A preparation process of 3-methyl-2-cinnamoylquinoxaline-1,4-dioxide

Abstract

The invention belongs to the technical field of organic synthesis, and in particular to a preparation process of 3-methyl-2-cinnamoylquinoxaline-1,4-dioxide. The present invention uses acetoquinone and benzaldehyde as raw materials, uses anhydrous ethanol as solvent, prepares quinocetone under the action of solid acid catalyst resin T-63MP and anhydrous sodium carbonate, and performs post-processing optimization process. The present invention solves the problem of low yield of large toxicity of traditional process organic solvent, significantly improves quinocetone yield, and total yield is increased to more than 97.0% from original 78 to 86%, significantly improves quinocetone product quality, and catalyst can be recycled, which can meet its application demand in the field of veterinary medicine, and has practical significance.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a preparation process of 3-methyl-2-cinnamoylquinoxaline-1,4-dioxide. Background Art

[0002] Quinocetone is a national first-class new veterinary drug pioneered by my country in the world. It inhibits the synthesis of bacterial DNA, inhibits the growth and reproduction of pathogenic microorganisms in the digestive tract, prevents or reduces the occurrence of diseases, protects the beneficial intestinal flora and intestinal wall from microorganisms or parasites, promotes the digestion and absorption of various nutrients, thereby accelerating animal growth and improving feed conversion rate. Quinocetone can also be used in aquaculture to resist bacteria and promote growth, improve survival rate, clarify water and improve water quality.

[0003] At present, there are two main methods for synthesizing quinocetone. One is to use benzofurazan as the starting material and react it with benzyl acetylacetone in one step (CN1197068A). This process requires aging and crystallization, and the main reaction raw material benzyl acetylacetone is difficult to purchase, making it difficult to industrialize on a large scale.

[0004] Another method is to use acetoquinone and benzaldehyde to undergo aldol condensation under the catalytic action of a base to obtain quinocetone. The raw materials used in this route are easily available, the conditions are not harsh, and large-scale industrialization is easily achieved. The literature and patents reported now are basically research on the improvement of this route: Patent CN102311397A uses acetoquinone as a raw material, an appropriate amount of methanol as a solvent, and 25% ammonia water as a catalyst to condense with benzaldehyde to generate quinocetone. CN105294581A uses a magnetic solid base prepared by magnetic magnesium aluminum hydrotalcite and a basic quaternary ammonium salt composite catalytic one-pot reaction technology to synthesize quinocetone; CN105566234A is a method for preparing quinocetone, which is the first time to use an ionic liquid catalyst to prepare quinocetone; in addition, CN106632100, CN 101402612, CN 104803928, CN 102311397, CN 110003124, and CN 102329272 also use this method. Due to the particularity of the quinoxaline structure and the instability of α, β-unsaturated carbonyl compounds, there are generally many side reactions, low yield, deep brick red product color, low purity, etc. This is because impurities are generated and difficult to remove, which makes purification difficult, and thus it is difficult to obtain a qualified product with high yield and high purity. Summary of the invention

[0005] The purpose of the present invention is to overcome the deficiencies of the prior art and provide a method for preparing 3-methyl-2-cinnamoylquinoxaline-1,4-dioxide (quinoctenone) and a post-treatment process.

[0006] In order to achieve the above object, the technical solution adopted by the present invention is as follows:

[0007]

[0008] The following steps are involved:

[0009] 1) Under nitrogen protection, dissolving acetoquinone in anhydrous ethanol, adjusting the pH, then adding a catalyst and a water absorbent, and dropping benzaldehyde to obtain a crude quinocetone product; the catalyst is a solid acid catalyst resin T-63MP;

[0010] 2) The crude quinocetone is recrystallized to obtain the refined quinocetone.

[0011] The molar ratio of the acetoquinol to the catalyst is 1:(0.1-0.15).

[0012] The water absorbing agent is anhydrous sodium carbonate, and the molar ratio of acequinoxaline to anhydrous sodium carbonate is 1:(0.2-0.4)

[0013] The molar ratio of acetoquinone to benzaldehyde is 1:(1.5-2.0).

[0014] The reaction temperature is 50-70°C, preferably 50-60°C, and the reaction is carried out under normal pressure.

[0015] Phosphoric acid was used to adjust the pH to 4-5.

[0016] The reaction time is 3 to 6 hours.

[0017] After the reaction is completed, the catalyst is recovered by filtration. The obtained mother liquor is cooled to 5-10°C, allowed to stand for 2-3 hours, and the crude yellow crystals are collected by filtration.

[0018] The specific process of recrystallization of crude quinocetone is as follows: the crude quinocetone is put into water, heated to 70-80°C, the liquid is dissolved and filtered under heat preservation, the filtrate is cooled to 10-15°C and crystallized, quinocetone is precipitated, the filter cake is rinsed with anhydrous ethanol twice, and then dried to obtain refined quinocetone.

[0019] The present invention has the following beneficial effects:

[0020] The invention provides a preparation process of 3-methyl-2-cinnamoylquinoxaline-1,4-dioxide. The new process solves the problems of more side reactions, low yield, dark brick red product color, low purity, etc. in the traditional process. The traditional process generates impurities which are difficult to remove, which makes purification difficult, and thus it is difficult to obtain a qualified product with high yield and high purity.

[0021] Due to the particularity of the structure of quinoxaline and the instability of α, β-unsaturated carbonyl compounds, side reactions are difficult to control. The present invention uses acetoquinone and benzaldehyde as raw materials, anhydrous ethanol as a solvent, sodium carbonate as a water absorbent, and solid acid catalyst resin T-63MP can efficiently catalyze the condensation reaction, and the post-treatment is simple, and the yield of quinocetone is significantly improved. The total yield is increased from the original 78-86% to more than 97.0%, the quality of the quinocetone product is significantly improved, and the catalyst can be recycled. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 It is the infrared spectrum of the final product of the present invention. DETAILED DESCRIPTION

[0023] The present invention is further described below in conjunction with embodiments. It should be noted that the following description is only for explaining the present invention and does not limit its contents.

[0024] Example 1

[0025] A preparation process of 3-methyl-2-cinnamoylquinoxaline-1,4-dioxide comprises the following steps:

[0026] Synthesis reaction: Weigh acetoquinone (17.64 g, 0.080 mol) and dissolve it in 200 ml of anhydrous ethanol solvent, adjust the pH value to 4 with phosphoric acid, add 0.008 mol of solid acid catalyst resin T-63MP and 0.025 mol of anhydrous sodium carbonate, stir and mix at 50°C to obtain a clear solution, then add (15.92 g, 0.15 mol) of benzaldehyde dropwise to react for 5 hours, filter and recover the catalyst, and after the mother liquor is cooled to 10°C, yellow crystals precipitate within 2.5 hours to obtain a crude quinocetone.

[0027] Post-treatment: The above crude quinocetone was added into 100 ml of water and heated to 70°C. After the liquid was dissolved, it was filtered under insulation. The filtrate was cooled for crystallization and filtered. The filter cake was rinsed with anhydrous ethanol twice and dried to obtain 23.8 g of quinocetone product (yield 97.2%, content> 98%).

[0028] Example 2

[0029] A preparation process of 3-methyl-2-cinnamoylquinoxaline-1,4-dioxide comprises the following steps:

[0030] Synthesis reaction: Weigh acetoquinone (17.64 g, 0.080 mol) and dissolve it in 200 ml of anhydrous ethanol solvent, adjust the pH value to 4 with phosphoric acid, add 0.010 mol of solid acid catalyst resin T-63MP and 0.016 mol of anhydrous sodium carbonate, stir and mix at 70°C to obtain a clear solution, then add (16.98 g, 0.16 mol) of benzaldehyde dropwise to react for 6 hours, filter and recover the catalyst, and after the mother liquor is cooled to 5°C, yellow crystals precipitate within 2 hours to obtain a crude quinocetone.

[0031] Post-treatment: The above crude quinocetone product was put into 100 ml of water and heated to about 80°C. After the liquid was dissolved, it was filtered under insulation. The filtrate was cooled for crystallization and filtered. The filter cake was rinsed with anhydrous ethanol twice and dried to obtain 23.97 g of quinocetone product (yield 97.8%, content>98%).

[0032] Example 3

[0033] A preparation process of 3-methyl-2-cinnamoylquinoxaline-1,4-dioxide comprises the following steps:

[0034] Synthesis reaction: Weigh 17.64 g of acetoquinone (0.080 mol) and dissolve it in 200 ml of anhydrous ethanol solvent. Use phosphoric acid to adjust the pH value to 5. Add 0.012 mol of solid acid catalyst resin T-63MP and 0.032 mol of anhydrous sodium carbonate. Stir and mix at 60°C to obtain a clear solution. Then add (15.92 g, 0.15 mol) of benzaldehyde dropwise to react for 3 hours. Filter and recover the catalyst. After the mother liquor is cooled to 10°C, yellow crystals precipitate within 3 hours to obtain a crude quinocetone.

Claims

1. A process for preparing 3-methyl-2-cinnamoylquinoxaline-1,4-dioxide, characterized in that: The following steps are involved: 1) Under nitrogen protection, acetoquinone is dissolved in anhydrous ethanol, phosphoric acid is used to adjust the pH value to 4-5, then a catalyst and a water absorbent are added, benzaldehyde is added dropwise, and after the reaction is completed, the catalyst is filtered and recovered, and the obtained mother liquor is cooled to 5-10° C., allowed to stand for 2-3 hours, and yellow crystals are collected by filtration to obtain a crude quinocetone product; the catalyst is a solid acid catalyst resin T-63MP; 2) Recrystallizing the crude quinocetone to obtain a refined quinocetone; putting the crude quinocetone into water, heating it to 70-80° C., filtering the solution under heat preservation after it is dissolved, cooling the filtrate to 10-15° C. and crystallizing the quinocetone, and precipitating the quinocetone; washing the filter cake with anhydrous ethanol twice, and drying it to obtain a refined quinocetone; The molar ratio of acetoquinol to the catalyst is 1:(0.1-0.15); The water absorbing agent is anhydrous sodium carbonate, and the molar ratio of acetoquinone to anhydrous sodium carbonate is 1:(0.2-0.4).

2. The process for preparing 3-methyl-2-cinnamoylquinoxaline-1,4-dioxide according to claim 1, characterized in that: The molar ratio of the acetoquinone to the catalyst is 1:(0.1-0.15).

3. The process for preparing 3-methyl-2-cinnamoylquinoxaline-1,4-dioxide according to claim 1, characterized in that: The molar ratio of acetoquinone to benzaldehyde is 1:(1.5-2.0).

4. The process for preparing 3-methyl-2-cinnamoylquinoxaline-1,4-dioxide according to claim 1, characterized in that: The reaction temperature is 50-70°C and the reaction is under normal pressure.

5. The process for preparing 3-methyl-2-cinnamoylquinoxaline-1,4-dioxide according to claim 1, characterized in that: The reaction time is 3 to 6 hours.

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