A process for the production of 6-chloropurine hydrochloride

Abstract

The application belongs to the field of 6-chloropurine production, and particularly relates to a production method of 6-chloropurine hydrochloride. The method comprises steps of S1 chlorination reaction and initial distillation, S2 dissolution and salt formation and crystallization, S3 beating and refining, S4 mother liquor resource treatment and recovery and reuse, etc. Through a treatment process of "solvent recovery-mother liquor combination-low temperature pH control alkaline washing-phase separation", a large amount of dilution wastewater generated by multiple water washing is converted into a small amount of high-concentration weak alkaline wastewater, the wastewater generation amount is reduced by more than 50% compared with the traditional process, and the subsequent wastewater treatment load and cost are greatly reduced. In addition, the method takes into account the recovery of chlorinating reagent, cosolvent and organic base in design, realizes the resource utilization of valuable raw materials, significantly reduces the raw material use cost, and makes the whole process have environmental friendliness and economic benefits.

Description

Technical Field

[0001] This invention belongs to the field of 6-chloropurine production, and specifically relates to a method for producing 6-chloropurine hydrochloride. Background Technology

[0002] 6-Chloropurine is a key intermediate in the synthesis of many antiviral and anticancer drugs (such as acyclovir and ganciclovir), and is also one of the main intermediates in the synthesis of adenine.

[0003] The traditional method for preparing 6-chloropurine usually involves chlorinating hypoxanthine (or its derivatives) with phosphorus oxychloride in the presence of an organic base (such as N,N-dimethylaniline), followed by concentration, pH adjustment, crystallization, pulping, and drying to obtain crude 6-chloropurine. Further purification is then carried out to obtain a high-purity product with a content of over 90%.

[0004] Chinese invention patent application CN102321086A, published on January 18, 2012, discloses a method for synthesizing adenine. The method first involves a chlorination reaction using acetylinosine and excess phosphorus oxychloride (as a chlorination reagent) catalyzed by N,N-dimethylaniline (as an organic base). After the reaction, excess POCl3 is removed by vacuum distillation. The residue is then slowly added to a large amount of cold water (approximately 300 ml of cold water is used for 0.1 mol of acetylinosine raw material). The pH is then adjusted to approximately 10 using 20% ​​NaOH solution. A large amount of solid is produced in the solution. The solution is filtered, and the filter cake is washed with dichloromethane. The filtrates are combined and separated into layers. The aqueous layer is washed with dichloromethane, and the aqueous layer is then a alkali solution of 6-chloropurine.

[0005] This process route has the following main problems: 1) Large volume of wastewater generated and difficult to treat: After the feed solution is concentrated, it needs to be added to a large excess of ice water. The mother liquor generated from pH adjustment, crystallization, and subsequent crude product refining processes usually contains unreacted raw materials, byproducts, organic bases, solvents, and inorganic salts, forming a mixed wastewater with high COD, high salinity, and complex composition. Assuming each batch processes 200-300 kg of hypoxanthine, approximately 4-5 tons of mixed wastewater require treatment. The biochemical treatment of this mixed wastewater is challenging, posing a significant environmental burden.

[0006] 2) Low resource utilization: The large amount of expensive and toxic reagent N,N-dimethylaniline used in the reaction is usually only simply treated or disposed of as hazardous waste, and cannot be effectively recycled and reused, resulting in high production costs and environmental unfriendliness.

[0007] US4405781A discloses a method for preparing 6-chloropurine salt, which involves reacting hypoxanthine with phosphorus oxychloride in the presence of an organic base to form 6-chloropurine, adding a solvent to the reaction mixture, reacting it with a strong acid to form the 6-chloropurine salt, and then separating the 6-chloropurine salt from the system. Finally, 6-chloropurine is obtained by reacting the 6-chloropurine salt with an alkaline substance. This reaction method optimizes the separation pathway of 6-chloropurine and improves the industrial separation efficiency of 6-chloropurine. However, the production wastewater involved in the process still contains solvents, organic amines such as N,N-dimethylaniline, unreacted raw materials, and by-products. The problems of difficult wastewater treatment and low resource utilization still exist. Summary of the Invention

[0008] The purpose of this invention is to provide a method for producing 6-chloropurine hydrochloride, which solves the problems of large wastewater generation and low resource utilization rate in existing production methods.

[0009] To achieve the above objectives, the technical solution adopted by the present invention is as follows: A method for producing 6-chloropurine hydrochloride includes the following steps: S1. Hypoxanthine reacts with a chlorinated reagent in the presence of an organic base, and the chlorinated reagent is recovered by vacuum distillation after the reaction. S2. Add a co-solvent to the distillation residue to dissolve it, pass hydrogen chloride gas through to form salt, and separate the solid and liquid to obtain the first wet product and the first mother liquor; S3. The first wet product is pulped with a co-solvent and then centrifuged to obtain the second wet product and the second mother liquor. The second wet product is dried to obtain the product. S4. After combining the first and second mother liquors, water is added and the pH of the aqueous phase is adjusted to 8-9 with alkali solution before phase separation; the co-solvent and the organic base are recovered by distillation of the organic phase.

[0010] The wastewater generated by this method is only the alkaline aqueous phase separated by phase separation, and this part of the wastewater can be utilized as a resource through subsequent rational treatment.

[0011] This invention is an improved invention. Through a unique "solvent recovery - mother liquor merging - low temperature pH controlled alkaline washing - phase separation" process, the massive amount of diluted wastewater that originally required multiple water washings is transformed into a small amount of high-concentration alkaline wastewater. The amount of wastewater generated is reduced by more than 50% compared with the traditional process, which greatly reduces the load and cost of subsequent wastewater treatment.

[0012] In addition, this method takes into account the recovery of chlorination reagents, cosolvents and organic bases during the design process, realizing the resource utilization of valuable raw materials, significantly reducing the cost of raw material use, and making the whole process both environmentally friendly and economically efficient.

[0013] Preferably, in step S4, the water is cold water with a temperature not exceeding 10°C, and the system temperature is controlled to not exceed 20°C after adding water; the alkali is sodium hydroxide, and the temperature during alkali addition and phase separation is controlled below 20°C. By controlling the temperature during alkali addition and phase separation, solvent evaporation and side reactions are effectively prevented.

[0014] More preferably, the aqueous phase obtained after phase separation is a sodium phosphate waste liquid, which is centrally treated for use as a phosphate fertilizer agent. This method enables the resource utilization of elements such as phosphorus in the wastewater, transforming the original problem of treating 6-chloropurine production wastewater into resource utilization, further improving the environmental friendliness and economic efficiency of industrial-scale 6-chloropurine production.

[0015] Preferably, during the organic phase distillation, the recovered flux is reused; multiple batches of organic phase distillation residues are collected, combined, and then subjected to vacuum distillation to recover pure organic base, which is then reused in the reaction of step S1. In a preferred embodiment, the flux used in step S2 and step S3 is of the same type to facilitate recovery and reuse. This method improves the efficiency of flux and organic base recovery, and the recovered organic base is relatively pure and can be directly used in the reaction of step S1.

[0016] Preferably, in step S2, when hydrogen chloride gas is introduced, the system temperature is controlled to be below 30°C; after the salt formation reaction, the system is aged at 15-25°C, and then cooled to 0-10°C to crystallize. Using these preferred reaction conditions can further improve the product yield and purity.

[0017] Preferably, the mass ratio of hypoxanthine in step S1 to the co-solvent in step S2 is 1:(8~13), and the co-solvent is selected from ethyl acetate and 1,2-dichloroethane; the mass ratio of the mixed mother liquor after combining the first and second mother liquors in step S4 to water is (2~5):1. Using the above-mentioned types and amounts of co-solvents provides good solubility and dispersibility of the raw materials, has a moderate boiling point, and can better promote the reaction. The mass ratio of hypoxanthine in step S1 to the co-solvent in step S2 is further preferably 1:(10~12). The mass ratio of the mixed mother liquor to water is further preferably (2.8~3.8):1.

[0018] Preferably, in step S3, the pulping temperature is 40-45℃, followed by cooling and centrifugation to obtain the second wet product and the second mother liquor; the cooling is to 0-10℃. This preferred pulping and separation process achieves better purification and separation results, further improving the purity and yield of the product.

[0019] Preferably, the mass ratio of hypoxanthine to the chlorinating reagent is 1:(6~11), and the chlorinating reagent is selected from phosphorus oxychloride. Under the above preferred conditions, the chlorination reaction can be carried out efficiently, and the raw material hypoxanthine can be fully converted.

[0020] Preferably, the mass ratio of hypoxanthine to organic base is 1:(1.7~3), and the organic base is selected from N,N-dimethylaniline. Under the control of the above-mentioned type and amount of organic base, the amount of organic base is appropriate, which further ensures the efficient progress of the chlorination reaction and avoids the excessive addition of organic base.

[0021] More preferably, the chlorination reaction in step S1 is carried out at a temperature of 100-105°C. Below this chlorination reaction temperature, the chlorination reaction is highly efficient, and the rapid reaction minimizes the occurrence of side reactions.

[0022] Compared with the prior art, the present invention achieves the following technical effects: 1. A brand-new industrial production concept for 6-chloropurine hydrochloride: For the first time, the treatment and resource utilization of wastewater from the production of 6-chloropurine hydrochloride are incorporated into the industrial production process of 6-chloropurine hydrochloride, realizing a closed loop of green and efficient production and raw material utilization of 6-chloropurine hydrochloride.

[0023] 2. A complete internal material circulation system has been established: 2.1 Key reagent reuse: The system enables efficient recovery and direct reuse of excess phosphorus oxychloride reactant, significantly reducing unit consumption and hazardous waste generation.

[0024] 2.2 Solvent closed-loop circulation: A closed-loop circulation of ethyl acetate was established between the "dissolution-pulping" unit and the "mother liquor recovery" unit. The recovered solvent can be directly used in production, and the solvent consumption per unit is less than 10%.

[0025] 2.3 Catalyst / Base Recovery: Through distillation of the organic phase of the mother liquor and combined distillation of multiple batches of residues, N,N-dimethylaniline, which has high value, was successfully recovered and reused in the reaction, realizing the resource utilization of valuable materials.

[0026] 3. Balance between process safety and economy: By precisely controlling the temperature and endpoint of key steps such as salt formation and alkali washing, operational safety is ensured; at the same time, a comprehensive material recovery system significantly reduces raw material costs, making the entire process both environmentally friendly and economically efficient.

[0027] 4. Excellent product yield and quality: Optimized salt formation, crystallization and pulping conditions, combined with efficient mother liquor treatment, reduce product loss in the mother liquor, and maintain a stable molar yield of 85-90% (based on hypoxanthine) and a purity of about 98%, which meets the standards for use as a raw material for the synthesis of other purine compounds. Attached Figure Description

[0028] Figure 1 This is a process flow diagram of the production method of 6-chloropurine hydrochloride according to Example 1 of the present invention. Detailed Implementation

[0029] (a) Preferred embodiment of the method for producing 6-chloropurine hydrochloride of the present invention To address the problems of large wastewater generation and difficult biochemical treatment in the current industrial production of 6-chloropurine, this invention proposes a method for the preparation of 6-chloropurine hydrochloride with low wastewater discharge and the resource utilization treatment of the mother liquor. This method reduces wastewater at the source, enables the recycling of key materials, and safely treats hazardous byproducts. It features a reasonable process flow, high resource recovery rate, and minimal wastewater generation, and has significant industrial application value and environmental significance.

[0030] The method for producing 6-chloropurine hydrochloride according to the present invention comprises the following reaction formula: The specific steps are as follows: (1) Chlorination reaction and initial distillation Compound of Formula 2 (i.e. hypoxanthine) reacts with a chlorinated reagent in the presence of an organic base. After the reaction, the chlorinated reagent is recovered by vacuum distillation, and the fraction is reused.

[0031] Specifically, this step involves chlorinating hypoxanthine and phosphorus oxychloride under anhydrous and oxygen-free conditions at 100-105 °C with N,N-dimethylaniline as a catalyst. After the reaction is complete, the reaction solution is transferred to a distillation apparatus, and excess phosphorus oxychloride is recovered by distillation at 70-75 °C under reduced pressure. The recovered phosphorus oxychloride fraction is directly reused in the next batch of reaction.

[0032] In this step, the mass ratio of phosphorus oxychloride to hypoxanthine is (6~11):1. In actual production, the phosphorus oxychloride recovered by distillation can be directly used to supplement fresh phosphorus oxychloride for the next batch, with a reuse rate of over 75%.

[0033] (2) Dissolution, salt formation and crystallization Add a co-solvent to the distillation residue to dissolve it, pass hydrogen chloride gas through it to form salt, and centrifuge to obtain the first wet product and the first mother liquor.

[0034] Specifically, the first co-solvent is added to the distillation residue. After dissolving, dry hydrogen chloride gas is slowly introduced to carry out the salt formation reaction. The reaction endpoint is determined by the content of free products in the feed solution being less than 5%. The reaction solution is cooled at low temperature and centrifuged to obtain the first wet filter cake and the first mother liquor. All of the first mother liquor is collected and temporarily stored.

[0035] When hydrogen chloride gas is introduced, the temperature of the reaction solution should be controlled below 30℃. After the salt formation reaction, the solution is kept at 15~25℃ for ripening, and then cooled to 0~10℃ for crystallization to improve product yield and purity. The ripening time can be controlled to be 0.5~1h.

[0036] In step (1), the amount of hypoxanthine added is 180~240 kg, and the corresponding amount of cosolvent is 1500~3000 kg. The above amount can be increased or decreased proportionally. Preferably, in step (1), the amount of hypoxanthine added is 240~250 kg, and the corresponding amount of cosolvent is controlled at 2000~3000 kg.

[0037] (3) Pulping and refining The first wet product was pulped with a co-solvent and then centrifuged to obtain the second wet product and the second mother liquor combined with the first mother liquor; the second wet product was dried to obtain the product.

[0038] Specifically, in this step, the first wet filter cake is pulped with a second co-solvent at 40-45°C, then cooled and centrifuged to obtain a second wet filter cake and a second mother liquor; the second mother liquor is combined with the first mother liquor to form a mixed mother liquor, which is temporarily stored for further processing; the second wet filter cake is dried to obtain 6-chloropurine hydrochloride.

[0039] In step (1), the amount of hypoxanthine added is 180~240 kg, and the corresponding amount of the second part of the cosolvent can be 630~1000 kg. The above amounts can be increased or decreased proportionally. Preferably, in step (1), the amount of hypoxanthine added is 240~250 kg, and the corresponding amount of the second part of the cosolvent is controlled to be 900~1000 kg.

[0040] (4) Resource utilization and recycling of mother liquor The mixed mother liquor was mixed with water at low temperature and the pH was adjusted to 8-9 with alkali before phase separation; the organic phase was distilled to recover the co-solvent for reuse, and the residue was collected; the residues from multiple batches were combined and distilled to recover the organic alkali for reuse.

[0041] Specifically, this step includes the following operations: 4.1 Alkali washing and phase separation: Add cold water to the mixed mother liquor obtained in step (3) and cool it to below 20°C. Under stirring and temperature control, add sodium hydroxide in batches to react. Stop adding alkali when the pH of the aqueous phase is 8 to 9. Let it stand to separate the phases and obtain an upper alkaline aqueous phase and a lower organic phase (taking 1,2-dichloroethane as an example).

[0042] In this step, the system temperature must be strictly controlled not to exceed 20 ℃ during the addition of alkali to prevent excessive solvent evaporation.

[0043] The mass ratio of the mixed mother liquor to cold water can be (2~5):1, for example (2.8~3.8):1. The temperature of the cold water should not exceed 10℃, for example, it can be 5~10℃.

[0044] 4.2 Solvent recovery: The lower organic phase is distilled under normal pressure to recover the co-solvent. The recovered co-solvent is recycled in step (2) or step (3) as the solvent. The main component of the distillation residue is N,N-dimethylaniline, which is collected separately.

[0045] 4.3 Recovery of alkaline solution and residues: The upper alkaline aqueous phase is treated as a high-concentration alkaline waste liquid for use as a phosphate fertilizer agent; multiple batches of distillation residues obtained in step 4.2 (rich in N,N-dimethylaniline) are collected, combined and subjected to vacuum distillation to recover pure N,N-dimethylaniline, which is then reused in the reaction of step (1).

[0046] The preferred embodiments described above will be illustrated below with specific examples.

[0047] Example 1 The process flow diagram for the production method of 6-chloropurine hydrochloride in this embodiment is as follows: Figure 1 As shown, the following steps are taken: (1) Chlorination reaction and initial distillation: Ensure the 3000 L reactor R1 is dry, anhydrous, and alcohol-free, and purge it with nitrogen through the bottom valve for 10 minutes. Transfer 2400 kg of phosphorus oxychloride to reactor R1 using a diaphragm pump, and start stirring and circulating the cooling liquid. Once the material temperature drops below 20 °C, add 240 kg of hypoxanthine to R1 through the vessel opening, followed by 430 kg of N,N-dimethylaniline. Stir at 20-30 °C for 10 minutes to ensure the mixture is homogeneous.

[0048] Turn on the steam and raise the material temperature to 100-105℃, then maintain the temperature for 30 minutes. After the temperature maintenance is complete, take a sample for HPLC analysis. The reaction is considered complete when the hypoxanthine content is below 1%.

[0049] (2) Dissolution, salt formation and crystallization: After the reaction is complete, turn on the circulating coolant to lower the feed temperature to 40-50℃. Transfer the feed liquid from reactor R1 to 3000L reactor R2 and distill under reduced pressure at 70-75℃ until no fraction remains (ensure reactor R2 and the receiving tank are dry before distillation; seal and store the fraction for reuse in the next batch). After distillation, stop the steam and add 2000 kg of 1,2-dichloroethane to reactor R2. Turn on the circulating coolant to lower the feed liquid temperature to 10-20℃ and maintain this temperature with stirring for 30 minutes to completely dissolve the residue. Transfer the feed liquid from reactor R2 to 5000L reactor R3 and flush reactor R2 and the pipelines with 1000 kg of 1,2-dichloroethane before introducing it into reactor R3. Slowly introduce hydrochloric acid gas into reactor R3 until the product concentration (free 6-chloropurine content) in the feed filtrate is below 5%, and control the feed liquid temperature below 30℃ during the gas introduction period. After the central control results are satisfactory, stop the aeration and maintain the temperature at 15-25℃ with stirring for 30 minutes. Turn on the circulating coolant to cool the liquid to 0-10℃. Centrifuge (excess hydrochloric acid gas will overflow; pay attention to nitrogen aeration and exhaust gas treatment), collect the filter solid, and temporarily store the filtrate in a 5000 L reactor (R4).

[0050] (3) Pulping and refining: 900 kg of 1,2-dichloroethane was transferred into reactor R2 beforehand. The collected filter solid was added into reactor R2 through the inlet. Stirring and steam were turned on, and the mixture was slurried at 40-45°C for 30 minutes. After slurrying, the circulating cooling liquid was turned on to cool the liquid to 0-10°C. The mixture was centrifuged, the filter solid was collected, and the filtrate was temporarily stored in reactor R4.

[0051] The filtered solid was dried at 80 °C until the moisture content did not exceed 0.5% (turning the material over every 4 hours). A bright yellow solid, 6-chloropurine hydrochloride, was obtained and weighed. A sample was taken to determine its purity and content.

[0052] (4) Resource utilization and recycling of mother liquor (post-treatment of mother liquor) Add 1100 kg of cold water (temperature below 10℃) to reactor R4 (total weight of mother liquor approximately 3800 ~ 4000 kg) and cool to below 20℃. Add sodium hydroxide to reactor R4 in batches while maintaining stirring, keeping the temperature of the feed solution below 20℃ during alkali addition. Stop adding feed when the pH of the upper aqueous phase reaches 8 ~ 9, and continue stirring for 30 minutes. Separate the phases; the upper aqueous phase is temporarily stored in tank V1, and the lower organic phase is transferred to reactor R2. Turn on steam in reactor R2 and distill at atmospheric pressure to recover 1,2-dichloroethane for reuse. The residue is temporarily stored in tank V2 (multiple batches are combined and distilled under reduced pressure to recover N,N-dimethylaniline for reuse, boiling point 193℃).

[0053] The upper alkaline aqueous phase is a sodium phosphate waste liquid, mainly composed of sodium phosphate and sodium chloride. 2400-2600 kg of waste liquid contains approximately 960-990 kg of sodium phosphate and approximately 350-380 kg of sodium chloride. This alkaline aqueous phase can be used for centralized treatment of phosphate fertilizer wastewater.

[0054] The results showed that processing 240 kg of hypoxanthine yielded approximately 362 kg of 6-chloropurine hydrochloride with a purity of 81.0% and a molar yield of 98.3%, resulting in a yield of approximately 87.2%. Approximately 1800 kg of phosphorus oxychloride fraction was recovered (for direct reuse), and approximately 3300 kg of 1,2-dichloroethane was recovered (for direct reuse). Approximately 2400-2600 kg of high-concentration alkaline solution was generated requiring further processing. After accumulating three batches of crude N,N-dimethylaniline, vacuum distillation recovered approximately 300 kg of N,N-dimethylaniline with a purity >98%, which was reused in production.

[0055] Traditional comparative processes, when treating the same amount of feedstock, generate approximately 5-6 tons of combined wastewater, and none of the solvents and organic alkalis are effectively recovered. The process of this invention offers significant advantages in wastewater reduction and resource recovery.

[0056] Example 2 The process flow diagram for the production method of 6-chloropurine hydrochloride in this embodiment is as follows: Figure 1 As shown, the following steps are taken: (1) Chlorination reaction and initial distillation: Ensure the 3000 L reactor R1 is dry, anhydrous, and alcohol-free, and purge it with nitrogen through the bottom valve for 10 minutes. Transfer 1650 kg of phosphorus oxychloride to reactor R1 using a diaphragm pump, and start stirring and circulating the cooling liquid. Once the material temperature drops below 20 °C, add 240 kg of hypoxanthine to R1 through the vessel opening, followed by 430 kg of N,N-dimethylaniline. Stir at 20-30 °C for 10 minutes to ensure the mixture is homogeneous.

[0057] Turn on the steam and raise the material temperature to 100-105℃, then maintain the temperature for 30 minutes. After the temperature maintenance is complete, take a sample for HPLC analysis. The reaction is considered complete when the hypoxanthine content is below 1%.

[0058] (2) Dissolution, salt formation and crystallization: After the reaction is complete, turn on the circulating coolant to lower the feed temperature to 40-50℃. Transfer the feed liquid from reactor R1 to 3000L reactor R2 and distill under reduced pressure at 70-75℃ until no fraction remains (ensure reactor R2 and the receiving tank are dry before distillation; seal and store the fraction for reuse in the next batch). After distillation, stop the steam and add 2000 kg of 1,2-dichloroethane to reactor R2. Turn on the circulating coolant to lower the feed liquid temperature to 10-20℃ and maintain this temperature with stirring for 30 minutes to completely dissolve the residue. Transfer the feed liquid from reactor R2 to 5000L reactor R3 and flush reactor R2 and the pipelines with 1000 kg of 1,2-dichloroethane before introducing it into reactor R3. Slowly introduce hydrochloric acid gas into reactor R3 until the product concentration (free 6-chloropurine content) in the feed filtrate is below 5%, and control the feed liquid temperature below 30℃ during the gas introduction period. After the central control results are satisfactory, stop the aeration and maintain the temperature at 15-25℃ with stirring for 30 minutes. Turn on the circulating coolant to cool the liquid to 0-10℃. Centrifuge (excess hydrochloric acid gas will overflow; pay attention to nitrogen aeration and exhaust gas treatment), collect the filter solid, and temporarily store the filtrate in a 5000 L reactor (R4).

[0059] (3) Pulping and refining: 900 kg of 1,2-dichloroethane was transferred into reactor R2 beforehand. The collected filter solid was added into reactor R2 through the inlet. Stirring and steam were turned on, and the mixture was slurried at 40-45°C for 30 minutes. After slurrying, the circulating cooling liquid was turned on to cool the liquid to 0-10°C. The mixture was centrifuged, the filter solid was collected, and the filtrate was temporarily stored in reactor R4.

[0060] The filtered solid was dried at 80 °C until the moisture content did not exceed 0.5% (turning the material over every 4 hours). A bright yellow solid, 6-chloropurine hydrochloride, was obtained and weighed. A sample was taken to determine its purity and content.

[0061] (4) Resource utilization and recycling of mother liquor (post-treatment of mother liquor) Add 1100 kg of cold water (below 10 °C) to reactor R4 (approximately 3800 ~ 4000 kg) and cool to below 20 °C. Add sodium hydroxide solid to reactor R4 in batches while maintaining stirring, keeping the temperature of the feed solution below 20 °C during alkali addition. Stop adding alkali when the pH of the upper aqueous phase reaches 8 ~ 9, and continue stirring for 30 minutes. Separate the phases; the upper aqueous phase is temporarily stored in tank V1, and the lower organic phase is transferred to reactor R2. Turn on steam in reactor R2 and perform atmospheric distillation to recover 1,2-dichloroethyl for reuse. The residue is temporarily stored in tank V2 (multiple batches are combined and distilled under reduced pressure to recover N,N-dimethylaniline for reuse, boiling point 193 °C).

[0062] The upper alkaline aqueous phase is a sodium phosphate waste liquid, mainly composed of sodium phosphate and sodium chloride. 2400-2600 kg of waste liquid contains approximately 960-990 kg of sodium phosphate and approximately 350-380 kg of sodium chloride. This alkaline aqueous phase can be used for centralized treatment of phosphate fertilizer wastewater.

[0063] The results showed that processing 240 kg of hypoxanthine yielded approximately 346 kg of 6-chloropurine hydrochloride with a purity of 97.5% and a molar yield of approximately 82.8%. Approximately 1230 kg of phosphorus oxychloride fraction was recovered (directly reused), and approximately 3300 kg of 1,2-dichloroethane was recovered (directly reused). Approximately 2400-2600 kg of high-concentration alkaline solution was generated requiring further processing. After accumulating three batches of crude N,N-dimethylaniline, vacuum distillation recovered approximately 300 kg of N,N-dimethylaniline with a purity >98%, which was reused in production.

[0064] Example 3 The process flow diagram for the production method of 6-chloropurine hydrochloride in this embodiment is as follows: Figure 1 As shown, the following steps are taken: (1) Chlorination reaction and initial distillation: Ensure the 3000 L reactor R1 is dry, anhydrous, and alcohol-free, and purge it with nitrogen through the bottom valve for 10 minutes. Transfer 2000 kg of phosphorus oxychloride to reactor R1 using a diaphragm pump, and start stirring and circulating the cooling liquid. Once the material temperature drops below 20 °C, add 180 kg of hypoxanthine to R1 through the vessel opening, followed by 320 kg of N,N-dimethylaniline. Stir at 20-30 °C for 10 minutes to ensure the mixture is homogeneous.

[0065] Turn on the steam and raise the material temperature to 100-105℃, then maintain the temperature for 30 minutes. After the temperature maintenance is complete, take a sample for HPLC analysis. The reaction is considered complete when the hypoxanthine content is below 1%.

[0066] (2) Dissolution, salt formation and crystallization: After the reaction is complete, turn on the circulating coolant to lower the feed temperature to 40-50℃. Transfer the feed liquid from reactor R1 to 3000L reactor R2 and distill under reduced pressure at 70-75℃ until no fraction remains (ensure reactor R2 and receiving tank are dry before distillation; seal and store the fraction for reuse in the next batch). After distillation, stop the steam and add 1000 kg of 1,2-dichloroethane to reactor R2. Turn on the circulating coolant to lower the feed liquid temperature to 10-20℃ and maintain this temperature with stirring for 30 minutes to completely dissolve the residue. Transfer the feed liquid from reactor R2 to 5000L reactor R3 and flush reactor R2 and its pipes with 500 kg of 1,2-dichloroethane. Slowly introduce hydrochloric acid gas into reactor R3 until the product concentration (free 6-chloropurine content) in the feed filtrate is below 5%, and maintain the feed liquid temperature below 30℃ during the gas introduction process. After the central control results are satisfactory, stop the aeration and maintain the temperature at 15-25℃ with stirring for 30 minutes. Turn on the circulating coolant to cool the liquid to 0-10℃. Centrifuge (excess hydrochloric acid gas will overflow; pay attention to nitrogen aeration and exhaust gas treatment), collect the filter solid, and temporarily store the filtrate in a 5000 L reactor (R4).

[0067] (3) Pulping and refining: 630 kg of 1,2-dichloroethane was transferred into reactor R2 beforehand. The collected filter solid was added into reactor R2 through the inlet. Stirring and steam were turned on, and the mixture was slurried at 40-45 °C for 30 minutes. After slurrying, the circulating cooling liquid was turned on to cool the liquid to 0-10 °C. The mixture was centrifuged, the filter solid was collected, and the filtrate was temporarily stored in reactor R4.

[0068] The filtered solid was dried at 80 °C until the moisture content did not exceed 0.5% (turning the material over every 4 hours). A bright yellow solid, 6-chloropurine hydrochloride, was obtained and weighed. A sample was taken to determine its purity and content.

[0069] (4) Resource utilization and recycling of mother liquor (post-treatment of mother liquor) Add 825 kg of cold water (below 10 °C) to reactor R4 (approximately 2000 ~ 2400 kg) and cool to below 20 °C. Add sodium hydroxide solid to reactor R4 in batches while maintaining stirring, keeping the feed temperature below 20 °C during alkali addition. Stop adding alkali when the pH of the upper aqueous phase reaches 8 ~ 9 (based on pH value), and continue stirring for 30 minutes. Separate the phases; the upper aqueous phase is temporarily stored in tank V1, and the lower organic phase is transferred to reactor R2. Turn on steam in reactor R2 and distill at atmospheric pressure to recover 1,2-dichloroethane for reuse. The residue is temporarily stored in tank V2 (multiple batches are combined and distilled under reduced pressure to recover N,N-dimethylaniline for reuse, boiling point 193 °C).

[0070] The upper alkaline aqueous phase is a sodium phosphate waste liquid, mainly composed of sodium phosphate and sodium chloride. 1800-2000 kg of waste liquid contains approximately 710-750 kg of sodium phosphate and approximately 260-290 kg of sodium chloride. This alkaline aqueous phase can be used for centralized treatment of phosphate fertilizer wastewater.

[0071] The results showed that processing 180 kg of hypoxanthine yielded approximately 270 kg of 6-chloropurine hydrochloride with a purity of 82.5% and a molar yield of 97.8%, resulting in a yield of approximately 88.3%. Approximately 1500 kg of phosphorus oxychloride fraction was recovered (for direct reuse), and approximately 1800 kg of 1,2-dichloroethane was recovered (for direct reuse). Approximately 1800-2000 kg of high-concentration alkaline solution was generated for further processing. The collected crude N,N-dimethylaniline was accumulated over three batches and then distilled under reduced pressure. A single batch yielded approximately 220 kg of N,N-dimethylaniline with a purity >98%, which was reused in production.

[0072] Example 4 The process flow diagram for the production method of 6-chloropurine hydrochloride in this embodiment is as follows: Figure 1 As shown, the following steps are taken: (1) Chlorination reaction and initial distillation: Ensure the 3000 L reactor R1 is dry, anhydrous, and alcohol-free, and purge it with nitrogen through the bottom valve for 10 minutes. Transfer 2400 kg of phosphorus oxychloride to reactor R1 using a diaphragm pump, and start stirring and circulating the cooling liquid. Once the material temperature drops below 20 °C, add 240 kg of hypoxanthine to R1 through the vessel opening, followed by 640 kg of N,N-dimethylaniline. Stir at 20-30 °C for 10 minutes to ensure the mixture is homogeneous.

[0073] Turn on the steam and raise the material temperature to 100-105℃, then maintain the temperature for 30 minutes. After the temperature maintenance is complete, take a sample for HPLC analysis. The reaction is considered complete when the hypoxanthine content is below 1%.

[0074] (2) Dissolution, salt formation and crystallization: After the reaction is complete, turn on the circulating coolant to lower the feed temperature to 40-50℃. Transfer the feed liquid from reactor R1 to 3000L reactor R2 and distill under reduced pressure at 70-75℃ until no fraction remains (ensure reactor R2 and the receiving tank are dry before distillation; seal and store the fraction for reuse in the next batch). After distillation, stop the steam and add 2000 kg of 1,2-dichloroethane to reactor R2. Turn on the circulating coolant to lower the feed liquid temperature to 10-20℃ and maintain this temperature with stirring for 30 minutes to completely dissolve the residue. Transfer the feed liquid from reactor R2 to 5000L reactor R3 and flush reactor R2 and the pipelines with 1000 kg of 1,2-dichloroethane before introducing it into reactor R3. Slowly introduce hydrochloric acid gas into reactor R3 until the product concentration (free 6-chloropurine content) in the feed filtrate is below 5%, and control the feed liquid temperature below 30℃ during the gas introduction period. After the central control results are satisfactory, stop the aeration and maintain the temperature at 15-25℃ with stirring for 30 minutes. Turn on the circulating coolant to cool the liquid to 0-10℃. Centrifuge (excess hydrochloric acid gas will overflow; pay attention to nitrogen aeration and exhaust gas treatment), collect the filter solid, and temporarily store the filtrate in a 5000 L reactor (R4).

[0075] (3) Pulping and refining: 900 kg of 1,2-dichloroethane was transferred into reactor R2 beforehand. The collected filter solid was added into reactor R2 through the inlet. Stirring and steam were turned on, and the mixture was slurried at 40-45°C for 30 minutes. After slurrying, the circulating cooling liquid was turned on to cool the liquid to 0-10°C. The mixture was centrifuged, the filter solid was collected, and the filtrate was temporarily stored in reactor R4.

[0076] The filtered solid was dried at 80 °C until the moisture content did not exceed 0.5% (turning the material over every 4 hours). A bright yellow solid, 6-chloropurine hydrochloride, was obtained and weighed. A sample was taken to determine its purity and content.

[0077] (4) Resource utilization and recycling of mother liquor (post-treatment of mother liquor) Add 1100 kg of cold water (below 10 °C) to reactor R4 (approximately 3900 ~ 4100 kg) and cool to below 20 °C. Add sodium hydroxide solid to reactor R4 in batches while maintaining stirring, keeping the temperature of the feed solution below 20 °C during alkali addition. Stop adding alkali when the pH of the upper aqueous phase reaches 8 ~ 9 (based on pH value), and continue stirring for 30 minutes. Separate the phases; the upper aqueous phase is temporarily stored in tank V1, and the lower organic phase is transferred to reactor R2. Turn on steam in reactor R2 and distill at atmospheric pressure to recover 1,2-dichloroethane for reuse. The residue is temporarily stored in tank V2 (multiple batches are combined and distilled under reduced pressure to recover N,N-dimethylaniline for reuse, boiling point 193 °C).

[0078] The upper alkaline aqueous phase is a sodium phosphate waste liquid, mainly composed of sodium phosphate and sodium chloride. 2400-2600 kg of waste liquid contains approximately 960-990 kg of sodium phosphate and approximately 350-380 kg of sodium chloride. This alkaline aqueous phase can be used for centralized treatment of phosphate fertilizer wastewater.

[0079] The results showed that processing 240 kg of hypoxanthine yielded approximately 350 kg of 6-chloropurine hydrochloride with a purity of 85.0% and a molar yield of 98.2%. Approximately 1800 kg of phosphorus oxychloride fraction was recovered (directly reused), and approximately 3300 kg of 1,2-dichloroethane was recovered (directly reused). Approximately 2400-2600 kg of high-concentration alkaline solution was generated requiring further processing. The collected crude N,N-dimethylaniline was accumulated over three batches and then distilled under reduced pressure. A single batch yielded approximately 450 kg of N,N-dimethylaniline with a purity >98%, which was reused in production.

[0080] Example 5 The process flow diagram for the production method of 6-chloropurine hydrochloride in this embodiment is as follows: Figure 1 As shown, the following steps are taken: (1) Chlorination reaction and initial distillation: Ensure the 3000 L reactor R1 is dry, anhydrous, and alcohol-free, and purge it with nitrogen through the bottom valve for 10 minutes. Transfer 2000 kg of phosphorus oxychloride to reactor R1 using a diaphragm pump, and start stirring and circulating the cooling liquid. Once the material temperature drops below 20 °C, add 200 kg of hypoxanthine to R1 through the vessel opening, followed by 360 kg of N,N-dimethylaniline. Stir at 20-30 °C for 10 minutes to ensure the mixture is homogeneous.

[0081] Turn on the steam and raise the material temperature to 100-105℃, then maintain the temperature for 30 minutes. After the temperature maintenance is complete, take a sample for HPLC analysis. The reaction is considered complete when the hypoxanthine content is below 1%.

[0082] (2) Dissolution, salt formation and crystallization: After the reaction is complete, turn on the circulating coolant to lower the feed temperature to 40-50°C. Transfer the feed liquid from reactor R1 to a 3000L reactor R2 and distill under reduced pressure at 70-75°C until no fraction remains (ensure reactor R2 and the receiving tank are dry before distillation; seal and store the fraction for the next batch). After distillation, stop the steam and transfer 1650 kg of ethyl acetate to reactor R2. Turn on the circulating coolant to lower the feed liquid temperature to 10-20°C and maintain this temperature with stirring for 30 minutes to completely dissolve the residue. Transfer the feed liquid from reactor R2 to a 5000L reactor R3, and flush reactor R2 and the pipelines with 850 kg of ethyl acetate before introducing it into reactor R3. Slowly introduce hydrochloric acid gas into reactor R3 until the product concentration (free 6-chloropurine content) in the feed filtrate is below 5%, and control the feed liquid temperature below 30°C during the gas introduction process. After the central control results are satisfactory, stop the aeration and maintain the temperature at 15-25℃ with stirring for 30 minutes. Turn on the circulating coolant to cool the liquid to 0-10℃. Centrifuge (excess hydrochloric acid gas will overflow; pay attention to nitrogen aeration and exhaust gas treatment), collect the filter solid, and temporarily store the filtrate in a 5000 L reactor (R4).

[0083] (3) Pulping and refining: 750 kg of ethyl acetate was transferred to reactor R2 beforehand. The collected filter solid was added to reactor R2 through the inlet. Stirring and steam were turned on, and the mixture was stirred at 40-45°C for 30 minutes. After stirring, the circulating cooling liquid was turned on to cool the liquid to 0-10°C. The mixture was centrifuged, the filter solid was collected, and the filtrate was temporarily stored in reactor R4.

[0084] The filtered solid was dried at 80 °C until the moisture content did not exceed 0.5% (turning the material over every 4 hours). A bright yellow solid, 6-chloropurine hydrochloride, was obtained and weighed. A sample was taken to determine its purity and content.

[0085] (4) Resource utilization and recycling of mother liquor (post-treatment of mother liquor) Add 1100 kg of cold water (below 10 °C) to reactor R4 (approximately 3100 ~ 3300 kg) and cool to below 20 °C. Add sodium hydroxide solid to reactor R4 in batches while maintaining stirring, keeping the temperature of the feed solution below 20 °C during alkali addition. Stop adding alkali when the pH of the aqueous phase reaches 8 ~ 9 (based on pH value), and continue stirring for 30 minutes. Separate the phases; the aqueous phase is temporarily stored in tank V1, and the organic phase is transferred to reactor R2. Turn on steam in reactor R2 and distill at atmospheric pressure to recover ethyl acetate for reuse. The residue is temporarily stored in tank V2 (multiple batches are combined and distilled under reduced pressure to recover N,N-dimethylaniline for reuse, boiling point 193 °C).

[0086] The lower alkaline aqueous phase is a sodium phosphate waste liquid, mainly composed of sodium phosphate and sodium chloride. 2400-2600 kg of waste liquid contains approximately 960-990 kg of sodium phosphate and approximately 350-380 kg of sodium chloride. This alkaline aqueous phase can be used for centralized treatment of phosphate fertilizer wastewater.

[0087] The results showed that processing 200 kg of hypoxanthine yielded approximately 300 kg of 6-chloropurine hydrochloride with a purity of 83.0% and a molar yield of approximately 88.3%. Approximately 1500 kg of phosphorus oxychloride fraction was recovered (for direct reuse), and approximately 2000 kg of ethyl acetate was recovered (for direct reuse). Approximately 2400-2600 kg of high-concentration alkaline solution was generated requiring further processing. After accumulating three batches of crude N,N-dimethylaniline, vacuum distillation recovered approximately 250 kg of N,N-dimethylaniline with a purity >98%, which was reused in production.

[0088] Finally, it should be noted that the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for producing 6-chloropurine hydrochloride, characterized in that, Includes the following steps: S1. Hypoxanthine reacts with a chlorinated reagent in the presence of an organic base, and the chlorinated reagent is recovered by vacuum distillation after the reaction. S2. Add a co-solvent to the distillation residue to dissolve it, pass hydrogen chloride gas through to form salt, and separate the solid and liquid to obtain the first wet product and the first mother liquor; S3. The first wet product is pulped with a co-solvent and then centrifuged to obtain the second wet product and the second mother liquor. The second wet product is dried to obtain the product. S4. After the first mother liquor and the second mother liquor are combined, water is added and the pH of the aqueous phase is adjusted to 8-9 with alkali before phase separation; the co-solvent and the organic alkali are recovered by distillation of the organic phase.

2. The method for producing 6-chloropurine hydrochloride as described in claim 1, characterized in that, In step S4, the water is cold water with a temperature not higher than 10°C, and the system temperature is controlled not to exceed 20°C after adding water; the alkali is sodium hydroxide, and the temperature of the alkali addition and phase separation process is controlled below 20°C.

3. The method for producing 6-chloropurine hydrochloride as described in claim 2, characterized in that, The aqueous phase obtained from the phase separation is sodium phosphate waste liquid, which is centrally processed for use as a phosphate fertilizer agent.

4. The method for producing 6-chloropurine hydrochloride as described in claim 1, characterized in that, During the organic phase distillation, the recovered flux is reused; multiple batches of organic phase distillation residues are collected, combined, and subjected to vacuum distillation to recover pure organic base, which is then reused in the reaction of step S1.

5. The method for producing 6-chloropurine hydrochloride as described in claim 1, characterized in that, In step S2, when hydrogen chloride gas is introduced, the system temperature is controlled to be below 30°C; after the salt formation reaction, the system is kept at 15~25°C for aging, and then cooled to 0~10°C for crystallization.

6. The method for producing 6-chloropurine hydrochloride as described in claim 1 or 5, characterized in that, The mass ratio of hypoxanthine in step S1 to co-solvent in step S2 is 1:(8~13), and the co-solvent is selected from ethyl acetate and 1,2-dichloroethane; the mass ratio of the mixed mother liquor after combining the first and second mother liquors in step S4 to water is (2~5):

1.

7. The method for producing 6-chloropurine hydrochloride as described in claim 1, characterized in that, In step S3, the pulping temperature is 40~45℃, followed by cooling and centrifugation to obtain the second wet product and the second mother liquor; the cooling is to reduce the temperature to 0~10℃.

8. The method for producing 6-chloropurine hydrochloride as described in claim 1, characterized in that, The mass ratio of hypoxanthine to the chlorinated reagent is 1:(6~11), and the chlorinated reagent is selected from phosphorus oxychloride.

9. The method for producing 6-chloropurine hydrochloride as described in claim 1 or 8, characterized in that, The mass ratio of hypoxanthine to organic base is 1:(1.7~3), wherein the organic base is selected from N,N-dimethylaniline.

10. The method for producing 6-chloropurine hydrochloride as described in claim 9, characterized in that, The temperature for the chlorination reaction in step S1 is 100~105℃.

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