Preparation method of 2, 4-dichlorothieno [3, 2, d] pyrimidine

Abstract

The invention relates to the technical field of compound preparation, in particular to a preparation method of 2, 4-dichlorothieno [3, 2, d] pyrimidine, which comprises the following steps: S1, adding methyl 3-aminothiophene-2-formate, water and glacial acetic acid into a reaction kettle, dropwise adding a potassium cyanate aqueous solution while stirring, and after dropwise adding, carrying out heat preservation reaction to obtain an intermediate I; s2, returning the intermediate I to a reaction kettle, adding water and a 30% sodium hydroxide solution for reaction, acidifying, and performing suction filtration to obtain an intermediate II; s3, dichloromethane, the intermediate II, a bismuth-based catalyst and diisopropylethylamine are added into the reaction kettle, phosphorus oxychloride is dropwise added for a reaction, after the reaction is quenched, aftertreatment is conducted, and a target product is obtained. The 2, 4-dichlorothieno [3, 2, d] pyrimidine prepared by the method has higher purity and yield, the reaction controllability is enhanced by controlling the reaction temperature, the dropping speed and the reaction time, and the safety risk caused by too violent reaction or out-of-control reaction is reduced.

Description

Technical Field

[0001] The invention relates to the technical field of compound preparation, and in particular to a method for preparing 2,4-dichlorothieno[3,2,d]pyrimidine. Background Art

[0002] 2,4-Dichlorothieno[3,2,d]pyrimidine (CAS No. 16234-14-3) is a heterocyclic compound in which the thiophene ring and the pyrimidine ring are connected by a carbon-carbon bond, and two chlorine atoms are substituted at the 2nd and 4th positions of the pyrimidine ring. Its chemical formula is C6H2Cl2N2S, its molecular weight is 205.064, its melting point is 136.0-140.0℃, and its boiling point is 274.8±22.0℃. 2,4-Dichlorothieno[3,2,d]pyrimidine is a white to off-white powder or crystal, and has good chemical and thermal stability. There are various methods for synthesizing 2,4-dichlorothieno[3,2-d]pyrimidine, such as a method for preparing 2,4-dichlorothieno[3,2-D]pyrimidine with publication number CN108358949A, which uses 3-aminothiophene-2-carboxamide, triphosgene and phosphorus oxychloride as raw materials, and synthesizes it in high yield in two steps through ring-closing reaction and chlorination reaction. In the application field, 2,4-dichlorothieno[3,2-d]pyrimidine can be used as a key starting material for the new anti-tumor drug JF1001, and at the same time, it can be used for the synthesis of PI3K inhibitors under non-low temperature conditions. In addition, it can also be used to synthesize other biologically active heterocyclic compounds, such as thieno[3,2-d]pyrimidine derivatives, which show potential pharmacological activities in anticancer, antiviral and antibacterial aspects.

[0003] In the prior art, in the synthesis method using 3-aminothiophene-2-carboxamide, triphosgene and phosphorus oxychloride as raw materials, although triphosgene has high reactivity, it is relatively expensive and has extremely high toxicity. It will release toxic gases when it comes into contact with water, which increases the difficulty and risk of operation. Summary of the invention

[0004] In order to solve the problems mentioned in the above background technology, the present invention provides a method for preparing 2,4-dichlorothieno[3,2,d]pyrimidine.

[0005] In order to achieve the above object, the present invention adopts the following technical solutions:

[0006] A method for preparing 2,4-dichlorothieno[3,2,d]pyrimidine comprises the following steps:

[0007] S1. Add methyl 3-aminothiophene-2-carboxylate, water and glacial acetic acid into a reaction kettle, control the temperature, slowly dropwise add potassium cyanate aqueous solution while stirring, and after the dropwise addition is completed, keep the temperature for reaction. After the reaction is completed, centrifuge and separate by centrifugation to obtain a wet product filter cake of dichlorothiophene pyrimidine intermediate I;

[0008] S2, return the wet filter cake of dichlorothiophene pyrimidine intermediate I to the reactor, add water and 30% sodium hydroxide solution, start stirring, increase the temperature, keep the temperature and stir to react, after the reaction is completed, cool to below 0°C, slowly add 36% hydrochloric acid to the system while stirring for acidification, filter to obtain the filter cake, wash, and dry to constant weight to obtain dichlorothiophene pyrimidine intermediate II;

[0009] The reaction equation of intermediate II is as follows:

[0010]

[0011] S3. Add dichloromethane, dichlorothiophene pyrimidine intermediate II, bismuth-based catalyst and diisopropylethylamine into the reaction kettle, start stirring to fully mix the raw materials, control the temperature at 0-5°C, slowly add phosphorus oxychloride while stirring, and after the addition is complete, heat up for the first time, and perform atmospheric distillation under reflux to remove dichloromethane in the reaction system. After the distillation is complete, continue to add phosphorus oxychloride to the reaction kettle, heat up for the second time, and keep the temperature for reaction for 5-6 hours. After the reaction is completed, cool to room temperature, add deionized water to quench the reaction, control the temperature below 20°C during the addition, and after the quenching reaction is completed, continue stirring for 1-2 hours, centrifuge to obtain a wet filter cake, and obtain 2,4-dichlorothiophene [3,2,d] pyrimidine through post-treatment.

[0012] The reaction equation is:

[0013]

[0014] Furthermore, in step S1, the temperature is controlled at 0-5°C, the insulation reaction time is 2-3h, the mass ratio of 3-aminothiophene-2-carboxylic acid methyl ester, water, glacial acetic acid and potassium cyanate aqueous solution is (2-3):10:(1-1.2):(3-3.5), and the mass ratio of potassium cyanate to water in the potassium cyanate aqueous solution is 1:2.

[0015] Furthermore, in step S2, the temperature is raised to 78-80° C., the stirring speed is 50-100 rpm, the reaction time is 1-2 h, and the mass ratio of water, sodium hydroxide solution and hydrochloric acid is (6-7): 1:1.

[0016] Furthermore, in step S3, the temperature is raised to 40-45°C for the first time and to 80-90°C for the second time. The mass ratio of dichloromethane, dichlorothiophene pyrimidine intermediate II, bismuth-based catalyst, diisopropylethylamine and phosphorus oxychloride is (260-270):(32-33):(0.5-2):(10-12):(100-110), and the mass ratio of phosphorus oxychloride added for the first time to phosphorus oxychloride added again is 2:1.

[0017] Furthermore, the bismuth-based catalyst in step S3 is prepared by the following steps:

[0018] A1. In a reactor equipped with a stirrer, a thermometer and a nitrogen inlet, dimethylformamide and azobisisobutyronitrile were added, stirred and heated to 70-75°C. Under nitrogen protection, a mixed solution of styrene and vinylphosphonic acid was slowly added dropwise, and the reaction was carried out for 12-16 hours. During the reaction, the mixture was stirred every 1 hour. After the reaction was completed, the mixture was cooled to room temperature, poured into ethanol for precipitation, filtered, washed and dried to obtain poly(styrene-co-vinylphosphonic acid);

[0019] A2, adding bismuth nitrate and potassium iodide to ethylene glycol, stirring until dissolved, heating to 100-110° C., keeping warm for 4-5 hours, after the reaction is completed, cooling to room temperature, filtering, washing the precipitate with deionized water, and drying to obtain bismuth oxyiodide;

[0020] A3. Add poly(styrene-co-vinylphosphonic acid) to dimethylformamide, add bismuth oxyiodide, and ultrasonically treat for 5-15 minutes. Evaporate the solvent using a rotary evaporator, pour into ethanol for precipitation, filter, wash, and anneal at 200-220° C. for 1-2 hours under nitrogen protection to obtain a bismuth-based catalyst.

[0021] Furthermore, in step A1, the mass ratio of dimethylformamide, azobisisobutyronitrile, styrene and vinylphosphonic acid is 50:(0.1-0.2):(10-11):(2-3).

[0022] Furthermore, in step A2, the mass ratio of bismuth nitrate, potassium iodide and ethylene glycol is (10-12):(8-9):(110-120).

[0023] Furthermore, in step A3, the mass ratio of poly(styrene-co-vinylphosphonic acid), dimethylformamide and bismuth oxyiodide is (8-10):50:(3-5).

[0024] Furthermore, the post-processing in step S3 is specifically as follows:

[0025] The wet filter cake is rinsed with 5% sodium bicarbonate solution to remove residual acid and impurities, and the filter cake is rinsed again with deionized water to remove residual sodium bicarbonate and other soluble impurities. The washed filter cake is returned to the reactor, isopropanol is added for pulping, stirred for 2-3 hours, centrifuged, ethyl acetate and isopropanol are added again, the temperature is controlled at 60-70°C, stirred until dissolved, activated carbon is added, decolorized for 1-2 hours, and filtered by heat preservation. The filtrate is heated to 40-45°C for concentration, slowly cooled to 0°C for heat preservation and crystallization, centrifuged, washed with isopropanol, and dried until constant weight is obtained to obtain 2,4-dichlorothieno[3,2,d]pyrimidine.

[0026] Beneficial effects of the present invention:

[0027] 1. In the technical solution of the present invention, a metal-organic framework is formed by coordination of poly(styrene-co-vinylphosphonic acid) and bismuth oxyiodide, which has a high degree of orderliness and porosity, and provides abundant active sites and mass transfer channels for catalytic reactions. Poly(styrene-co-vinylphosphonic acid) is an organic ligand, and its chain structure makes the catalyst have a large specific surface area, which is conducive to the adsorption of substrates and the desorption of products. Bismuth oxyiodide, as a metal precursor, forms a stable coordination bond with the phosphonic acid group in poly(styrene-co-vinylphosphonic acid), ensuring the structural stability and catalytic activity of the catalyst. Bismuth ions, as active sites, are evenly distributed in the metal-organic framework, have a specific electronic configuration and coordination environment, and can attract and activate substrates such as phosphorus oxychloride molecules. In addition, the prepared catalyst has a stable structure and high catalytic activity, so that it can still maintain a high catalytic efficiency after repeated use.

[0028] 2. In the technical solution of the present invention, by controlling the reaction temperature, the dripping speed and the reaction time, the controllability of the reaction is enhanced, and the safety risks caused by excessively violent or out-of-control reactions are reduced. By optimizing the reaction conditions and selecting efficient catalysts, the consumption of raw materials and the waste of energy can be reduced, thereby improving the cost-effectiveness of the production process, reducing the cost of subsequent purification and treatment, and further improving the overall economic benefits. The raw materials and reagents used are relatively easy to obtain and safe, and are suitable for large-scale industrial production. DETAILED DESCRIPTION

[0029] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0030] Unless otherwise specified, the raw materials used in the present invention are all conventional products purchased from the market.

[0031] Preparation Example 1

[0032] The bismuth-based catalyst is prepared by the following steps:

[0033] A1. In a reactor equipped with a stirrer, a thermometer and a nitrogen inlet, 50 g of dimethylformamide and 0.1 g of azobisisobutyronitrile were added, stirred and heated to 70 ° C. Under nitrogen protection, a mixed solution of 10 g of styrene and 2 g of vinylphosphonic acid was slowly added dropwise, and the reaction was carried out for 12 h. During the reaction, the mixture was stirred every 1 h. After the reaction was completed, the mixture was cooled to room temperature, poured into ethanol for precipitation, filtered, washed and dried to obtain poly(styrene-co-vinylphosphonic acid);

[0034] A2, 10g bismuth nitrate (BiNO 33 ·5H2O) and 8g potassium iodide are added to 110g ethylene glycol, stirred until dissolved, heated to 100°C, and kept warm for 4h. After the reaction is completed, it is cooled to room temperature, filtered, and the precipitate is washed with deionized water and dried to obtain bismuth oxyiodide;

[0035] A3. Add 8 g of poly(styrene-co-vinylphosphonic acid) to 50 g of dimethylformamide, add 3 g of bismuth oxyiodide, and ultrasonically treat for 5 min. Evaporate the solvent using a rotary evaporator, pour into ethanol for precipitation, filter, wash, and anneal at 200 ° C for 1-2 h under nitrogen protection to obtain a bismuth-based catalyst.

[0036] Preparation Example 2

[0037] The bismuth-based catalyst is prepared by the following steps:

[0038] A1. In a reactor equipped with a stirrer, a thermometer and a nitrogen inlet, 50 g of dimethylformamide and 0.15 g of azobisisobutyronitrile were added, stirred and heated to 72 ° C. Under nitrogen protection, a mixed solution of 10.5 g of styrene and 2.5 g of vinylphosphonic acid was slowly added dropwise, and the reaction was carried out for 14 h, during which stirring was performed every 1 h. After the reaction was completed, the mixture was cooled to room temperature, poured into ethanol for precipitation, filtered, washed and dried to obtain poly(styrene-co-vinylphosphonic acid);

[0039] A2, 11g bismuth nitrate (BiNO 33 ·5H2O) and 8.5g potassium iodide were added to 115g ethylene glycol, stirred until dissolved, heated to 105°C, and kept warm for 4.5h. After the reaction was completed, cooled to room temperature, filtered, washed with deionized water, and dried to obtain bismuth oxyiodide;

[0040] A3. Add 9 g of poly(styrene-co-vinylphosphonic acid) to 50 g of dimethylformamide, add 4 g of bismuth oxyiodide, and ultrasonically treat for 10 min. Evaporate the solvent using a rotary evaporator, pour into ethanol for precipitation, filter, wash, and anneal at 210° C. for 1.5 h under nitrogen protection to obtain a bismuth-based catalyst.

[0041] Preparation Example 3

[0042] The bismuth-based catalyst is prepared by the following steps:

[0043] A1. In a reactor equipped with a stirrer, a thermometer and a nitrogen inlet, 50 g of dimethylformamide and 0.2 g of azobisisobutyronitrile were added, stirred and heated to 75 ° C. Under nitrogen protection, a mixed solution of 11 g of styrene and 3 g of vinylphosphonic acid was slowly added dropwise, and the reaction was carried out for 16 h. During the reaction, stirring was performed every 1 h. After the reaction was completed, the mixture was cooled to room temperature, poured into ethanol for precipitation, filtered, washed, and dried to obtain poly(styrene-co-vinylphosphonic acid);

[0044] A2, 12g bismuth nitrate (BiNO 33 ·5H2O) and 9g potassium iodide are added to 120g ethylene glycol, stirred until dissolved, heated to 110°C, and kept warm for 5h. After the reaction is completed, it is cooled to room temperature, filtered, and the precipitate is washed with deionized water and dried to obtain bismuth oxyiodide;

[0045] A3. Add 10 g of poly(styrene-co-vinylphosphonic acid) to 50 g of dimethylformamide, add 5 g of bismuth oxyiodide, and ultrasonically treat for 15 min. Evaporate the solvent using a rotary evaporator, pour into ethanol for precipitation, filter, wash, and anneal at 220° C. for 2 h under nitrogen protection to obtain a bismuth-based catalyst.

[0046] Example 1

[0047] A method for preparing 2,4-dichlorothieno[3,2,d]pyrimidine comprises the following steps:

[0048] S1. Add 20 g of 3-aminothiophene-2-carboxylic acid methyl ester, 100 g of water and 10 g of glacial acetic acid into a reaction kettle, control the temperature at 0°C, and dropwise add 30 g of potassium cyanate aqueous solution while stirring. After the dropwise addition is completed, keep the temperature for reaction for 2 h. After the reaction is completed, centrifuge to obtain a wet product filter cake of dichlorothiophene pyrimidine intermediate I;

[0049] S2, the wet filter cake of dichlorothiophene pyrimidine intermediate I obtained in step S1 was returned to the reactor, 60g of water and 10g of 30% sodium hydroxide solution were added, the temperature was raised to 78°C, and the reaction was stirred at a speed of 50rpm for 1h. After the reaction was completed, the temperature was lowered to below 0°C, 10g of 36% hydrochloric acid was added dropwise while stirring for acidification, and the filter cake was filtered out by suction, washed, and dried to constant weight to obtain dichlorothiophene pyrimidine intermediate II;

[0050] S3, add 260g of dichloromethane, 32g of dichlorothiophene pyrimidine intermediate II, 0.5g of bismuth-based catalyst obtained in Preparation Example 1 and 10g of diisopropylethylamine into the reactor, control the temperature to 0°C, add 67g of phosphorus oxychloride dropwise while stirring, and after the addition is completed, heat it to 40°C for the first time and distill it under normal pressure. After the distillation is completed, continue to add 33g of phosphorus oxychloride dropwise to the reactor, heat it to 80°C for the second time, and keep the temperature for reaction for 5h. After the reaction is completed, cool it to room temperature, add 200g of deionized water dropwise to quench the reaction, and after the quenching reaction is completed, continue stirring for 1h, centrifuge to obtain a wet product filter cake, and use The wet filter cake was washed with 300 g of 5% sodium bicarbonate solution, and the filter cake was washed again with 300 g of deionized water. The washed filter cake was returned to the reactor, 100 g of isopropanol was added for pulping, stirred for 2 h, and centrifuged. 50 g of ethyl acetate and 50 g of isopropanol were added again, the temperature was controlled at 60 ° C, and stirred until dissolved. 10 g of activated carbon was added, decolorized for 1 h, and the filter was filtered by heat preservation. The filtrate was heated to 40 ° C for concentration, slowly cooled to 0 ° C for heat preservation and crystallization, centrifuged, washed with isopropanol, and dried until constant weight was obtained to obtain 2,4-dichlorothieno[3,2,d]pyrimidine.

[0051] Example 2

[0052] A method for preparing 2,4-dichlorothieno[3,2,d]pyrimidine comprises the following steps:

[0053] S1. Add 25g of 3-aminothiophene-2-carboxylic acid methyl ester, 100g of water and 11g of glacial acetic acid into a reaction kettle, control the temperature at 2°C, and dropwise add 32.5g of potassium cyanate aqueous solution while stirring. After the dropwise addition is completed, keep the temperature for reaction for 2.5h. After the reaction is completed, centrifuge to obtain a wet product filter cake of dichlorothiophene pyrimidine intermediate I;

[0054] S2, the wet filter cake of dichlorothiophene pyrimidine intermediate I obtained in step S1 was returned to the reactor, 65g of water and 10g of 30% sodium hydroxide solution were added, the temperature was raised to 79°C, and the reaction was stirred at 60rpm for 1.5h. After the reaction was completed, the temperature was lowered to below 0°C, 10g of 36% hydrochloric acid was added dropwise while stirring for acidification, and the filter cake was filtered, washed, and dried to constant weight to obtain dichlorothiophene pyrimidine intermediate II;

[0055] S3, add 265g of dichloromethane, 32.5g of dichlorothiophene pyrimidine intermediate II, 1g of bismuth-based catalyst obtained in Preparation Example 2 and 11g of diisopropylethylamine into the reactor, control the temperature to 2°C, add 70g of phosphorus oxychloride dropwise while stirring, and after the addition is completed, heat it to 42°C for the first time and distill it under normal pressure. After the distillation is completed, continue to add 30g of phosphorus oxychloride dropwise to the reactor, heat it to 85°C for the second time, and keep the temperature for reaction for 5.5h. After the reaction is completed, cool it to room temperature, add 200g of deionized water dropwise to quench the reaction, and after the quenching reaction is completed, continue stirring for 1.5h, centrifuge to obtain a wet product filter cake, and use The wet filter cake was washed with 300 g of 5% sodium bicarbonate solution, and the filter cake was washed again with 300 g of deionized water. The washed filter cake was returned to the reactor, 100 g of isopropanol was added for pulping, stirred for 2.5 h, centrifuged, 50 g of ethyl acetate and 50 g of isopropanol were added again, the temperature was controlled at 65 ° C, stirred until dissolved, 10 g of activated carbon was added, decolorization was performed for 1.5 h, and the filter was filtered by heat preservation. The filtrate was heated to 42 ° C for concentration, slowly cooled to 0 ° C for heat preservation and crystallization, centrifuged, washed with isopropanol, and dried until constant weight was obtained to obtain 2,4-dichlorothieno[3,2,d]pyrimidine.

[0056] Example 3

[0057] A method for preparing 2,4-dichlorothieno[3,2,d]pyrimidine comprises the following steps:

[0058] S1. Add 30 g of methyl 3-aminothiophene-2-carboxylate, 100 g of water and 12 g of glacial acetic acid into a reaction kettle, control the temperature at 5 ° C, and add 35 g of potassium cyanate aqueous solution dropwise while stirring. After the addition is completed, keep the temperature for reaction for 3 hours. After the reaction is completed, centrifuge to obtain a wet product filter cake of dichlorothiophene pyrimidine intermediate I;

[0059] S2, returning the wet filter cake of dichlorothiophene pyrimidine intermediate I obtained in step S1 to the reactor, adding 70g of water and 10g of 30% sodium hydroxide solution, heating to 80°C, stirring and reacting at a speed of 100rpm for 2h, cooling to below 0°C after the reaction, adding 10g of 36% hydrochloric acid dropwise while stirring for acidification, filtering to obtain a filter cake, washing, and drying to constant weight to obtain dichlorothiophene pyrimidine intermediate II;

[0060] S3, add 270g of dichloromethane, 33g of dichlorothiophene pyrimidine intermediate II, 2g of bismuth-based catalyst obtained in Preparation Example 3 and 12g of diisopropylethylamine into the reactor, control the temperature to 5°C, add 73g of phosphorus oxychloride dropwise while stirring, and after the addition is completed, heat it to 45°C for the first time and distill it under normal pressure. After the distillation is completed, continue to add 27g of phosphorus oxychloride dropwise to the reactor, heat it to 90°C for the second time, and keep the temperature for reaction for 6h. After the reaction is completed, cool it to room temperature, add 200g of deionized water dropwise to quench the reaction, continue stirring for 2h after the quenching reaction is completed, centrifuge to obtain a wet product filter cake, and use 3 00g5% sodium bicarbonate solution was used to rinse the wet filter cake, and 300g deionized water was used to rinse the filter cake again. The washed filter cake was returned to the reactor, 100g isopropanol was added for pulping, stirred for 3h, centrifuged, 50g ethyl acetate and 50g isopropanol were added again, the temperature was controlled at 70°C, stirred until dissolved, 10g activated carbon was added, decolorized for 2h, and filtered by heat preservation. The filtrate was heated to 45°C for concentration, slowly cooled to 0°C for heat preservation and crystallization, centrifuged, washed with isopropanol, and dried until constant weight was obtained to obtain 2,4-dichlorothieno[3,2,d]pyrimidine.

[0061] Comparative Example 1

[0062] The difference between this comparative example and Example 1 is that styrene is used instead of the bismuth-based catalyst prepared in Preparation Example 1, and the remaining steps are the same as those in Example 1.

[0063] Comparative Example 2

[0064] The difference between this comparative example and Example 2 is that vinylphosphonic acid is used instead of the bismuth-based catalyst prepared in Preparation Example 2, and the remaining steps are the same as Example 2.

[0065] Comparative Example 3

[0066] The difference between this comparative example and Example 3 is that bismuth nitrate acid is used instead of the bismuth-based catalyst prepared in Preparation Example 2, and the remaining steps are the same as Example 3.

[0067] Comparative Example 4

[0068] The difference between this comparative example and Example 1 is that the poly(styrene-co-vinylphosphonic acid) prepared in Step A1 of Preparation Example 1 is used to replace the bismuth-based catalyst prepared in Preparation Example 1, and the remaining steps are the same as in Example 1.

[0069] Comparative Example 5

[0070] The difference between this comparative example and Example 2 is that potassium iodide is used instead of the bismuth-based catalyst prepared in Preparation Example 2, and the remaining steps are the same as those in Example 2.

[0071] Comparative Example 6

[0072] The difference between this comparative example and Example 3 is that the bismuth oxyiodide prepared in step A2 of Preparation Example 3 is used to replace the bismuth-based catalyst prepared in Preparation Example 2, and the remaining steps are the same as Example 3.

[0073] The yields and production rates of Examples 1-3 and Comparative Examples 1-6 are shown in Table 1:

[0074] Table 1. Yield and production results of Examples 1-3 and Comparative Examples 1-6

[0075] serial number Yield (%) Yield (%) Example 1 86.3 78.8 Example 2 87.7 80.1 Example 3 88.0 82.2 Comparative Example 1 60.5 55.1 Comparative Example 2 63.1 57.9 Comparative Example 3 65.6 60.4 Comparative Example 4 70.3 65.5 Comparative Example 5 68.2 63.2 Comparative Example 6 75.2 70.4

[0076] As shown in Table 1, the yield and productivity of Examples 1-3 are higher than those of Comparative Examples 1-6. In Examples 1-3, bismuth-based catalysts are used, which may have higher activity and selectivity, thereby promoting the reaction and improving the yield and productivity of the product. In the preparation process of bismuth-based catalysts, catalytic sites with specific structures and activities may be formed through steps such as polymerization, compounding and annealing, which are conducive to the reaction. The reaction conditions in Examples 1-3 may have been optimized to ensure the efficient conduct of the reaction, which may help to reduce the occurrence of side reactions and improve the selectivity of the main reaction, thereby increasing the yield and productivity of the product. Different catalysts or catalyst precursors are used in Comparative Examples 1-6 to replace special bismuth-based catalysts, which may not have the same activity and selectivity as bismuth-based catalysts, and may not have formed a complete catalytic structure or active site, resulting in reduced reaction efficiency, and decreased product yield and productivity. Potassium iodide is used as a substitute for the catalyst in Comparative Example 5, but potassium iodide may not have the ability to catalyze the reaction, so the reaction efficiency is greatly reduced, and the product yield and productivity also decrease accordingly.

[0077] In summary, the bismuth-based catalyst prepared in Preparation Example 1-3 exhibits a significant catalytic effect in the preparation of 2,4-dichlorothieno[3,2,d]pyrimidine, so that the 2,4-dichlorothieno[3,2,d]pyrimidine prepared in Example 1-3 has a higher purity and yield.

[0078] In the description of the specification, the description with reference to the terms "embodiment", "various embodiments" and the like means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or preparation example are included in at least one embodiment or preparation example of the present invention. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment or preparation example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or preparation examples in a suitable manner.

[0079] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A method for preparing 2,4-dichlorothieno[3,2,d]pyrimidine, characterized in that: The following steps are involved: S1. Add methyl 3-aminothiophene-2-carboxylate, water and glacial acetic acid into a reaction kettle, control the temperature, and dropwise add an aqueous solution of potassium cyanate while stirring. After the dropwise addition is completed, heat the reaction and, after the reaction is completed, centrifuge to obtain a wet product filter cake of dichlorothiophene pyrimidine intermediate I; S2, return the wet filter cake of dichlorothiophene pyrimidine intermediate I to the reactor, add water and 30% sodium hydroxide solution, heat up, keep warm and stir to react, after the reaction is completed, cool to below 0°C, add 36% hydrochloric acid dropwise while stirring for acidification, filter to obtain the filter cake, wash, and dry to constant weight to obtain dichlorothiophene pyrimidine intermediate II; S3. Add dichloromethane, dichlorothiophene pyrimidine intermediate II, bismuth-based catalyst and diisopropylethylamine into the reaction kettle, control the temperature to 0-5°C, add phosphorus oxychloride dropwise while stirring, and after the addition is completed, heat up for the first time and distill at normal pressure. After the distillation is completed, continue to add phosphorus oxychloride dropwise into the reaction kettle, heat up for the second time, and keep the temperature for reaction for 5-6 hours. After the reaction is completed, cool to room temperature and add deionized water to quench the reaction. After the quenching reaction is completed, continue stirring for 1-2 hours, centrifuge to obtain a wet filter cake, and obtain 2,4-dichlorothiophene [3,2,d] pyrimidine through post-treatment.

2. The method for preparing 2,4-dichlorothieno[3,2,d]pyrimidine according to claim 1, characterized in that: In step S1, the temperature is controlled at 0-5° C., the insulation reaction time is 2-3 hours, the mass ratio of 3-aminothiophene-2-carboxylic acid methyl ester, water, glacial acetic acid and potassium cyanate aqueous solution is (2-3):10:(1-1.2):(3-3.5), and the mass ratio of potassium cyanate to water in the potassium cyanate aqueous solution is 1:

2.

3. The method for preparing 2,4-dichlorothieno[3,2,d]pyrimidine according to claim 1, characterized in that: In step S2, the temperature is raised to 78-80° C., the stirring speed is 50-100 rpm, the reaction time is 1-2 h, and the mass ratio of water, sodium hydroxide solution and hydrochloric acid is (6-7): 1:

1.

4. The method for preparing 2,4-dichlorothieno[3,2,d]pyrimidine according to claim 1, characterized in that: In step S3, the temperature is raised to 40-45° C. for the first time and to 80-90° C. for the second time. The mass ratio of dichloromethane, dichlorothiophene pyrimidine intermediate II, bismuth-based catalyst, diisopropylethylamine and phosphorus oxychloride is (260-270): (32-33): (0.5-2): (10-12): (100-110), and the mass ratio of phosphorus oxychloride added for the first time to phosphorus oxychloride added again is 2:

1.

5. The method for preparing 2,4-dichlorothieno[3,2,d]pyrimidine according to claim 1, characterized in that: The bismuth-based catalyst in step S3 is prepared by the following steps: A1. In a reactor equipped with a stirrer, a thermometer and a nitrogen inlet, dimethylformamide and azobisisobutyronitrile were added, stirred and heated to 70-75°C. Under nitrogen protection, a mixed solution of styrene and vinylphosphonic acid was slowly added dropwise, and the reaction was carried out for 12-16 hours, during which the mixture was stirred every 1 hour. After the reaction was completed, the mixture was cooled to room temperature, poured into ethanol for precipitation, filtered, washed and dried to obtain poly(styrene-co-vinylphosphonic acid); A2, adding bismuth nitrate and potassium iodide to ethylene glycol, stirring until dissolved, heating to 100-110° C., keeping warm for 4-5 hours, after the reaction is completed, cooling to room temperature, filtering, washing the precipitate with deionized water, and drying to obtain bismuth oxyiodide; A3. Add poly(styrene-co-vinylphosphonic acid) to dimethylformamide, add bismuth oxyiodide, and ultrasonically treat for 5-15 minutes. Evaporate the solvent using a rotary evaporator, pour into ethanol for precipitation, filter, wash, and anneal at 200-220° C. for 1-2 hours under nitrogen protection to obtain a bismuth-based catalyst.

6. The method for preparing 2,4-dichlorothieno[3,2,d]pyrimidine according to claim 5, characterized in that: In step A1, the mass ratio of dimethylformamide, azobisisobutyronitrile, styrene and vinylphosphonic acid is 50:(0.1-0.2):(10-11):(2-3).

7. The method for preparing 2,4-dichlorothieno[3,2,d]pyrimidine according to claim 5, characterized in that: The mass ratio of bismuth nitrate, potassium iodide and ethylene glycol in step A2 is (10-12): (8-9): (110-120).

8. The method for preparing 2,4-dichlorothieno[3,2,d]pyrimidine according to claim 5, characterized in that: In step A3, the mass ratio of poly(styrene-co-vinylphosphonic acid), dimethylformamide and bismuth oxyiodide is (8-10):50:(3-5).

9. The method for preparing 2,4-dichlorothieno[3,2,d]pyrimidine according to claim 1, characterized in that: The post-processing in step S3 is specifically as follows: The wet filter cake is rinsed with 5% sodium bicarbonate solution to remove residual acid and impurities, and the filter cake is rinsed again with deionized water to remove residual sodium bicarbonate and other soluble impurities. The washed filter cake is returned to the reactor, isopropanol is added for pulping, stirred for 2-3 hours, centrifuged, ethyl acetate and isopropanol are added again, the temperature is controlled at 60-70°C, stirred until dissolved, activated carbon is added, decolorized for 1-2 hours, and filtered by heat preservation. The filtrate is heated to 40-45°C for concentration, slowly cooled to 0°C for heat preservation and crystallization, centrifuged, washed with isopropanol, and dried until constant weight is obtained to obtain 2,4-dichlorothieno[3,2,d]pyrimidine.

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