Synthetic method of pyrazine-2-alcohol

Abstract

The invention discloses a synthesis method of pyrazine-2-alcohol, the synthesis route of the method is as follows: glycine is taken as an initial raw material, and a target product pyrazine-2-alcohol is obtained through esterification-ammonolysis-condensation three-step reaction process, the esterification-ammonolysis-condensation reaction process can be continuously carried out, so that the post-treatment process is greatly reduced, the yield is increased, and the production cost is reduced. Compared with non-continuous production, the method has the advantages that double periodic production times can be completed within the same time, and meanwhile, the wastewater amount and the equipment cost can be effectively reduced. The method has the advantages of low raw material cost, simplicity in operation, high product yield, environmental friendliness and the like, is suitable for large-scale production, and has a certain industrial prospect.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of pyrazine-2-ol. BACKGROUND

[0002] Pyrazine-2-ol, also known as hydroxypyrazine, has a molecular formula of C4H4N2O and a CAS number of 6270-63-9, and is white to light yellow crystals or powder in appearance. Pyrazine-2-ol is an important intermediate for synthesizing sulfonamide drugs, and is mainly used for synthesizing sulfamethoxypyrazine (SMPZ) and is also used for synthesizing 2-halogenated pyrazine and 2-cyanopyrazine and other drug intermediates.

[0003] At present, there are few literatures about pyrazine-2-ol, and therefore, a synthesis method of pyrazine-2-ol with low cost, simple operation, high product yield and environmental friendliness needs to be provided. SUMMARY

[0004] In order to solve the defects in the prior art, the application provides a synthesis method of pyrazine-2-ol.

[0005] In order to solve the above technical problems, the application provides the following technical solutions: The application provides a synthesis method of pyrazine-2-ol, and the synthesis route is as follows:

[0006] The specific synthesis steps are as follows: S1, glycin is used as a raw material, esterification reaction is carried out with methanol under the catalysis of concentrated sulfuric acid, after the reaction is completed, the reaction liquid is transferred into a reaction kettle while hot, is cooled to 10 DEG C under stirring, and is neutralized to neutral under the condition of cold preservation by adding liquid alkali; then, ammonia methanol solution is added, the kettle is closed and heated, the temperature is stabilized, and pressure is kept after heating, and ammonolysis reaction is carried out; after the ammonolysis reaction is completed, nitrogen gas is introduced for replacement for three times, methanol is distilled out under reduced pressure, water is added and stirred for about 5 hours, and then the target product of formula (2) is obtained by filtration and drying. S2, the compound of formula (2) obtained in step S1 is used as a raw material, liquid alkali is used as a catalyst, purified water is used as a solvent, ethylene glycol is added, condensation reaction is carried out, hydrochloric acid aqueous solution is added dropwise after the reaction is completed, and the system is neutralized to weak acidity, and then the target product of pyrazine-2-ol is obtained by concentration, filtration, and water washing.

[0007] Preferably, in the step S1, the molar ratio of the glycin, concentrated sulfuric acid and methanol is (0.5-1.5) :(0.05-0.15) :(2-4), the esterification reaction temperature is 50-100 DEG C, and the reaction time is 4-8 hours.

[0008] Preferably, in step S1, the mass ratio of the methanol solution of ammonia to glycine is (7-10):(1-3), the ammonolysis reaction temperature is 40-80℃, the pressure is 0.4-1.0MPa, and the reaction time is 3-5h.

[0009] Preferably, in step S1, the concentrated sulfuric acid is concentrated sulfuric acid with a mass fraction of 98%.

[0010] Preferably, in step S1, the molar concentration of the ammonia methanol solution is 7M.

[0011] Preferably, in step S1, the molar ratio of glycine, concentrated sulfuric acid, and methanol is 1:0.1:3, the esterification reaction temperature is 80°C, and the reaction time is 6 hours; the mass ratio of the methanol solution of ammonia to glycine is 5:1, the ammonolysis reaction temperature is 70°C, the pressure is 0.4 MPa, and the reaction time is 4 hours.

[0012] Preferably, in step S2, the molar ratio of the compound of formula (2), glyoxal and sodium hydroxide in the liquid alkali is (0.5~1.0): (1.1~1.3): (0.2~0.4), the condensation reaction temperature is -10~10℃, and the reaction time is 4~6h.

[0013] Preferably, in step S2, the temperature range is 0–5°C.

[0014] Preferably, in step S2, the molar ratio of the compound of formula (2), glyoxal and sodium hydroxide in the liquid alkali is (1:1.2:0.3), the condensation reaction temperature is 0℃, and the reaction time is 5h.

[0015] Compared with the prior art, the present invention has the following beneficial effects: This invention avoids the use of highly toxic and difficult-to-preserve reaction raw materials and reagents, and rationally designs the synthesis route, enabling the first two steps of the reaction to proceed continuously. This greatly simplifies the operation process, reduces the post-processing by half, effectively controls the amount of waste, and saves a significant amount of manpower and material costs. The yield of the first two steps of the reaction product is 89%, the yield of the condensation reaction is 87%, and the overall reaction yield is over 77%. In addition, this method also has the advantages of low raw material cost, green synthesis, and environmental friendliness, making it suitable for industrial-scale production. Detailed Implementation

[0016] The preferred embodiments of the present invention are described below. It should be understood that the preferred embodiments described herein are for illustration and explanation only and are not intended to limit the present invention.

[0017] Example 1

[0018] Preparation of glycine methylamine (Formula 2): 112.5 g (1.5 mol) of glycine and 143.99 g (3 mol) of methanol were added to a 1 L reaction flask. 15 g (0.15 mol) of concentrated sulfuric acid (98%) was added dropwise under stirring at room temperature. After the addition was complete, the temperature was raised to 80 °C and reacted for 6 h. After the reaction was completed, the temperature was cooled to 10 °C under stirring. Approximately 40 g of liquid alkali (30 wt%) was added dropwise to neutralize the sulfuric acid until neutral. The above materials were then transferred to a 1 L reaction flask. In a high-pressure reactor, 562.5 g of ammonia in methanol (7M) was added. The reactor was closed and the temperature was raised to 60°C. After the temperature stabilized, the pressure was maintained at 0.4-0.5 MPa. After the reaction was complete as monitored by liquid phase, nitrogen gas was introduced to purge the reaction three times. The reaction solution was transferred to a flask while hot and the methanol was recovered by vacuum distillation at 30°C. The distillation was stopped when no more solvent was distilled off. At this point, a large amount of solid product was observed to precipitate. 2 L of water was added and the mixture was stirred at room temperature for 5 h. The mixture was then filtered, washed with water until neutral, and dried to obtain 98.8 g of white fine crystalline product with a purity of 99.5% and a total product yield of 89.0%.

[0019] Preparation of pyrazine-2-ol: 74.8 g (1.0 mol) of compound (2), 400.0 g of purified water, and 75.5 g (1.3 mol) of glyoxal were added to a 2 L reaction flask. 53.4 g (0.40 mol) of 30% liquid alkali was added to a dropping funnel and slowly added to the reaction flask with stirring at 0 °C. As the liquid alkali was added, the system gradually thickened. After the addition was completed, the temperature was controlled at 0 °C and the reaction was carried out for 5 h. The reaction was stopped when the content of the raw material was lower than 1% by liquid chromatography. Then the reaction was restored to room temperature, and hydrochloric acid aqueous solution was added to neutralize the pH to 6-7. After the pH stabilized, the system was desolventized and concentrated to 100-180 mL. The product was filtered, washed with water, and dried to obtain 82.6 g of white solid powder product with a purity of 99.2% and a yield of 86.0%.

[0020] Example 2

[0021] Preparation of glycine methylamine (Formula 2): 37.5 g (0.5 mol) of glycine and 64.0 g (2 mol) of methanol were added to a 1 L reaction flask. 5 g (0.05 mol) of concentrated sulfuric acid (98%) was added dropwise with stirring at room temperature. After the addition was complete, the temperature was raised to 80 °C and reacted for 6 h. After the reaction was completed, the temperature was cooled to 10 °C with stirring. Approximately 12 g of liquid alkali (30 wt%) was added dropwise to neutralize the sulfuric acid until neutral. The above materials were then transferred to a 1 L reaction flask. In a high-pressure reactor, 261.5 g of ammonia in methanol (7M) was added. The reactor was closed and the temperature was raised to 60°C. After the temperature stabilized, the pressure was maintained at 0.4-0.5 MPa. After the reaction was complete as monitored by liquid phase, nitrogen gas was introduced to purge the reaction three times. The reaction solution was transferred to a flask while hot and the methanol was recovered by vacuum distillation at 30°C. The distillation was stopped when no more solvent was distilled off. At this point, a large amount of solid product was observed to precipitate. 2 L of water was added and the mixture was stirred at room temperature for 5 h. The mixture was then filtered, washed with water until neutral, and dried to obtain 31.4 g of white fine crystalline product with a purity of 98.7% and a total product yield of 85.0%.

[0022] Preparation of pyrazine-2-ol: 37.1 g (0.5 mol) of compound (2) and 200.0 g of purified water and 63.8 g (1.1 mol) of glyoxal were added to a 2 L reaction flask. 26.7 g (0.20 mol) of 30% liquid alkali was added to a dropping funnel and slowly added to the reaction flask with stirring at 0 °C. As the liquid alkali was added, the system gradually thickened. After the addition was completed, the temperature was controlled at 0 °C and the reaction was stopped when the content of the raw material was lower than 1% by liquid chromatography. Then the reaction was restored to room temperature, and hydrochloric acid aqueous solution was added to neutralize the pH to 6-7. After the pH stabilized, the system was desolventized and concentrated to between 50-90 mL. The product was filtered, washed with water, and dried to obtain 41.0 g of white solid powder product with a purity of 98.8% and a yield of 85.4%.

[0023] Example 3

[0024] Preparation of glycine methylamine (Formula 2): 75.0 g (1.0 mol) glycine and 72.0 g (4 mol) methanol were added to a 1 L reaction flask. 10.0 g (0.10 mol) concentrated sulfuric acid (98%) was added dropwise with stirring at room temperature. After the addition was complete, the temperature was raised to 80 °C and reacted for 6 h. After the reaction was completed, the mixture was cooled to 10 °C with stirring. Approximately 24 g of liquid alkali (30 wt%) was added dropwise to neutralize the sulfuric acid until neutral. The above mixture was then transferred to a 1 L reaction flask. In a high-pressure reactor, 523.0 g of ammonia in methanol (7M) was added. The reactor was closed and the temperature was raised to 60°C. After the temperature stabilized, the pressure was maintained at 0.4-0.5 MPa. After the reaction was complete as monitored by liquid phase, nitrogen gas was introduced to purge the reaction three times. The reaction solution was transferred to a flask while hot and the methanol was recovered by vacuum distillation at 30°C. The distillation was stopped when no more solvent was distilled off. At this point, a large amount of solid product was observed to precipitate. 2 L of water was added and the mixture was stirred at room temperature for 5 h. The mixture was then filtered, washed with water until neutral, and dried to obtain 63.6 g of white fine crystalline product with a purity of 99.0% and a total product yield of 86.0%.

[0025] Preparation of pyrazine-2-ol: 74.0 g (1 mol) of compound (2) and 400.0 g of purified water and 69.64 g (1.2 mol) of glyoxal were added to a 2 L reaction flask. 40.05 g (0.30 mol) of 30% liquid alkali was added to a dropping funnel and slowly added to the reaction flask with stirring at 0 °C. As the liquid alkali was added, the system gradually thickened. After the addition was completed, the temperature was controlled at 0 °C and the reaction was carried out for 5 h. The reaction was stopped when the content of the raw material was lower than 1% by liquid chromatography. Then the reaction was restored to room temperature and hydrochloric acid aqueous solution was added to neutralize the pH to 6-7. After the pH stabilized, the system was desolventized and concentrated to 100-180 mL. The product was filtered, washed with water and dried to obtain 81.5 g of white solid powder product with a purity of 98.9% and a yield of 85.0%.

[0026] The esterification-ammonolysis-condensation reaction process of this invention can be carried out continuously, which greatly reduces the post-processing. Compared with discontinuous production, it can complete twice the number of production cycles in the same time, while also effectively reducing wastewater and equipment costs. This method has the advantages of low raw material costs, simple operation, high product yield, and environmental friendliness, making it suitable for large-scale production and showing promising industrialization prospects.

[0027] Finally, it should be noted that the above descriptions are merely preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for synthesizing pyrazin-2-ol, characterized in that, Its synthetic route is as follows: The specific synthesis steps are as follows: S1. Using glycine as raw material, the compound of formula (1) was synthesized by esterification reaction with methanol under the catalysis of concentrated sulfuric acid. After the reaction was completed, the reaction solution was transferred to the reaction vessel while hot, cooled to 10°C with stirring, and neutralized to neutral by adding liquid alkali under cold conditions. Then, a methanol solution of ammonia was added, the vessel was closed and the temperature was raised. After the temperature stabilized, the pressure was maintained and the ammonolysis reaction was carried out. After the ammonolysis reaction was completed by liquid phase monitoring, nitrogen gas was introduced to replace the gas three times, methanol was distilled off under reduced pressure, water was added and stirred for about 5 hours, and the mixture was filtered and dried to obtain compound of formula (2). S2. Using the compound of formula (2) obtained in step S1 as raw material, liquid alkali as catalyst, purified water as solvent, ethylene glycol is added to carry out condensation reaction. After the reaction is completed, hydrochloric acid aqueous solution is added dropwise to neutralize to weak acidity. Then the system is concentrated, filtered, and washed with water to obtain the target product pyrazine-2-ol.

2. The method for synthesizing pyrazine-2-ol according to claim 1, characterized in that, In step S1, the molar ratio of glycine, concentrated sulfuric acid and methanol is (0.5-1.5): (0.05-0.15): (2-4), the esterification reaction temperature is 50-100℃, and the reaction time is 4-8h.

3. The method for synthesizing pyrazine-2-ol according to claim 1, characterized in that, In step S1, the mass ratio of the methanol solution of ammonia to glycine is (7-10): (1-3), the ammonolysis reaction temperature is 40-80℃, the pressure is 0.4-1.0MPa, and the reaction time is 3-5h.

4. The method for synthesizing pyrazine-2-ol according to claim 1, characterized in that, In step S1, the concentrated sulfuric acid is concentrated sulfuric acid with a mass fraction of 98%.

5. The method for synthesizing pyrazine-2-ol according to claim 1, characterized in that, In step S1, the molar concentration of the ammonia methanol solution is 7M.

6. The method for synthesizing pyrazine-2-ol according to claim 1, characterized in that, In step S1, the molar ratio of glycine, concentrated sulfuric acid, and methanol is 1:0.1:3, the esterification reaction temperature is 80℃, and the reaction time is 6h; the mass ratio of the methanol solution of ammonia to glycine is 5:1, the ammonolysis reaction temperature is 70℃, the pressure is 0.4MPa, and the reaction time is 4h.

7. The method for synthesizing pyrazine-2-ol according to claim 1, characterized in that, In step S2, the molar ratio of the compound of formula (2), glyoxal and sodium hydroxide in the liquid alkali is (0.5~1.0): (1.1~1.3): (0.2~0.4), the condensation reaction temperature is -10~10℃, and the reaction time is 4~6h.

8. The method for synthesizing pyrazine-2-ol according to claim 1, characterized in that, In step S2, the temperature range is 0 to 5°C.

9. The method for synthesizing pyrazine-2-ol according to claim 1, characterized in that, In step S2, the molar ratio of the compound of formula (2), glyoxal and sodium hydroxide in the liquid alkali is (1:1.2:0.3), the condensation reaction temperature is 0℃, and the reaction time is 5h.

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