Preparation process of caffeine with high yield and its application in cosmetics

Abstract

The present invention relates to the technical field of chemical process, in particular to the IPC C07D473 field, and more specifically, to a preparation process of caffeine with high yield and its application in cosmetics. The present invention prepares caffeine through six steps: the formation of dimethyl 4AU, the formation of dimethyl NAU, the formation of dimethyl FAU, the formation of theophylline sodium salt, methylation reaction, and the purification of caffeine. During the purification process of the present invention, high-purity caffeine can be obtained by centrifugation only once, and the liquid obtained after purification can also recover caffeine through operations such as decolorization and concentration. The recovered caffeine and product one can be jointly purified continuously, which can improve the yield of the final high-quality caffeine. The caffeine prepared by the present invention not only has high purity, but also has high yield, is white in color and has extremely low cytotoxicity. When applied in the field of cosmetics, it can improve the soothing, anti-wrinkle and anti-hair loss effects of cosmetics.

Description

Technical Field

[0001] The present invention relates to the field of chemical process technology, in particular to the field of IPC C07D473, and more specifically to a preparation process of high-yield caffeine and application thereof in cosmetics. Background Art

[0002] Caffeine (1,3,7-trimethylxanthine) is a xanthine alkaloid compound, which is widely used in the fields of food, medicine, chemical industry, etc. At present, the route of synthesizing caffeine is mostly to carry out a series of synthetic routes with cyanoacetic acid and dimethylurea as raw materials, and finally obtain caffeine, but in the synthesis process, due to the various steps, the loss of caffeine is very large, resulting in low final yield and high cost. In addition, in recent years, it has been found that adding caffeine as a cosmetic raw material into cosmetics can make the cosmetics have certain anti-wrinkle, soothing and anti-stripping effects, but in the preparation process of caffeine, the addition of raw materials such as dimethyl sulfate and the occurrence of side reactions in the sub-reaction process will produce toxic substances, and these situations will eventually affect the safety of caffeine.

[0003] In the prior art, a patent document with publication number CN 102344451B discloses a method for preparing caffeine, wherein impurities are removed by adding an oxidant and a reductant, and then high-purity caffeine is prepared through three separations. However, due to the large number of separations, the yield is relatively low.

[0004] Patent document with publication number CN105294692A discloses a method for refining caffeine. By adding polyvinyl pyrrolidone and introducing ozone, heavy metal manganese ions in caffeine can be eliminated, thereby improving the quality of caffeine. However, the improvement in the yield of caffeine is not obvious. Summary of the invention

[0005] In order to solve the above problems, the first aspect of the present invention provides a process for preparing high-yield caffeine, the steps of which are as follows:

[0006] S1. Formation of dimethyl 4AU: Mix cyanoacetic acid and dimethyl urea, add a water absorbent, and react at 60-120°C for 0.5-2h to obtain substance 1; mix substance 1 with an alkaline solution, and react at 80-100°C for 30-60min to obtain dimethyl 4AU;

[0007] S2, generation of dimethyl NAU: after mixing the dimethyl 4AU obtained in step S1 with sodium nitrite, adjusting the pH to 2.0-3.5, and controlling the temperature to keep at 20-60°C for 0.5-1h, the obtained product is washed several times until the pH is 6-7, i.e. dimethyl NAU;

[0008] S3. Generation of dimethyl FAU: Prepare an aqueous solution with a concentration of 10 - 30% of the dimethyl NAU obtained in step S2 and mix it with a catalyst, then carry out a hydrogenation reaction. The reaction pressure is 0.3 - 0.4 MPa, and the reaction time is 30 - 100 min. After obtaining dimethyl DAU, adjust the pH value to 2 - 5, raise the temperature to 80 - 100 °C, and react for 0.5 - 1 h to obtain dimethyl FAU;

[0009] S4. Generation of theophylline sodium salt: Mix the dimethyl FAU obtained in step S3 with an ion-exchange membrane caustic soda solution. After adjusting the alkalinity of the solution to 1.5 - 2.5 mmol / L, react at 80 - 100 °C for 0.5 - 1 h to obtain theophylline sodium salt;

[0010] S5. Methylation reaction: Mix the theophylline sodium salt obtained in step S4 with dimethyl sulfate, adjust the pH value to 9 - 10, and keep the temperature at 30 - 60 °C for 0.5 - 2 h to obtain Product 1;

[0011] S6. Refinement of caffeine: Refine Product 1 obtained in step S5 twice to obtain caffeine with a high yield.

[0012] In step S1, the molar ratio of the cyanoacetic acid, dimethylurea, and the water absorbent is 1:(0.5 - 1):(0.7 - 2).

[0013] Preferably, the water absorbent in step S1 is one or more of acetic anhydride, soda lime, anhydrous calcium chloride, and quicklime; more preferably, it is acetic anhydride.

[0014] Preferably, the alkaline solution in step S1 is an aqueous solution of sodium hydroxide; the mass concentration of sodium hydroxide in the alkaline solution is 20 - 40%.

[0015] Preferably, the weight ratio of Substance 1 to the alkaline solution in step S1 is 1:(0.5 - 2).

[0016] Preferably, the molar ratio of dimethyl 4AU to sodium nitrite in step S2 is 1:1.

[0017] In step S2, during the nitrosation reaction of dimethyl 4AU and sodium nitrite, side reactions are likely to occur. The side reactions will generate nitrogen-containing genotoxic substances, affecting the purity and safety of caffeine. The applicant found through a large number of experiments that when the molar ratio of dimethyl 4AU to sodium nitrite is 1:1 and dimethyl NAU is generated under specific conditions in step S2, it can not only improve the yield of dimethyl NAU but also reduce the probability of side reactions during the nitrosation reaction, thereby reducing the content of toxic substances, and further improving the safety and yield of the prepared caffeine. While reducing costs, it can also be applied in the cosmetics field.

[0018] Preferably, the catalyst described in step S3 is one or more of Raney nickel catalyst, supported nickel catalyst, organotin catalyst, and platinum catalyst; more preferably, it is Raney nickel catalyst.

[0019] Preferably, the addition amount of the catalyst described in step S3 is 1-5% of the mass of the dimethyl NAU aqueous solution.

[0020] Preferably, the weight ratio of the sodium salt of theophylline to dimethyl sulfate in step S5 is (2-3):1.

[0021] In some preferred embodiments, in the methylation reaction of step S5, the weight ratio of the sodium salt of theophylline to dimethyl sulfate is (2-3):1, which can further improve the safety of caffeine. This may be because although dimethyl sulfate is one of the main raw materials for the methylation reaction, it belongs to highly toxic products and has strong irritation and corrosiveness. If its addition amount is too much, when the prepared caffeine is applied to cosmetics, it will cause skin irritation, flushing, etc., affecting the use effect of cosmetics; however, if the addition amount of dimethyl sulfate is too little, it will lead to incomplete reaction with the sodium salt of theophylline, affecting the yield of the finally obtained caffeine. The applicant found through a large number of experiments that when the weight ratio of the sodium salt of theophylline to dimethyl sulfate is controlled to be (2-3):1, and the caffeine prepared under specific conditions in step S5 can further improve the safety of caffeine and the soothing effect in cosmetics, while also improving the yield of caffeine. However, to significantly improve the yield of caffeine, only adjusting the synthesis steps is not enough.

[0022] Preferably, the specific steps of the two refinements in step S6 include: First refinement: Dissolve the first product in water, adjust the concentration of the solid substance in the system to 10-20 wt%, add sulfuric acid to adjust the pH to 2.5-3, then add potassium permanganate, keep warm at 70-90 °C for 1 h, add modified activated carbon, continue to keep warm at 70-90 °C for 1 h, and recover the activated carbon by passing the solution through a carbon filtration filter to obtain the first liquid;

[0023] Second refinement: Add water to the first liquid to adjust the solid-liquid ratio in the system to 1:(5-10), add sulfuric acid to adjust the pH of the first liquid to 2.5-3, then add potassium permanganate, keep warm at 70-90 °C for 1 h, add modified activated carbon, continue to keep warm at 70-90 °C for 1 h, recover the activated carbon by passing the solution through a carbon filtration filter, then cool and crystallize, and centrifuge in a centrifuge to obtain wet product caffeine and the second liquid.

[0024] Preferably, the addition amount of the potassium permanganate is 1-3% of the weight of the caffeine.

[0025] In order to improve the purity of caffeine, the applicant purified the product one (crude caffeine) obtained in step S5 through a specific secondary refining method. This may be because the caffeine obtained through the preparation process of steps S1 - S5 contains a relatively large amount of impurities. Through a large number of experiments, the applicant found that by adding an appropriate amount of potassium permanganate, it can have strong oxidizing properties without damaging the structure of caffeine, thereby removing the impurities generated in the synthesis step and improving the purity of caffeine.

[0026] Preferably, the specific steps for the modified activated carbon are as follows: Place the activated carbon in a 1 - 5wt% hydrochloric acid solution, keep it at 70 - 90°C for 0.5 - 2h, filter out the moisture, and repeatedly rinse it with deionized water until it is neutral, then dry it to constant weight at 100 - 140°C for standby;

[0027] Put 5 - 25g of the dried activated carbon into a tubular furnace, introduce gas, react at 400 - 600°C for 1 - 3h, then switch to an inert gas and cool it to room temperature with the furnace, and the modified activated carbon is obtained.

[0028] Preferably, the gas is one or more of ammonia, argon, and oxygen; further preferably, it is ammonia and argon.

[0029] Preferably, the flow rate ratio of ammonia to argon is 1:(2 - 4); further preferably, it is 1:3.

[0030] Preferably, the inert gas is any one of helium and argon; further preferably, it is argon.

[0031] Preferably, the methylene blue adsorption value of the activated carbon ≥ 100mg / g, the specific surface area > 800m 2 / g, and the particle size is 100 - 500 mesh; further preferably, the methylene blue adsorption value of the activated carbon ≥ 120mg / g, the specific surface area > 1000m 2 / g, and the particle size is 20 - 325 mesh.

[0032] In some preferred embodiments, the activated carbon is purchased from the wood powder activated carbon produced by Suzhou Like Environmental Protection Technology Co., Ltd.

[0033] Preferably, the weight ratio of potassium permanganate to modified activated carbon is 1:(0.8 - 3).

[0034] The applicant unexpectedly found that after the reaction of potassium permanganate with crude caffeine, adding a certain amount of activated carbon could further improve the purity and colority of caffeine. This may be due to the large specific surface area and good adsorption property of the activated carbon, which can adsorb impurities such as floating substances in the solution, thereby improving the purity of caffeine. However, the activated carbon purchased on the market has limited adsorption of impurities and residual potassium permanganate in the solution, and there is also a possibility of adsorbing caffeine, resulting in a decrease in the caffeine yield. The applicant creatively found that modifying the activated carbon purchased on the market can improve the purity and yield of caffeine. This may be because through the specific modification method of the present invention, the content of surface active groups of the activated carbon can be increased, thereby enhancing the non-polarity of the surface of the modified activated carbon, and greatly strengthening the adsorption capacity for organic impurities and impurities obtained after the oxidation reaction of potassium permanganate and potassium permanganate. Moreover, when the weight ratio of the potassium permanganate to the modified activated carbon is 1:(0.8 - 3), the two raw materials act synergistically to improve the yield of caffeine while increasing the purity of caffeine. And subsequently, the modified activated carbon can be recycled through a carbon filter with a specific pore size and pressure, improving the economic benefits.

[0035] Preferably, the pore size of the carbon filter is 10 - 20 μm, and the pressure is 0.05 - 0.5 mpa.

[0036] Preferably, the pore size of the centrifuge filter cloth is 10 - 50 μm, and the centrifuge speed is 700 - 1200 r / min.

[0037] Preferably, the cooling process is as follows: under the action of cooling circulating water at 5 - 15 °C, the solution is continuously stirred until the solution temperature drops below 18 °C.

[0038] Preferably, Liquid Two can recover caffeine through operations such as decolorization and concentration, and co-refining the recovered caffeine with Product One can improve the yield of the final high-quality caffeine.

[0039] Preferably, the specific operation for recovering caffeine is as follows: Take 200 kg of the mixed solution of Liquid Two, clarify and remove impurities through a ultrafiltration tubular ceramic membrane with a molecular weight cut-off of 10000 Da, the obtained clarified liquid is decolorized and desalted through a nanofiltration membrane with a molecular weight cut-off of 500 - 20002 Da, 50 kg of deionized water is added to wash out the caffeine in the concentrated solution and incorporated into the decolorized liquid, the concentrated solution is discharged, and the decolorized liquid enters a nanofiltration system with a molecular weight cut-off of 100 - 200 Da for concentration. The concentrated solution obtained by controlling the temperature at 40 - 50 °C is cooled, crystallized, and filtered to obtain the recovered caffeine.

[0040] In the prior art, in order to improve the purity of caffeine, there are generally two centrifugation processes in the refining step of caffeine. Although the two centrifugations can improve the purity of caffeine, some caffeine will also be involved in the waste liquid due to the centrifugation effect, which will ultimately affect the yield of caffeine. The applicant has proven through a large number of experiments that with the specific two-step refining method of this application, high-purity caffeine can be obtained with only one centrifugation, and the liquid two obtained after refining can recover caffeine through operations such as decolorization and concentration. The recovered caffeine can be jointly refined with product one to improve the yield of the final high-quality caffeine.

[0041] The second aspect of the present invention provides the application of the high-yield caffeine in cosmetics, which can be applied to cosmetics such as emulsions, creams, lotions, essences, facial masks, shampoos, and anti-hair loss liquids.

[0042] Beneficial effects:

[0043] 1. By limiting the molar ratio of dimethyl 4AU and sodium nitrite and generating dimethyl NAU under specific conditions in step S2, the present invention can improve the yield of dimethyl NAU while also improving the safety and yield of the prepared caffeine.

[0044] 2. By limiting the weight ratio of theophylline sodium salt and dimethyl sulfate in the methylation reaction in step S5, the present invention can further improve the safety of caffeine.

[0045] 3. By adding an appropriate amount of potassium permanganate during the secondary refining process, the present invention can improve the purity of caffeine.

[0046] 4. By modifying activated carbon in a specific manner, the present invention can enhance the adsorption capacity for organic impurities and impurities obtained after the oxidation reaction of potassium permanganate and potassium permanganate. By limiting the weight ratio of potassium permanganate and modified activated carbon, the present invention can improve the purity of caffeine while also improving the yield of caffeine.

[0047] 5. During the secondary refining process, the present invention can recycle the modified activated carbon through a carbon filter with a specific pore size and pressure, improving economic benefits.

[0048] 6. During the secondary refining process, the present invention can obtain high-purity caffeine with only one centrifugation, and the liquid two obtained after refining can recover caffeine through operations such as decolorization and concentration. The recovered caffeine can be jointly refined with the product to improve the yield of the final high-quality caffeine.

[0049] 7. The caffeine prepared by the present invention not only has high purity and high yield, is white in color and has extremely low cytotoxicity, but also can improve the soothing, anti-wrinkle and anti-hair loss effects of cosmetics when applied in the cosmetics field. Description of the drawings

[0050] Figure 1 Cell viability graphs of caffeine prepared in Example 1 at different concentrations in the MTT assay;

[0051] Figure 2 Graph of the changing trend of caffeine prepared in Example 1 at different concentrations in the TNF-α content detection;

[0052] Figure 3 Graph of the changing trend of caffeine prepared in Example 1 at different concentrations in the IL-6 content detection;

[0053] Figure 4 Graph of the changing trend of caffeine prepared in Example 1 at different concentrations in the MMP-1 content detection;

[0054] Figure 5 Graph of the changing trend of caffeine prepared in Example 1 at different concentrations in the 5α-reductase inhibition assay. Detailed implementation manners

[0055] Examples

[0056] Example 1

[0057] Example 1 provides a preparation process of caffeine with high yield, and the steps are as follows:

[0058] S1. Generation of dimethyl 4AU: Take cyanoacetic acid and dimethylurea, mix them, add a water absorbent, react at 90 °C for 1 h to obtain Substance 1; mix Substance 1 with an alkali solution and react at 90 °C for 40 min to obtain dimethyl 4AU;

[0059] S2. Generation of dimethyl NAU: Mix the dimethyl 4AU obtained in step S1 with sodium nitrite, adjust the pH to 3.0 with formic acid, and keep the temperature at 40 °C for 0.5 h. After washing the product several times until the pH is 7, it is dimethyl NAU;

[0060] S3. Generation of dimethyl FAU: Prepare an aqueous solution with a concentration of 20% of the dimethyl NAU obtained in step S2 and mix it with a catalyst, carry out a hydrogenation reaction, the reaction pressure is 0.3 MPa, and the reaction time is 70 min. After obtaining dimethyl DAU, add formic acid to adjust the pH value to 3, raise the temperature to 90 °C, and react for 0.5 h to obtain dimethyl FAU;

[0061] S4. Generation of theophylline sodium salt: Mix the dimethyl FAU obtained in step S3 with an ion-exchange membrane caustic soda solution, adjust the alkalinity of the solution to 2 mmol / L, and react at 90 °C for 0.5 h to obtain theophylline sodium salt;

[0062] S5, Methylation reaction: Mix the theophylline sodium salt obtained in step S4 with dimethyl sulfate, add sodium hydroxide to adjust the pH value to 9, keep the temperature at 40 °C for 1 h to obtain Product 1.

[0063] S6, Purification of caffeine: Purify Product 1 obtained in step S5 twice to obtain caffeine with high yield.

[0064] In step S1, the molar ratio of cyanoacetic acid, dimethylurea and the water absorbent is 1:1:1.

[0065] The water absorbent described in step S1 is acetic anhydride.

[0066] The alkali solution described in step S1 is an aqueous solution of sodium hydroxide; the mass concentration of sodium hydroxide in the alkali solution is 30%.

[0067] In step S1, the weight ratio of Substance 1 to the alkali solution is 1:1.

[0068] In step S2, the molar ratio of dimethyl 4AU and sodium nitrite is 1:1.

[0069] The catalyst described in step S3 is a Raney nickel catalyst.

[0070] The Raney nickel catalyst is purchased from the Raney nickel catalyst RTH-2110 produced by Dalian General Chemical Co., Ltd.

[0071] In step S3, the addition amount of the catalyst is 3% of the mass of the dimethyl NAU aqueous solution.

[0072] In step S5, the weight ratio of the theophylline sodium salt to dimethyl sulfate is 2.5:1.

[0073] The specific steps of the two purifications in step S6 include: First purification: Dissolve Product 1 in water, adjust the concentration of solid substances in the system to 15 wt%, add sulfuric acid to adjust the pH to 2.5, then add potassium permanganate, keep the temperature at 80 °C for 1 h, add modified activated carbon, continue to keep the temperature at 80 °C for 1 h, filter the solution through a carbon filter to recover the activated carbon to obtain Liquid 1.

[0074] Second purification: Add water to Liquid 1 to adjust the solid-liquid ratio in the system to 1:8, add sulfuric acid to adjust the pH to 2.5, then add potassium permanganate, keep the temperature at 80 °C for 1 h, add modified activated carbon, continue to keep the temperature at 80 °C for 1 h, filter the solution through a carbon filter to recover the activated carbon, then cool and crystallize, and centrifuge in a centrifuge to obtain wet caffeine and Liquid 2.

[0075] The addition amount of the potassium permanganate is 2% of the weight of caffeine.

[0076] The specific steps for the modified activated carbon are as follows: Place the activated carbon in a 3% hydrochloric acid solution, let it stand at 80 °C for 1 h, filter out the moisture, and repeatedly rinse with deionized water until neutral. Then dry it at 120 °C to constant weight for standby.

[0077] Put 20 g of the dried activated carbon into a tubular furnace, introduce gas, react at 500 °C for 2 h, then switch to an inert gas and cool it to room temperature with the furnace, and thus obtain the modified activated carbon.

[0078] The gas is ammonia and argon.

[0079] The flow rate ratio of the ammonia and argon is 1:3.

[0080] The inert gas is argon.

[0081] The methylene blue adsorption value of the activated carbon is ≥ 120 mg / g, the specific surface area is > 1000 m 2 / g, and the particle size is 20 - 325 mesh.

[0082] The activated carbon is purchased as the wood powder activated carbon produced by Suzhou Like Environmental Protection Technology Co., Ltd.

[0083] The weight ratio of the potassium permanganate and the modified activated carbon is 1:2.

[0084] The pore diameter of the carbon filter is 15 μm, and the pressure is 0.2 mPa.

[0085] The pore diameter of the centrifuge filter cloth is 30 μm, and the centrifuge speed is 900 r / min.

[0086] The cooling process is as follows: Under the action of cooling circulating water at 10 °C, continuously stir the solution until the solution cools down to 15 °C.

[0087] Recover caffeine from the liquid two through operations such as decolorization and concentration; conduct secondary refining on the recovered caffeine and the product one together.

[0088] The specific operation for the recovered caffeine is as follows: Take 200 kg of the mixed liquid of the liquid two, clarify and remove impurities through a 10000 Dal ultrafiltration tubular ceramic membrane, conduct decolorization and desalting on the obtained clarified liquid through a 1000 Dal nanofiltration membrane, add 50 kg of deionized water to wash out the caffeine in the concentrated liquid, merge it into the decolorized liquid, discharge the concentrated liquid, and the decolorized liquid enters a 150 Dal nanofiltration system for concentration. The concentrated liquid obtained by controlling the temperature at 45 °C is cooled, crystallized, and filtered to obtain the recovered caffeine. The purity of the obtained caffeine is 99.9%, and the yield is 85.2%.

[0089] Example 2

[0090] Example 2 provides a preparation process for caffeine with a high yield, and the steps are as follows:

[0091] S1. Generation of dimethyl 4AU: Cyanacetic acid and dimethylurea are mixed, and a water absorbent is added. The mixture is reacted at 60 °C for 0.5 h to obtain Substance 1; Substance 1 is mixed with an alkali solution and reacted at 80 °C for 30 min to obtain dimethyl 4AU;

[0092] S2. Generation of dimethyl NAU: Dimethyl 4AU obtained in step S1 and sodium nitrite are mixed, and formic acid is added to adjust the pH to 2.0. The temperature is controlled at 20 °C and kept warm for 0.5 h. The product is washed repeatedly until the pH is 6 to obtain dimethyl NAU;

[0093] S3. Generation of dimethyl FAU: Dimethyl NAU obtained in step S2 is prepared into an aqueous solution with a concentration of 10% and mixed with a catalyst, and hydrogenation reaction is carried out. The reaction pressure is 0.3 MPa and the reaction time is 30 min. After obtaining dimethyl DAU, formic acid is added to adjust the pH value to 2, and the temperature is raised to 80 °C and reacted for 0.5 h to obtain dimethyl FAU;

[0094] S4. Generation of theophylline sodium salt: Dimethyl FAU obtained in step S3 is mixed with an ion-exchange membrane caustic soda solution. After adjusting the alkalinity of the solution to 1.5 mmol / L, it is reacted at 80 °C for 0.5 h to obtain theophylline sodium salt;

[0095] S5. Methylation reaction: Theophylline sodium salt obtained in step S4 and dimethyl sulfate are mixed, and sodium hydroxide is added to adjust the pH value to 10. The mixture is kept warm and reacted at 30 °C for 0.5 h to obtain Product 1;

[0096] S6. Refining of caffeine: Product 1 obtained in step S5 is refined twice to obtain caffeine with a high yield.

[0097] In step S1, the molar ratio of the cyanacetic acid, dimethylurea and the water absorbent is 1:0.5:0.7.

[0098] The water absorbent described in step S1 is acetic anhydride.

[0099] The alkali solution described in step S1 is an aqueous solution of sodium hydroxide; the mass concentration of sodium hydroxide in the alkali solution is 20%.

[0100] In step S1, the weight ratio of Substance 1 to the alkali solution is 1:2.

[0101] In step S2, the molar ratio of dimethyl 4AU and sodium nitrite is 1:1.

[0102] The catalyst described in step S3 is a Raney nickel catalyst.

[0103] The Raney nickel catalyst is purchased from the Raney nickel catalyst RTH-2110 produced by Dalian General Chemical Co., Ltd.

[0104] The addition amount of the catalyst described in step S3 is 1% of the mass of the dimethyl NAU aqueous solution.

[0105] The weight ratio of the sodium theophyllinate and dimethyl sulfate described in step S5 is 3:1.

[0106] The specific steps of the two - stage refining in step S6 are as follows: First - stage refining: Dissolve product one in water, adjust the concentration of solid substances in the system to 10 wt%, add sulfuric acid to adjust the pH to 2.5, then add potassium permanganate, keep the temperature at 70 °C for 1 h, add modified activated carbon, continue to keep the temperature at 70 °C for 1 h, pass the solution through a carbon - filtering filter to recover the activated carbon, and obtain liquid one;

[0107] Second - stage refining: Add water to liquid one to adjust the solid - liquid ratio in the system to 1:5, add sulfuric acid to adjust the pH to 2.5, then add potassium permanganate, keep the temperature at 70 °C for 1 h, add modified activated carbon, continue to keep the temperature at 70 °C for 1 h, pass the solution through a carbon - filtering filter to recover the activated carbon, then cool and crystallize, and centrifuge in a centrifuge to obtain wet - product caffeine and liquid two.

[0108] The addition amount of the potassium permanganate is 1% of the weight of caffeine.

[0109] The specific steps of the modified activated carbon are as follows: Place the activated carbon in a 1% hydrochloric acid solution, place it at 70 °C for 0.5 h, filter the water, and repeatedly rinse with deionized water until neutral, then dry it at 100 °C to constant weight for standby;

[0110] Put 20 g of the dried activated carbon into a tubular furnace, introduce gas, react at 400 °C for 1 h, then switch to an inert gas and cool with the furnace to room temperature to obtain the modified activated carbon.

[0111] The gas is ammonia and argon.

[0112] The flow - rate ratio of the ammonia and argon is 1:2.

[0113] The inert gas is argon.

[0114] The methylene - blue adsorption value of the activated carbon is ≥120 mg / g, the specific surface area is > 1000 m 2 / g, and the particle size is 20 - 325 mesh.

[0115] The activated carbon is purchased from the wood - powder activated carbon produced by Suzhou Like Environmental Protection Technology Co., Ltd.

[0116] The weight ratio of the potassium permanganate and the modified activated carbon is 1:0.8.

[0117] The pore diameter of the carbon - filtering filter is 10 μm, and the pressure is 0.05 mPa.

[0118] The pore size of the centrifuge filter cloth is 10 μm, and the rotation speed of the centrifuge is 700 r / min.

[0119] The cooling process is as follows: Under the action of cooling circulating water at 5°C, the solution is continuously stirred until the temperature of the solution drops to 15°C.

[0120] Caffeine is recovered from liquid two through operations such as decolorization and concentration; the recovered caffeine is refined together with product one.

[0121] The specific operation for recovering caffeine is as follows: Take 200 kg of the mixed solution of liquid two, clarify and remove impurities through an ultrafiltration tubular ceramic membrane with a molecular weight cut-off of 10,000 Da. The obtained clarified solution is decolorized and desalted through a nanofiltration membrane with a molecular weight cut-off of 500 Da. 50 kg of deionized water is added to wash out the caffeine in the concentrated solution, which is then incorporated into the decolorized solution. The concentrated solution is discharged, and the decolorized solution enters a nanofiltration system with a molecular weight cut-off of 100 Da for concentration. The concentrated solution obtained with the temperature controlled at 40°C is cooled, crystallized, and filtered to obtain the recovered caffeine. The purity of the obtained caffeine is 99.5%, and the yield is 84.7%.

[0122] Example 3

[0123] Example 3 provides a preparation process for caffeine with a high yield, and the steps are as follows:

[0124] S1. Generation of dimethyl 4AU: Cyanacetic acid and dimethylurea are mixed and a water absorbent is added, and the reaction is carried out at 120°C for 2 h to obtain substance one; substance one is mixed with an alkali solution and the reaction is carried out at 100°C for 60 min to obtain dimethyl 4AU.

[0125] S2. Generation of dimethyl NAU: The dimethyl 4AU obtained in step S1 and sodium nitrite are mixed, and formic acid is added to adjust the pH to 3.5, and the temperature is controlled at 60°C for heat preservation for 1 h. The obtained product is washed several times until the pH is 7, which is dimethyl NAU.

[0126] S3. Generation of dimethyl FAU: The dimethyl NAU obtained in step S2 is prepared into an aqueous solution with a concentration of 30% and mixed with a catalyst, and hydrogenation reaction is carried out. The reaction pressure is 0.4 MPa and the reaction time is 100 min. After obtaining dimethyl DAU, formic acid is added to adjust the pH value to 5, and then the temperature is raised to 100°C and the reaction is carried out for 1 h to obtain dimethyl FAU.

[0127] S4. Generation of theophylline sodium salt: The dimethyl FAU obtained in step S3 is mixed with an ion-exchange membrane caustic soda solution, and the alkalinity of the solution is adjusted to 2.5 mmol / L, and the reaction is carried out at 100°C for 1 h to obtain theophylline sodium salt.

[0128] S5, Methylation reaction: Mix the theophylline sodium salt obtained in step S4 with dimethyl sulfate, add sodium hydroxide to adjust the pH value to 10, keep the temperature at 60 °C for 2 h to react, and obtain Product 1;

[0129] S6, Purification of caffeine: Purify the Product 1 obtained in step S5 twice to obtain caffeine with a high yield.

[0130] In step S1, the molar ratio of cyanoacetic acid, dimethylurea and the water absorbent is 1:1:2.

[0131] The water absorbent described in step S1 is acetic anhydride.

[0132] The alkali solution described in step S1 is an aqueous solution of sodium hydroxide; the mass concentration of sodium hydroxide in the alkali solution is 40%.

[0133] In step S1, the weight ratio of Substance 1 to the alkali solution is 2:1.

[0134] In step S2, the molar ratio of dimethyl 4AU and sodium nitrite is 1:1.

[0135] The catalyst described in step S3 is a Raney nickel catalyst.

[0136] The Raney nickel catalyst is purchased from the Raney nickel catalyst RTH-2110 produced by Dalian General Chemical Co., Ltd.

[0137] In step S3, the addition amount of the catalyst is 5% of the mass of the dimethyl NAU aqueous solution.

[0138] In step S5, the weight ratio of the theophylline sodium salt to dimethyl sulfate is 2:1.

[0139] The specific steps of the two purifications in step S6 include: The first purification: Dissolve Product 1 in water, adjust the concentration of the solid substance in the system to 20 wt%, add sulfuric acid to adjust the pH to 3, add potassium permanganate, keep the temperature at 90 °C for 1 h, add modified activated carbon, continue to keep the temperature at 90 °C for 1 h, pass the solution through a carbon filtration filter to recover the activated carbon, and obtain Liquid 1;

[0140] The second purification: Add water to Liquid 1 to adjust the solid-liquid ratio in the system to 1:5, add sulfuric acid to adjust the pH to 3, add potassium permanganate, keep the temperature at 90 °C for 1 h, add modified activated carbon, continue to keep the temperature at 90 °C for 1 h, pass the solution through a carbon filtration filter to recover the activated carbon, then cool and crystallize, and centrifuge in a centrifuge to obtain wet caffeine and Liquid 2.

[0141] The addition amount of the potassium permanganate is 3% of the weight of the caffeine.

[0142] The specific steps for the modified activated carbon are as follows: Place the activated carbon in a 5 wt% hydrochloric acid solution, leave it at 90 °C for 2 h, filter out the moisture, and repeatedly rinse it with deionized water until it is neutral. Then dry it at 140 °C to constant weight for standby.

[0143] Put 20 g of the dried activated carbon into a tubular furnace, introduce gas, react at 600 °C for 3 h, then switch to an inert gas and cool it to room temperature with the furnace, and thus obtain the modified activated carbon.

[0144] The gas is ammonia and argon.

[0145] The flow rate ratio of the ammonia and argon is 1:4.

[0146] The inert gas is argon.

[0147] The methylene blue adsorption value of the activated carbon is ≥120 mg / g, the specific surface area is >1000 m 2 / g, and the particle size is 20 - 325 mesh.

[0148] The activated carbon is purchased as the wood powder activated carbon produced by Suzhou Like Environmental Protection Technology Co., Ltd.

[0149] The weight ratio of the potassium permanganate and the modified activated carbon is 1:3.

[0150] The pore diameter of the carbon filter is 20 μm, and the pressure is 0.5 mPa.

[0151] The pore diameter of the centrifuge filter cloth is 50 μm, and the centrifuge speed is 1200 r / min.

[0152] The cooling process is as follows: Under the action of cooling circulating water at 15 °C, continuously stir the solution until the solution cools down to 15 °C.

[0153] Recover caffeine from the liquid II through operations such as decolorization and concentration; jointly refine the recovered caffeine and the product I.

[0154] The specific operation for recovering caffeine is as follows: Take 200 kg of the mixed liquid of liquid II, clarify and remove impurities through a 10000 Dal ultrafiltration tubular ceramic membrane, the obtained clarified liquid is decolorized and desalted through a 2000 Dal nanofiltration membrane, add 50 kg of deionized water to wash out the caffeine in the concentrated liquid, merge it into the decolorized liquid, discharge the concentrated liquid, and the decolorized liquid enters a 200 Dal nanofiltration system for concentration. The concentrated liquid obtained by controlling the temperature at 50 °C is cooled, crystallized, and filtered to obtain the recovered caffeine. The purity of the obtained caffeine is 99.6%, and the yield is 84.8%.

[0155] Comparative Example 1

[0156] Comparative Example 1 provides a high-yield caffeine and its preparation method. The specific implementation manner is the same as that of Example 1. The difference lies in that: the molar ratio of dimethyl 4AU to sodium nitrite in step S2 is 1:2. The purity of the obtained caffeine is 96.8%, and the yield is 81.8%.

[0157] Comparative Example 2

[0158] Comparative Example 2 provides a high-yield caffeine and its preparation method. The specific implementation manner is the same as that of Example 1. The difference lies in that: the weight ratio of sodium theophyllinate to dimethyl sulfate in step S5 is 1:1. The purity of the obtained caffeine is 97.3%, and the yield is 82.3%.

[0159] Comparative Example 3

[0160] Comparative Example 3 provides a high-yield caffeine and its preparation method. The specific implementation manner is the same as that of Example 1. The difference lies in that: the activated carbon is not modified. The purity of the obtained caffeine is 97.9%, and the yield is 83.0%.

[0161] Comparative Example 4

[0162] Comparative Example 4 provides a high-yield caffeine and its preparation method. The specific implementation manner is the same as that of Example 1. The difference lies in that: in step S6, after the first refined activated carbon is recovered, solid one and liquid one are obtained by centrifugation in a centrifuge.

[0163] The aperture of the centrifuge filter cloth is 30 μm, and the centrifuge speed is 900 r / min. The purity of the obtained caffeine is 99.9%, and the yield is 83.3%.

[0164] Comparative Example 5

[0165] Comparative Example 5 provides a high-yield caffeine and its preparation method. The specific implementation manner is the same as that of Example 1. The difference lies in that: the recovered caffeine and product one are not jointly subjected to secondary refinement. The purity of the obtained caffeine is 99.4%, and the yield is 83.4%.

[0166] The caffeine prepared in Example 1 of the present application is subjected to cosmetic efficacy testing.

[0167] 1. Soothing efficacy test

[0168] Experimental principle: In this test, an inflammation model is established by stimulating macrophages Raw264.7 with lipopolysaccharide (LPS). The soothing efficacy of the test sample is evaluated by detecting the change in the secretion amount of related inflammatory factors after the sample acts.

[0169] Experimental materials: Reagents: high-glucose DMEM culture medium (Gibco), fetal bovine serum (Gibco), PBS (Gibco), MTT (Sigma), DMSO (Sinopharm), trypsin (Gibco); Equipment: CO2 incubator (Thermo, 160i), biological safety cabinet (ESCO, LA2-6A1), inverted microscope (Leica, DMi8), microplate reader (Tecan, Spark), micro-oscillator (Qilin Bell, TS-92).

[0170] Experimental methods:

[0171] ①Cytotoxicity test:

[0172] 1) Cell seeding: 1×10 4 The cells were seeded into a 96-well plate at a seeding density of 100 cells / well and incubated overnight in an incubator (37° C., 5% CO 2 ).

[0173] 2) Experimental grouping: The experiment set up a zero adjustment group, a control group, a positive control group and a sample group (Example 1). In the sample group, 8 concentration gradients were set for each sample, and 3 replicate wells were set under each concentration gradient.

[0174] 3) Solution preparation: Prepare sample working solutions of different concentrations according to the test concentration setting table (Table 1).

[0175] Table 1

[0176]

[0177] 4) Administration: Administration was performed when the cell plating rate in the 96-well plate reached 40% to 60%. 200 μL of culture medium containing 10% PBS was added to each well of the control group; 200 μL of culture medium containing 10% DMSO was added to each well of the positive control group; 200 μL of culture medium containing the corresponding concentration of sample was added to each well of the sample group; the zero adjustment group had no cell inoculation and only 200 μL of cell culture medium was added. After administration, the 96-well plate was placed in an incubator (37°C, 5% CO2) for incubation.

[0178] 5) Detection: After incubating the cells for 24 hours, discard the supernatant, add culture medium containing 0.5 mg / mL MTT, and incubate at 37°C in the dark for 4 hours. After the incubation, discard the supernatant, add 100 μL DMSO to each well, and read the OD value at 490 nm.

[0179] 6) Calculation of relative cell viability: Calculate according to the formula:

[0180] Relative cell viability = (OD of sample well - OD of zero-adjusting well) / (OD of solvent control well - OD of zero-adjusting well) * 100%.

[0181] ②Inflammatory factor detection:

[0182] 1) Cell seeding: Seed cells into a 24-well plate at an inoculation density of 1×10 5 cells / well and incubate overnight in an incubator (37°C, 5% CO2).

[0183] 2) Solution preparation: Prepare the working solution of the test substance according to the experimental design (Table 2).

[0184] Table 2

[0185]

[0186] 3) Drug administration: According to the experimental design in Table 3, when the cell confluence rate in the 24-well plate reaches 40% - 60%, perform grouped drug administration. The drug dosage per well is 1.0 mL, and each group has 3 replicate wells. Continue to culture in an incubator (37°C, 5% CO2) for 2 h.

[0187] 4) LPS stimulation: After 2 h of culture, according to the experimental design, add 200 μL of LPS working solution prepared from the corresponding test substance working solution to the wells that have received the drug. Shake the well plate left and right to mix the drugs inside. The final concentration of LPS is 1 μg / mL, and continue to culture in an incubator (37°C, 5% CO2) for 22 h.

[0188] 5) Sample collection: After incubation, collect the cell culture supernatant into an EP tube (Note: Determine the amount of collected samples according to the detection index). After collection, place the samples in a -80°C refrigerator for freezing and storage.

[0189] 6) Detection of TNF-α content: Detect according to the operation manual of the Mouse TNF-α ELISA kit.

[0190] Detection of IL-6 content: Detect according to the operation manual of the Mouse IL-6 ELISA kit.

[0191] Experimental results:

[0192] ① Cytotoxicity: Set 8 drug concentrations and conduct a cytotoxicity detection experiment on macrophages. The MTT detection results are shown in Table 3.

[0193] Table 3

[0194]

[0195] Using the 8 concentrations of the sample caffeine as the abscissa and the relative cell viability value as the ordinate, plot the relative cell viability graph (see Figure 1 ).

[0196] Therefore, according to the MTT results, the sample caffeine did not show macrophage toxicity within the concentration range of 0.078% (m / V).

[0197] ② Detection results of TNF-α content

[0198] Based on the experimental method, cell supernatants were collected for the detection of TNF-α content. The detection results are shown in Table 4, and the change trend is as Figure 2 shown.

[0199] Table 4

[0200]

[0201] Note: When performing statistical analysis using the t-test method, compared with the BC group, the significance in the NC group is indicated by #, p-value < 0.05 is indicated by #, and p-value < 0.01 is indicated by ##. When comparing the sample group and the PC group with the NC group, the significance is indicated by *, p-value < 0.05 is indicated by *, and p-value < 0.01 is indicated by **.

[0202] Compared with the BC group, the secretion of the macrophage inflammatory mediator TNF-α in the NC group increased significantly (p < 0.01), indicating that the LPS stimulation condition in this experiment was effective.

[0203] Compared with the NC group, at the administration concentration of 100 μg / mL of dexamethasone in the PC group, the secretion of the macrophage inflammatory mediator TNF-α decreased significantly (p < 0.01), indicating that this experiment was effective.

[0204] Compared with the NC group, when the administration concentrations of caffeine were 0.078%, 0.070%, and 0.060% (m / V), the secretion of the macrophage inflammatory mediator TNF-α decreased significantly (p < 0.05).

[0205] ③ Detection results of IL-6 content

[0206] Based on the experimental method, cell supernatants were collected for the detection of IL-6 content. The detection results are shown in Table 5, and the change trend is as Figure 3 shown.

[0207] Table 5

[0208]

[0209] Note: When performing statistical analysis using the t-test method, compared with the BC group, the significance in the NC group is indicated by #, p-value < 0.05 is indicated by #, and p-value < 0.01 is indicated by ##. When comparing the sample group and the PC group with the NC group, the significance is indicated by *, p-value < 0.05 is indicated by *, and p-value < 0.01 is indicated by **.

[0210] Compared with the BC group, the secretion of IL-6, an inflammatory factor in macrophages, in the NC group was significantly increased (p < 0.01), indicating that the LPS stimulation conditions in this experiment were effective.

[0211] Compared with the NC group, the secretion of macrophage inflammatory factor IL-6 in the PC group was significantly reduced at a dexamethasone concentration of 100 μg / mL (p < 0.01), indicating that this experiment was effective.

[0212] Compared with the NC group, the secretion of IL-6, an inflammatory factor in macrophages, was significantly reduced when caffeine was administered at concentrations of 0.078%, 0.070% and 0.060% (m / V) (p < 0.01).

[0213] Experimental conclusion: An inflammatory model was established based on lipopolysaccharide (LPS)-stimulated macrophage Raw264.7 cells. When caffeine was administered at concentrations of 0.078%, 0.070% and 0.060% (m / V), the secretion of macrophage inflammatory factors TNF-α and IL-6 was significantly reduced (p < 0.05), indicating that it has a soothing effect.

[0214] 2. Anti-wrinkle efficacy test

[0215] Experimental materials: Reagents: high-glucose DMEM culture medium (Gibco), fetal bovine serum (Gibco), PBS (Gibco), MTT (Sigma), DMSO (Sinopharm), trypsin (Gibco); Equipment: CO2 incubator (Thermo, 160i), biological safety cabinet (ESCO, LA2-6A1), inverted microscope (Leica, DMi8), microplate reader (Tecan, Spark), micro-oscillator (Qilin Bell, TS-92).

[0216] Experimental methods:

[0217] 1) Cell seeding: According to the appropriate seeding density (5×10 4 The cells were seeded into 24-well plates (100 μl / well) and incubated overnight in an incubator (37° C., 5% CO 2 ).

[0218] 2) Experimental grouping: The experiment set up a blank control group, a negative control group, a positive control group and a sample group (caffeine prepared in Example 1). The sample group was set up with 3 concentration gradients.

[0219] 3) Solution preparation: Prepare working solutions of the test substance of different concentrations according to the test concentration setting table (Table 6).

[0220] Table 6

[0221]

[0222]

[0223] 4) Administration: Administration is carried out when the cell seeding rate in the 24-well plate reaches 40% - 60%. For the blank control group and the negative control group, 1 mL of cell culture medium is added to each well; for the positive control group, 1 mL of culture medium containing 100 μg / mL of vitamin C and 7 μg / mL of vitamin E is added to each well; for the sample group, 1 mL of culture medium containing the test substance at the corresponding concentration is added to each well. After the administration is completed, the 24-well plate is placed in an incubator (37°C, 5% CO₂) for culture.

[0224] 5) UVA irradiation: After the cells are cultured for 24 h, the negative control group, the positive control group, and the sample group are irradiated with UVA with a total dose of 9 J / cm 2 . At the same time, the blank control group is placed in the same environment (UVA irradiation dose is 0 J / cm 2 ).

[0225] 6) Collection of cell supernatant: After incubation for 24 h, the cell culture supernatant is collected into an EP tube and stored frozen in a -80°C refrigerator.

[0226] 7) ELISA detection: The content of MMP-1 is detected and analyzed according to the operation manual of the ELISA detection kit.

[0227] Experimental results: According to the specific experimental method, the content of MMP-1 is detected. The detection results are shown in Table 7, and the change trend is as Figure 4 shown.

[0228] Table 7

[0229]

[0230] Note: When performing statistical analysis using T-Test, when comparing the NC group with the BC group, the significance is indicated by #, P-value < 0.05 is indicated by #, and P-value < 0.01 is indicated by ##; when comparing the PC group and the sample group with the NC group, the significance is indicated by *, P-value < 0.05 is indicated by *, and P-value < 0.01 is indicated by **.

[0231] The results show that compared with the BC group, after the fibroblasts in the NC group are irradiated with UVA with a total dose of 9 J / cm 2 , the content of MMP-1 increases significantly (P < 0.05), indicating that the UVA stimulation is effective.

[0232] Compared with the NC group, vitamin C and vitamin E in the PC group can significantly reduce the content of MMP-1 (P < 0.05).

[0233] Compared with the NC group, caffeine samples at concentrations of 2.00% and 0.125% had a significant effect of reducing the content of MMP-1 in fibroblasts induced by UVA radiation (P<0.05).

[0234] Experimental conclusion: After fibroblasts received UVA radiation with a total dose of 9 J / cm 2 , the content of MMP-1 increased significantly. After the sample caffeine acted on the cells for 24 h at concentrations of 2.00% and 0.125% (m / V), the content of MMP-1 in fibroblasts after UVA radiation decreased significantly, showing an anti-wrinkle effect.

[0235] 3. Anti-hair loss efficacy test

[0236] Experimental principle: Androgenetic alopecia (AGA) is caused by the conversion of testosterone (T) into more active dihydrotestosterone (DHT) under the action of 5α-reductase. DHT is sensitive to hair follicles and affects hair follicle development, resulting in hair loss. By analyzing whether the test substance can inhibit 5α-reductase and thus inhibit the production of DHT, it can be used as one of the bases for judging whether it has anti-hair loss and hair growth-promoting effects.

[0237] Experimental materials: Type II 5α-reductase: extracted from rat prostate tissue and stored at -80°C; positive control (PC): finasteride 0.4 μM; sample preparation (TA, sample of Example 1): the reaction concentration in the experimental system was 5%, 2.5%, 1.25%; blank control: phosphate buffer solution (PBS).

[0238] Experimental steps:

[0239] 1. Preparation of type II 5α-reductase: taken from the prostate of male rats. Homogenize at a ratio of 1:5 with pre-cooled buffer in a glass homogenizer at 0°C, centrifuge at 3000 g for 10 min, take the supernatant and centrifuge at 10000 g for 45 min. Aliquot the supernatant into EP tubes, 1 mL per tube, which is the enzyme extract and store it in a -80°C refrigerator.

[0240] 2. Determination of type II 5α-reductase activity: In a 2 mL reaction system, it contains: 0.25 mL of phosphate buffer, 0.70 mL of enzyme extract, 0.1 mL of testosterone solution (0.5 mg / mL), 0.35 mL of NADPH solution (1 mg / mL), and 0.6 mL of 10% ethanol (0.4 μM finasteride in the positive control tube and sample solution in the sample tube). In the control tube, the enzyme extract is replaced with phosphate buffer, and 2.0 mL of dichloromethane is added to terminate the reaction; in the sample tube, the reaction is carried out at 37 °C for 30 min. After the reaction, 2.0 mL of dichloromethane is added to stop the reaction. After shaking for 1 min, it is centrifuged at 3000 r / min for 10 min. The upper aqueous phase is removed, about 1.0 mL of the organic phase is taken out and evaporated to dryness. The residue is dissolved in 1.0 mL of methanol, and the peak area of testosterone (T) is determined by high performance liquid chromatography. Each reaction is set with 3 parallel tubes.

[0241] Result analysis:

[0242] Experimental results: The sample inhibition rates are shown in Table 8 and Figure 5 as follows. After statistical analysis, compared with the complete reaction group, the average peak area of testosterone (T) in the positive control group increased, and the inhibition rate of type II 5α-reductase was 73.55%, showing a statistical difference (p < 0.05); the average peak area of testosterone (T) increased at the concentrations of 2.5% and 1.25% (w / w) of the sample, and the inhibition rates of type II 5α-reductase were 30.41% and 48.16% respectively, showing a statistical difference (p < 0.05). Under the experimental conditions, the sample "caffeine" has an anti-hair loss effect at the concentrations of 2.5% and 1.25% (w / w).

[0243] Table 8

[0244]

[0245] Experimental conclusion: After statistical analysis, compared with the complete reaction group, under the experimental conditions, the caffeine prepared in Example 1 has an anti-hair loss effect at the concentrations of 2.5% and 1.25% (w / w).

Claims

1. A preparation process of caffeine, characterized in that, The steps include: S1. Generation of dimethyl 4AU: Mix cyanoacetic acid and dimethylurea, add a water absorbent, and react at 60 - 120 °C for 0.5 - 2 h to obtain Substance 1; mix Substance 1 with an alkali solution and react at 80 - 100 °C for 30 - 60 min to obtain dimethyl 4AU; S2. Generation of dimethyl NAU: After mixing the dimethyl 4AU obtained in step S1 and sodium nitrite, adjust the pH to 2.0 - 3.5, and keep the temperature at 20 - 60 °C for 0.5 - 1 h. After washing the product multiple times until the pH is 6 - 7, it is dimethyl NAU; S3. Generation of dimethyl FAU: Prepare an aqueous solution with a concentration of 10 - 30% of the dimethyl NAU obtained in step S2 and mix it with a catalyst, and carry out a hydrogenation reaction. The reaction pressure is 0.3 - 0.4 MPa, and the reaction time is 30 - 100 min. After obtaining dimethyl DAU, adjust the pH value to 2 - 5, raise the temperature to 80 - 100 °C, and react for 0.5 - 1 h to obtain dimethyl FAU; S4. Generation of theophylline sodium salt: Mix the dimethyl FAU obtained in step S3 with an ion-exchange membrane caustic soda solution, adjust the alkalinity of the solution to 1.5 - 2.5 mmol / L, and react at 80 - 100 °C for 0.5 - 1 h to obtain theophylline sodium salt; S5. Methylation reaction: Mix the theophylline sodium salt obtained in step S4 and dimethyl sulfate, adjust the pH value to 9 - 10, and keep the temperature at 30 - 60 °C for 0.5 - 2 h to obtain Product 1; S6. Refinement of caffeine: Refine Product 1 obtained in step S5 twice to obtain caffeine; In step S2, the molar ratio of the dimethyl 4AU and sodium nitrite is 1:1; In step S5, the weight ratio of the theophylline sodium salt and dimethyl sulfate is (2 - 3):1; The specific steps of the two refinements in step S6 include: First refinement: Dissolve Product 1 in water, adjust the concentration of solid substances in the system to 10 - 20 wt%, add sulfuric acid to adjust the pH to 2.5 - 3, then add potassium permanganate, keep the temperature between 70 - 90 °C for 1 h, add modified activated carbon, continue to keep the temperature between 70 - 90 °C for 1 h, and pass the solution through a carbon filtration filter to recover the activated carbon to obtain Liquid 1; Second refinement: Add water to Liquid 1 to adjust the solid-liquid ratio in the system to 1:(5 - 10), add sulfuric acid to adjust the pH to 2.5 - 3, then add potassium permanganate, keep the temperature between 70 - 90 °C for 1 h, add modified activated carbon, continue to keep the temperature between 70 - 90 °C for 1 h, pass the solution through a carbon filtration filter to recover the activated carbon, then cool and crystallize, and centrifuge in a centrifuge to obtain wet caffeine and Liquid 2; The specific steps of the modified activated carbon are: Place the activated carbon in a 1 - 5 wt% hydrochloric acid solution, place it at 70 - 90 °C for 0.5 - 2 h, filter the water, and repeatedly rinse with deionized water until neutral, and dry it to constant weight at 100 - 140 °C for standby; Put 5 - 25 g of the dried activated carbon into a tubular furnace, introduce gas, react at 400 - 600 °C for 1 - 3 h, then switch to an inert gas and cool it to room temperature with the furnace to obtain the modified activated carbon.

2. The preparation process of caffeine according to claim 1, characterized in that, The molar ratio of cyanoacetic acid, dimethylurea and the water absorbent described in step S1 is 1:(0.5 - 1):(0.7 - 2); the weight ratio of the first substance and the alkali solution described in step S1 is 1:(0.5 - 2); the addition amount of the catalyst described in step S3 is 1 - 5% of the mass of the dimethyl NAU aqueous solution.

3. The preparation process of caffeine according to claim 1, characterized in that, The addition amount of the potassium permanganate is 1 - 3% of the weight of caffeine; the weight ratio of the potassium permanganate and the modified activated carbon is 1:(0.8 - 3).

4. The preparation process of caffeine according to claim 1, characterized in that, The methylene blue adsorption value of the activated carbon ≥ 100 mg / g, the specific surface area > 800 m 2 / g, and the particle size is 100 - 500 mesh.

5. The preparation process of caffeine according to claim 4, characterized in that, In the two refining steps described in step S6, the liquid two recovers caffeine through decolorization and concentration operations, and the recovered caffeine and the first product are refined together.

6. The preparation process of caffeine according to claim 5, characterized in that, The pore diameter of the carbon filter is 10 - 20μm, and the pressure is 0.05 - 0.5mpa; the pore diameter of the centrifuge filter cloth is 10 - 50μm, and the centrifuge speed is 700 - 1200r / min.

Images