Efficient and environmentally friendly process and device for the continuous synthesis of guanine

Abstract

This invention discloses a highly efficient and environmentally friendly continuous synthesis process and apparatus for guanine, including the following steps for crude guanine synthesis: 2,4-diamino-6-hydroxypyrimidine, sodium nitrite, and first water are mixed uniformly to obtain a suspension; the suspension and first hydrochloric acid solution are passed through a pipeline for mixing and reaction, and the reaction solution is injected into a reaction flask with continuous stirring; after all the reaction solution in the pipeline has been injected into the reaction flask, stirring continues to ensure uniform mixing, followed by evaporation to remove water until no water is distilled off; formamide and a catalyst are added to the reaction flask, and formylation and cyclization reactions are carried out sequentially, followed by filtration to obtain crude guanine and formamide mother liquor. The process of this invention is shorter, the reaction is safer and more controllable, it reduces waste, produces high-purity guanine, and has a high reaction yield. The purity of the guanine product is greater than 99.6%, and the total yield of guanine product is greater than 89%.

Description

Technical Field

[0001] This invention relates to the field of guanine production technology, and in particular to a highly efficient and environmentally friendly continuous synthesis process and apparatus for guanine. Background Technology

[0002] Current guanine production processes primarily use methyl cyanoacetate as a starting material, which is cyclized with guanidine hydrochloride or guanidine nitrate to obtain 2,4-diamino-6-hydroxypyrimidine; then, it undergoes nitrosation with sodium nitrite in an acidic medium to obtain 2,4-diamino-5-nitroso-6-hydroxypyrimidine; subsequently, using a metal catalyst, hydrogen is introduced to reduce the nitroso group to 2,4,5-triamino-6-hydroxypyrimidine, which reacts with sulfuric acid to form a relatively stable sulfate; finally, cyclization is performed in formamide or formic acid to obtain crude guanine. This process is lengthy and complex, involving highly hazardous processes such as nitrosation and hydrogenation, and requires metal catalysts, liquid alkali, sulfuric acid, and formic acid. Byproduct and wastewater treatment is difficult, resulting in high production and environmental costs. Furthermore, the excessive use of acid and nitrite in the nitrosation reaction leads to increased impurities in subsequent reactions. To obtain high-purity guanine, the nitrosation product must be purified before proceeding to the next process step. Therefore, high-purity guanine cannot be obtained through continuous production processes in existing technologies. Summary of the Invention

[0003] The purpose of this invention is to overcome the above-mentioned technical deficiencies and propose an efficient and environmentally friendly continuous synthesis process and apparatus for guanine, thereby solving the technical problem that high-purity guanine cannot be obtained through continuous processes in the prior art.

[0004] In a first aspect, the present invention provides a highly efficient and environmentally friendly continuous synthesis process for guanine, comprising the following steps:

[0005] S100, crude guanine synthesis; and optionally,

[0006] S200, formamide mother liquor recovery;

[0007] S300, refined crude guanine;

[0008] The steps involved in the synthesis of crude guanine include:

[0009] S101. Mix 2,4-diamino-6-hydroxypyrimidine, sodium nitrite and first water evenly to obtain a suspension;

[0010] S102. The suspension and the first hydrochloric acid solution are passed into the pipeline for mixing and reaction, and the reaction solution is injected into the reaction flask and stirred continuously.

[0011] S103. After all the reaction liquid in the pipeline has been injected into the reaction flask, continue stirring to mix the reaction liquid evenly, and then evaporate to remove water until no water is distilled out.

[0012] S104. Add formamide and catalyst to the reaction flask, and carry out formylation reaction at 100-160℃ and cyclization reaction at 160-175℃ in sequence. Then, filter to obtain crude guanine and formamide mother liquor.

[0013] Secondly, the present invention provides a highly efficient and environmentally friendly continuous synthesis apparatus for guanine, which includes a pipeline and a reaction flask connected in sequence.

[0014] This efficient and environmentally friendly continuous guanine synthesis apparatus is used to perform the efficient and environmentally friendly continuous guanine synthesis process provided in the first aspect of the present invention.

[0015] Compared with the prior art, the beneficial effects of the present invention include:

[0016] The process flow of this invention is shorter, the reaction is safe and controllable, and it reduces the originally required dangerous processes. It does not use metal catalysts, liquid alkali, sulfuric acid and formic acid, which can reduce the three wastes. The guanine product has high purity and high reaction yield. The purity of the guanine product is greater than 99.6%, and the total yield of guanine product obtained from the reaction is greater than 89%. Attached Figure Description

[0017] Figure 1 This is a schematic diagram of one embodiment of the high-efficiency and environmentally friendly continuous guanine synthesis device provided by the present invention;

[0018] Figure 2 This refers to the liquid chromatography detection data of guanine (fresh hydrochloric acid) obtained in Example 1 of this invention;

[0019] Figure 3 These are the liquid chromatography detection data of guanine (using hydrochloric acid mother liquor) obtained in Example 1 of this invention;

[0020] Figure 4 This refers to the liquid chromatography detection data of guanine (fresh hydrochloric acid) obtained in Example 2 of this invention;

[0021] Figure 5 This refers to the liquid chromatography detection data of guanine (using hydrochloric acid mother liquor) obtained in Example 2 of this invention;

[0022] Figure 6 This refers to the liquid chromatography detection data of guanine (fresh hydrochloric acid) obtained in Example 3 of this invention;

[0023] Figure 7 These are the liquid chromatography detection data of guanine (using hydrochloric acid mother liquor) obtained in Example 3 of this invention;

[0024] Figure 8This refers to the liquid chromatography detection data of guanine (fresh hydrochloric acid) obtained in Example 4 of this invention;

[0025] Figure 9 This refers to the liquid chromatography detection data of guanine (using hydrochloric acid mother liquor) obtained in Example 4 of this invention;

[0026] Figure 10 This refers to the liquid chromatography detection data of guanine (fresh hydrochloric acid) obtained in Example 5 of this invention;

[0027] Figure 11 This is the liquid phase detection data of guanine (using hydrochloric acid mother liquor) obtained in Example 5 of the present invention. Detailed Implementation

[0028] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0029] In a first aspect, the present invention provides an efficient and environmentally friendly continuous synthesis process for guanine, comprising the following steps: S100, synthesis of crude guanine; and optionally, S200, recovery of formamide mother liquor; and S300, purification of crude guanine.

[0030] In this embodiment, the steps for synthesizing the crude guanine product include:

[0031] S101. Mix 2,4-diamino-6-hydroxypyrimidine, sodium nitrite and first water evenly to obtain a suspension;

[0032] S102. The suspension and the first hydrochloric acid solution are passed into the pipeline for mixing and reaction, and the reaction solution is injected into the reaction flask and stirred continuously.

[0033] S103. After all the reaction liquid in the pipeline has been injected into the reaction flask, continue stirring to mix the reaction liquid evenly, and then evaporate to remove water until no water is distilled out.

[0034] S104. Add formamide and catalyst to the reaction flask, and carry out formylation reaction at 100-160℃ and cyclization reaction at 160-175℃ in sequence. Then, filter to obtain crude guanine and formamide mother liquor.

[0035] As is known to those skilled in the art, nitrosation is a violently exothermic reaction that can easily lead to system instability. This invention addresses this by pre-mixing a suspension containing 2,4-diamino-6-hydroxypyrimidine, sodium nitrite, and a first water solution with a first hydrochloric acid solution in a pipeline. This increases mass and heat transfer efficiency, making the nitrosation reaction more stable and controllable, and eliminating the need for a hydrogenation process. When the reaction liquid exits the pipeline, the nitrosation reaction is essentially complete. A reaction flask is then used to receive the nitrosation products for the next reaction. The exothermic reaction is minimal once the reaction liquid enters the flask, eliminating the need for temperature control. However, continuous stirring is necessary after the reaction liquid enters the flask to ensure uniform mixing and prevent the raw materials from being trapped or not participating in the reaction due to direct heating and subsequent reactions. Furthermore, the inventors discovered during experiments that if evaporation and dehydration are not performed before the formylation reaction, the reaction becomes too vigorous, generating a large amount of gas and causing material overflow, thus hindering the reaction and ultimately preventing the continuous synthesis of guanine. Therefore, the process of this invention reduces the risk of the reaction and enables continuous production.

[0036] In step S101, the mass ratio of 2,4-diamino-6-hydroxypyrimidine to sodium nitrite and first water is 1:(0.5-0.7):(7.5-11).

[0037] In step S102, the mass fraction of the first hydrochloric acid solution is 30% to 35%, and the ratio of 2,4-diamino-6-hydroxypyrimidine to the first hydrochloric acid solution is 1 g: (3 to 5) mL.

[0038] In step S102, the inner diameter of the pipeline is 2-20 mm, further 4-15 mm, and further 4-10 mm; the length of the pipeline is 5-20 m, and further 10-15 m.

[0039] In step S102, the flow rate of the suspension into the pipeline is 15–20 mL / min, and the flow rate of the first hydrochloric acid solution into the pipeline is 5–10 mL / min. Setting the flow rate too high will cause the reactants to solidify and clog the pipeline immediately after mixing, while setting the flow rate too low will result in an excessively long reaction time.

[0040] In step S102, the suspension and the first hydrochloric acid solution are introduced into the pipeline by a peristaltic pump to carry out a mixing reaction.

[0041] In step S102, when the suspension and the first hydrochloric acid solution are mixed and reacted in the pipeline, the pipeline is immersed in cold water at 0-20°C to further increase the heat and mass transfer efficiency, making the nitrosation reaction, which originally released a large amount of heat and nitrogen dioxide, safer and more controllable.

[0042] In step S103, during the evaporation and dehydration process, the temperature is raised to 100°C and evaporated until no more water distills out or only a very small amount of water distills out. It should be noted that the presence of a large amount of nitrosation products during the evaporation and dehydration process will prevent the water from being completely evaporated; therefore, the water should be evaporated until no more water distills out or only a very small amount of water distills out.

[0043] In step S104, the catalyst is at least one of sodium sulfide, sodium thiosulfate, or sodium dithionite. Compared with other common catalysts, the above catalyst is more effective in reducing impurities in crude guanine and improving the purity of guanine.

[0044] In step S104, the mass ratio of 2,4-diamino-6-hydroxypyrimidine to formamide and catalyst is 1:(5-7):(0.1-0.2).

[0045] In step S104, during the formylation reaction, the temperature is increased from 100℃ to 160℃ at a heating rate of 0.1–0.3℃ / min. The formylation reaction must be heated slowly to prevent material spillage. The total time for the entire heating and holding stages is 4–6 hours. During the cyclization reaction, the temperature is increased from 160℃ to 175℃ at a heating rate of 0.1–0.5℃ / min. The heating rate for the high-temperature cyclization reaction can be appropriately accelerated. The total time for the entire heating and holding stages is 3–5 hours.

[0046] The cyclization reaction can be a cyclization reflux reaction or a cyclization dehydration reaction, preferably a cyclization dehydration reaction. The inventors further discovered during experiments that, compared to using a reflux method for the cyclization reaction, the cyclization dehydration reaction of this invention is more effective in improving the purity of crude guanine.

[0047] In this embodiment, the steps for recovering the formamide mother liquor include:

[0048] S201. The formamide mother liquor obtained after filtration in step S104 is subjected to a first vacuum distillation by a water pump to obtain a pre-distillate whose main component is ammonia.

[0049] S202. The formamide mother liquor after the first vacuum distillation is subjected to a second vacuum distillation using an oil pump to recover formamide.

[0050] In the first vacuum distillation process, the temperature is first raised to 110-130℃ to start vacuum distillation, and then continuously raised to 140-160℃ until no more fractions are distilled off.

[0051] In the second vacuum distillation process, the temperature is first raised to 80-100℃ to start vacuum distillation, and then continuously raised to 120-140℃ until no more fractions are distilled off.

[0052] After the first vacuum distillation, the oil pump must be cooled down before changing it to prevent formamide from being drawn into the oil pump and reducing the recovery rate.

[0053] The receiver needs to be replaced before the second vacuum distillation to prevent the recovered formamide from mixing with the foredistillate.

[0054] In the first vacuum distillation process, the temperature of the coolant flowing through the condenser jacket is 10–20°C, while in the second vacuum distillation process, the temperature is 5–10°C. The main component of the first fraction is ammonia water. If the jacket temperature is too high, ammonia gas will escape from the water, producing a strong odor. If the temperature is too low, energy consumption will be high, and the fraction may solidify in the jacket. The second vacuum distillation uses an oil pump with a higher vacuum level. If the temperature is too high, formamide cannot be liquefied and collected, and will be sucked into the pump, damaging the pump body and reducing the recovery rate. If the temperature is too low, formamide may solidify in the jacket.

[0055] The formamide recovered in step S202 can be used in the reaction in step S104. If the amount is insufficient, a certain amount of new formamide will be added.

[0056] In this embodiment, the purification steps of the above-mentioned crude guanine product include:

[0057] S301. Add crude guanine to the second hydrochloric acid solution and allow it to dissolve completely into a dark brown, clear solution.

[0058] S302. Add activated carbon to a dark brown clear liquid and stir to decolorize it. Then filter it while it is hot. After cooling, filter the filtrate to obtain guanine hydrochloride and hydrochloric acid mother liquor.

[0059] S303. Guanine hydrochloride is dissolved in the second water, and then the pH is adjusted to 6-8 with ammonia. The guanine product is obtained by filtration.

[0060] This invention further improves the purity of guanine by adding a secondary purification process.

[0061] The mass fraction of the second hydrochloric acid solution is 7% to 10%; the ratio of crude guanine to the second hydrochloric acid solution is 1 g: (10 to 20) mL.

[0062] In the process of fully dissolving crude guanine into a clear, dark brown solution, it is necessary to heat to 80–90°C.

[0063] The ratio of activated carbon to dark brown clear liquid is (0.01-0.03) g: 1 mL, and more specifically (0.015-0.03) g: 1 mL.

[0064] The temperature for decolorization by stirring should not exceed 90℃, and should be further set at 80-90℃, with a stirring time of 20-40 minutes. During the decolorization process, excessively high temperatures or prolonged decolorization times will lead to an increase in the xanthine content of the impurities.

[0065] The temperature of the filtrate after cooling is 10–20°C.

[0066] The hydrochloric acid mother liquor can be reused in the purification steps of other batches of crude guanine. This invention, by using the hydrochloric acid mother liquor, helps to improve the yield of guanine. When it cannot be dissolved into a clear, dark brown solution, an appropriate amount of hydrochloric acid mother liquor or concentrated hydrochloric acid can be added. However, if the acidity of the hydrochloric acid mother liquor is greater than 20%, it should not be reused; if it is, the final product will have a high xanthine content.

[0067] The mass ratio of guanine hydrochloride to the second water is 1:(5-20).

[0068] The process of dissolving guanine hydrochloride in the second water requires heating to 50–60°C.

[0069] In this embodiment, the above-mentioned efficient and environmentally friendly continuous synthesis process of guanine also includes: S400, wastewater treatment and recovery of ammonium salt.

[0070] The above-mentioned wastewater treatment and ammonium salt recovery steps include: neutralizing the hydrochloric acid mother liquor in step S302 with the alkaline wastewater distilled in step S104 and / or the alkaline wastewater generated by the rinsing water separator, adjusting the pH to 6-8, and then filtering, concentrating, cooling and crystallizing to obtain ammonium salt.

[0071] During the formylation reaction, formamide decomposes under conditions of water, alkali, and high temperature to produce ammonia and carbon dioxide, and further forms ammonium salts. Water is also released during the cyclization reaction, which is a cyclization dehydration reaction. The ammonium salts are carried out by the water released from S104, forming alkaline wastewater. The ammonium salts formed by neutralizing the hydrochloric acid mother liquor in the alkaline wastewater can be used in the synthesis of guanidine hydrochloride.

[0072] In the process of neutralizing hydrochloric acid mother liquor with alkaline wastewater distilled in step S104 and / or alkaline wastewater generated by rinsing the water separator, ammonia water can be added when the alkaline wastewater is insufficient.

[0073] The hydrochloric acid mother liquor is the hydrochloric acid mother liquor with a concentration greater than 20% that cannot be reused in step S302, so as to achieve high-value utilization of both alkaline wastewater and hydrochloric acid mother liquor at the same time.

[0074] Please see Figure 1 Secondly, the present invention provides a highly efficient and environmentally friendly continuous synthesis apparatus for guanine, which includes a pipeline 1 and a reaction flask 2 connected in sequence.

[0075] This efficient and environmentally friendly continuous guanine synthesis apparatus is used to perform the efficient and environmentally friendly continuous guanine synthesis process provided in the first aspect of the present invention.

[0076] In this embodiment, the feed end of pipeline 1 is connected to the suspension storage tank 5 through the first peristaltic pump 3, and the feed end of pipeline 1 is connected to the hydrochloric acid storage tank 6 through the second peristaltic pump 4, so that the suspension and the first hydrochloric acid solution are introduced into pipeline 1 for reaction.

[0077] In this embodiment, pipe 1 is immersed in a cold water tank to cool it down.

[0078] Example 1

[0079] A highly efficient and environmentally friendly continuous synthesis process for guanine includes the following steps:

[0080] (1) Synthesis of crude guanine: 50 g of 2,4-diamino-6-hydroxypyrimidine and 30 g of sodium nitrite were added to 450 mL of water to prepare a suspension. The flow rate of the peristaltic pump for injecting the suspension was set to 15 mL / min, and the flow rate of the peristaltic pump for injecting 150 mL of 35% hydrochloric acid was set to 5 mL / min. The two solutions were mixed and reacted in a pipe (with an inner diameter of 6 mm and a length of 10 m) that was immersed in cold water at 20 °C. The reaction solution was then injected into a reaction flask and stirred continuously. After all the reaction solution in the pipe was injected into the reaction flask, the mixture was stirred thoroughly for 30 minutes. The temperature was raised to 100 °C to evaporate and remove water until no water was distilled off. 330 g of formamide and 10 g of sodium sulfide were added, and the temperature was gradually raised to 160 °C for formylation reaction. The heating time was controlled for 4 hours and the temperature was maintained for 1 hour. The temperature was then raised to 175 °C for cyclization and dehydration reaction. The heating time was controlled for 1 hour and the temperature was maintained for 3 hours. The crude guanine and the formamide mother liquor were obtained by filtration.

[0081] (2) Formamide mother liquor recovery: 175.3 g of formamide mother liquor was first distilled under reduced pressure at 120°C using a water pump, and the temperature was continuously raised to 150°C until no more distillate was distilled off, with 15 g of the first distillate; then the receiver was changed, and the formamide was distilled off under reduced pressure at 90°C using an oil pump, and the temperature was continuously raised to 130°C until no more distillate was distilled off, with 153 g of formamide recovered.

[0082] (3) Refining of crude guanine (fresh hydrochloric acid): 900 mL of 8% hydrochloric acid and crude guanine obtained in step (1) were added to the reactor and heated to 90°C to fully dissolve it into a dark brown clear solution. Then 13.5 g of activated carbon was added and the mixture was stirred and decolorized for 30 minutes. The mixture was then filtered while hot and the filtrate was cooled to 10°C. The filtrate and hydrochloric acid mother liquor were obtained by suction filtration.

[0083] (4) Refining of crude guanine (using hydrochloric acid mother liquor): The above hydrochloric acid mother liquor and another batch of crude guanine obtained in step (1) were put into the reactor and heated to 90°C. It failed to dissolve completely into a dark brown clear solution. 30 mL of hydrochloric acid was added and dissolved completely into a dark brown clear solution. Then 13.5 g of activated carbon was added and stirred for decolorization for 30 minutes. Then, the solution was filtered while hot and the filtrate was cooled to 10°C. Guanine hydrochloride (after using hydrochloric acid mother liquor) and hydrochloric acid mother liquor were obtained by suction filtration.

[0084] Add 800 mL of water to each of the two batches of guanine hydrochloride from steps (3) and (4) above, heat to 50°C, adjust the pH to 7 with ammonia, filter to obtain the guanine product, dry and weigh. The first batch weighed 52.5 g with a purity of 99.94%; the second batch weighed 56.7 g with a purity of 99.95%.

[0085] (5) Wastewater treatment and ammonium salt recovery: Collect the alkaline wastewater distilled during the reaction, combine it with the alkaline wastewater used to rinse the water separator, neutralize the hydrochloric acid mother liquor, add ammonia water, adjust the pH to 7, filter out insoluble impurities, concentrate the filtrate to obtain ammonium salt, dry it and weigh it to 122.5 grams.

[0086] Table 1. Liquid chromatography data of guanine (fresh hydrochloric acid) obtained in Example 1

[0087] Retention time area Area percentage Peak Theoretical number of plates 3.206 0.62 0.00 0.13 4733 4.753 0.88 0.01 0.16 8960 10.634 16280.00 99.94 1121.32 12262 13.543 4.35 0.03 0.24 12696 17.998 4.70 0.02 0.21 15593 total 16290.55 100.00

[0088] Table 2. Liquid chromatography data of guanine (using hydrochloric acid mother liquor) obtained in Example 1.

[0089] Retention time area Area percentage Peak Theoretical number of plates 3.202 0.61 0.00 0.13 13089 4.752 1.11 0.01 0.18 9028 4.918 1.35 0.01 0.19 9412 10.599 13846.06 99.95 984.72 13090 13.540 3.85 0.03 0.20 10926 total 13852.99 100.00

[0090] Example 2

[0091] A highly efficient and environmentally friendly continuous synthesis process for guanine includes the following steps:

[0092] (1) Synthesis of crude guanine: 50 g of 2,4-diamino-6-hydroxypyrimidine and 35 g of sodium nitrite were added to 400 mL of water to prepare a suspension. The flow rate of the peristaltic pump for injecting the suspension was set to 20 mL / min, and the flow rate of the peristaltic pump for injecting 180 mL of 33% hydrochloric acid was set to 9 mL / min. The two solutions were then introduced into a pipeline (6 mm inner diameter and 15 m length) soaked in 10 °C cold water to mix and react. The reaction solution was then injected into a reaction flask and stirred continuously. After all the reaction solution in the pipeline was injected into the reaction flask, the mixture was stirred thoroughly for 30 minutes. The temperature was raised to 100 °C to evaporate and remove water until no water was distilled off. 350 g of formamide and 10 g of sodium thiosulfate were added, and the temperature was gradually raised to 160 °C for formylation reaction. The heating time was controlled for 4 hours and the temperature was maintained for 1 hour. The temperature was then raised to 175 °C for cyclization and dehydration reaction. The heating time was controlled for 1 hour and the temperature was maintained for 3 hours. The crude guanine and the formamide mother liquor were obtained by filtration.

[0093] (2) Formamide mother liquor recovery: 205.3 g of formamide mother liquor was first distilled under reduced pressure at 120°C using a water pump, and the temperature was continuously raised to 150°C until no more distillate was distilled off, with 16 g of the first distillate; then the receiver was replaced, and the formamide was distilled off under reduced pressure at 90°C using an oil pump, and the temperature was continuously raised to 130°C until no more distillate was distilled off, with 183 g of formamide recovered.

[0094] (3) Refining of crude guanine (fresh hydrochloric acid): 1000 mL of 7% hydrochloric acid and crude guanine obtained in step (1) were added to the reactor and heated to 90°C to fully dissolve it into a dark brown clear solution. Then 15 g of activated carbon was added and the mixture was stirred and decolorized for 30 minutes. The mixture was then filtered while hot and the filtrate was cooled to 15°C. The filtrate and hydrochloric acid mother liquor were obtained by suction filtration.

[0095] (4) Refining of crude guanine (using hydrochloric acid mother liquor): The above hydrochloric acid mother liquor and another batch of crude guanine obtained in step (1) were put into the reactor and heated to 90°C. It failed to dissolve completely into a dark brown clear solution. 35 mL of hydrochloric acid was added and dissolved completely into a dark brown clear solution. Then 15 g of activated carbon was added and stirred for decolorization for 30 minutes. Then the solution was filtered while hot. The filtrate was cooled to 15°C and filtered to obtain guanine hydrochloride (after using hydrochloric acid mother liquor) and hydrochloric acid mother liquor.

[0096] Add 700 mL of water to each of the two batches of guanine hydrochloride from steps (3) and (4) above, heat to 50°C, adjust the pH to 7 with ammonia, filter to obtain the guanine product, dry and weigh. The first batch weighed 51.9 g with a purity of 99.94%; the second batch weighed 57.9 g with a purity of 99.95%.

[0097] (5) Wastewater treatment and ammonium salt recovery: Collect the alkaline wastewater distilled during the reaction, combine it with the alkaline wastewater used to rinse the water separator, neutralize the hydrochloric acid mother liquor, add ammonia water, adjust the pH to 7, filter out insoluble impurities, concentrate the filtrate to obtain ammonium salt, dry it and weigh it to 120.8 grams.

[0098] Table 3. Liquid chromatography data of guanine (fresh hydrochloric acid) obtained in Example 2

[0099] Retention time area Area percentage Peak Theoretical number of plates 3.199 0.70 0.00 0.15 13515 4.752 0.89 0.005 0.17 11550 5.150 0.89 0.005 0.13 12566 5.641 1.84 0.01 0.23 11196 10.629 16763.02 99.94 1145.21 12034 13.531 5.95 0.04 0.30 9861 total 16773.30 100

[0100] Table 4. Liquid chromatography data of guanine (using hydrochloric acid mother liquor) obtained in Example 2

[0101] Retention time area Area percentage Peak Theoretical number of plates 3.199 0.68 0.00 0.14 13534 4.752 0.87 0.01 0.17 12051 4.909 1.36 0.01 0.19 7411 10.608 13848.14 99.95 979.45 12959 13.556 3.91 0.03 0.21 11348 total 13854.96 100.00

[0102] Example 3

[0103] A highly efficient and environmentally friendly continuous synthesis process for guanine includes the following steps:

[0104] (1) Synthesis of crude guanine: 50 g of 2,4-diamino-6-hydroxypyrimidine and 35 g of sodium nitrite were added to 450 mL of water to prepare a suspension. The flow rate of the peristaltic pump for injecting the suspension was set to 15 mL / min, and the flow rate of the peristaltic pump for injecting 180 mL of 35% hydrochloric acid was set to 6 mL / min. The two solutions were mixed and reacted in a pipe (with an inner diameter of 6 mm and a length of 10 m) that was immersed in cold water at 10 °C. The reaction solution was then injected into a reaction flask and stirred continuously. After all the reaction solution in the pipe was injected into the reaction flask, the mixture was stirred thoroughly for 30 minutes. The temperature was raised to 100 °C to evaporate and remove water until no water was distilled off. 330 g of formamide and 10 g of sodium dithionite were added, and the temperature was gradually raised to 160 °C for formylation reaction. The heating time was controlled for 4 hours and the temperature was maintained for 1 hour. The temperature was then raised to 175 °C for cyclization and dehydration reaction. The heating time was controlled for 1 hour and the temperature was maintained for 3 hours. The crude guanine and the formamide mother liquor were obtained by filtration.

[0105] (2) Formamide mother liquor recovery: 172.1 g of formamide mother liquor was first distilled under reduced pressure at 120°C using a water pump, and the temperature was continuously raised to 150°C until no more distillate was distilled off, with 14 g of the first distillate; then the receiver was changed, and the formamide was distilled off under reduced pressure at 90°C using an oil pump, and the temperature was continuously raised to 130°C until no more distillate was distilled off, with 151 g of formamide recovered.

[0106] (3) Refining of crude guanine (fresh hydrochloric acid): 1000 mL of 7% hydrochloric acid and crude guanine obtained in step (1) were added to the reactor and heated to 90°C to fully dissolve it into a dark brown clear solution. Then 15 g of activated carbon was added and the mixture was stirred and decolorized for 30 minutes. The mixture was then filtered while hot and the filtrate was cooled to 15°C. The filtrate and hydrochloric acid mother liquor were obtained by suction filtration.

[0107] (4) Refining of crude guanine (using hydrochloric acid mother liquor): The above hydrochloric acid mother liquor and another batch of crude guanine obtained in step (1) were put into the reactor and heated to 90°C. It failed to dissolve completely into a dark brown clear solution. 30 mL of hydrochloric acid was added and dissolved completely into a dark brown clear solution. Then 15 g of activated carbon was added and stirred for decolorization for 30 minutes. Then the solution was filtered while hot. The filtrate was cooled to 15°C and filtered to obtain guanine hydrochloride (after using hydrochloric acid mother liquor) and hydrochloric acid mother liquor.

[0108] Add 700 mL of water to each of the two batches of guanine hydrochloride from steps (3) and (4) above, heat to 50°C, adjust the pH to 7 with ammonia, filter to obtain the guanine product, dry and weigh. The first batch weighed 52.3 g with a purity of 99.96%; the second batch weighed 57.6 g with a purity of 99.96%.

[0109] (5) Wastewater treatment and ammonium salt recovery: Collect the alkaline wastewater distilled during the reaction, combine it with the alkaline wastewater used to rinse the water separator, neutralize the hydrochloric acid mother liquor, add ammonia water, adjust the pH to 7, filter out insoluble impurities, concentrate the filtrate to obtain ammonium salt, dry it and weigh it to 117.6 grams.

[0110] Table 5. Liquid chromatography data of guanine (fresh hydrochloric acid) obtained in Example 3.

[0111]

[0112]

[0113] Table 6. Liquid chromatography data of guanine (using hydrochloric acid mother liquor) obtained in Example 3.

[0114] Retention time area Area percentage Peak Theoretical number of plates 3.199 0.75 0.00 0.16 14082 4.753 1.09 0.01 0.18 7540 5.639 0.85 0.00 0.11 11549 10.624 16211.86 99.96 1113.72 12166 13.530 4.28 0.03 0.21 9391 total 16218.84 100.00

[0115] Example 4

[0116] A highly efficient and environmentally friendly continuous synthesis process for guanine includes the following steps:

[0117] (1) Synthesis of crude guanine: 50 g of 2,4-diamino-6-hydroxypyrimidine and 30 g of sodium nitrite were added to 450 mL of water to prepare a suspension. The flow rate of the peristaltic pump for injecting the suspension was set to 15 mL / min, and the flow rate of the peristaltic pump for injecting 180 mL of 33% hydrochloric acid was set to 6 mL / min. The two solutions were mixed and reacted in a pipe (with an inner diameter of 6 mm and a length of 10 m) that was immersed in cold water at 5 °C. The reaction solution was then injected into a reaction flask and stirred continuously. After all the reaction solution in the pipe was injected into the reaction flask, the mixture was stirred thoroughly for 30 minutes. The temperature was raised to 100 °C to evaporate and remove water until no water was distilled off. 360 g of formamide and 10 g of sodium dithionite were added, and the temperature was gradually raised to 160 °C for formylation reaction. The heating time was controlled for 4 hours and the temperature was maintained for 1 hour. The temperature was then raised to 175 °C for cyclization and dehydration reaction. The heating time was controlled for 1 hour and the temperature was maintained for 3 hours. The crude guanine and the formamide mother liquor were obtained by filtration.

[0118] (2) Formamide mother liquor recovery: 212.1 g of formamide mother liquor was first distilled under reduced pressure at 120°C using a water pump, and the temperature was continuously raised to 150°C until no more distillate was distilled off, with 15 g of the first distillate; then the receiver was replaced, and the formamide was distilled off under reduced pressure at 90°C using an oil pump, and the temperature was continuously raised to 130°C until no more distillate was distilled off, with 193 g of formamide recovered.

[0119] (3) Refining of crude guanine (fresh hydrochloric acid): 900 mL of 8% hydrochloric acid and the crude guanine obtained in step (1) were added to the reactor and heated to 90°C to fully dissolve it into a dark brown clear solution. Then 13.5 g of activated carbon was added and the mixture was stirred and decolorized for 30 minutes. The mixture was then filtered while hot and the filtrate was cooled to 20°C. The filtrate and hydrochloric acid mother liquor were obtained by suction filtration.

[0120] (4) Refining of crude guanine (using hydrochloric acid mother liquor): The above hydrochloric acid mother liquor and another batch of crude guanine obtained in step (1) were put into the reactor and heated to 90°C. It failed to dissolve completely into a dark brown clear solution. 30 mL of hydrochloric acid was added and dissolved completely into a dark brown clear solution. Then 13.5 g of activated carbon was added and stirred for decolorization for 30 minutes. Then the solution was filtered while hot. The filtrate was cooled to 20°C and filtered to obtain guanine hydrochloride (after using hydrochloric acid mother liquor) and hydrochloric acid mother liquor.

[0121] Add 800 mL of water to each of the two batches of guanine hydrochloride from steps (3) and (4) above, heat to 60°C, adjust the pH to 7 with ammonia, filter to obtain the guanine product, dry and weigh. The first batch was 52.0 g with a purity of 99.93%; the second batch was 57.2 g with a purity of 99.90%.

[0122] (5) Wastewater treatment and ammonium salt recovery: Collect the alkaline wastewater distilled during the reaction, combine it with the alkaline wastewater used to rinse the water separator, neutralize the hydrochloric acid mother liquor, add ammonia water, adjust the pH to 7, filter out insoluble impurities, concentrate the filtrate to obtain ammonium salt, dry it and weigh it to 123.6 grams.

[0123] Table 7. Liquid chromatography data of guanine (fresh hydrochloric acid) obtained in Example 4.

[0124] Retention time area Area percentage Peak Theoretical number of plates 3.196 0.79 0.00 0.17 13598 4.754 1.19 0.01 0.19 9350 4.987 1.04 0.00 0.11 5542 5.633 2.72 0.02 0.34 11387 10.615 17816.96 99.93 1201.21 11651 13.504 6.74 0.04 0.34 10033 total 17829.45 100

[0125] Table 8. Liquid chromatography data of guanine (using hydrochloric acid mother liquor) obtained in Example 4.

[0126] Retention time area Area percentage Peak Theoretical number of plates 3.194 0.89 0.00 0.20 15082 4.754 1.40 0.01 0.21 10675 5.640 1.30 0.01 0.17 11649 10.645 19048.98 99.90 1262.39 11277 13.539 8.78 0.05 0.50 13442 25.105 6.04 0.03 0.22 18128 total 19067.39 100

[0127] Example 5

[0128] A highly efficient and environmentally friendly continuous synthesis process for guanine includes the following steps:

[0129] (1) Synthesis of crude guanine: 50 g of 2,4-diamino-6-hydroxypyrimidine and 30 g of sodium nitrite were added to 450 mL of water to prepare a suspension. The flow rate of the peristaltic pump for injecting the suspension was set to 15 mL / min, and the flow rate of the peristaltic pump for injecting 180 mL of 33% hydrochloric acid was set to 6 mL / min. The two solutions were mixed and reacted in a pipe (with an inner diameter of 6 mm and a length of 10 m) that was immersed in cold water at 5 °C. The reaction solution was then injected into a reaction flask and stirred continuously. After all the reaction solution in the pipe was injected into the reaction flask, the mixture was stirred thoroughly for 30 minutes. The temperature was raised to 100 °C to evaporate and remove water until no water was distilled off. 360 g of formamide and 10 g of sodium dithionite were added, and the temperature was gradually raised to 160 °C for a formylation reaction. The heating time was controlled for 4 hours and the temperature was maintained for 1 hour. The temperature was then raised to 175 °C for a cyclization reflux reaction. The heating time was controlled for 1 hour and the temperature was maintained for 3 hours. The crude guanine and the formamide mother liquor were obtained by filtration.

[0130] (2) Formamide mother liquor recovery: 210.1 g of formamide mother liquor was first distilled under reduced pressure at 120°C using a water pump, and the temperature was continuously raised to 150°C until no more distillate was distilled off, with 16 g of the first distillate; then the receiver was replaced, and the formamide was distilled off under reduced pressure at 90°C using an oil pump, and the temperature was continuously raised to 130°C until no more distillate was distilled off, with 189 g of formamide recovered.

[0131] (3) Refining of crude guanine (fresh hydrochloric acid): 900 mL of 8% hydrochloric acid and the crude guanine obtained in step (1) were added to the reactor and heated to 90°C to fully dissolve it into a dark brown clear solution. Then 13.5 g of activated carbon was added and the mixture was stirred and decolorized for 30 minutes. The mixture was then filtered while hot and the filtrate was cooled to 20°C. The filtrate and hydrochloric acid mother liquor were obtained by suction filtration.

[0132] (4) Refining of crude guanine (using hydrochloric acid mother liquor): The above hydrochloric acid mother liquor and another batch of crude guanine obtained in step (1) were put into the reactor and heated to 90°C. It failed to dissolve completely into a dark brown clear solution. 30 mL of hydrochloric acid was added and dissolved completely into a dark brown clear solution. Then 13.5 g of activated carbon was added and stirred for decolorization for 30 minutes. Then the solution was filtered while hot. The filtrate was cooled to 20°C and filtered to obtain guanine hydrochloride (after using hydrochloric acid mother liquor) and hydrochloric acid mother liquor.

[0133] Add 800 mL of water to each of the two batches of guanine hydrochloride from steps (3) and (4) above, heat to 60°C, adjust the pH to 7 with ammonia, filter to obtain the guanine product, dry and weigh. The first batch weighed 51.3 g with a purity of 99.69%; the second batch weighed 55.8 g with a purity of 99.72%.

[0134] (5) Wastewater treatment and ammonium salt recovery: Collect the alkaline wastewater distilled during the reaction, combine it with the alkaline wastewater used to rinse the water separator, neutralize the hydrochloric acid mother liquor, add ammonia water, adjust the pH to 7, filter out insoluble impurities, concentrate the filtrate to obtain ammonium salt, dry it and weigh it to 126.6 grams.

[0135] Table 9. Liquid chromatography data of guanine (fresh hydrochloric acid) obtained in Example 5.

[0136] Retention time area Area percentage Peak Theoretical number of plates 3.197 0.70 0.01 0.14 13905 5.174 0.39 0.01 0.06 14476 5.786 1.16 0.02 0.14 11782 9.334 11.27 0.15 0.91 13628 10.629 7319.13 99.69 562.04 15828 13.709 9.04 0.12 0.59 18510 total 7341.69 100

[0137] Table 10. Liquid chromatography data of guanine (using hydrochloric acid mother liquor) obtained in Example 5

[0138]

[0139]

[0140] Example 5 is a comparative experiment with Example 4, the only difference being that, after the low-temperature formylation reaction, the water generated during the high-temperature cyclization reaction in Example 5 was continuously refluxed. The results of Example 5 show that if the water generated during the high-temperature cyclization dehydration step is not distilled off, both the main guanine peak and the two impurity peaks before and after it are significantly increased. That is, the present invention can further improve the purity of guanine by using a cyclization dehydration reaction instead of a cyclization reflux reaction.

[0141] In summary, using the process of this invention, each batch of guanine product is an off-white solid with a purity greater than 99.6%, and the total yield of guanine product is greater than 89% (based on a 50 / 50 split between the initial and final yields). This invention also reduces wastewater and energy consumption, lowering the overall production and environmental costs of the process.

[0142] The specific embodiments of the present invention described above do not constitute a limitation on the scope of protection of the present invention. Any other corresponding changes and modifications made in accordance with the technical concept of the present invention should be included within the scope of protection of the claims of the present invention.

Claims

1. A continuous synthesis process for guanine, characterized in that, Includes the following steps: S100, crude guanine synthesis; And optional location, S200, formamide mother liquor recovery; S300, refined crude guanine; The steps for synthesizing crude guanine include: S101. Mix 2,4-diamino-6-hydroxypyrimidine, sodium nitrite and first water evenly to obtain a suspension; S102. The suspension and the first hydrochloric acid solution are introduced into the pipeline for mixing and reaction, and the reaction solution is injected into the reaction flask and stirred continuously. S103. After all the reaction liquid in the pipeline has been injected into the reaction bottle, continue stirring to mix the reaction liquid evenly, and then evaporate and remove water until no water is distilled out. S104. Add formamide and catalyst to the reaction flask, and carry out formylation reaction at 100~160℃ and cyclization reaction at 160~175℃ in sequence. Then, filter to obtain crude guanine and formamide mother liquor. In step S102, the inner diameter of the pipeline is 2~20mm, and the length of the pipeline is 5~20m; the flow rate of the suspension into the pipeline is 15~20mL / min, and the flow rate of the first hydrochloric acid solution into the pipeline is 5~10mL / min. In step S102, when the suspension and the first hydrochloric acid solution are mixed and reacted in the pipeline, the pipeline is immersed in cold water at 0~20℃. The cyclization reaction is a cyclization dehydration reaction.

2. The continuous synthesis process of guanine according to claim 1, characterized in that, In step S101, the mass ratio of 2,4-diamino-6-hydroxypyrimidine to sodium nitrite and first water is 1:(0.5~0.7):(7.5~11); in step S102, the mass fraction of the first hydrochloric acid solution is 30%~35%, and the volume ratio of 2,4-diamino-6-hydroxypyrimidine to the first hydrochloric acid solution is 1g:(3~5)mL; in step S104, the catalyst is at least one of sodium sulfide, sodium thiosulfate, or sodium dithionite; the mass ratio of 2,4-diamino-6-hydroxypyrimidine to formamide and catalyst is 1:(5~7):(0.1~0.2).

3. The continuous synthesis process of guanine according to claim 1, characterized in that, In step S104, during the formylation reaction, the temperature is increased from 100°C to 160°C at a heating rate of 0.1~0.3°C / min, and the total time for the entire heating and holding stages is 4~6 hours; during the cyclization reaction, the temperature is increased from 160°C to 175°C at a heating rate of 0.1~0.5°C / min, and the total time for the entire heating and holding stages is 3~5 hours.

4. The continuous synthesis process of guanine according to claim 1, characterized in that, The steps for recovering the formamide mother liquor include: S201. The formamide mother liquor obtained after filtration in step S104 is subjected to a first vacuum distillation using a water pump to obtain the fore fraction. S202, The formamide mother liquor after the first vacuum distillation is subjected to a second vacuum distillation using an oil pump to recover formamide; wherein... In the first vacuum distillation process, the temperature is first raised to 110~130℃ to start vacuum distillation, and then continuously raised to 140~160℃ until no more distillate is distilled off; the temperature of the cooling liquid flowing through the condenser jacket is 10~20℃. In the second vacuum distillation process, the temperature is first raised to 80~100℃ to start vacuum distillation, and then continuously raised to 120~140℃ until no more distillate is distilled off; the temperature of the cooling liquid introduced into the condenser jacket is 5~10℃.

5. The continuous synthesis process of guanine according to claim 1, characterized in that, The steps for refining crude guanine include: S301. Add crude guanine to the second hydrochloric acid solution and allow it to dissolve completely into a dark brown, clear solution. S302. Add activated carbon to a dark brown clear liquid and stir to decolorize it. Then filter it while it is hot. After cooling, filter the filtrate to obtain guanine hydrochloride and hydrochloric acid mother liquor. S303. Guanine hydrochloride is dissolved in the second water, then the pH is adjusted to 6-8 with ammonia, and the product is obtained by suction filtration; wherein, The mass fraction of the second hydrochloric acid solution is 7%~10%; the ratio of crude guanine to the second hydrochloric acid solution is 1g:(10~20)mL; During the process of fully dissolving the crude guanine into a clear, dark brown solution, the temperature needs to be heated to 80-90°C. The ratio of activated carbon to dark brown clear liquid is (0.01~0.03) g: 1 mL; The temperature for stirring and decolorizing shall not exceed 90°C; The temperature of the filtrate after cooling is 10~20℃; The hydrochloric acid mother liquor is used in the purification steps of other batches of crude guanine. The mass ratio of guanine hydrochloride to the second water is 1:(5~20); The guanine hydrochloride needs to be heated to 50-60°C during the process of dissolving in the second water.

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