Synthesis process of 2-acetylpyrazine

Abstract

According to the invention, pyrazine is used as a raw material, acetic anhydride is used as an acetylation reagent, and 2-acetylpyrazine is prepared under the condition of a metal supported catalyst. The method has the advantages of simple operation, few steps, good selectivity, few by-products and high product quality, and avoids the process route which easily causes by-products and impurities, such as high reagent toxicity, more reaction components, violent reaction and the like in the prior art. The product system is simple to purify, high in purity and stable in process route.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of chemical organic synthesis, and particularly relates to a synthesis process of 2 The present application relates to the technical field of chemical organic synthesis, and particularly relates to a synthesis process of 2 BACKGROUND

[0002] 2-Acetylpyrazine is a kind of heterocyclic compound with important industrial and biological activity, which can be used as a key component in food essence. Its unique popcorn fragrance, nut fragrance and roasted meat fragrance make it an important flavor additive for baked foods, meat products and snack foods. Acetylpyrazine is a key intermediate for the synthesis of various drugs, and its derivatives have significant biological activities such as anti-tumor and antibacterial. It can also be used as a raw material for compounds containing pyrazine. Therefore, 2-acetylpyrazine has very important uses.

[0003] At present, the synthesis of acetylpyrazine mainly has the following methods: Grignard reagent method, cyanopyrazine reacts with methyl Grignard reagent. Although this reaction has high efficiency, the acquisition of cyanopyrazine itself has great difficulty, and the use of Grignard reagent will bring in more impurities, and the reaction process cannot guarantee environmental protection and toxicity, which has great challenge to the quality of the product. Moreover, considering the use of acetylpyrazine as a food additive and a drug intermediate, this method will lead to complicated purification, increasing the cost of process and time cost.

[0004] Oxidation method, that is, in the presence of main catalyst metal porphyrin and co-catalyst iodine or azo compound, 2-(1-bromoethyl)pyrazine is oxidized in DMSO or DMF by air at 120-140℃ for 3-5 hours; distillation under reduced pressure. Although high yield and purity can be obtained, the system of the method is relatively heavy, and the co-catalyst is easy to cause impurities difficult to remove from the product, such as iodine impurities; and the oxidation reaction also causes oxidation impurities, making it difficult to guarantee the quality of the product.

[0005] Electrochemical synthesis method, in a single-chamber electrolytic cell, pyrazine, hexafluoroisopropanol, pyruvic acid, ammonium iodide are added to a 1,2-dichloroethane solution containing 0.1M lithium perchlorate, graphite sheet electrode is used as anode and graphite sheet is used as cathode, electrolysis is carried out under constant current, stirring is carried out at 70℃, column chromatography is used for separation, and acetylpyrazine is obtained with a yield of 18%. This method has low yield and is difficult to produce on a large scale.

[0006] Vinyl ether method, by adding raw material pyrazine and vinyl n-butyl ether in an organic solvent, then adding oxidant and trifluoroacetic acid, 2 Acetylpyrazine, the oxidizing agent is sodium persulfate, potassium persulfate or ammonium persulfate. Although this method uses n-butyl vinyl ether as an acetyl precursor raw material, it overcomes the low yield, harsh storage and transportation conditions of using acetaldehyde and pyruvic acid as acetyl precursors. However, the use of trifluoroacetic acid and oxidizing agent is uncontrollable, and oxidation leads to a more complex system. When used in food additives or pharmaceutical intermediates, the use has very high requirements for even trace amounts of impurities, which is a great challenge for purification.

[0007] There are also reports of using ethyl pyrazine as a raw material to prepare acetylpyrazine by oxidation with dichromate dihydrate, but the actual yield is low and has no practical production significance. In addition, there are also methods of preparing acetylpyrazine by adding tert-butyl hydroperoxide, ferrous sulfate to the acetaldehyde and pyrazine sulfuric acid solution at low temperature. However, although the yield of this method is improved, the system composition is still complex, and both the reaction process and the post-treatment are difficult to meet the production and environmental protection requirements. Even if the yield of the subsequent method is further improved by adding dichloromethane, tert-butyl formic acid, and ferrous sulfate to the acetaldehyde and pyrazine sulfuric acid solution, it still cannot meet the production requirements and results. Literature also reports a more complex multi-step method, which first cyclizes o-phenylenediamine with glyoxal to obtain quinoxaline, then oxidizes quinoxaline with potassium permanganate, decarboxylates in toluene to obtain pyrazine carboxylic acid, and esterifies to obtain acetylpyrazine. Although it claims to reach the level of industrial production, it is obvious that the steps are numerous and not ideal for industrial production.

[0008] In general industrial production, 2-acetylpyrazine is obtained by addition of Grignard reagent of halogenated alkane and 2-cyanopyrazine, but this method mostly uses a large amount of diethyl ether, the reaction is not safe and the conditions are complex, and the industrial wastewater causes great pressure on the environment.

[0009] Therefore, there is still a need to provide a more simple and industrial 2-acetylpyrazine synthesis process. SUMMARY

[0010] The purpose of the present application is to provide a simple and industrial 2-acetylpyrazine synthesis process.

[0011] The process comprises the following steps: pyrazine and acetic anhydride are reacted under the condition of a catalyst and a solvent to obtain acetylpyrazine.

[0012] The reaction is preferably carried out under inert gas protection, and the inert gas can be argon or nitrogen.

[0013] The catalyst is prepared by the following method: Aqueous solution of metal salt with concentration of 0.01-0.2 mol / L is prepared, and the metal salt solution is mixed with the carrier in the proportion of 2 mL solution to 1 g carrier, heated to 60-80℃ with stirring for 2 h, cooled to room temperature, filtered, and the solid is dried in an oven at 120℃ for 4-10 h to obtain a solid, which is ground to obtain a powder, and the powder is heated to 500℃ in a muffle furnace at a heating rate of 2℃ / min, and calcined for 6-8 h to obtain a metal-loaded catalyst.

[0014] The metal salt can be a salt of a transition metal, preferably one selected from FeCl3, CoCl2, NiCl2, CuSO4, SnCl4, (NH4)6Mo7O 24 , NH4VO3; more preferably SnCl4.

[0015] The carrier can be a carrier commonly used in the art, such as molecular sieve, activated carbon, alumina, etc. Preferably one selected from silica gel, HZSM-5, β molecular sieve, MCM-41, SBA-15; more preferably HZSM-5.

[0016] The molar ratio of pyrazine to acetic anhydride is pyrazine:acetic anhydride = 1:1.5-3; preferably 1:2.

[0017] The solvent can be a solvent commonly used in the art, and according to the properties of 2-acetylpyrazine, preferably one selected from DMF, DMSO, dichloromethane, chloroform, tetrahydrofuran; more preferably DMSO.

[0018] The reaction temperature is 60-100℃, preferably 60-80℃, preferably 80℃.

[0019] Unless otherwise specified, all technical and scientific terms used in the present application have the same meaning as commonly understood by one of ordinary skill in the art to which the present application belongs. Without deviating from the common sense in the art, the above-mentioned preferred conditions can be combined arbitrarily to obtain each preferred example of the present application.

[0020] The present application has the following beneficial effects: the catalyst is stable and meets the needs of industrial catalysts, and can be designed as a continuous production process; the yield and selectivity are high, and the post-treatment is simple. The catalyst can be reused to reduce production costs. The system is simple and does not involve other toxic and difficult-to-classify impurities, which can greatly reduce the subsequent application cost. DETAILED DESCRIPTION

[0021] The present application will be further illustrated by the following examples, but the present application is not limited to the scope of the examples.

[0022] Example 1 Preparation method of metal-loaded catalyst The direct impregnation method was used: 0.05 mol / L aqueous solutions of metal salts FeCl3, CoCl2, NiCl2, CuSO4, SnCl4, (NH4)6Mo7O 24

[0001] Example 2 Catalyst performance test Under nitrogen protection, 0.1 mol of pyrazine, 0.2 mol of acetic anhydride, 1 g of catalyst, 80 ml of dimethyl sulfoxide were added into a 200 ml reaction kettle, and heated to 80°C for 6 h. After filtering the solid catalyst, the system composition was detected by HPLC, and the selectivity and conversion rate were calculated.

[0024] a indicates no metal loading; b indicates no carrier added.

[0025] It can be seen that in the blank test, without adding any catalyst, only 15% conversion rate was obtained; and the conventional catalyst carrier showed certain catalytic activity, because the reaction belongs to the Friedel-Crafts reaction, and the solid carrier often has acidity, which is the conventional catalyst for Friedel-Crafts reaction; the metal Sn-loaded catalyst obtained the highest activity level.

[0026] Example 3 Catalyst loading 0.01 mol / L, 0.05 mol / L, 0.1 mol / L, 0.15 mol / L, and 0.2 mol / L SnCl4 aqueous solutions were respectively configured, and catalysts with different loadings were prepared according to the above method, and the reaction was carried out according to the performance test experiment.

[0027] It can be seen that with the increase of metal loading, the activity of the catalyst also increases, but since the loading capacity of the carrier is limited, when the metal solution concentration increases to 0.05 mol / L or more, it no longer increases.

[0028] Example 4 Catalyst recycling performance The recovered catalyst was directly used for the next new reaction.

[0029] ​The catalyst of this invention initially showed a slight decrease, possibly due to the loss of adsorbed unstable metals. After two cycles, the region stabilized and was able to maintain a high level of activity.

[0030] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A process for synthesizing 2-acetylpyrazine, characterized in that: Pyrazine and acetic anhydride react under the conditions of a catalyst and a solvent to yield acetylpyrazine; The catalyst is prepared by the following method: Prepare an aqueous solution of a metal salt with a concentration of 0.01~0.2 mol / L. Mix the metal salt solution with the support at a ratio of 2 mL solution to 1 g support, heat to 60~80℃ and stir for 2 h, cool to room temperature, filter, and dry the solid in a crucible in an oven at 120℃ for 4~10 h. Grind the solid to obtain powder, place the powder in a muffle furnace and heat to 500℃ at a heating rate of 2℃ / min, and calcine for 6~8 h to obtain a metal-supported catalyst. The metal salt is selected from FeCl3, CoCl2, NiCl2, CuSO4, SnCl4, and (NH4)6Mo7O. 24 One of NH4VO3; The carrier is selected from one of silica gel, HZSM-5, β molecular sieve, MCM-41, and SBA-15.

2. The process according to claim 1, characterized in that: The molar ratio of pyrazine to acetic anhydride is pyrazine:acetic anhydride = 1:1.5~3; preferably 1:

2.

3. The process according to claim 1, characterized in that: The solvent is selected from DMF, DMSO, dichloromethane, chloroform, and tetrahydrofuran; DMSO is preferred.

4. The process according to claim 1, characterized in that: The reaction temperature is 60~100℃, preferably 60~80℃, and more preferably 80℃.

5. The process according to claim 1, characterized in that: The metal salt in the metal salt solution is SnCl4.

6. The process according to claim 1, characterized in that: The concentration of the metal salt solution is 0.05~0.1 mol / L.

7. The process according to claim 1, characterized in that: The carrier is HZSM-5.

8. The process according to claim 1, characterized in that: The reaction was carried out under nitrogen protection.

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