, 4- dimethylamino
Pyridine, triethylamine, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate or diisopropylethylamine, acid are the concentrated sulfuric acid, to toluene sulphur
Acid or polyphosphoric acids；
(2) preparation (II) of 3- amino -2- hydroxy acetophenone
In atent solvent, under Catalyzed by Anhydrous Aluminium Chloride, compound I occurs Fries and resets, and hydrolyzes through dilute hydrochloric acid, obtains 3-
Amino -2- hydroxy acetophenone, reaction equation are as follows:
(II)
Wherein, atent solvent is chloroform, ethyl acetate, nitrobenzene, methylene chloride, carbon tetrachloride or carbon disulfide.
2. the preparation method of 3- amino -2- hydroxy acetophenone according to claim 1, which is characterized in that in step (1)
Polar solvent is methanol or ethyl alcohol, and alkali is pyridine or triethylamine, and acid is the concentrated sulfuric acid.
3. the preparation method of 3- amino -2- hydroxy acetophenone according to claim 1, which is characterized in that in step (2)
Atent solvent is chloroform, methylene chloride or ethyl acetate.
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| CN107098822B (en) * | 2017-06-07 | 2021-05-28 | 上海微巨实业有限公司 | Preparation method for pranlukast key intermediate 3-amino-2-hydroxyacetophenone |
| KR102195387B1 (en) * | 2018-12-28 | 2020-12-24 | 노승호 | Method for preparing p-Hydroxyacetophenone |
Citations (3)
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| CN101450943A (en) * | 2008-11-10 | 2009-06-10 | 河北科技大学 | Method for synthesizing drug pranlukast from tetrahydrofuran path |
| CN102079688A (en) * | 2011-01-28 | 2011-06-01 | 内蒙古工业大学 | Method for preparing 2,3-dichlorotoluene |
| CN104693074A (en) * | 2013-12-06 | 2015-06-10 | 太原理工大学 | Preparation method of 2-amino-4-sulfo-6-acetaminophenol |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0395144A (en) * | 1989-08-04 | 1991-04-19 | Ono Pharmaceut Co Ltd | Production of aminophenol derivative |
| JPH1129540A (en) * | 1997-07-04 | 1999-02-02 | Showa Kako Kk | Production of ester derivative |
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2017
- 2017-02-28 CN CN201710110644.XA patent/CN106831457B/en active Active
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|---|---|---|---|---|
| CN101450943A (en) * | 2008-11-10 | 2009-06-10 | 河北科技大学 | Method for synthesizing drug pranlukast from tetrahydrofuran path |
| CN102079688A (en) * | 2011-01-28 | 2011-06-01 | 内蒙古工业大学 | Method for preparing 2,3-dichlorotoluene |
| CN104693074A (en) * | 2013-12-06 | 2015-06-10 | 太原理工大学 | Preparation method of 2-amino-4-sulfo-6-acetaminophenol |
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| 普仑司特中间体2- 乙酰胺基-6-乙酮基苯酚的合成;裴玉琼 等;《广东化工》;20151215;第42卷(第23期);第19-20页 |
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