CN112125903A - A kind of synthetic method of caffeine - Google Patents

Abstract

The invention discloses a method for synthesizing caffeine, and relates to the technical field of preparation of heterocyclic compounds containing purine ring systems. The method comprises the following steps: after mixing cyanoacetic acid and acetic anhydride for reaction at 30-80° C., adding solvent and dimethylurea, the reflux reaction is completed, cooling to room temperature, filtering, concentrating the filtrate, combining the solids to obtain the dimethylcyanacetoacetate, adding the liquid After adjusting the pH to 8-11 with alkali, react at 80-100 ℃ to generate dimethyl 4AU; completely dissolve dimethyl-4AU in formic acid, add sodium nitrite, react at room temperature, add catalyst, keep at 30-70 ℃, After the reaction is completed, the catalyst is recovered, and the mother liquor is concentrated to recover formic acid to obtain dimethyl FAU; the dimethyl FAU is added with water and liquid caustic soda, and the ring-closure reaction is performed to obtain theophylline sodium salt; the theophylline sodium salt is subjected to methylation reaction and purification to obtain caffeine. The method of the invention is easy to obtain raw materials, moderate reaction conditions and easy to control, few steps, simple and convenient operation, high yield, greatly improved product quality, and easy realization of industrialized production.

Description

A kind of synthetic method of caffeine

technical field

The invention relates to the technical field of preparation of heterocyclic compounds containing purine ring systems, in particular to a method for synthesizing caffeine.

Background technique

Caffeine (Caffeine) alias: 1,3,7-trimethylxanthine or 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione. Caffeine is a kind of xanthine compound, which has nerve stimulant effect. It is used in food, medicine and other fields.

The currently known method for industrially synthesizing caffeine is mainly the dimethylurea method. That is, cyanoacetic acid and dimethylurea are used as raw materials, and the intermediate product theophylline sodium salt is first generated through the steps of condensation, cyclization, sublimation, water washing, hydrogenation, acylation ring closure, and filtration, and then crude coffee is generated through methylation and filtration. The finished caffeine is produced through the steps of refining, crystallization, filtration, drying, granulation and pulverization.

This process does not require high equipment, the reaction is simple and easy to carry out, and it is easy to realize industrialization. Therefore, it has been adopted by various manufacturers for many years. However, this process has many shortcomings, such as complicated process steps, long routes, many side reactions, and long production cycle; in order to ensure the quality of subsequent finished products in actual production, it is necessary to increase filtration and separation operations in multiple intermediate steps, so that some impurities leave with the mother liquor. The reaction system, resulting in a large amount of sewage discharge, high COD and salinity, brings a lot of challenges to environmental protection; the influence of impurities makes the crude caffeine need to be refined twice to obtain qualified finished products; The single-step reaction also inhibited the improvement of the yield, and the total yield was less than 60%; in addition, due to the large amount of equipment used in this process, and it was a batch reaction, the labor and energy used were more, and a lot of costs were increased; at the same time, due to The batch reaction causes accidental factors between batches, which brings hidden dangers to the stability of quality.

In view of the above process defects, various manufacturers and experts and scholars have done a lot of research over the years. Liu Hui et al. invented a preparation method for N,N-1,3-dimethyl-4,5-diaminocarbazine (dimethyl DAU), and developed a new hydrogenation reduction system, which can make The reaction is more stable and controllable, and the improvement of catalytic activity makes the quality of dimethyl DAU stable, yield and quality improved; Guo Yuemin et al. removed reducing impurities by adding an oxidizing agent after the closed-loop reaction, and adding a reducing agent in the refining process of crude caffeine to remove oxidation. The steps of removing the impurities, improve the product yield and purity, save the separation of 1,3-dimethyl-4-amino-5-carboxamido ureaazine (dimethyl FAU), and shorten the production cycle; Liu Hui et al. invented a closed-loop reaction method, which uses a low-basicity catalytic system containing ethylamine to carry out the closed-loop reaction to avoid side reactions that are prone to occur under the high-basicity closed-loop reaction in the prior art, resulting in theophylline sodium salt (referred to as "tea sodium salt"). ") poor appearance, high salinity in the waste liquid, improve the yield of tea sodium, reduce environmental pressure; The pressure of environmental protection increased the yield of methylation to 97.8%; Gong Huaizheng et al. invented a new refining process, using a new decolorizing material carbon fiber filter to replace powder carbon decolorization, reducing carbon usage, saving energy and reducing consumption; Zhu Zhaoyou et al. In the research of caffeine crystallization process and equipment, a segmented tubular continuous crystallization method has been invented to replace the original batch crystallization, which reduces equipment investment, reduces energy consumption, and reduces cooling water consumption by about 60%. .

However, the above researches are all based on the existing process. The development and improvement of the reaction system, equipment, raw materials, etc. are carried out in a single step to reduce the reaction steps, improve the reaction yield, improve the product quality or produce beneficial environmental protection. effect, but did not substantially change the original process or significantly reduce the reaction steps.

SUMMARY OF THE INVENTION

The technical problem to be solved by the present invention is to provide a method for synthesizing caffeine, which has easy-to-obtain raw materials, mild and easy-to-control reaction conditions, few steps, simple operation, high yield, up to more than 70%, and greatly improved product quality , it is easy to realize industrial production, and provides a new synthetic route for the production of caffeine and theophylline sodium salt.

In order to solve the above-mentioned technical problems, the technical scheme adopted in the present invention is: a synthetic method of caffeine, comprising the steps:

Step 1: Formation of Dimethyl 4AU (1,3-Dimethyl-4-imidocarbazine)

After mixing cyanoacetic acid and acetic anhydride at 30-80°C for reaction, add solvent and dimethylurea, after the reflux reaction is completed, lower the reaction to room temperature, filter, concentrate the filtrate, and combine the solids to obtain dimethylcyanacetamide, which is added to The liquid alkali is adjusted to pH=8～11 and reacted at 80～100℃ to generate dimethyl 4AU;

Step 2: Generation of dimethyl FAU (1,3-dimethyl-4-amino-5-carboxamidoureaazine)

The dimethyl 4AU is completely dissolved in formic acid, sodium nitrite is added, and after the reaction at room temperature, the catalyst and water are added, and the temperature is kept at 30 to 70° C. After the reaction is completed, the catalyst is recovered, and the mother liquor is concentrated to recover formic acid to obtain dimethyl FAU;

Step 3: Generate theophylline sodium salt

Dimethyl FAU is added with water and liquid caustic soda, and the closed-loop reaction is carried out to obtain theophylline sodium salt;

Step 4: Generate Caffeine

Theophylline sodium salt is methylated and refined to obtain caffeine.

Preferably, in step 1, the solvent is one of toluene, benzene, dichloromethane, chloroform and cyclohexane.

Preferably, in step 1, the molar ratio of cyanoacetic acid:dimethylurea:acetic anhydride is 1:1-1.3:1-1.3.

Preferably, in step 1, cyanoacetic acid and acetic anhydride are mixed and reacted at 30-80°C for 1-5 hours, a solvent and dimethylurea are added, and after refluxing for 1-5 hours, the reaction is lowered to room temperature, filtered, and the The filtrate was concentrated, and the solids were combined to obtain dimethylcyanacetamide, which was adjusted to pH=8-11 by adding liquid caustic soda and reacted at 80-100° C. for half an hour to generate dimethyl 4AU.

Preferably, in step 2, the mass ratio of dimethyl 4AU to formic acid is 1:4-10.

Preferably, in step 2, the temperature at which sodium nitrite is added is -10 to 10° C., and the molar ratio of sodium nitrite:dimethyl 4AU is 1 to 1.5:1.

Preferably, in step 2, the catalyst is one of Raney nickel, palladium carbon and platinum carbon, and the mass ratio of the catalyst to dimethyl 4AU is 0.005-0.05:1.

Further preferably, in step 2, the palladium content in the palladium carbon is 5wt%, and the platinum content in the platinum carbon is 5wt%.

Preferably, in step 2, dimethyl 4AU is completely dissolved in formic acid, sodium nitrite is added, and the catalyst is added after the reaction at room temperature for 1 to 5 hours, and the temperature is kept at 30 to 70 ° C for 3 to 7 hours, and the catalyst is recovered after the reaction is completed. The mother liquor is concentrated to recover formic acid to obtain dimethyl FAU.

Preferably, in step 3, dimethyl FAU is added with water and stirred to raise the temperature to 70 °C, liquid caustic soda is added, the temperature is kept at 90 to 100 °C for 0.5 to 2 hours, and the temperature is cooled and filtered to obtain theophylline sodium salt.

Preferably, in step 3, the alkalinity is adjusted to 1.5-3.0.

The beneficial effect that adopts the above-mentioned technical scheme to produce is: the present invention has developed a kind of new caffeine synthesis method, has the following advantages compared with the prior art:

(1) the reaction steps of the present invention are greatly reduced, the prior art needs 6 steps, and the present invention only needs 4 steps to complete, reducing the multiple washing and separating steps, improving the stability of product quality, improving product yield, and reducing Reduce the amount of sewage and reduce the difficulty of environmental protection;

(2) the present invention adds solvent in the condensation reaction that generates dimethyl cyanacetamide, ensures the anhydrous condition of the reaction, makes the reaction more thoroughly carried out, and reduces the occurrence of side reactions;

(3) the present invention merges the three steps of subsynthesis, hydrogenation reduction and acylation in the prior art into one step, greatly reducing the reaction steps and the reaction time;

(4) the present invention uses formic acid to carry out reduction reaction as a solvent, completely eliminates the use of hydrogen in the existing technology, and reduces safety risks;

(5) The method of the present invention has few reaction steps, mild reaction conditions, easy operation, high yield, stable product quality, small amount of sewage discharge, eases the difficulty of environmental protection treatment, and is easy to industrialize.

Detailed ways

The present invention will be described in further detail below through specific embodiments, but these specific embodiments do not constitute any limitation to the present invention.

Example 1

1 mol of cyanoacetic acid and 1.2 mol of acetic anhydride were mixed and reacted at 40°C for 1 hour, 2 mol of toluene and 1.2 mol of dimethylurea were added, and after refluxing for 3 hours, the reaction was cooled to room temperature, filtered, and the filtrate was concentrated. Combine the solids, add liquid caustic soda to adjust pH=9, react at 90° C. for half an hour, and filter at room temperature to obtain dimethyl 4AU.

Take 20 g of dimethyl 4AU, completely dissolve it in 150 g of formic acid, cool down to 0°C, add 1 molar equivalent of sodium nitrite of dimethyl 4AU, and react at room temperature for 4 hours. Then 0.6 g of catalyst (5% platinum carbon) was added, and the reaction was continued at 30° C. for 5 hours. The catalyst was recovered by filtration, and the mother liquor was concentrated to recover formic acid to obtain dimethyl FAU.

The dimethyl FAU obtained in the previous step was added to the four-necked flask, 100 ml of water was added, the temperature was raised to 70°C, liquid caustic soda was added, the alkalinity was adjusted to 2.0, and the temperature was raised to 90°C for 0.5 hour. It was cooled to 18°C and filtered to obtain theophylline sodium salt with a yield of 92.1%.

Theophylline sodium salt obtains caffeine through methylation and refining processes. The overall yield was 81.0%. Purity 99.98%.

Example 2

1 mol of cyanoacetic acid and 1.02 mol of acetic anhydride were mixed and reacted at 30°C for 5 hours, 2 mol of benzene and 1.02 mol of dimethylurea were added, and after refluxing for 3 hours, the reaction was cooled to room temperature, filtered, and the filtrate was concentrated. Combine the solids, add liquid caustic soda to adjust pH=8, react at 80° C. for half an hour, and filter at room temperature to obtain dimethyl 4AU.

Take 20 g of dimethyl 4AU, completely dissolve it in 80 g of formic acid, cool down to -10°C, add 1.2 molar equivalent of sodium nitrite of dimethyl 4AU, and react at room temperature for 2.5 hours. Then 0.2 g of catalyst (5% palladium on carbon) was added, and the temperature was controlled at about 50° C. to continue the reaction for 3 hours. The catalyst was recovered by filtration, and the mother liquor was concentrated to recover formic acid to obtain dimethyl FAU.

The dimethyl FAU obtained in the previous step was added to the four-necked flask, 100 ml of water was added, the temperature was raised to 70° C., liquid caustic soda was added, the alkalinity was adjusted to 1.5, and the temperature was raised to 95° C. for 1 hour. Cooling and cold filtration to obtain theophylline sodium salt with a yield of 85.5%.

Theophylline sodium salt obtains caffeine through methylation and refining processes. The overall yield was 74.8%. Purity 99.98%.

Example 3

1 mol of cyanoacetic acid and 1.3 mol of acetic anhydride were mixed and reacted at 75°C for 3 hours, 2 mol of solvent trichloromethane and 1.3 mol of dimethylurea were added, and after refluxing for 5 hours, the reaction was cooled to room temperature, filtered, and the filtrate was concentrated. Combine the solids, add liquid caustic soda to adjust pH=10, react at 100° C. for half an hour, and filter at room temperature to obtain dimethyl 4AU.

20 g of dimethyl 4AU was taken, completely dissolved in 200 g of formic acid, cooled to 10° C., 1.5 molar equivalent of sodium nitrite of dimethyl 4AU was added, and the reaction was carried out at room temperature for 5 hours. Then 1 g of catalyst (Raney nickel) was added, and the temperature was controlled at about 70° C. to continue the reaction for 7 hours. The catalyst was recovered by filtration, and the mother liquor was concentrated to recover formic acid to obtain dimethyl FAU.

The dimethyl FAU obtained in the previous step was added to the four-necked flask, 100 ml of water was added, the temperature was raised to 70° C., liquid caustic soda was added, the alkalinity was adjusted to 3.0, and the temperature was raised to 98° C. for 2 hours. After cooling and cold filtration, theophylline sodium salt was obtained with a yield of 80.6%.

Theophylline sodium salt obtains caffeine through methylation and refining processes. The overall yield was 70.8%. Purity 99.96%.

Comparative Example

The existing caffeine production process is:

Step 1: Generation of dimethyl 4AU (1,3-dimethyl-4-imidocarbazine)

After mixing 1 mol of cyanoacetic acid and 1 to 1.2 mol of dimethylurea, 1.1 to 1.5 mol of acetic anhydride is added below 80°C to carry out the condensation reaction, and the maximum temperature of the condensation reaction does not exceed 120°C. The condensation reaction is completed to generate dimethyl cyanacetamide. At 40-45 DEG C, the dimethyl cyanoacetyl urea is added to the ionic membrane liquid caustic soda, adjusted to pH=9-10, and the temperature is kept at 80-90 DEG C for 30-40 minutes to generate dimethyl 4AU.

Step 2: Dimethyride to generate xylenuric acid (1,3-dimethyl-4-imino-5-isonitrosoureaazine)

The sodium nitrite solution with a mass ratio of 20% to 30% is added to the dimethyl 4AU feed liquid, and it is added to the dilute sulfuric acid at 4 to 15°C with a concentration of 15% to 20%, and the feeding time is controlled at 20 to 20%. Within 30 minutes, the final temperature is 40 to 45° C., and the pH is adjusted to 2.0 to 3.0 to generate xylene violet acid.

The submerged xylene violet acid was repeatedly washed with water until it became neutral for hydrogenation reduction.

Step 3: Hydrogenation reduction to form dimethyl DAU (N,N-1,3-dimethyl-4,5-dicarbazine)

Using Raney nickel as a catalyst, the dimethicuric acid is reduced with hydrogen. The amount of the catalyst is 3-10% of the quality of the dimethicuric acid, and the material concentration of the dimethicuric acid is 10-20%, and the hydrogen pressure is adjusted. The reaction is carried out at 0.34-0.39 MPa, and the end point temperature is controlled below 90° C. by cooling with low-temperature water to generate dimethyl DAU.

Step 4: Acylation to Dimethyl FAU (1,3-Dimethyl-4-amino-5-carboxamidoureaazine)

Formic acid is added to the dimethyl DAU feed liquid, the pH value is adjusted to 3.2 to 3.5, and the temperature is kept at 90 to 100°C for 30 to 60 minutes to generate dimethyl FAU.

Step 5: Close the loop to generate theophylline sodium salt

Add an appropriate amount of water, stir and heat up to 70 DEG C, add liquid caustic soda, keep the temperature at 90-100 DEG C for 0.5-2 hours, cool down and cold filter to obtain theophylline sodium salt with a yield of 83.1%.

Step 6: Generate Caffeine

Theophylline sodium salt and dimethyl sulfate are reacted with methylation, primary refining and secondary refining to obtain caffeine, and the total yield is 58.1%. Purity 99.85%.

Claims (10)

1. a synthetic method of caffeine, is characterized in that, comprises the steps: Step 1: Generation of Dimethyl 4AU After mixing cyanoacetic acid and acetic anhydride at 30-80°C for reaction, add solvent and dimethylurea, after the reflux reaction is completed, lower the reaction to room temperature, filter, concentrate the filtrate, and combine the solids to obtain dimethylcyanacetamide, which is added to The liquid alkali is adjusted to pH=8～11 and reacted at 80～100℃ to generate dimethyl 4AU; Step 2: Generation of Dimethyl FAU The dimethyl 4AU is completely dissolved in formic acid, sodium nitrite is added, and after the reaction at room temperature, the catalyst and water are added, and the temperature is kept at 30 to 70° C. After the reaction is completed, the catalyst is recovered, and the mother liquor is concentrated to recover formic acid to obtain dimethyl FAU; Step 3: Generate theophylline sodium salt Dimethyl FAU is added with water and liquid caustic soda, and the closed-loop reaction is carried out to obtain theophylline sodium salt; Step 4: Generate Caffeine Theophylline sodium salt is methylated and refined to obtain caffeine. 2. the synthetic method of a kind of caffeine according to claim 1, is characterized in that in described step 1, solvent is a kind of in toluene, benzene, methylene dichloride, chloroform and cyclohexane. 3. the synthetic method of a kind of caffeine according to claim 1, is characterized in that in described step 1, the mol ratio of cyanoacetic acid: dimethylurea: acetic anhydride is 1:1～1.3:1～1.3. 4. the synthetic method of a kind of caffeine according to claim 1 is characterized in that in described step 1, after cyanoacetic acid and acetic anhydride are mixed, react at 30～80 ℃ for 1～5 hour, add solvent and dimethyl formaldehyde Urea, after refluxing for 1 to 5 hours, the reaction was lowered to room temperature, filtered, the filtrate was concentrated, and the solids were combined to obtain dimethyl cyanacetamide, add liquid alkali to adjust pH=8 to 11, and react at 80 to 100 ° C for half an hour , producing dimethyl 4AU. 5. the synthetic method of a kind of caffeine according to claim 1, is characterized in that in described step 2, the mass ratio of dimethyl 4AU and formic acid is 1:4～10. 6. the synthetic method of a kind of caffeine according to claim 1 is characterized in that in described step 2, the temperature that adds sodium nitrite is-10～10 ℃, and sodium nitrite: the mol ratio of dimethyl 4AU 1 to 1.5:1. 7. the synthetic method of a kind of caffeine according to claim 1 is characterized in that in described step 2, catalyzer is a kind of in Raney nickel, palladium carbon and platinum carbon, the quality of catalyzer and dimethyl 4AU The ratio is 0.005-0.05:1; the mass ratio of water and dimethyl 4AU is 1-5:1. 8. the synthetic method of a kind of caffeine according to claim 1 is characterized in that in described step 2, dimethyl 4AU is completely dissolved in formic acid, sodium nitrite is added, after room temperature reaction 1～5 hour, The catalyst is then added, and the temperature is kept at 30 to 70° C. for 3 to 7 hours. After the reaction is completed, the catalyst is recovered, and the mother liquor is concentrated to recover formic acid to obtain dimethyl FAU. 9. the synthetic method of a kind of caffeine according to claim 1, it is characterized in that in described step 3, dimethyl FAU is heated to 70 DEG C with stirring and is warmed up to 70 DEG C, adds liquid caustic soda, and is incubated at 90 ~ 100 DEG C for 0.5 ~ 2 hours , Cooling and cold filtration to obtain theophylline sodium salt. 10 . The method for synthesizing caffeine according to claim 1 , wherein in the step 3, the alkalinity is adjusted to 1.5-3.0. 11 .