A method for preparing 4,6-dichloro-5-nitro-2-propylthio-pyrimidine by continuous flow reaction

Abstract

The present invention discloses a method for continuously preparing 4,6-dichloro-5-nitro-2-propylthio-pyrimidine. A mixed acid solution composed of 4,6-dihydroxy-2-propylthio-pyrimidine, nitric acid and sulfuric acid or nitric acid is mixed and then enters a tubular nitration reactor for nitration reaction to obtain a wet product of 4,6-dihydroxy-5-nitro-2-propylthio-pyrimidine. The wet product is added to a solvent, mixed with a chlorination reagent and then enters a tubular chlorination reactor for chlorination reaction, and 4,6-dichloro-5-nitro-2-propylthio-pyrimidine is obtained after post-treatment. The novel preparation method provided by the present invention adopts a tubular reactor, and sulfuric acid is used instead of acetic acid in the nitration reaction. Sulfuric acid can be recycled and reused, and operations such as water precipitation and beating are eliminated, and no waste water is generated. The chlorination reaction uses the mixed acid remaining in the nitrated product as a catalyst, and there is no need to add an alkali acid-binding agent, so the cost is lower, it is easier to realize process automation, the production process has higher safety, is convenient to operate, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to a new method for preparing 4,6-dichloro-5-nitro-2-propylsulfanylpyrimidine by continuous flow reaction. Background Art

[0002] 4,6-Dichloro-5-nitro-2-propylsulfanylpyrimidine is a key intermediate for the preparation of ticagrelor, and its structural formula is shown in formula (1):

[0003]

[0004] Ticagrelor is a new type of selective small molecule anticoagulant drug developed by AstraZeneca. It is the first platelet adenosine diphosphate P2Y12 receptor antagonist that can directly take effect through reversible binding and oral administration, belonging to the antiplatelet drug class. It has a significant inhibitory effect on platelet aggregation induced by ADP. This drug has a fast oral onset and can effectively improve the symptoms of patients with acute coronary syndrome (ACS), and has broad clinical application prospects.

[0005] Currently, the synthetic routes reported in the literature for 4,6-dichloro-5-nitro-2-propylsulfanylpyrimidine mainly use 4,6-dihydroxy-2-propylsulfanylpyrimidine as the main starting material, and are nitrated with nitric acid and chlorinated with phosphorus oxychloride to generate 4,6-dichloro-5-nitro-2-propylsulfanylpyrimidine.

[0006] At present, there are mainly the following methods for the first-step nitration reaction: 1) Direct nitration method, that is, using nitric acid as a solvent and nitrating reagent. For example, WO99 / 05142, CN102924457, and WO2011 / 017108 etc. reported that the raw material was slowly added to pre-cooled fuming nitric acid or concentrated nitric acid, stirred until the reaction was completed, and then poured into ice for quenching and crystallization. The product was obtained by filtration and separation. Since there is no solvent in this method, the raw material reacts directly with nitric acid, the temperature is difficult to control, various side reactions are easily triggered, and there are risks of runaway temperature and material flushing. A large amount of acidic wastewater is generated during the post-treatment of the reaction; 2) Raw material addition method. For example, WO2011 / 101740, WO2012 / 085665, CN103896857 etc. reported that acetic acid was used as a solvent, first formulated into a mixed acid with nitric acid, and then the raw material was added at the reaction temperature. After detecting the end of the reaction, the reaction solution was added to ice water for quenching and crystallization. The product was obtained by filtration and separation. This method introduces acetic acid as a solvent, and the temperature control is slightly better than the first one, but it generates a large amount of wastewater, and can only be produced intermittently, with low efficiency and great hidden dangers; 3) Nitric acid addition method. For example, CN111116592 or Synthetic Chemistry, 2015, 23(007): 650 - 652 etc. reported that the raw material was first dissolved in the nitration reaction solvent acetic acid, and nitric acid was slowly added dropwise. After the reaction was completed, it was added to ice water for quenching and crystallization. The product was obtained by filtration and separation. This method generates a large amount of wastewater, the heat release of the nitration reaction is large, and the reaction parameters are not easy to control. It is an intermittent batch operation, with a small production scale and poor product stability; 4) The combination method of autoclave and tube reactor. For example, Wu Qianqian etc. (Chinese Journal of Pharmaceuticals, 2013, 44(6): 3) reported a method combining an autoclave and a tube reactor. Although it utilized the characteristic of fast heat transfer of the tube reactor and reduced the hidden dangers brought by the strong exothermic nitration reaction to a certain extent, the author found during reproduction that the reaction solution was a solid-liquid two-phase system, which was prone to blockage during long-term operation and could not be directly scaled up for production. There are various problems such as high equipment requirements, large consumption of acetic acid, high cost, complex post-treatment and a large amount of wastewater generated.

[0007] The second step of the chlorination reaction is mainly prepared by reacting the raw material with a chlorinating reagent. Common chlorinating reagents include phosphorus oxychloride, thionyl chloride, BTC, phosgene, phosphorus pentachloride, etc. For example, W097 / 03084, WO2011 / 017108, WO2011 / 101740, CN103896857 report using phosphorus oxychloride as the chlorinating reagent and solvent, adding a base to bind the acid and reacting. CN104003943 mentions using thionyl chloride as the chlorinating reagent and solvent, adding triethylamine or pyridine as the acid-binding agent, and obtaining the product through reaction. CN102659691 uses phosphorus pentachloride as the chlorinating reagent. WO2019 / 016111 uses phosgene as the chlorinating reagent. Since phosgene is highly toxic and has limited industrial applications, safer solid phosgene BTC is often used for chlorination. Wu Qianqian et al. (Chinese Journal of Pharmaceutical Industry, 2013, 44(6):3) used solid phosgene BTC as the chlorinating reagent. The above chlorination reactions are all traditional batch production methods in a kettle, with prominent problems such as large safety hazards and low automation levels.

[0008] Existing production processes are all batch production in an intermittent kettle scheme. Nitration and chlorination are both dangerous processes. Conducted with traditional kettle processes and intermittent kettle operations, the reaction cycle is long, the reaction parameters are not easy to control, the automation level is low, the output is low, the quality is poor, there are many three wastes, and resource waste is serious. Accidents such as explosions are likely to occur, posing certain safety hazards. Therefore, it is particularly important to study a new preparation method to overcome the deficiencies of the existing processes. Summary of the Invention

[0009] To solve the defects existing in the prior art, the purpose of the present invention is to provide a method for continuously flowing reaction to prepare 4,6-dichloro-5-nitro-2-propylthio-pyrimidine. The present invention is improved on the basis of the traditional kettle process, and a tubular reaction technology is adopted for nitration and chlorination reactions, providing a safer and more effective production route to overcome the deficiencies of the existing processes.

[0010] The present invention discloses a method for continuously flowing reaction to prepare 4,6-dichloro-5-nitro-2-propylthio-pyrimidine, which is characterized by including the following steps:

[0011] 1) Nitration reaction: Dissolve 4,6-dihydroxy-2-propylthio-pyrimidine in sulfuric acid as material A, and use nitric acid or a mixed acid composed of nitric acid and sulfuric acid as material B. The two materials are respectively metered and transported to a mixer by metering pumps for rapid mixing, and then enter a nitration tubular reactor to carry out a nitration reaction at a certain temperature and residence time. After the reaction is completed, the nitration reaction solution enters a post-treatment device, and after post-treatment, the nitrated product 4,6-dihydroxy-5-nitro-2-propylthio-pyrimidine is obtained. The reaction equation is as follows:

[0012]

[0013] 2) Chlorination reaction: The nitrated product 4,6-dihydroxy-5-nitro-2-propylthio-pyrimidine obtained in step 1) is mixed with a solvent as material C, and a chlorination reagent is used as material D. The acid remaining in the nitrated product 4,6-dihydroxy-5-nitro-2-propylthio-pyrimidine serves as a catalyst. The two materials are respectively metered and transported to a mixer through metering pumps for rapid mixing, and then enter a chlorination tubular reactor. The chlorination reaction is carried out at a certain temperature and residence time. After the reaction is completed, the chlorination reaction liquid directly flows into metered water, and the temperature is kept below 30°C. After a batch of materials is received, the obtained reaction liquid is washed successively with saturated sodium bicarbonate, saturated brine and water, and 4,6-dichloro-5-nitro-2-propylthio-pyrimidine is obtained after vacuum distillation. The reaction equation is as follows:

[0014]

[0015] Furthermore, the present invention also defines that the concentration of sulfuric acid used in the nitration reaction in step 1) is 60 wt.% to 98 wt.%, and the concentration of nitric acid used in the nitration reaction is 20 wt.% to 98 wt.%.

[0016] Furthermore, the present invention also defines that the molar flow ratio of 4,6-dihydroxy-2-propylthio-pyrimidine, sulfuric acid, and nitric acid in step 1) is 1:5 to 20:1 to 3, the reaction temperature is 10 to 90°C, and the residence time is 0.5 min to 60 min. Here, the sulfuric acid includes the sulfuric acid used as a solvent and the sulfuric acid in the mixture.

[0017] Furthermore, the present invention also defines that the post-treatment method in step 1) is to cool the collected nitration reaction liquid to below 0°C until sufficient crystallization occurs. The filter cake obtained by centrifugal filtration is the crude nitrated product, which is directly used in the chlorination reaction without drying. The remaining sulfuric acid and nitric acid in this crude product serve as the catalyst for the next step, avoiding the addition of new reagents; the filtrate is collected and recycled.

[0018] Furthermore, the present invention also defines that a spherical mixer is uniformly filled in the nitration tubular reactor in step 1).

[0019] Furthermore, the present invention also defines that the diameter of the nitration tubular reactor is larger than the diameter of the spherical mixer; the diameter of the nitration tubular reactor is 1 to 10 mm, and the diameter of the spherical mixer is 0.5 to 5 mm.

[0020] Furthermore, the present invention also defines that the solvent in step 2) is dichloromethane or toluene, and the mass ratio of 4,6-dihydroxy-5-nitro-2-propylthio-pyrimidine to the solvent is 1:5 to 20.

[0021] Further, the present invention also defines that the chlorinating reagent in step 2) is phosphorus oxychloride or thionyl chloride, and the molar flow ratio of 4,6-dihydroxy-5-nitro-2-propylthio-pyrimidine to the chlorinating reagent is 1:1 to 25.

[0022] Further, the present invention also defines that the reaction temperature in step 2) is 90 - 130°C; the reaction system pressure is 0.1 - 0.8 MPa; and the residence time is 1 - 60 min.

[0023] Further, the present invention also defines that the chlorination tubular reactor in step 2) is a coiled tube reactor or a vertical tubular reactor, and its tube diameter is 1 - 10 mm.

[0024] Further, both the nitration tubular reactor and the chlorination tubular reactor in the present invention are tubular reactors. To distinguish different reactions, "nitration" or "chlorination" is added in front of the tubular reactor.

[0025] Compared with the prior art, the advantages of the present invention are mainly reflected in:

[0026] 1) In the nitration reaction of the present invention, sulfuric acid is used instead of acetic acid, the raw material cost is lower, the recovered sulfuric acid can be recycled, the generation amount of three wastes is small, and the post-treatment is simple. The nitration reaction liquid can be directly cooled and crystallized, and the nitrated product can be obtained by centrifugal separation. The obtained wet nitrated product can be directly used in the chlorination reaction, the post-treatment is simple, and no additional waste water is generated, which is more environmentally friendly;

[0027] 2) The present invention defines the use of the defined chlorination reaction step. Without adding an alkali acid-binding agent, the residual acid in the nitrated product is directly used as a catalyst, which greatly reduces the amount of three wastes and the cost. The tubular chlorination reaction speed is fast and the efficiency is higher;

[0028] 3) The present invention uses a tubular reactor instead of a traditional kettle reactor for nitration reaction and chlorination reaction. Due to the good heat and mass transfer effect of the tubular reactor, the reaction parameters can be controlled more precisely, and the safety coefficient is high, avoiding the following disadvantages of the traditional kettle process: batch production, small production scale, long production cycle, low output, poor quality, serious resource waste, etc.;

[0029] 4) The tubular process adopted by the present invention is easier to realize process automation, improve the safety of the production process, is convenient to operate, has a high degree of continuity, and is suitable for industrial production compared with the traditional kettle process using a continuous operation mode. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] [00:5] Figure 1 is the reaction flow chart of the present invention.

[0031] In the figure: 1 - first metering pump; 2 - second metering pump; 3 - third metering pump; 4 - fourth metering pump; 5 - nitration tubular reactor; 6 - chlorination tubular reactor. Detailed implementation mode

[0032] The present invention will be further described in detail below in conjunction with embodiments.

[0033] Example 1

[0034] Weigh 1 kg of 4,6-dihydroxy-2-propylthio-pyrimidine and add it to 3.2 kg of sulfuric acid (98%). Stir slowly at room temperature until dissolved to obtain a raw material solution. The raw material solution is pumped into a nitration tube reactor 5 (with a tube diameter of 1.77 mm) filled with 1 mm spherical mixers through a first metering pump 1 (the flow rate of the raw material solution is 15.8 mL / min). At the same time, 5.1 kg of nitric acid (20%) is pumped into the nitration tube reactor 5 through a second metering pump 2 (with a flow rate of 6.6 mL / min). The temperature of the nitration tube reactor 5 is controlled at 90°C by an oil bath, and the nitration reaction is carried out with a residence time of 0.5 min. After the reaction is completed, the reaction solution is collected at the outlet into a receiving bottle, cooled to about -6°C, fully crystallized, and then centrifuged and filtered to obtain the crude product of the nitrated product 4,6-dihydroxy-5-nitro-2-propylthio-pyrimidine. The prepared nitrated product 4,6-dihydroxy-5-nitro-2-propylthio-pyrimidine is added to 5.9 kg of toluene, stirred at room temperature to obtain a solution, and the obtained solution is pumped into a chlorination tube reactor 6 (a coil-type reactor with a tube diameter of 1.77 mm) through a third metering pump 3 (with a flow rate of 11.6 mL / min). At the same time, 19.4 kg of phosphorus oxychloride solution is pumped into the chlorination tube reactor 6 through a fourth metering pump 4 (with a flow rate of 7.9 mL / min). The temperature of the tube reactor is controlled at 130°C by an oil bath, the pressure of the reaction system is controlled at 0.16 Mpa by a back pressure valve, and the chlorination reaction is carried out with a residence time of 1 min. After the reaction is completed, the reaction solution at the outlet is slowly injected into water, and the temperature is kept below 30°C. It is washed successively with saturated sodium bicarbonate, saturated brine and water, and then distilled under reduced pressure to obtain 1355 g of the product, with a yield of 94.3% and a content of 99.8% measured by HPLC.

[0035] Example 2

[0036] Weigh 1 kg of 4,6-dihydroxy-2-propylthio-pyrimidine and add it to 5.8 kg of sulfuric acid (90%). Stir slowly at room temperature until dissolved, and then pump it into a nitration tubular reactor 5 (with a pipe diameter of 3.87 mm) filled with 2-mm spherical mixers through a first metering pump 1 (with a raw material liquid flow rate of 34.9 mL / min). At the same time, pump 1.4 kg of nitric acid (50%) into the nitration tubular reactor 5 through a second metering pump 2 (with a flow rate of 7.1 mL / min). Control the temperature of the tubular reactor at 60 °C through a water bath, and carry out the nitration reaction with a residence time of 10 min. After the reaction is completed, collect the reaction liquid at the outlet into a receiving bottle, cool it to about -6 °C, crystallize it fully, and then centrifuge and filter to obtain the crude nitrated product. Add the nitrated product 4,6-dihydroxy-5-nitro-2-propylthio-pyrimidine prepared in the previous step to 12 kg of toluene, stir at room temperature, and pump it into a chlorination tubular reactor 6 (a coiled tube reactor with a pipe diameter of 3.87 mm) through a third metering pump 3 (with a flow rate of 32.5 mL / min). At the same time, pump 9.2 kg of thionyl chloride solution into the chlorination tubular reactor 6 through a fourth metering pump 4 (with a flow rate of 12.5 mL / min). Control the temperature of the tubular reactor at 120 °C through an oil bath, control the pressure of the reaction system at 0.13 Mpa through a back pressure valve, and carry out the chlorination reaction with a residence time of 15 min. After the reaction is completed, slowly inject the reaction liquid at the outlet into water, keep the temperature below 30 °C, wash it successively with saturated sodium bicarbonate, saturated brine and water, and carry out vacuum distillation to obtain 1361 g of the product, with a yield of 95.2% and a content of 99.3% measured by HPLC.

[0037] Example 3

[0038] Weigh 1.5 kg of 4,6-dihydroxy-2-propylthio-pyrimidine and add it to 14.8 kg of sulfuric acid (80%). Slowly stir it at room temperature until it dissolves, and then pump it into a nitration tubular reactor (with a pipe diameter of 5 mm) filled with 2.5-mm spherical mixers through the first metering pump 1 (the flow rate of the raw material liquid is 44.9 mL / min). At the same time, pump 845.7 g of nitric acid (90%) into the nitration tubular reactor 5 through the second metering pump 2 (with a flow rate of 5.1 mL / min). Control the temperature of the tubular reactor at 30 °C through a water bath, and carry out the nitration reaction with a residence time of 30 min. After the reaction is completed, collect the reaction solution at the outlet into a receiving bottle, cool it down to about -6 °C, crystallize it fully, and then carry out centrifugal filtration to obtain the crude nitrated product. Add the nitrated product 4,6-dihydroxy-5-nitro-2-propylthio-pyrimidine prepared in the previous step to 26.4 kg of dichloromethane, stir it at room temperature, and pump it into a chlorination tubular reactor (a vertical tubular reactor with a pipe diameter of 5 mm) through the third metering pump 3 (with a flow rate of 45.9 mL / min). At the same time, pump 4.5 kg of phosphorus oxychloride solution into the chlorination tubular reactor 6 through the fourth metering pump 4 (with a flow rate of 6.1 mL / min). Control the temperature of the tubular reactor at 100 °C through an oil bath, control the pressure of the reaction system at 0.58 Mpa through a back pressure valve, and carry out the chlorination reaction with a residence time of 40 min. After the reaction is completed, slowly inject the reaction solution at the outlet into water, keep the temperature below 30 °C, wash it successively with saturated sodium bicarbonate, saturated brine and water, and carry out vacuum distillation to obtain 2011 g of the product, with a yield of 93.6% and a content of 99.5% measured by HPLC.

[0039] Example 4

[0040] Weigh 3 kg of 4,6-dihydroxy-2-propylthio-pyrimidine and add it to 45.8 kg of sulfuric acid (62%). Stir slowly at room temperature until dissolved, and then pump it into a nitration tube reactor (with a tube diameter of 10 mm) filled with 5-mm spherical mixers through the first metering pump 1 (the flow rate of the raw material liquid is 84.4 mL / min). At the same time, pump a mixed acid solution composed of 1.1 kg of nitric acid (98%) and 5.1 kg of sulfuric acid (62%) into the nitration tube reactor 5 through the second metering pump 2 (the flow rate is 10.6 mL / min). Control the temperature of the tube reactor at 10 °C through a water bath, and carry out the nitration reaction with a residence time of 60 min. After the reaction is completed, collect the reaction solution at the outlet into a receiving bottle, cool it down to about -6 °C, crystallize it fully, and then filter it by centrifugation to obtain the crude nitrated product. Add the nitrated product 4,6-dihydroxy-5-nitro-2-propylthio-pyrimidine prepared in the previous step to 69 kg of dichloromethane, stir at room temperature, and pump it into a chlorination tube reactor (a vertical tube reactor with a tube diameter of 10 mm) through the third metering pump 3 (the flow rate is 86.3 mL / min). At the same time, pump 3.6 kg of thionyl chloride solution into the chlorination tube reactor 6 through the fourth metering pump 4 (the flow rate is 3.7 mL / min). Control the temperature of the tube reactor at 90 °C through an oil bath, control the pressure of the reaction system at 0.45 Mpa through a back pressure valve, and carry out the chlorination reaction with a residence time of 60 min. After the reaction is completed, slowly inject the reaction solution at the outlet into water, keep the temperature below 30 °C, wash it successively with saturated sodium bicarbonate, saturated brine and water, and carry out vacuum distillation to obtain 4018 g of the product, with a yield of 93.4% and a content of 99.6% measured by HPLC.

[0041] Example 5

[0042] Sulfuric acid recycling and reuse: Weigh 1 kg of 4,6-dihydroxy-2-propylthio-pyrimidine and add it to 5.8 kg of 90% sulfuric acid (recycled filtrate). Stir slowly at room temperature until dissolved, and then pump it into a nitration tubular reactor (with a pipe diameter of 3.87 mm) filled with 2-mm spherical mixers through the first metering pump 1 (the flow rate of the raw material liquid is 34.9 mL / min). At the same time, pump 1.4 kg of 50% nitric acid into the nitration tubular reactor 5 through the second metering pump 2 (the flow rate is 7.1 mL / min). Control the temperature of the tubular reactor at 60 °C through a water bath, and carry out the nitration reaction with a residence time of 10 min. After the reaction is completed, collect the reaction liquid at the outlet into a receiving bottle, cool it to about -6 °C, crystallize it fully, and then filter it by centrifugation to obtain the crude nitrated product. Add the nitrated product 4,6-dihydroxy-5-nitro-2-propylthio-pyrimidine prepared in the previous step to 12 kg of toluene, stir at room temperature, and pump it into a chlorination tubular reactor 6 (coiled tubular reactor, with a pipe diameter of 3.87 mm) through the third metering pump 3 (the flow rate is 32.5 mL / min). At the same time, pump 9.2 kg of thionyl chloride solution into the chlorination tubular reactor 6 through the fourth metering pump 4 (the flow rate is 12.5 mL / min). Control the temperature of the tubular reactor at 120 °C through an oil bath, control the pressure of the reaction system at 0.13 Mpa through a back pressure valve, and carry out the chlorination reaction with a residence time of 15 min. After the reaction is completed, slowly inject the reaction liquid at the outlet into water, keep the temperature below 30 °C, wash it successively with saturated sodium bicarbonate, saturated brine and water, and distill it under reduced pressure to obtain 1349 g of the product, with a yield of 94.2% and a content of 99.5% measured by HPLC.

Claims

1. A method for preparing 4,6-dichloro-5-nitro-2-propylthio pyrimidine by continuous flow reaction, characterized in that It includes the following steps: 1) Nitration reaction Dissolve 4,6-dihydroxy-2-propylthio pyrimidine in sulfuric acid as material A, and use nitric acid or a mixed acid composed of nitric acid and sulfuric acid as material B. The two materials are respectively metered and transported to a mixer by metering pumps for rapid mixing, and then enter a nitration tubular reactor. The nitration reaction is carried out at a certain temperature and residence time. After the reaction is completed, the nitration reaction liquid enters a post-treatment device. After post-treatment, the nitrated product 4,6-dihydroxy-5-nitro-2-propylthio pyrimidine is obtained. The concentration of sulfuric acid used in the nitration reaction is 60wt.% - 98wt.%, and the concentration of nitric acid used in the nitration reaction is 20wt.% - 98wt.%. The post-treatment method is to cool the collected nitration reaction liquid to below 0°C until sufficient crystallization occurs, and the filter cake obtained by centrifugal filtration is the crude nitrated product. This crude nitrated product is directly used in the chlorination reaction, and the residual sulfuric acid and nitric acid in the crude product serve as catalysts in the chlorination reaction. The filtrate is collected and recycled. The reaction temperature is 10 - 90°C, and the residence time is 0.5min - 60min; 2) Chlorination reaction Mix the nitrated product 4,6-dihydroxy-5-nitro-2-propylthio pyrimidine prepared in step 1) with a solvent uniformly as material C, and use a chlorinating reagent as material D. The acid remaining in the nitrated product 4,6-dihydroxy-5-nitro-2-propylthio pyrimidine serves as a catalyst. The two materials are respectively metered and transported to a mixer by metering pumps for rapid mixing, and then enter a chlorination tubular reactor. The chlorination reaction is carried out at a certain temperature and residence time. After the reaction is completed, the chlorination reaction liquid directly flows into a measured amount of water, and the temperature is maintained below 30°C. After a batch of materials is received, the obtained reaction liquid is washed successively with saturated sodium bicarbonate, saturated brine, and water, and 4,6-dichloro-5-nitro-2-propylthio pyrimidine is obtained after vacuum distillation. The chlorinating reagent is phosphorus oxychloride or thionyl chloride, and the reaction temperature is 90 - 130°C; the pressure of the reaction system is 0.1 - 0.8MPa.

2. The method for preparing 4,6-dichloro-5-nitro-2-propylthio-pyrimidine by continuous flow reaction according to claim 1, characterized in that The molar flow ratio of 4,6-dihydroxy-2-propylthio pyrimidine, sulfuric acid, and nitric acid in step 1) is 1:5 - 20:1 - 3.

3. The method for preparing 4,6-dichloro-5-nitro-2-propylthio-pyrimidine by continuous flow reaction according to claim 1, wherein The nitration tubular reactor in step 1) is uniformly filled with a spherical mixer.

4. The method for preparing 4,6-dichloro-5-nitro-2-propylthio-pyrimidine by continuous flow reaction according to claim 3, characterized in that The diameter of the nitration tubular reactor is larger than the diameter of the spherical mixer; the diameter of the nitration tubular reactor is 1 - 10mm, and the diameter of the spherical mixer is 0.5 - 5mm.

5. The method for preparing 4,6-dichloro-5-nitro-2-propylthio-pyrimidine by continuous flow reaction according to claim 1, wherein The solvent in step 2) is dichloromethane or toluene, and the mass ratio of 4,6-dihydroxy-5-nitro-2-propylthio pyrimidine to the solvent is 1:5 - 20.

6. The method for preparing 4,6-dichloro-5-nitro-2-propylthio-pyrimidine by continuous flow reaction according to claim 1, wherein The molar flow ratio of 4,6-dihydroxy-5-nitro-2-propylthio pyrimidine to the chlorinating reagent in step 2) is 1:1 - 25.

7. The method for preparing 4,6-dichloro-5-nitro-2-propylthio-pyrimidine by continuous flow reaction according to claim 1, characterized in that The residence time in step 2) is 1 - 60min.

8. The method for preparing 4,6-dichloro-5-nitro-2-propylthio-pyrimidine by continuous flow reaction according to claim 1, characterized in that The chlorination tubular reactor in step 2) is a coiled tube reactor or a vertical tubular reactor, and its diameter is 1 - 10mm.

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