CN105753781A - Environment-friendly synthetic method of 4-bromomethyl quinolinone - Google Patents
Environment-friendly synthetic method of 4-bromomethyl quinolinone Download PDFInfo
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- CN105753781A CN105753781A CN201610206923.1A CN201610206923A CN105753781A CN 105753781 A CN105753781 A CN 105753781A CN 201610206923 A CN201610206923 A CN 201610206923A CN 105753781 A CN105753781 A CN 105753781A
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- China
- Prior art keywords
- organic solvent
- antifebrin
- quinoline ketone
- bromomethyl
- acetyl bromide
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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
Abstract
The invention discloses an environment-friendly synthetic method of 4-bromomethyl quinolinone. The environment-friendly synthetic method comprises the following steps: adding acetoacetanilide bromide as a raw material into an anhydrous organic solvent; taking out moisture generated in reaction by virtue of the organic solvent as a water carrier while heating, condensing the moisture-containing organic solvent, adding the organic solvent into a reaction kettle filled with phosphorus pentoxide, and carrying out dehydration under stirring; continuously distilling the organic solvent in the reaction kettle filled with phosphorus pentoxide, returning the distilled anhydrous organic solvent to an acetoacetanilide bromide reaction kettle as the water carrier, carrying out dehydration cyclization on acetoacetanilide bromide so as to generate 4-bromomethyl quinolinone, cooling the system to the room temperature, carrying out filter pressing by directly utilizing a filter press, washing by virtue of an organic solvent, and drying, so as to obtain the product. According to the environment-friendly synthetic method, the yield of reaches 95% or above, and the purity of 4-bromomethyl quinolinone is more than or equal to 99.5%; and the product quality is good, waste acid and wastewater are not generated, the production efficiency is high, the cost is low, and large-scale production is easily realized.
Description
Technical field
The present invention relates to the field of chemical synthesis, the green synthesis method of a kind of 4-bromomethyl quinoline ketone.
Background technology
4-bromomethyl quinoline ketone is the centre of novel anti-ulcer agent Rebamipide (rebamipide, trade name mucosta)
Body, 4-bromomethyl quinoline ketone has bigger market.Common technique is produced for using the concentrated sulfuric acid to carry out dehydration closed-loop reaction
Product (journal Medicinal Chemistry, 1988,31 (10): 1910-18)；After having reacted, the method using elutriation will
4-bromomethyl quinoline ketone separates out from acid, washs to PH >=6 with substantial amounts of water afterwards, then is dried by product, and this method produces
Substantial amounts of Waste Sulfuric Acid, low concentration acid water, easily cause environmental pollution.
Summary of the invention
It is an object of the invention to provide the green synthesis method of a kind of 4-bromomethyl quinoline ketone, to solve in above-mentioned background technology
The problem proposed.
For achieving the above object, the present invention provides following technical scheme:
The green synthesis method of a kind of 4-bromomethyl quinoline ketone, raw material includes acetyl bromide antifebrin, organic solvent, five oxygen
Change two phosphorus, water, it is characterised in that directly in the organic solvent of heating, carry out high temperature cyclization dehydration, utilize organic molten
Agent is prone to form azeotropic mixture with water and takes the water of reaction abjection out of reaction system, recycles the strong absorptive of phosphorus pentoxide, will
Organic solvent is dried, then is taken out of by the moisture content that reaction system generates as water entrainer by dry organic solvent, final
To 4-bromomethyl quinoline ketone.
As the further scheme of the present invention: method particularly includes: with acetyl bromide antifebrin as raw material, by acetyl bromide second
Anilide adds in anhydrous organic solvent；The moisture content that reaction is generated by organic solvent as water entrainer is utilized under conditions of heating
Taking out of, aqueous organic solvent enters a reactor equipped with phosphorus pentoxide after condensation and is stirred dehydration；Again will
The organic solvent of this phosphorus pentoxide reactor carries out continuous still, and the anhydrous organic solvent distilled is returned to acetyl bromide
As water entrainer in antifebrin reactor, acetyl bromide antifebrin dehydration cyclization should after generating 4-bromomethyl quinoline ketone again
System is cooled to room temperature, directly uses filter press press filtration, then obtains product after organic solvent washing, drying；Yield reaches 95%
Above, purity >=99.5%.
As the present invention further scheme: described acetyl bromide antifebrin, organic solvent, the quality of phosphorus pentoxide
Proportioning is: 1: 5～10: 1～2.
As the present invention further scheme: described organic solvent is 8: 1 with the mass ratio of acetyl bromide antifebrin, institute
The mass ratio stating acetyl bromide antifebrin and phosphorus pentoxide is 1: 2.
As the present invention further scheme: the organic solvent in described is dichloromethane, chloroform, carbon tetrachloride, dichloro
Ethane or tetrachloroethanes.
As the present invention further scheme: reaction temperature is 50～120 DEG C, the regular cyclization of Blang gram is observed in reaction,
Under conditions of high temperature is the most anhydrous, reacts the direction towards generating water and carry out, it is easy to form five-membered ring or the hexatomic ring of stable performance.
As the present invention further scheme: in building-up process, the water content of described organic solvent is less than 20ppm；Described
The content of acetyl bromide antifebrin is 99.5%, impurity content 0.5%.
As the present invention further scheme: the consumption of described phosphorus pentoxide by 5～10 times of removing moisture content amount.
As the present invention further scheme: utilize the high dehydrated of phosphorus pentoxide indirectly to remove acetyl bromide acetyl
Water cyclization in aniline molecule.
Compared with prior art, the invention has the beneficial effects as follows: mainly solve prior art to use sulfuric acid produce as cyclization agent
Raw more waste water, and owing to the oxidisability of sulfuric acid makes the 4-bromomethyl quinoline ketone being prone to make generation in course of reaction aoxidize further
Become impurity, make product purity reduce, good product quality of the present invention, do not have spent acid to produce, produce without waste water, production efficiency
Height, low cost, it is easy to large-scale production.
Detailed description of the invention
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, aobvious
So, described embodiment is only a part of 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 not making creative work premise, all
Belong to the scope of protection of the invention.
Embodiment 1
In 5000L enamel reaction still, after putting into 4000 kilograms of dichloroethanes, 500 kilograms of acetyl bromide antifebrins, stir
After mixing uniformly；In another one 2000L reactor, put into 1000 kilograms of dichloroethanes and five oxidations of 1000 kilograms simultaneously
Two phosphorus, start 5000L reactor and 2000L reactor are warming up to dichloroethanes backflow simultaneously, and reaction temperature is 83 DEG C；
After refluxing 1 hour, the dichloroethanes condensation distilled out by 5000L reactor enters 2000L reactor, is reacted by 2000L
Enter 5000L reactor after dichloroethanes condensation after still dehydration distillation, control two reactor distillation speeds and synchronize；Reaction
After 12 hours, it is cooled to normal temperature；By filter press, 4-bromomethyl quinoline ketone is separated, then by this 4-bromomethyl quinoline ketone with two
After chloroethanes carries out making beating washing, then after filter press separates, the wet product vacuum drying containing dichloroethane solvent that will obtain,
Obtain 442 kg white powder solids；Yield 95.08%, purity 99.67% (HPLC).
Embodiment 2
In 5000L enamel reaction still, after putting into 4000 kilograms of dichloroethanes, 500 kilograms of acetyl bromide antifebrins, stir
After mixing uniformly；In another one 2000L reactor, put into 1000 kilograms of dichloroethanes and five oxidations of 1000 kilograms simultaneously
Two phosphorus, start 5000L reactor and 2000L reactor are warming up to dichloroethanes backflow simultaneously, and reaction temperature is 83 DEG C；
After refluxing 1 hour, the dichloroethanes condensation distilled out by 5000L reactor enters 2000L reactor, is reacted by 2000L
Enter 5000L reactor after dichloroethanes condensation after still dehydration distillation, control two reactor distillation speeds and synchronize；Reaction
After 24 hours, it is cooled to normal temperature；By filter press, 4-bromomethyl quinoline ketone is separated, then by this 4-bromomethyl quinoline ketone with two
After chloroethanes carries out making beating washing, then after filter press separates, the wet product vacuum drying containing dichloroethane solvent that will obtain,
Obtain 436 kg white powder solids；Yield 93.08%, purity 99.09% (HPLC).
Embodiment 3
In 5000L enamel reaction still, after putting into 4000 kilograms of dichloromethane, 500 kilograms of acetyl bromide antifebrins, stir
After mixing uniformly；In another one 2000L reactor, put into 1000 kilograms of dichloromethane and five oxidations of 1000 kilograms simultaneously
Two phosphorus, start 5000L reactor and 2000L reactor to be warming up to methylene chloride reflux simultaneously, and reaction temperature is 39 DEG C；
After refluxing 1 hour, the dichloromethane condensation distilled out by 5000L reactor enters 2000L reactor, is reacted by 2000L
Enter 5000L reactor after dichloromethane condensation after still dehydration distillation, control two reactor distillation speeds and synchronize；Reaction
After 36 hours, it is cooled to normal temperature；By filter press, 4-bromomethyl quinoline ketone is separated, then by this 4-bromomethyl quinoline ketone with two
After chloroethanes carries out making beating washing, then after filter press separates, the wet product vacuum drying containing dichloroethane solvent that will obtain,
Obtain 390 kg white powder solids；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, and do not carrying on the back
In the case of the spirit or essential attributes of the present invention, it is possible to realize the present invention in other specific forms.Therefore, no matter from
From the point of view of which point, all should regard embodiment 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 by fall in the implication of equivalency and scope of claim
Change is included in the present invention.
Although moreover, it will be appreciated that this specification is been described by according to embodiment, but the most each embodiment only comprises
One independent technical scheme, this narrating mode of specification is only the most for clarity sake, and those skilled in the art should be by
Specification is as an entirety, and the technical scheme in each embodiment can also be through appropriately combined, and forming those skilled in the art can
With other embodiments understood.
Claims (9)
1. a green synthesis method for 4-bromomethyl quinoline ketone, raw material include acetyl bromide antifebrin, organic solvent,
Phosphorus pentoxide, water, it is characterised in that directly carrying out high temperature cyclization dehydration in the organic solvent of heating, utilization has
Machine solvent is prone to form azeotropic mixture with water and the water of reaction abjection is taken out of reaction system, the strong water suction of recycling phosphorus pentoxide
Property, organic solvent is dried, then the moisture content that reaction system generates is taken out of as water entrainer by dry organic solvent,
Finally give 4-bromomethyl quinoline ketone.
The green synthesis method of 4-bromomethyl quinoline ketone the most according to claim 1, it is characterised in that concrete grammar
For: with acetyl bromide antifebrin as raw material, acetyl bromide antifebrin is added in anhydrous organic solvent；Bar in heating
Utilizing organic solvent to be taken out of by the moisture content that reaction generates as water entrainer under part, aqueous organic solvent enters one after condensation
The individual reactor equipped with phosphorus pentoxide is stirred dehydration；Again the organic solvent of this phosphorus pentoxide reactor is carried out continuously
Distillation, it is interior as water entrainer, acetyl bromide that the anhydrous organic solvent distilled is returned to acetyl bromide antifebrin reactor
This system is cooled to room temperature after generating 4-bromomethyl quinoline ketone by antifebrin dehydration cyclization again, directly uses filter press press filtration,
Product is obtained again after organic solvent washing, drying；Yield reaches more than 95%, purity >=99.5%.
The green synthesis method of 4-bromomethyl quinoline ketone the most according to claim 1 and 2, it is characterised in that described
Acetyl bromide antifebrin, organic solvent, the quality proportioning of phosphorus pentoxide be: 1: 5～10: 1～2.
The green synthesis method of 4-bromomethyl quinoline ketone the most according to claim 3, it is characterised in that described organic
Solvent is 8: 1 with the mass ratio of acetyl bromide antifebrin, described acetyl bromide antifebrin and the mass ratio of phosphorus pentoxide
It is 1: 2.
The green synthesis method of 4-bromomethyl quinoline ketone the most according to claim 1 and 2, it is characterised in that described
In organic solvent be dichloromethane, chloroform, carbon tetrachloride, dichloroethanes or tetrachloroethanes.
The green synthesis method of 4-bromomethyl quinoline ketone the most according to claim 1, it is characterised in that reaction temperature
It it is 50～120 DEG C.
The green synthesis method of 4-bromomethyl quinoline ketone the most according to claim 1 and 2, it is characterised in that synthesis
During, the water content of described organic solvent is less than 20ppm；The content of described acetyl bromide antifebrin is 99.5%, miscellaneous
Matter content 0.5%.
The green synthesis method of 4-bromomethyl quinoline ketone the most according to claim 1 and 2, it is characterised in that described
The consumption of phosphorus pentoxide by 5～10 times of removing moisture content amount.
The green synthesis method of 4-bromomethyl quinoline ketone the most according to claim 1 and 2, it is characterised in that utilize
The high dehydrated of phosphorus pentoxide removes acetyl bromide antifebrin intramolecular water cyclization indirectly.
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| CN201610206923.1A CN105753781B (en) | 2016-04-06 | 2016-04-06 | A kind of green synthesis method of 4 bromomethyl quinoline ketone |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113277978A (en) * | 2021-06-02 | 2021-08-20 | 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 |
| CN115073371A (en) * | 2022-07-14 | 2022-09-20 | 四川沃肯精细化工有限公司 | Preparation method of 4-bromomethyl quinolinone |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113277978A (en) * | 2021-06-02 | 2021-08-20 | 河南师范大学 | Preparation method of 2, 4-disubstituted quinoline compound |
| 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 |
| CN115073371A (en) * | 2022-07-14 | 2022-09-20 | 四川沃肯精细化工有限公司 | Preparation method of 4-bromomethyl quinolinone |
| 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 |
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