CN105753781B - A kind of green synthesis method of 4 bromomethyl quinoline ketone - Google Patents
A kind of green synthesis method of 4 bromomethyl quinoline ketone Download PDFInfo
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- CN105753781B CN105753781B CN201610206923.1A CN201610206923A CN105753781B CN 105753781 B CN105753781 B CN 105753781B CN 201610206923 A CN201610206923 A CN 201610206923A CN 105753781 B CN105753781 B CN 105753781B
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- organic solvent
- antifebrin
- acetyl bromide
- bromomethyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of green synthesis method of 4 bromomethyl quinoline ketone, and using acetyl bromide antifebrin as raw material, acetyl bromide antifebrin is added in anhydrous organic solvent；The moisture content for reacting generation is taken out of by the use of organic solvent as water entrainer under conditions of heating, aqueous organic solvent enters a reactor equipped with phosphorus pentoxide after condensation and is stirred dehydration；The organic solvent of the phosphorus pentoxide reactor is subjected to continuous still again, the anhydrous organic solvent distilled is returned in acetyl bromide antifebrin reactor and is used as water entrainer, the system is cooled to room temperature again after acetyl bromide antifebrin dehydration cyclization 4 bromomethyl quinoline ketone of generation, directly use filter press press filtration, then with after organic solvent washing, drying product；Yield is up to more than 95%, purity >=99.5%.Good product quality of the present invention, produced without spent acid, no waste water produces, and production efficiency is high, and cost is low, is easy to large-scale production.
Description
Technical field
The present invention relates to the field of chemical synthesis, specifically a kind of green synthesis method of 4- bromomethyl quinolines ketone.
Background technology
4- bromomethyl quinoline ketone is in new anti-ulcer agent Rebamipide (rebamipide, trade name mucosta)
Mesosome, 4- bromomethyl quinoline ketone have larger market.Common technique is to carry out dehydration closed-loop reaction using the concentrated sulfuric acid to obtain
Product (journal Medicinal Chemistry, 1988,31 (10)：1910-18)；After the completion of reaction, using the side of elutriation
Method separates out 4- bromomethyl quinoline ketone from acid, is dried afterwards with substantial amounts of water washing to PH >=6, then by product, the production of this method
Raw substantial amounts of Waste Sulfuric Acid, low concentration acid water, easily causes environmental pollution.
The content of the invention
It is an object of the invention to provide a kind of green synthesis method of 4- bromomethyl quinolines ketone, to solve above-mentioned background skill
The problem of being proposed in art.
To achieve the above object, the present invention provides following technical scheme：
A kind of green synthesis method of 4- bromomethyl quinolines ketone, raw material include acetyl bromide antifebrin, organic solvent, five
Aoxidize two phosphorus, water, it is characterised in that high temperature cyclization dehydration is carried out directly in the organic solvent of heating, using organic molten
Agent is easy to take the water for reacting abjection out of reaction system with water formation azeotropic mixture, recycles the strong absorptive of phosphorus pentoxide, will
Organic solvent is dried, then takes the moisture content that reaction system generates out of using dry organic solvent as water entrainer, final
To 4- bromomethyl quinoline ketone.
As the further scheme of the present invention：Specific method is：Using acetyl bromide antifebrin as raw material, by acetyl bromide
Antifebrin is added in anhydrous organic solvent；The water of generation will be reacted by the use of organic solvent as water entrainer under conditions of heating
Part is taken out of, and aqueous organic solvent enters a reactor equipped with phosphorus pentoxide after condensation and is stirred dehydration；Again
The organic solvent of the phosphorus pentoxide reactor is subjected to continuous still, the anhydrous organic solvent distilled is returned to bromination second
Water entrainer is used as in acyl antifebrin reactor, again will after acetyl bromide antifebrin dehydration cyclization generation 4- bromomethyl quinoline ketone
The system is cooled to room temperature, directly uses filter press press filtration, then with after organic solvent washing, drying product；Yield is up to 95%
More than, purity >=99.5%.
As further scheme of the invention：The acetyl bromide antifebrin, organic solvent, the matter of phosphorus pentoxide
Measuring proportioning is：1: 5~10: 1~2.
As further scheme of the invention：The mass ratio of the organic solvent and acetyl bromide antifebrin is 8: 1,
The mass ratio of the acetyl bromide antifebrin and phosphorus pentoxide is 1: 2.
As further scheme of the invention：Organic solvent in described is dichloromethane, chloroform, carbon tetrachloride, two
Chloroethanes or tetrachloroethanes.
As further scheme of the invention：Reaction temperature is 50~120 DEG C, and Blang gram rule cyclization is observed in reaction,
Under conditions of high temperature is completely anhydrous, reacts and carried out towards the direction of generation water, be easily formed the five-membered ring or hexa-atomic of stable performance
Ring.
As further scheme of the invention：In building-up process, the water content of the organic solvent is less than 20ppm；Institute
The content for stating acetyl bromide antifebrin is 99.5%, impurity content 0.5%.
As further scheme of the invention：The dosage of the phosphorus pentoxide by 5~10 times of removing moisture content amount.
As further scheme of the invention：High dehydrated using phosphorus pentoxide is removed acetyl bromide indirectly
The water cyclization of antifebrin intramolecular.
Compared with prior art, the beneficial effects of the invention are as follows：Mainly solves to use sulfuric acid in the prior art as cyclization
Agent produces more waste water, and because the oxidisability of sulfuric acid makes to be easy to make the 4- bromomethyl quinoline ketone of generation further in course of reaction
Oxidation becomes impurity, reduces product purity, good product quality of the present invention, is produced without spent acid, and no waste water produces, production efficiency
Height, cost is low, is easy to large-scale production.
Embodiment
Below in conjunction with the embodiment of the present invention, the technical scheme in the embodiment of the present invention is clearly and completely described,
Obviously, described embodiment is only part of the embodiment of the present invention, rather than whole embodiments.Based in the present invention
Embodiment, the every other embodiment that those of ordinary skill in the art are obtained under the premise of creative work is not made, all
Belong to the scope of protection of the invention.
Embodiment 1
In 5000L enamel reaction stills, after putting into 4000 kilograms of dichloroethanes, 500 kilograms of acetyl bromide antifebrins, stir
After mixing uniformly；1000 kilograms of dichloroethanes and the five of 1000 kilograms oxidations two are put into another 2000L reactor simultaneously
Phosphorus, start that 5000L reactors and 2000L reactors are warming up into dichloroethanes backflow simultaneously, reaction temperature is 83 DEG C；Backflow 1
After hour, the dichloroethanes condensation that 5000L reactors distill out is entered into 2000L reactors, 2000L reactors are dehydrated and distilled
Enter 5000L reactors after dichloroethanes condensation afterwards, control two reactor distillation speeds synchronous；After reaction 12 hours, drop
Temperature is to normal temperature；4- bromomethyl quinolines ketone is separated by filter press, then the 4- bromomethyl quinoline ketone is beaten with dichloroethanes
After plasm scouring, then after filter press separates, the wet product vacuum drying containing dichloroethane solvent that will obtain, obtain 442 kilograms it is white
Toner foam solid；Yield 95.08%, purity 99.67% (HPLC).
Embodiment 2
In 5000L enamel reaction stills, after putting into 4000 kilograms of dichloroethanes, 500 kilograms of acetyl bromide antifebrins, stir
After mixing uniformly；1000 kilograms of dichloroethanes and the five of 1000 kilograms oxidations two are put into another 2000L reactor simultaneously
Phosphorus, start that 5000L reactors and 2000L reactors are warming up into dichloroethanes backflow simultaneously, reaction temperature is 83 DEG C；Backflow 1
After hour, the dichloroethanes condensation that 5000L reactors distill out is entered into 2000L reactors, 2000L reactors are dehydrated and distilled
Enter 5000L reactors after dichloroethanes condensation afterwards, control two reactor distillation speeds synchronous；After reaction 24 hours, drop
Temperature is to normal temperature；4- bromomethyl quinolines ketone is separated by filter press, then the 4- bromomethyl quinoline ketone is beaten with dichloroethanes
After plasm scouring, then after filter press separates, the wet product vacuum drying containing dichloroethane solvent that will obtain, obtain 436 kilograms it is white
Toner foam solid；Yield 93.08%, purity 99.09% (HPLC).
Embodiment 3
In 5000L enamel reaction stills, after putting into 4000 kilograms of dichloromethane, 500 kilograms of acetyl bromide antifebrins, stir
After mixing uniformly；1000 kilograms of dichloromethane and the five of 1000 kilograms oxidations two are put into another 2000L reactor simultaneously
Phosphorus, start that 5000L reactors and 2000L reactors are warming up into methylene chloride reflux simultaneously, reaction temperature is 39 DEG C；Backflow 1
After hour, the dichloromethane condensation that 5000L reactors distill out is entered into 2000L reactors, 2000L reactors are dehydrated and distilled
Enter 5000L reactors after dichloromethane condensation afterwards, control two reactor distillation speeds synchronous；After reaction 36 hours, drop
Temperature is to normal temperature；4- bromomethyl quinolines ketone is separated by filter press, then the 4- bromomethyl quinoline ketone is beaten with dichloroethanes
After plasm scouring, then after filter press separates, the wet product vacuum drying containing dichloroethane solvent that will obtain, obtain 390 kilograms it is white
Toner foam solid；Yield 83.9%, purity 94.52% (HPLC).
It is obvious to a person skilled in the art that the invention is not restricted to the details of above-mentioned one exemplary embodiment, Er Qie
In the case of 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, embodiment all should be regarded as exemplary, and be nonrestrictive, the scope of the present invention is by appended power
Profit requires rather than described above limits, it is intended that all in the implication and scope of the equivalency of claim by falling
Change is included in the present invention.
Moreover, it will be appreciated that although the present specification is described in terms of embodiments, not each embodiment is only wrapped
Containing an independent technical scheme, this narrating mode of specification is only that those skilled in the art should for clarity
Using specification as an entirety, the technical solutions in the various embodiments may also be suitably combined, forms those skilled in the art
It is appreciated that other embodiment.
Claims (7)
1. a kind of green synthesis method of 4- bromomethyl quinolines ketone, raw material includes acetyl bromide antifebrin, organic solvent, five oxygen
Change two phosphorus, water, it is characterised in that the acetyl bromide antifebrin, organic solvent, the quality proportioning of phosphorus pentoxide are：1∶5
~10: 1~2；High temperature cyclization dehydration is carried out directly in the organic solvent of heating, is easy to be formed with water using organic solvent
Azeotropic mixture takes the water for reacting abjection out of reaction system, recycles the strong absorptive of phosphorus pentoxide, organic solvent is done
It is dry, then take the moisture content that reaction system generates out of using dry organic solvent as water entrainer, finally give 4- bromomethyl quinolines
Ketone, specific method are：Using acetyl bromide antifebrin as raw material, acetyl bromide antifebrin is added in anhydrous organic solvent；
The moisture content for reacting generation is taken out of by the use of organic solvent as water entrainer under conditions of heating, aqueous organic solvent is through supercooling
Enter a reactor equipped with phosphorus pentoxide after solidifying and be stirred dehydration；Again by the organic molten of the phosphorus pentoxide reactor
Agent carries out continuous still, and the anhydrous organic solvent distilled is returned in acetyl bromide antifebrin reactor as band water
The system is cooled to room temperature again after generating 4- bromomethyl quinoline ketone, directly used by agent, acetyl bromide antifebrin dehydration cyclization
Filter press press filtration, then with organic solvent washing, drying after product；Yield is up to more than 95%, purity >=99.5%.
2. the green synthesis method of 4- bromomethyl quinolines ketone according to claim 1, it is characterised in that the organic solvent
Mass ratio with acetyl bromide antifebrin is 8: 1, and the mass ratio of the acetyl bromide antifebrin and phosphorus pentoxide is 1:
2。
3. the green synthesis method of 4- bromomethyl quinolines ketone according to claim 1, it is characterised in that described is organic molten
Agent is dichloromethane, chloroform, carbon tetrachloride, dichloroethanes or tetrachloroethanes.
4. the green synthesis method of 4- bromomethyl quinolines ketone according to claim 1, it is characterised in that reaction temperature 50
~120 DEG C.
5. the green synthesis method of 4- bromomethyl quinolines ketone according to claim 1, it is characterised in that in building-up process,
The water content of the organic solvent is less than 20ppm；The content of the acetyl bromide antifebrin is 99.5%, impurity content
0.5%.
6. the green synthesis method of 4- bromomethyl quinolines ketone according to claim 1, it is characterised in that five oxidation two
The dosage of phosphorus by 5~10 times of removing moisture content amount.
7. the green synthesis method of 4- bromomethyl quinolines ketone according to claim 1, it is characterised in that utilize five oxidations two
The high dehydrated water cyclization for being removed acetyl bromide antifebrin intramolecular indirectly of phosphorus.
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| CN113277978B (en) * | 2021-06-02 | 2022-06-03 | 河南师范大学 | Preparation method of 2, 4-disubstituted quinoline compound |
| CN114907260A (en) * | 2022-05-27 | 2022-08-16 | 河南省科学院高新技术研究中心 | Method for preparing 4-bromomethylquinolinone by using ionic liquid |
| CN115073371B (en) * | 2022-07-14 | 2023-05-30 | 四川沃肯精细化工有限公司 | Preparation method of 4-bromomethylquinolinone |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101172953A (en) * | 2007-12-04 | 2008-05-07 | 王俊华 | Method of preparing telmisartan midbody of angiotensin medicament for treating hypertension |
| WO2010107816A2 (en) * | 2009-03-16 | 2010-09-23 | Promega Corporation | Nucleic acid binding dyes and uses therefor |
| CN104356152A (en) * | 2014-11-07 | 2015-02-18 | 白银摩尔化工有限责任公司 | Method for producing high-purity triisopropyl borate through system external circulation reaction dehydration |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2017526691A (en) * | 2014-09-01 | 2017-09-14 | ユーシーエル ビジネス ピーエルシー | Quinolones as inhibitors of class IV bromodomain proteins |
-
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- 2016-04-06 CN CN201610206923.1A patent/CN105753781B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101172953A (en) * | 2007-12-04 | 2008-05-07 | 王俊华 | Method of preparing telmisartan midbody of angiotensin medicament for treating hypertension |
| WO2010107816A2 (en) * | 2009-03-16 | 2010-09-23 | Promega Corporation | Nucleic acid binding dyes and uses therefor |
| CN104356152A (en) * | 2014-11-07 | 2015-02-18 | 白银摩尔化工有限责任公司 | Method for producing high-purity triisopropyl borate through system external circulation reaction dehydration |
Non-Patent Citations (3)
| Title |
|---|
| A Facile route to the synthesis of substituted 2-hydrazinoquinolines and its ring closer reactions and their biological activity;Krishnadatt Sharma，等;《Indian journal of heterocyclic chemistry》;20051231;第15卷;第161-168页 * |
| SYNTHESIS AND BIOLOGICAL ACTIVITY OF 2-(SUBSTITUTED QUINOLIN-6-YL)-4H-1-BENZOPYRAN-4-ONES;SATISH M. BHALEKAR，等;《Indian journal of heterocyclic chemistry》;20070630;第16卷;337-340 * |
| 瑞巴匹特羧乙酯的合成;张立娟，等;《武汉工程大学学报》;20090331;第31卷(第3期);第23-25页 * |
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