CN116120245A - Preparation process of 3-methyl-2-cinnamoyl quinoxaline-1, 4-dioxide - Google Patents
Preparation process of 3-methyl-2-cinnamoyl quinoxaline-1, 4-dioxide Download PDFInfo
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- CN116120245A CN116120245A CN202211474967.4A CN202211474967A CN116120245A CN 116120245 A CN116120245 A CN 116120245A CN 202211474967 A CN202211474967 A CN 202211474967A CN 116120245 A CN116120245 A CN 116120245A
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- quinocetone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/06—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing polymers
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
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- Y02P20/584—Recycling of catalysts
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Abstract
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation process of 3-methyl-2-cinnamoyl quinoxaline-1, 4-dioxide. According to the invention, mequindox and benzaldehyde are used as raw materials, absolute ethyl alcohol is used as a solvent, quinocetone is prepared under the action of solid acid catalyst resin T-63MP and absolute sodium carbonate, and a post-treatment optimization process is performed. The invention solves the problem of high toxicity and low yield of the organic solvent in the traditional process, obviously improves the yield of the quinocetone from the original 78-86% to more than 97.0%, obviously improves the quality of the quinocetone product, and can recycle the catalyst, thereby meeting the application requirements of the catalyst in the field of veterinary medicines and having practical significance.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation process of 3-methyl-2-cinnamoyl quinoxaline-1, 4-dioxide.
Background
Quinocetone is a new national grade veterinary drug which is initiated internationally in China. By inhibiting the synthesis of bacterial DNA, the growth and reproduction of pathogenic microorganisms in digestion are inhibited, the occurrence of diseases is prevented or reduced, beneficial intestinal flora and intestinal wall are protected from being affected by microorganisms or parasites, the digestion and absorption of various nutrients are promoted, the growth of animals is accelerated, and the feed conversion rate is improved. The quinocetone can also be used for resisting bacteria and promoting growth of aquaculture, improving survival rate, clarifying water and improving water quality.
Currently, there are two main synthetic methods for quinocetone. One is synthesized by one-step reaction of benzofurazan as a starting material with benzylidene acetylacetone (CN 1197068A). The process needs to be aged and crystallized, and the main reaction raw material benzylidene acetylacetone is difficult to purchase and industrialized on a large scale;
the other is to use mequindox and benzaldehyde to generate aldol condensation under the catalysis of alkali to obtain quinocetone. The raw materials used in the route are easy to obtain, the condition requirements are not harsh, and large-scale industrialization is easy to realize. The literature and patents reported so far are essentially all under study for improvements to this route: patent CN102311397a uses mequindox as raw material, and uses proper amount of methanol as solvent, uses 25% ammonia water as catalyst, and makes it undergo the process of condensation with benzaldehyde so as to obtain the quinocetone. CN105294581a adopts a magnetic solid alkali prepared by using magnetic magnalium hydrotalcite and alkaline quaternary salt compound catalysis one-pot reaction technology to synthesize quinocetone; CN105566234a is a preparation method of quinocetone, wherein an ionic liquid catalyst is adopted for the first time to prepare quinocetone; in addition, the methods are adopted in CN 106632100, CN 101402612, CN 104803928, CN102311397, CN 110003124 and CN 102329272, and due to the specificity of the quinoxaline structure and the instability of the a, beta-unsaturated carbonyl compounds, the problems of more side reactions, low yield, dark brick red color, low purity and the like of products exist generally, and the problems of difficult purification due to the generation and difficult removal of impurities are caused, so that qualified products with high yield and high purity are difficult to obtain.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a preparation method and a post-treatment process of 3-methyl-2-cinnamoyl quinoxaline-1, 4-dioxide (quinocetone).
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
the method comprises the following steps:
1) Under the protection of nitrogen, mequindox is dissolved in absolute ethyl alcohol, the pH value is regulated, then a catalyst and a water absorbent are added, benzaldehyde is added dropwise, and a crude product of quinocetone is obtained; the catalyst is solid acid catalyst resin T-63MP;
2) Recrystallizing the crude product of the quinocetone to obtain a refined product of the quinocetone.
The mol ratio of mequindox to the catalyst is 1 (0.1-0.15).
The water absorbent is anhydrous sodium carbonate, and the mol ratio of the mequindox to the anhydrous sodium carbonate is 1 (0.2-0.4)
The molar ratio of mequindox to benzaldehyde is 1 (1.5-2.0).
The reaction temperature is 50-70 ℃, preferably 50-60 ℃, and the reaction is normal pressure reaction.
And adjusting the pH value to 4-5 by adopting phosphoric acid.
The reaction time is 3-6 h.
And filtering to recover the catalyst after the reaction is finished, cooling the obtained mother solution to 5-10 ℃, standing for 2-3 h, and filtering to collect a yellow crystal crude product.
The specific process of recrystallization of the crude product of the quinocetone is as follows: adding the crude product of the quinocetone into water, heating to 70-80 ℃, filtering in a heat preservation state after the feed liquid is dissolved, cooling the filtrate to 10-15 ℃ for crystallization, separating out the quinocetone, adding absolute ethyl alcohol into a filter cake for washing twice, and drying to obtain a refined product of the quinocetone.
The invention has the following beneficial effects:
the invention provides a preparation process of 3-methyl-2-cinnamoyl quinoxaline-1, 4-dioxide, which solves the problems of more side reactions, low yield, dark brick color, low purity and the like existing in the traditional process, and the traditional process is difficult to purify due to the fact that impurities are generated and are difficult to remove, so that a qualified product with high yield and high purity is difficult to obtain.
Because of the specificity of the quinoxaline structure and the instability of alpha, beta-unsaturated carbonyl compounds, the side reaction is difficult to control, the invention adopts mequindox and benzaldehyde as raw materials, absolute ethyl alcohol as a solvent and sodium carbonate as a water absorbent, the solid acid catalyst resin T-63MP can catalyze condensation reaction with high efficiency, the post-treatment is simple, the quinocetone yield is obviously improved, the total yield is improved to more than 97.0 percent from the original 78-86 percent, the quality of the quinocetone product is obviously improved, and the catalyst can be recycled.
Drawings
FIG. 1 is an infrared spectrum of the final product of the present invention.
Detailed Description
The present invention will be further illustrated by the following examples, which are given by way of illustration only and are not intended to be limiting.
Example 1
A process for preparing 3-methyl-2-cinnamoyl quinoxaline-1, 4-dioxide, comprising the steps of:
and (3) synthesis reaction: mequindox (17.64 g,0.080 mol) is weighed and dissolved in 200ml absolute ethanol solvent, phosphoric acid is adopted to adjust the pH value to be 4, solid acid catalyst resin T-63MP 0.008mol and absolute sodium carbonate 0.025mol are added, after stirring and mixing at 50 ℃ to obtain clear solution, benzaldehyde (15.92 g,0.15 mol) is added dropwise for reacting for 5h, the catalyst is recovered by filtration, and after the obtained mother liquor is cooled to 10 ℃, yellow crystals are separated out within 2.5h, thus obtaining a quinocetone crude product.
Post-treatment: and adding 100ml of water into the crude quinocetone, heating to 70 ℃, filtering in a state of heat preservation after the feed liquid is dissolved, cooling, crystallizing and filtering the filtrate, adding absolute ethyl alcohol into the filter cake twice for washing, and drying and discharging to obtain 23.8 g of quinocetone product (the yield is 97.2 percent, and the content is more than 98 percent).
Example 2
A process for preparing 3-methyl-2-cinnamoyl quinoxaline-1, 4-dioxide, comprising the steps of:
and (3) synthesis reaction: mequindox (17.64 g,0.080 mol) is weighed and dissolved in 200ml absolute ethanol solvent, phosphoric acid is adopted to adjust the pH value to be 4, solid acid catalyst resin T-63MP 0.010mol and absolute sodium carbonate 0.016mol are added, after stirring and mixing at 70 ℃ to obtain clear solution, benzaldehyde (16.98 g,0.16 mol) is added dropwise for reaction for 6 hours, the catalyst is recovered by filtration, and after the obtained mother liquor is cooled to 5 ℃, yellow crystals are separated out within 2 hours to obtain a coarse product of quinocetone.
Post-treatment: the crude product of the quinocetone is put into 100ml of water, heated to about 80 ℃, filtered in a state of heat preservation after the feed liquid is dissolved, cooled and crystallized, filtered, and the filter cake is washed by adding absolute ethyl alcohol twice and then dried and discharged to obtain 23.97 g of quinocetone product (the yield is 97.8 percent, and the content is more than 98 percent).
Example 3
A process for preparing 3-methyl-2-cinnamoyl quinoxaline-1, 4-dioxide, comprising the steps of:
and (3) synthesis reaction: mequindox (17.64 g,0.080 mol) is weighed and dissolved in 200ml absolute ethanol solvent, phosphoric acid is adopted to adjust the pH value to 5, solid acid catalyst resin T-63MP 0.012mol and absolute sodium carbonate 0.032mol are added, after stirring and mixing at 60 ℃ to obtain clear solution, benzaldehyde (15.92 g,0.15 mol) is added dropwise for reaction for 3 hours, the catalyst is recovered by filtration, and after the obtained mother liquor is cooled to 10 ℃, yellow crystals are separated out within 3 hours to obtain a quinocetone crude product.
Claims (9)
1. A process for preparing 3-methyl-2-cinnamoyl quinoxaline-1, 4-dioxide, comprising the steps of:
1) Under the protection of nitrogen, mequindox is dissolved in absolute ethyl alcohol, the pH value is regulated, then a catalyst and a water absorbent are added, benzaldehyde is added dropwise, and a crude product of quinocetone is obtained; the catalyst is solid acid catalyst resin T-63MP;
2) Recrystallizing the crude product of the quinocetone to obtain a refined product of the quinocetone.
2. The process for preparing 3-methyl-2-cinnamoyl quinoxaline-1, 4-dioxide according to claim 1, wherein: the mol ratio of mequindox to the catalyst is 1 (0.1-0.15).
3. The process for preparing 3-methyl-2-cinnamoyl quinoxaline-1, 4-dioxide according to claim 1, wherein: the water absorbent is anhydrous sodium carbonate, and the molar ratio of the mequindox to the anhydrous sodium carbonate is 1 (0.2-0.4).
4. The process for preparing 3-methyl-2-cinnamoyl quinoxaline-1, 4-dioxide according to claim 1, wherein: the molar ratio of mequindox to benzaldehyde is 1 (1.5-2.0).
5. The process for preparing 3-methyl-2-cinnamoyl quinoxaline-1, 4-dioxide according to claim 1, wherein: the reaction temperature is 50-70 ℃, preferably 50-60 ℃, and the reaction is normal pressure reaction.
6. The process for preparing 3-methyl-2-cinnamoyl quinoxaline-1, 4-dioxide according to claim 1, wherein phosphoric acid is used to adjust pH to 4-5.
7. The process for preparing 3-methyl-2-cinnamoyl quinoxaline-1, 4-dioxide according to claim 1, wherein the reaction time is 3 to 6h.
8. The process for preparing 3-methyl-2-cinnamoyl quinoxaline-1, 4-dioxide according to claim 1, wherein the catalyst is recovered by filtration after the reaction is finished, the obtained mother liquor is cooled to 5-10 ℃, and then left to stand for 2-3 hours, and a yellow crystal crude product is collected by filtration.
9. The process for preparing 3-methyl-2-cinnamoyl quinoxaline-1, 4-dioxide according to claim 1, wherein the specific process of recrystallization of crude quinocetone is: adding the crude product of the quinocetone into water, heating to 70-80 ℃, filtering in a heat preservation state after the feed liquid is dissolved, cooling the filtrate to 10-15 ℃ for crystallization, separating out the quinocetone, adding absolute ethyl alcohol into a filter cake for washing twice, and drying to obtain a refined product of the quinocetone.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211474967.4A CN116120245A (en) | 2022-11-23 | 2022-11-23 | Preparation process of 3-methyl-2-cinnamoyl quinoxaline-1, 4-dioxide |
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| CN202211474967.4A CN116120245A (en) | 2022-11-23 | 2022-11-23 | Preparation process of 3-methyl-2-cinnamoyl quinoxaline-1, 4-dioxide |
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| CN202211474967.4A Pending CN116120245A (en) | 2022-11-23 | 2022-11-23 | Preparation process of 3-methyl-2-cinnamoyl quinoxaline-1, 4-dioxide |
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