A process for the production of 2,6-dimethoxy-4-aminopyrimidine in a microchannel

Abstract

The application discloses a method for preparing 2,6-dimethoxy-4-amino pyrimidine in a microchannel, and the method comprises the following steps: taking 2,4,6-trichloropyrimidine as raw material, and reacting with a sodium methoxide solution in a microreactor to obtain a methanol solution of 2,6-dimethoxy-4-chloropyrimidine; after post-treatment, 2,6-dimethoxy-4-chloropyrimidine is dissolved in toluene to obtain a toluene solution of 2,6-dimethoxy-4-chloropyrimidine; the toluene solution is reacted with a mixed solution of sodium cyanate, methanol, a palladium catalyst, a ligand and toluene to obtain (4,6-dimethoxypyrimidin-2-yl) methyl tert-butylcarbamate; and then, the (4,6-dimethoxypyrimidin-2-yl) methyl tert-butylcarbamate is reacted with hydrochloric acid to obtain 2,6-dimethoxy-4-amino pyrimidine. Compared with a traditional synthesis route, the method has the advantages of simple synthesis, simple operation, high yield, and no need of using highly toxic and high-risk materials, and the synthesis steps are greatly shortened by adopting a continuous synthesis mode of a microreactor.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a novel synthetic route for the preparation and application of 2,6-dimethoxy-4-aminopyrimidine. Background Technology

[0002] The existing methods for synthesizing 2,6-dimethoxy-4-aminopyrimidine mainly include the following: (1) Diaminouracil Hydrochloride [J]. Organic Syntheses, 1957, 37: 15-17 and Synthesis of Purine Antiviral SAgents, Hypoxanthine and 6-Mercaptopurine [J] Russian Journal of Organic Chemistry, 2002, 38(7):

[0003] Sections 1053-1055 mention a method that uses urea and ethyl cyanoacetate as starting materials, and through steps such as cyclization, chlorination, and methoxylation, finally synthesizes 2,6-dimethoxy-4-aminopyrimidine. The main problem with this method is that it uses ethyl cyanoacetate, which is highly toxic, as a raw material.

[0004] (2) In the literature Preparation of 4-Aminouracil [P].US2804459,1957.08.27 and Preparation of Cyanoacetyl Ureas [P].US2553022,1951-05-15, Russell D et al. reported a method for synthesizing 2,6-dihydroxy-4-aminopyrimidine from cyanoacetylurea as a raw material, followed by chlorination with phosphorus oxychloride to obtain 2,6-dihydroxy-4-aminopyrimidine, and finally reaction with sodium methoxide to obtain 2,6-dimethoxy-4-aminopyrimidine. However, the first step of this method uses water as a solvent, which leads to the decomposition of the material and affects the yield. (3) In the Chinese journal Guangdong Chemical Industry, 1993(4):49-50, it is recorded that trichloropyrimidine is first generated by reacting phosphorus oxychloride with barbituric acid, and then aminated to obtain 2,6-dimethoxy-4-aminopyrimidine and 4,6-dichloro-4,6-dichloro-2-aminopyrimidine. The former is then subjected to methylation to obtain 4-amino-2,6-dimethoxypyrimidine. Alternatively, a method of methylation followed by separation can be used. This method generates a large number of isomers during the amination process, resulting in more impurities and a low yield. (4) In Chemical Times, 2020, 34(09):12, a green process for synthesizing 4-amino-2,6-dimethoxypyrimidine in one step using sodium 4-amino-2,6-dihydroxypyrimidine as raw material and dimethyl carbonate as a green methyl reagent is described. This process avoids the generation of phosphorus-containing wastewater, but the yield is low. Therefore, it is necessary to study a synthetic route and preparation method for 2,6-dimethoxy-4-aminopyrimidine with simple reaction conditions and high product yield. Summary of the Invention

[0005] To address the shortcomings of existing technologies, the present invention aims to provide a method for preparing 2,6-dimethoxy-4-aminopyrimidine with simple reaction conditions and high product yield.

[0006] To achieve the above objectives, the present invention adopts the following technical solution:

[0007] A method for preparing 2,6-dimethoxy-4-aminopyrimidine includes the following steps:

[0008] S1. Preparation of 2,6-dimethoxy-4-chloropyrimidine: A methanol solution of trichloropyrimidine and a methanol solution of sodium methoxide were separately added to a microreactor via a metering pump. The resulting reaction solution was distilled in a reaction flask to recover methanol. Then, water and toluene were added, and the mixture was extracted and separated. The aqueous phase was discarded to obtain the toluene organic phase of 2,6-dimethoxy-4-chloropyrimidine. The reaction equation is as follows:

[0009]

[0010] S2. Sodium cyanate, palladium catalyst, ligand, methanol, acid-binding agent, and toluene were added to a flask and stirred to obtain a sodium cyanate mixture. The sodium cyanate mixture and a toluene solution of 2,6-dimethoxy-4-chloropyrimidine were separately metered into a microreactor and heated to react. After the reaction was completed, a toluene solution of (4,6-dimethoxypyrimidin-2-yl)carbamate was obtained. Water was added for phase separation, the aqueous phase was discarded, and the toluene was recovered by distillation. Methanol was then added to obtain a methanol solution of (4,6-dimethoxypyrimidin-2-yl)carbamate. The reaction equation is as follows:

[0011]

[0012] S3. Preparation of 2,6-dimethoxy-4-aminopyrimidine: Dilute hydrochloric acid and a methanol solution of (4,6-dimethoxypyrimidin-2-yl)carbamate tert-methyl ester were separately pumped into a microreactor for reaction. The reaction solution was transferred to a reaction flask, and the pH was adjusted to neutral by adding liquid alkali. The precipitated material was filtered to remove the methanol-water solution. The filter cake was washed with water to obtain wet 2,6-dimethoxy-4-aminopyrimidine, which was then dried to obtain dry 2,6-dimethoxy-4-aminopyrimidine. The reaction equation is as follows:

[0013]

[0014] Preferably, in step S1 above, the sodium alkoxide is sodium methoxide and the solvent is methanol.

[0015] Preferably, in step S1, the molar ratio of trichloropyrimidine, sodium methoxide, and methanol is (1):(2.0-2.2):(10-22).

[0016] Preferably, in step S1, the reaction temperature of trichloropyrimidine and sodium methoxide solution in the microreactor is 0–25°C, and the reaction residence time is 30–180 seconds.

[0017] Preferably, in step S2, the palladium catalyst is one of palladium chloride, palladium acetate, DBA palladium, triphenylphosphine palladium chloride, etc.; the ligand is one of triphenylphosphine, dppf, etc.; and the acid-binding agent is one of diisopropylethylamine, triethylamine, etc.

[0018] Preferably, in step S2 above,

[0019] The molar ratio of 2,6-dimethoxy-4-chloropyrimidine, sodium cyanate, palladium catalyst, ligand, acid-binding agent, methanol, and toluene was modified to (1): (1.00~1.30): (0.03~0.10): (0.05~0.15): (0.08~2.00): (1.00~10.00): (5.50~17.00).

[0020] Preferably, in step S2, the reaction temperature of the toluene solution of 2,6-dimethoxy-4-chloropyrimidine in the sodium cyanate solution in the microreactor is 120–155°C, and the reaction time is 80–120 s; more preferably, the reaction temperature of the toluene solution of 2,6-dimethoxy-4-chloropyrimidine in the sodium cyanate solution in the microreactor is 110°C, and the reaction time is 120 s.

[0021] Preferably, in step S3, the solvent is methanol and the dilute acid is 1-10% dilute hydrochloric acid.

[0022] Preferably, in step S3 above, the molar ratio of tert-methyl (4,6-dimethoxypyrimidin-2-yl)carbamate to dilute hydrochloric acid is 1:(1.0 to 5.0).

[0023] Preferably, in step S3 above, the methanol solution of (4,6-dimethoxypyrimidin-2-yl)carbamate and dilute hydrochloric acid are reacted in a microreactor at a temperature of 50-60°C for a reaction time of 30-50 s; more preferably, the methanol solution of (4,6-dimethoxypyrimidin-2-yl)carbamate and dilute hydrochloric acid are reacted in a microreactor at a temperature of 20-30°C for a reaction residence time of 180 s.

[0024] Application of 2,6-dimethoxy-4-aminopyrimidine in the preparation of the antibacterial drug sulfadisoxin.

[0025] The reaction equation of this invention is as follows:

[0026]

[0027] The advantages of the synthetic route and method in this invention are mainly reflected in the following aspects:

[0028] 1. The raw materials have a high degree of safety.

[0029] The raw materials used in this invention, such as trichloropyrimidine, sodium cyanate, methanol, and palladium chloride, are relatively stable and have low toxicity. Existing processes such as Diaminouracil Hydrochloride [J]. Organic Syntheses, 1957, 37: 15-17 and Synthesis of Purine Antiviral SAgents, Hypoxanthine and 6-Mercaptopurine [J] Russian Journal of Organic Chemistry, 2002, 38(7): 1053-1055 use ethyl cyanoacetate, which is highly toxic. The raw materials used in this invention have relatively low toxicity and are safer in both experimental and production processes.

[0030] 2. Short production cycle, fewer processes, and lower cost.

[0031] Traditional processes, whether using cyanoacetamide as a raw material to first synthesize 2,6-dihydroxy-4-aminopyrimidine followed by chlorination and methylation, or using phosphorus oxychloride and barbituric acid to generate trichloropyrimidine, followed by ammoniation to obtain 4-amino-2,6-dichloropyrimidine, and then methylation, all suffer from drawbacks such as long processing times and complex steps. In contrast, the reaction process in this invention is simple and quick. This synthetic route involves no complex reactions, and the use of a microreactor significantly shortens the reaction time, effectively reducing production time, costs, and energy consumption. Furthermore, the reaction primarily uses organic solvents, which are easy to recover, resulting in less waste. Therefore, it has high practicality in production.

[0032] 3. High yield and low impurity generation.

[0033] For manufacturing enterprises, synthetic routes with high product yield and high purity are often the first choice. The synthetic route of this invention has a high yield, with a yield of approximately 96% from trichloropyrimidine to tert-methyl (4,6-dimethoxypyrimidin-2-yl)carbamate, and a yield of approximately 95% from tert-methyl (4,6-dimethoxypyrimidin-2-yl)carbamate to 2,6-dimethoxy-4-aminopyrimidine, resulting in an overall yield of approximately 91.2%. The yield is high, and fewer impurities are generated. The existing process, which uses cyanoacetamide as a raw material to first synthesize 2,6-dihydroxy-4-aminopyrimidine, followed by chlorination and methoxylation, uses water as a solvent in the first step, leading to material decomposition, affecting yield, and is also time-consuming and generates a lot of wastewater. The synthesis method using phosphorus oxychloride and barbituric acid produces more impurities and isomers, with an overall yield of approximately 78.8%. While the synthesis of 4-amino-2,6-dimethoxypyrimidine using sodium 4-amino-2,6-dihydroxypyrimidine as a raw material and dimethyl carbonate as a green methyl reagent generates less wastewater, the yield is low, approximately 40.0%. Therefore, this method is more practical in comparison.

[0034] 4. Simple to operate and highly repeatable.

[0035] The operation in this invention mainly involves preparing the materials into a solution or mixing several reagents and then adding them to the microreactor through a metering pump. The operation is relatively simple, and it has high operability and repeatability in both laboratory and workshop production, making it suitable for workshop production.

[0036] 5. Continuous synthesis, high yield, and reliable safety.

[0037] This invention develops a continuous synthesis method using a microchannel reactor, which yields significantly higher yields than a batch reactor. The method is simple to operate and can be directly applied to production facilities under laboratory-scale conditions, eliminating the need for complex pilot-scale production. It is safe, reliable, and the process is stable.

[0038] Beneficial effects: This invention has the advantages of simple operation, low energy consumption, low production cost and wide applicability. The reaction process is novel, shorter than conventional synthesis routes, and the process conditions are robust. The continuous production in microreactors is suitable for large-scale preparation of 2,6-dimethoxy-4-aminopyrimidine. Attached Figure Description

[0039] Figure 1 The 1H NMR spectrum of 2,6-dimethoxy-4-chloropyrimidine; 1 H-NMR: 6.75(s,1H),3.93(s,3H),3.92(s,3H);

[0040] Figure 2 1H NMR spectrum of tert-methyl (4,6-dimethoxypyrimidin-2-yl)carbamate 1 H-NMR: 7.39(s,1H), 6.93(s,1H), 3.93(s,3H), 3.90(s,3H), 3.78(s,3H);

[0041] Figure 3 The 1H NMR spectrum of 2,6-dimethoxy-4-aminopyrimidine 1 H-NMR: 6.60(s,2H), 5.42(s,1H), 3.77(s,3H), 3.76(s,3H);

[0042] Figure 4 Liquid chromatogram of 2,6-dimethoxy-4-aminopyrimidine (ADMP is the English name of 2,6-dimethoxy-4-aminopyrimidine);

[0043] Figure 5 Schematic diagram of continuous synthesis using a microreactor. Detailed Implementation

[0044] The present invention will now be described in detail with reference to the accompanying drawings and specific embodiments.

[0045] Example 1

[0046] A method for preparing 2,6-dimethoxy-4-aminopyrimidine via microchannels, the reaction formula of which is as follows:

[0047]

[0048] S1. Preparation of a toluene solution of 2,6-dimethoxy-4-chloropyrimidine: 50 g (0.273 mol) of 2,4,6-trichloropyrimidine and 150 g of anhydrous methanol were added to a 2,4,6-trichloropyrimidine methanol solution preparation vessel and stirred to dissolve, yielding 200 g of the prepared 2,4,6-trichloropyrimidine methanol solution. 103 g of a 30% sodium methoxide methanol solution (equivalent to 30.8 g / 0.571 mol sodium methoxide) was added to a sodium methoxide solution temporary storage vessel. Using a metering pump, 2,4,6-trichloropyrimidine and sodium methoxide solution were separately added to a microreactor at a feed ratio of 1.94:1. The reaction solution was controlled at a temperature of 0–5 °C and a residence time of 120 s in the microreactor. The reaction solution was then transferred to a post-processing vessel and heated and distilled to recover methanol. After methanol recovery, the mixture was cooled to 20–30°C, and 200 g of water and 300 g of toluene were added. The mixture was stirred and the phases were separated. The aqueous phase was discarded to obtain a toluene solution (350 g) of 2,6-dimethoxy-4-chloropyrimidine.

[0049] S2. Preparation of a methanol solution of (4,6-dimethoxypyrimidin-2-yl)carbamate tert-methyl ester: In another external reaction vessel, add 2.53 g (0.014 mol) palladium chloride, 3.75 g (0.014 mol) triphenylphosphine, 28.89 g (0.286 mol) triethylamine, 10.5 g (0.3269 mol) methanol, 18.6 g (0.286 mol) sodium cyanate, and 150 g toluene, and stir until homogeneous to obtain 214.27 g of mixed liquid. Add the toluene solution (350 g) of 2,6-dimethoxy-4-chloropyrimidin from step S1 and the above mixed liquid to a microreactor at a feed ratio of 1.63:1. Control the temperature of the reaction solution in the microreactor at 120–125 °C and the residence time at 120 s. The reaction solution was then transferred to a post-processing vessel, 100g of water was added, and after stirring and phase separation, the aqueous phase was discarded to obtain a toluene layer. After vacuum distillation of the toluene, 140g of methanol was added to dissolve the residue, yielding a methanol solution (200g) of tert-methyl (4,6-dimethoxypyrimidin-2-yl)carbamate.

[0050] S3. Preparation of 2,6-dimethoxy-4-aminopyrimidine: A methanol solution of (4,6-dimethoxypyrimidin-2-yl)carbamate tert-methyl ester was fed into a microreactor at a 1:1 ratio using a metering pump, along with 200g of 5% dilute hydrochloric acid. The reaction mixture was kept at a temperature of 50–60°C and a residence time of 30s. After the reaction, the solution was transferred to a post-treatment vessel, and the pH was adjusted to neutral by adding alkali. A solid precipitated, and the filter cake was collected by filtration and dried to obtain 40g of 2,6-dimethoxy-4-aminopyrimidine, with a total yield of 94%.

[0051] Example 2

[0052] S1. Preparation of a toluene solution of 2,6-dimethoxy-4-chloropyrimidine: 50 g (0.273 mol) of 2,4,6-trichloropyrimidine and 150 g of anhydrous methanol were added to a 2,4,6-trichloropyrimidine methanol solution preparation vessel and stirred to dissolve, yielding 200 g of the prepared 2,4,6-trichloropyrimidine methanol solution. 108 g of a 30% sodium methoxide methanol solution (equivalent to 32.4 g / 0.601 mol sodium methoxide) was added to a sodium methoxide solution temporary storage vessel. The 2,4,6-trichloropyrimidine methanol solution and sodium methoxide solution were pumped into a microreactor at a feed ratio of 1.85:1 using a metering pump. The reaction solution was controlled at a temperature of 0–5 °C and a residence time of 90 s in the microreactor. The reaction solution was then transferred to a post-processing vessel and heated and distilled to recover methanol. After methanol recovery, the mixture was cooled to 20–30°C, and 200 g of water and 300 g of toluene were added. The mixture was stirred and the phases were separated. The aqueous phase was discarded to obtain a toluene solution (360 g) of 2,6-dimethoxy-4-chloropyrimidine.

[0053] S2. Preparation of a methanol solution of (4,6-dimethoxypyrimidin-2-yl)carbamate tert-methyl ester: In another external reaction vessel, add 2.25 g (0.010 mol) palladium acetate, 3.21 g (0.012 mol) triphenylphosphine, 33.60 g (0.26 mol) diisopropylethylamine, 11.5 g (0.36 mol) methanol, 18.1 g (0.278 mol) sodium cyanate, and 231.3 g toluene, and stir until homogeneous to obtain 300 g of mixed solution. Add the 360 ​​g toluene solution of 2,6-dimethoxy-4-chloropyrimidin from step S1 and the above mixed solution at a feed ratio of 1.2:1 to each other into a microreactor. Control the temperature of the reaction solution in the microreactor at 130–155 °C and the residence time at 80 s. Then, transfer the reaction solution to a post-processing vessel, add 100 g of water, stir and separate the phases, discard the aqueous phase, and obtain the toluene layer. After distilling toluene under reduced pressure, 150g of methanol was added to dissolve the residue, yielding a methanol solution (210g) of tert-methyl (4,6-dimethoxypyrimidin-2-yl)carbamate.

[0054] S3. Preparation of 2,6-dimethoxy-4-aminopyrimidine: A methanol solution of (4,6-dimethoxypyrimidin-2-yl)carbamate tert-methyl ester was fed into a microreactor at a 1:1 ratio using a metering pump, along with 210 g of 5% dilute hydrochloric acid. The reaction mixture was kept at a temperature of 50–60 °C and a residence time of 40 s. After the reaction, the solution was transferred to a post-treatment vessel, and the pH was adjusted to neutral by adding alkali. A solid precipitated, and the filter cake was collected by filtration and dried to obtain 40.8 g of 2,6-dimethoxy-4-aminopyrimidine, with a total yield of 96%.

[0055] Example 3

[0056] S1. Preparation of a toluene solution of 2,6-dimethoxy-4-chloropyrimidine: 50 g (0.273 mol) of 2,4,6-trichloropyrimidine and 150 g of anhydrous methanol were added to a 2,4,6-trichloropyrimidine methanol solution preparation vessel and stirred to dissolve, obtaining the prepared 2,4,6-trichloropyrimidine methanol solution. 105 g of a 30% sodium methoxide methanol solution (equivalent to 31.5 g / 0.583 mol sodium methoxide) was added to a sodium methoxide solution temporary storage vessel. 2,4,6-trichloropyrimidine and sodium methoxide solution were fed into a microreactor at a ratio of 1.9:1 using a metering pump. The reaction solution was controlled at a temperature of 0–5 °C and a residence time of 90 s in the microreactor. The reaction solution was then transferred to a post-processing vessel and heated and distilled to recover methanol. After methanol recovery, the mixture was cooled to 20–30°C, and 200 g of water and 300 g of toluene were added. The mixture was stirred and the phases were separated. The aqueous phase was discarded to obtain a toluene solution (360 g) of 2,6-dimethoxy-4-chloropyrimidine.

[0057] S2. Preparation of a methanol solution of (4,6-dimethoxypyrimidin-2-yl)carbamate tert-methyl ester: In another external reaction vessel, add 2.4 g (0.011 mol) palladium chloride, 7.20 g (0.013 mol) triphenylphosphine, 30.0 g (0.23 mol) triethylamine, 12.0 g (0.375 mol) methanol, 18.4 g (0.283 mol) sodium cyanate, and 200 g toluene, and stir until homogeneous to obtain 270 g of mixed liquid. Add the toluene solution (360 g) of 2,6-dimethoxy-4-chloropyrimidin from step S1 and the above mixed liquid at a feed ratio of 1.33:1 to each other into a microreactor. Control the temperature of the reaction solution in the microreactor at 130–145 °C and the residence time at 120 s. Then, transfer the reaction solution to a post-processing vessel, add 100 g of water, stir and separate the phases, discard the aqueous phase, and obtain the toluene layer. After distilling toluene under reduced pressure, 140g of methanol was added to dissolve the residue, yielding a methanol solution (205g) of tert-methyl (4,6-dimethoxypyrimidin-2-yl)carbamate.

[0058] S3. Preparation of 2,6-dimethoxy-4-aminopyrimidine: A methanol solution of (4,6-dimethoxypyrimidin-2-yl)carbamate tert-methyl ester was fed into a microreactor at a 1:1 ratio using a metering pump, along with 205 g of 5% dilute hydrochloric acid. The reaction mixture was kept at a temperature of 50–60 °C and a residence time of 50 s. After the reaction, the solution was transferred to a post-treatment vessel, and the pH was adjusted to neutral by adding alkali. A solid precipitated, and the filter cake was collected and dried to obtain 40.38 g of 2,6-dimethoxy-4-aminopyrimidine, with a total yield of 95%.

[0059] Conventional batch reaction comparative experiment:

[0060] Comparative Experiment Example 1

[0061] S1. Preparation of 2,6-dimethoxy-4-chloropyrimidine: 50 g (0.272 mol) of 2,4,6-trichloropyrimidine and 600 ml of anhydrous methanol were added to a four-necked flask. After stirring and dissolving, the mixture was cooled to 0 °C. A solution of 30.8 g (0.571 mol) of sodium methoxide and 100 ml of methanol was slowly added dropwise. After the sodium methoxide solution was added, the mixture was kept at 0 °C and stirred for 2 hours. Then, the temperature was raised to 20-25 °C and stirred for another hour. The methanol was then recovered by vacuum distillation. 500 ml of dichloromethane and 200 ml of water were added to the residue. After phase separation, the organic phase was concentrated to dryness under vacuum to obtain 42.8 g of 2,6-dimethoxy-4-chloropyrimidine, with a yield of 90%.

[0062] S2. Preparation of tert-methyl (4,6-dimethoxypyrimidin-2-yl)carbamate: 40.0 g (0.229 mol) of 2,6-dimethoxy-4-chloropyrimidine, 18.6 g (0.286 mol) of sodium cyanate, 2.13 g (0.012 mol) of palladium chloride, 3.15 g (0.012 mol) of triphenylphosphine, 24.3 g (0.240 mol) of triethylamine, 8.8 g (0.275 mol) of methanol, and 300 ml of toluene were added to a four-necked flask. The mixture was heated to 110 °C with stirring and kept at this temperature for 15 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered to remove the catalyst and insoluble salts, water was added to the filtrate, and the toluene layer was obtained after phase separation. After distilling most of the toluene, methanol was added to slurry the mixture, filtered, and dried to obtain 41.5 g of tert-methyl (4,6-dimethoxypyrimidin-2-yl)carbamate, with a yield of 85%.

[0063] S3. Preparation of 2,6-dimethoxy-4-aminopyrimidine: 40 g (0.187 mol) of tert-methyl (4,6-dimethoxypyrimidin-2-yl)carbamate was added to a four-necked flask, along with 150 ml of 5% dilute hydrochloric acid and 30 ml of methanol. The temperature was maintained at 20–30 °C for 3 h. The pH was then adjusted to neutral by adding liquid alkali, causing a solid to precipitate. The filter cake was collected by filtration and dried to obtain 27.5 g of 2,6-dimethoxy-4-aminopyrimidine, with a yield of 95%.

[0064] Comparative Experiment Example 2

[0065] S1. Preparation of 2,6-dimethoxy-4-chloropyrimidine: 50 g (0.272 mol) of 2,4,6-trichloropyrimidine and 600 ml of anhydrous methanol were added to a four-necked flask. After stirring and dissolving, the mixture was cooled to 0 °C. A solution of 32.3 g (0.600 mol) of sodium methoxide and 110 ml of methanol was slowly added dropwise. After the sodium methoxide solution was added, the mixture was kept at 0 °C and stirred for 2 hours. Then, the temperature was raised to 20-25 °C and stirred for another hour. The methanol was then recovered by vacuum distillation. 500 ml of dichloromethane and 200 ml of water were added to the residue. After phase separation, the organic phase was concentrated to dryness under reduced pressure to obtain 43.5 g of 2,6-dimethoxy-4-chloropyrimidine, with a yield of 91.5%.

[0066] S2. Preparation of tert-methyl (4,6-dimethoxypyrimidin-2-yl)carbamate: 40.0 g (0.229 mol) of 2,6-dimethoxy-4-chloropyrimidine, 18.6 g (0.286 mol) of sodium cyanate, 3.9 g (0.022 mol) of palladium chloride, 8.9 g (0.034 mol) of triphenylphosphine, 63.3 g (0.458 mol) of potassium carbonate, 73 g (2.29 mol) of methanol, and 400 ml of toluene were added to a four-necked flask. The mixture was heated to 110 °C with stirring and kept at this temperature for 15 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered to remove the catalyst and insoluble salts, water was added to the filtrate, and the toluene layer was obtained after phase separation. Most of the toluene was distilled, methanol was added and the mixture was slurried, filtered, and dried to obtain 42.7 g of tert-methyl (4,6-dimethoxypyrimidin-2-yl)carbamate, with a yield of 87.4%.

[0067] S3. Preparation of 2,6-dimethoxy-4-aminopyrimidine: 40 g (0.187 mol) of tert-methyl (4,6-dimethoxypyrimidin-2-yl)carbamate, 150 ml of 5% dilute hydrochloric acid, and 20 ml of ethanol were added to a four-necked flask. The temperature was controlled at 20-30℃ and kept at that temperature for 3 h. The pH was adjusted to neutral by adding liquid alkali, and a solid precipitated. The filter cake was collected by filtration and dried to obtain 27.2 g of 2,6-dimethoxy-4-aminopyrimidine, with a yield of 94%.

[0068] Other comparative experiments:

[0069]

[0070] Preparation of S1: 2,6-Dihydroxy-4-aminopyrimidine: At room temperature, 378 g of anhydrous methanol was added to a dry 2L four-necked flask, and stirring was started. 162 g (3.00 mol) of sodium methoxide solid was added, followed by the slow addition of 100 g (1.67 mol) of urea, and then the slow dropwise addition of 137 g (1.38 mol) of methyl cyanoacetate. After the dropwise addition was completed, the temperature was raised to reflux for 5.5 h. After the reflux was completed, methanol was recovered until completely dry. After the recovery was completed, 1200 g of water was added, and the temperature was raised to 65-70 °C. The pH was then adjusted to 7 with 50% sulfuric acid at this temperature. The material was then heated to 80 °C and stirred for 30 minutes. The mixture was filtered while hot, and the filter cake was washed with a large amount of room temperature water. After drying, 108.7 g of 2,6-dihydroxy-4-aminopyrimidine was obtained, with a yield of 62%.

[0071] Preparation of S2: 2,6-Dichloro-4-aminopyrimidine: At room temperature, 600 g (3.91 mol) of phosphorus oxychloride was added to a dry 1L four-necked flask, followed by 75 g (0.590 mol) of 2,6-dihydroxy-4-aminopyrimidine. 15 g (0.124 mol) of N,N-dimethylaniline was slowly added while stirring. After the addition was complete, the temperature was raised to a suitable level, and then 60 g (0.495 mol) of N,N-dimethylaniline was slowly added dropwise. After the addition was complete, the mixture was stirred and kept at this temperature for 7 hours. After the temperature was maintained, approximately 300 g of phosphorus oxychloride was recovered. After the recovery, the temperature of the remaining chlorination solution was maintained at 90–100 °C. 350 g of room temperature tap water was prepared in another 2L four-necked flask. The chlorination solution was slowly added dropwise to the tap water at a temperature below 35 °C to quench the chlorination. After quenching, ammonia was added dropwise at a temperature below 35 °C to adjust the pH to 6–7. After the addition was complete, N,N-dimethylaniline was recovered by atmospheric distillation. The material was then cooled to 70°C, filtered, and washed with tap water at 70°C. After drying, 75.5 g of 2,6-dichloro-4-aminopyrimidine was obtained, with a yield of 78%.

[0072] Preparation of S3: 2,6-Dimethoxy-4-aminopyrimidine: 308 g of methanol and 40 g (0.244 mol) of 2,6-dichloro-4-aminopyrimidine were added to a dry four-necked flask, and stirring was started. 36.2 g (0.905 mol) of sodium hydroxide solid was slowly added under cooling conditions. After the addition was complete, the temperature was raised to reflux and maintained for 15 h. After the reflux period, the mixture was filtered while hot. The filter cake was washed with a small amount of methanol, and the washings were added to the filtrate. After filtration, methanol was recovered under reduced pressure until completely dry. After recovery, 150 ml of water was added, and the material was cooled to room temperature and filtered. The filter cake was washed with a small amount of cold water. After drying, 30.29 g of 2,6-dimethoxy-4-aminopyrimidine was obtained, with a yield of 80%.

[0073] The yields of 2,6-dimethoxy-4-chloropyrimidine, (4,6-dimethoxypyrimidin-2-yl)carbamate tert-methyl ester, and 2,6-dimethoxy-4-aminopyrimidine prepared in Examples 1-3, as well as the 2,6-dimethoxy-4-aminopyrimidine prepared in the comparative examples, were calculated, and the results are shown in Table 1.

[0074] Table 1

[0075]

[0076]

Claims

1. A method for preparing 2,6-dimethoxy-4-aminopyrimidine via microchannels, characterized in that, Includes the following steps: S1. Preparation of 2,6-dimethoxy-4-chloropyrimidine: A methanol solution of trichloropyrimidine and a methanol solution of sodium methoxide were added to a microreactor via a metering pump for reaction. The resulting reaction solution was distilled in a reaction flask to recover methanol. Then, water and toluene were added, and the phases were extracted and separated. The aqueous phase was discarded to obtain the toluene organic phase of 2,6-dimethoxy-4-chloropyrimidine. S2. Preparation of N-(2,6-dimethoxy-4-pyrimidinyl)carbamate: Sodium cyanate, palladium catalyst, methanol, acid-binding agent, ligand and toluene were added and stirred to obtain a sodium cyanate mixture. The sodium cyanate mixture and the toluene solution of 2,6-dimethoxy-4-chloropyrimidin were separately pumped into a microreactor and heated to react. After the reaction was completed, a toluene solution of N-(2,6-dimethoxy-4-pyrimidinyl)carbamate was obtained. Water was added for extraction and phase separation. The aqueous phase was discarded and the toluene was recovered by distillation. Methanol was then added to obtain a methanol solution of N-(2,6-dimethoxy-4-pyrimidinyl)carbamate. S3. Preparation of 2,6-dimethoxy-4-aminopyrimidine: Dilute hydrochloric acid and methanol solution of N-(2,6-dimethoxy-4-pyrimidinyl)carbamate were separately pumped into a microreactor for reaction using a metering pump. The reaction solution was transferred to a reaction flask, and liquid alkali was added to adjust the pH to neutral. The precipitated material was filtered to remove the methanol aqueous solution. The filter cake was washed with water to obtain wet 2,6-dimethoxy-4-aminopyrimidine. After drying, dry 2,6-dimethoxy-4-aminopyrimidine was obtained. In step S1, the reaction temperature in the microreactor is 0~25℃, and the reaction residence time is 30~180 seconds; In step S2, the reaction temperature of the toluene solution of 2,6-dimethoxy-4-chloropyrimidine with the sodium cyanate solution in the microreactor is 120-155°C, and the reaction time is 80-120 s; the palladium catalyst is one of palladium chloride, palladium acetate, DBA palladium, and triphenylphosphine palladium chloride; the ligand is one of triphenylphosphine and dppf; and the acid-binding agent is one of diisopropylethylamine and triethylamine. In step S3, the methanol solution of N-(2,6-dimethoxy-4-pyrimidinyl)carbamate and dilute hydrochloric acid are reacted in a microreactor at a temperature of 50-60°C for a time of 30-50 seconds.

2. The method for preparing 2,6-dimethoxy-4-aminopyrimidine via microchannels according to claim 1, characterized in that, In step S1, the molar ratio of trichloropyrimidine, sodium methoxide, and methanol is 1:(2.0~2.2):(10~22).

3. The method for preparing 2,6-dimethoxy-4-aminopyrimidine via microchannels according to claim 1, characterized in that, In step S2, the molar ratio of 2,6-dimethoxy-4-chloropyrimidine, sodium cyanate, palladium catalyst, ligand, acid-binding agent, methanol, and toluene is 1:(1.00~1.30):(0.03~0.10):(0.05~0.15):(0.08~2.00):(1.00~10.00):(5.50~17.00).

4. The method for preparing 2,6-dimethoxy-4-aminopyrimidine via microchannels according to claim 1, characterized in that, In step S3, the molar ratio of N-(2,6-dimethoxy-4-pyrimidinyl)carbamate to dilute hydrochloric acid is 1:(1.0~5.0).

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