Preparation method of heterocyclic thioether compound

Abstract

The invention relates to the technical field of chemical synthesis, in particular to a preparation method of a heterocyclic thioether compound, which is technically characterized in that the synthesis process is # imgabs0 #, in which substituent groups are defined as follows: R1 is H or C1-C6-alkyl or halogen; r2 is H or C1-C6-alkyl or halogen; r3 is a C1-C6-alkyl group; r4 is an organic inert group which has no influence on the actual reaction. The preparation method solves the problems of high preparation cost, low yield, difficult catalyst recovery and troublesome subsequent treatment of the original preparation method, and compared with the prior art, the preparation method has the advantages that the catalyst consumption is increased, the conversion rate is increased, and the yield is increased; the reaction solvent of the reaction system is removed in a distillation manner, and then the catalyst is separated, so that the problem that the catalyst is difficult to recycle is solved, the catalyst can be directly recycled, the raw material cost is greatly reduced, the post-treatment process is reduced, the emission of three wastes is reduced, and the method is suitable for large-scale commercial production.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, and in particular to a method for preparing a heterocyclic thioether compound. Background Art

[0002] Heterocyclic sulfide compounds have a wide range of applications in many fields, including organic synthesis, pesticides, pharmaceutical intermediates, dye industry, semiconductive polymers, etc.

[0003] For example, heterocyclic sulfide compounds are often used as intermediates and reaction solvents in organic synthesis. Their stable molecular structure and good solubility make them one of the indispensable raw materials for the synthesis of complex organic compounds. In the field of pesticides, heterocyclic sulfide compounds are important intermediates in the synthesis of pesticides, helping to produce pesticide products with high efficiency in killing pests of crops. In the pharmaceutical industry, heterocyclic sulfide compounds also play an important role. As key raw materials, they participate in multiple synthesis reaction steps and promote the formation of drug molecules. They play an indispensable role in the drug research and development process and provide a basis for the production of a variety of drugs. In the dye industry, heterocyclic sulfide compounds are also very important in the pharmaceutical industry. Cyclic sulfide compounds are used to synthesize a variety of dye intermediates, providing basic raw materials for colorful textiles and plastic products. This application demonstrates the key role of heterocyclic sulfide compounds in improving product color and quality. Semiconductive polyheterocyclic sulfide is a semicrystalline polymer with a sub-heterocyclic sulfide as the main chain, which has excellent thermal stability. The conductivity of untreated polyheterocyclic sulfide is within the range of semiconductors. After specific treatment, its conductivity can be significantly improved, making it a good conductive polymer. Heterocyclic sulfide usually has flexible and changeable structure and high activity, which makes them a major trend in the development of chemical pesticides. For example, sulfur-containing heterocyclic compounds have a wide range of biological and pharmaceutical activities, such as anticancer, antitumor, antioxidant, antiviral, antiphlegm and antibacterial, and are widely used in medicine, pesticides and industry.

[0004] However, the current preparation cost of heterocyclic sulfide compounds is high and the yield is low. Organic solvents need to be added during the reaction, the catalyst is not easy to recover, and the subsequent processing process is cumbersome. Summary of the invention

[0005] The invention solves the problems of high preparation cost, low yield, difficult catalyst recovery and troublesome post-processing in the original preparation method. Compared with the prior art, no other organic solvent is required in the reaction process, the amount of catalyst is increased, the conversion rate is improved and the yield is increased. The reaction system first removes the reaction solvent by distillation, and then separates the catalyst, which solves the problem of difficult catalyst recovery and can be directly recycled, greatly reducing the cost of raw materials, reducing the post-processing process, reducing the discharge of three wastes, and is suitable for large-scale commercial production.

[0006] The technical solution of the present invention is:

[0007] A method for preparing a heterocyclic sulfide compound, the technical key points of which are that the synthesis process is:

[0008]

[0009] Wherein, the substituents are defined as follows:

[0010] R1 is H or C1-C6-alkyl or halogen;

[0011] R2 is H or C1-C6-alkyl or halogen;

[0012] R3 is C1-C6-alkyl;

[0013] R4 is an organic inert group that has no effect on the actual reaction;

[0014] The specific steps include:

[0015] Step 1, adding a heterocyclic amine and a copper catalyst into dialkyl disulfide, and stirring to form a mixed system;

[0016] Step 2: adding an organic nitrite dropwise to the mixed system formed in step 1, and then stirring to react. After the reaction is completed, concentrating the excess reaction solvent, filtering and separating the copper catalyst, and concentrating the filtrate to recover the excess dialkyl disulfide to obtain a dark oily crude product, and distilling the crude product to obtain a heterocyclic sulfide compound product.

[0017] In the above-mentioned method for preparing heterocyclic sulfide compounds, the copper catalyst is copper element or copper salt, the physical form of the copper element is one or more combinations of copper turnings, copper rods, copper wires, copper balls, copper particles, and copper powder; and the copper salt is copper chloride or copper bromide.

[0018] In the above-mentioned method for preparing heterocyclic sulfide compounds, in step 1, the molar ratio of the heterocyclic amine to the copper catalyst is 1:1.9-1:1.1.

[0019] In the above-mentioned method for preparing heterocyclic thioether compounds, the R4 substituent in the organic nitrite is a C1-C6-alkyl or C2-C6-alkenyl.

[0020] In the above-mentioned method for preparing heterocyclic thioether compounds, the organic nitrite is ethyl nitrite, tert-butyl nitrite, isoamyl nitrite or n-butyl nitrite.

[0021] In the above-mentioned method for preparing heterocyclic sulfide compounds, in step 1, the molar ratio of the heterocyclic amine to the organic nitrite is 1:1.1-1:1.0.

[0022] In the above-mentioned method for preparing heterocyclic sulfide compounds, in step 1, the amount of the dialkyl disulfide used is 1.5-2 times the molar amount of the heterocyclic amine.

[0023] In the above-mentioned method for preparing heterocyclic sulfide compounds, in step 2, the stirring reaction time is 2-6 hours.

[0024] In the above-mentioned method for preparing heterocyclic sulfide compounds, in step 2, the reaction temperature is 50°C-55°C.

[0025] Beneficial effects of the present invention:

[0026] 1. The present invention uses heterocyclic amine as raw material, organic nitrite as diazotizing agent, dialkyl disulfide as alkylating agent and solvent, adds copper catalyst at set temperature, and the reaction is finished. Excess dialkyl disulfide can be recovered and used as alkylating agent and solvent. The preparation process is simple, and the raw materials dialkyl disulfide and organic nitrite used have been commercialized on a large scale in China and the world and are low in price.

[0027] 2. The present invention solves the problem of large amount of waste water generated by the traditional diazotization method. At the same time, the alkylating agent is used as the solvent, which saves the step of separating the solvent. The excess alkylating agent can be directly used after being recovered, which reduces the cost of three waste treatment, the cost of using solvents, and the environmental pollution.

[0028] 3. Compared with the prior art with publication number CN1210269C, the dosage of the catalyst is increased, so that the product conversion rate is increased, and the finished product yield is improved to more than 92%; and in the prior art with publication number CN1210269C, the catalyst is removed by washing with acid water, and the catalyst cannot be recycled. This patent optimizes the catalyst recovery process. After the reaction is completed, the solvent is first concentrated and then the catalyst is separated. This method solves the problem that the catalyst is difficult to separate after being dissolved in the system, and achieves the purpose of recycling the catalyst, which not only reduces the treatment of the three wastes, but also reduces the cost of raw materials. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 is the product test result of Example 1 of the present invention;

[0030] Figure 2 is the product test result of Example 7 of the present invention;

[0031] Figure 3 is the product test result of Example 11 of the present invention;

[0032] Figure 4 This is the product test result of Example 15 of the present invention. DETAILED DESCRIPTION

[0033] Take the production of 4,6-dichloropyrimidine-2-methyl sulfide as an example

[0034] Example 1

[0035] The specific synthesis steps are as follows:

[0036] Step 1, add 163.9g (1 mol) of 4,6-dichloropyrimidine-2-amine and 100g (1.56 mol) of copper powder to 141.3g (1.5 mol) of dimethyl disulfide, heat to 51-52°C, and stir to mix. The molar ratio of 4,6-dichloropyrimidine-2-amine to copper powder is 1:1.56. The amount of dimethyl disulfide used is 1.5 times the molar amount of 4,6-dichloropyrimidine-2-amine.

[0037] Step 2, 106.2g (1.03mol) of tert-butyl nitrite is added dropwise to the above mixed system, and the molar ratio of 4,6-dichloropyrimidine-2-amine to tert-butyl nitrite is 1:1.03. Stir the reaction for 4 hours, and when the reaction is finished, concentrate and recover the excess dimethyl disulfide for the next use, and then cool and filter out the copper powder, which is directly used for the next batch, and the filtrate is obtained as a dark oily crude product, and the crude product is distilled to obtain 180.9g of 4,6-dichloropyrimidine-2-methyl sulfide product.

[0038] After testing, the product yield can reach 92.8%, and the GC purity must reach 99.2%. Figure 1 The test results.

[0039] Example 2

[0040] The specific synthesis steps are as follows:

[0041] Step 1, add 163.9g (1 mol) of 4,6-dichloropyrimidine-2-amine and 110g (1.72 mol) of copper powder to 188.4g (2 mol) of dimethyl disulfide, heat to 50-52°C, and stir to mix. The molar ratio of 4,6-dichloropyrimidine-2-amine to copper powder is 1:1.72. The amount of dimethyl disulfide used is twice the molar amount of 4,6-dichloropyrimidine-2-amine.

[0042] Step 2, 113.4g (1.1mol) of tert-butyl nitrite is added dropwise to the above system, and the molar ratio of 4,6-dichloropyrimidine-2-amine to tert-butyl nitrite is 1:1.1. Stir the reaction for 4 hours, and when the reaction is finished, concentrate and recover the excess dimethyl disulfide for the next use, and then cool and filter out the copper powder, which is directly used for the next batch, and obtain a dark oily crude product from the filtrate, and the crude product is distilled to obtain 179.7g of 4,6-dichloropyrimidine-2-methyl sulfide product, with a GC purity of 99.5% and a yield of 92.2%.

[0043] Example 3

[0044] The specific synthesis steps are as follows:

[0045] Step 1, add 163.9g (1 mol) of 4,6-dichloropyrimidine-2-amine and 100g (1.56 mol) of copper powder to 141.3g (1.5 mol) of dimethyl disulfide, heat to 51-52°C, and stir to mix. The molar ratio of 4,6-dichloropyrimidine-2-amine to copper powder is 1:1.56. The amount of dimethyl disulfide used is 1.5 times the molar amount of 4,6-dichloropyrimidine-2-amine.

[0046] Step 2, 117.15g (1.0mol) of isoamyl nitrite is added dropwise to the above system, the molar ratio of 4,6-dichloropyrimidine-2-amine to isoamyl nitrite is 1:1.0. Stir the reaction for 4 hours, and when the reaction is finished, concentrate and recover the excess dimethyl disulfide for the next use, then cool and filter out the copper powder, which is directly used for the next batch, and obtain a dark oily crude product from the filtrate, and the crude product is distilled to obtain 180.1g of 4,6-dichloropyrimidine-2-methyl sulfide product, with a GC purity of 99.2% and a yield of 92.4%.

[0047] Example 4

[0048] The specific synthesis steps are as follows:

[0049] Step 1, add 163.9g (1 mol) of 4,6-dichloropyrimidine-2-amine and 266g (1.56 mol) of cupric chloride to 141.3g (1.5 mol) of dimethyl disulfide, heat to 51-52°C, and stir to mix. The molar ratio of 4,6-dichloropyrimidine-2-amine to cupric chloride is 1:1.56. The amount of dimethyl disulfide used is 1.5 times the molar amount of 4,6-dichloropyrimidine-2-amine.

[0050] Step 2, 106.2g (1.03mol) of n-butyl nitrite is added dropwise to the above system, and the molar ratio of 4,6-dichloropyrimidine-2-amine to n-butyl nitrite is 1:1.03. Stir the reaction for 4 hours, and when the reaction is finished, concentrate and recover the excess dimethyl disulfide for the next use, and then cool and filter out the copper powder, which is directly used for the next batch, and obtain a dark oily crude product from the filtrate, and the crude product is distilled to obtain 179.9g of 4,6-dichloropyrimidine-2-methyl sulfide product, with a GC purity of 99.1% and a yield of 92.3%.

[0051] Take the production of 4,6-dichloropyrimidine-2-ethyl sulfide as an example

[0052] Example 5

[0053] The specific synthesis steps are as follows:

[0054] Step 1, add 121.18g (1 mol) of 4,6-dichloropyrimidine-2-amine and 100g (1.56 mol) of copper powder to 141.3g (1.5 mol) of dimethyl disulfide, heat to 51-52°C, and stir to mix. The molar ratio of 4,6-dichloropyrimidine-2-amine to copper powder is 1:1.56. The amount of dimethyl disulfide used is 1.5 times that of 4,6-dichloropyrimidine-2-amine.

[0055] Step 2, 106.2g (1.03mol) of tert-butyl nitrite is added dropwise to the above mixed system, and the molar ratio of 4,6-dichloropyrimidine-2-amine to tert-butyl nitrite is 1:1.03. Stir the reaction for 4 hours, and when the reaction is finished, concentrate and recover the excess dimethyl disulfide for the next use, and then cool and filter out the copper powder, which is directly used for the next batch, and obtain a dark oily crude product from the filtrate, and the crude product is distilled to obtain 193.2g of 4,6-dichloropyrimidine-2-ethyl sulfide product, with a GC purity of 99.8% and a yield of 92.5%.

[0056] Example 6

[0057] The specific synthesis steps are as follows:

[0058] Step 1, add 121.18g (1 mol) of 4,6-dichloropyrimidine-2-amine and 110g (1.72 mol) of copper powder to 188.4g (2 mol) of dimethyl disulfide, heat to 50-52°C, and stir to mix. The molar ratio of 4,6-dichloropyrimidine-2-amine to copper powder is 1:1.72. The amount of dimethyl disulfide used is twice the molar amount of 4,6-dichloropyrimidine-2-amine.

[0059] Step 2, 107.2g (1.04mol) of tert-butyl nitrite is added dropwise to the above system, and the molar ratio of 4,6-dichloropyrimidine-2-amine to tert-butyl nitrite is 1:1.04. Stir and react for 2 hours. After the reaction is completed, the excess dimethyl disulfide is concentrated and recovered for the next use, and then the copper powder is filtered out by cooling. The copper powder is directly used for the next batch. The filtrate is obtained as a dark oily crude product, and the crude product is distilled to obtain 192.2g of 4,6-dichloropyrimidine-2-ethyl sulfide product, with a GC purity of 99.5% and a yield of 92.0%.

[0060] Example 7

[0061] The specific synthesis steps are as follows:

[0062] Step 1, add 121.18g (1 mol) of 4,6-dichloropyrimidine-2-amine and 100g (1.56 mol) of copper powder to 141.3g (1.5 mol) of dimethyl disulfide, heat to 51-52°C, and stir to mix. The molar ratio of 4,6-dichloropyrimidine-2-amine to copper powder is 1:1.56. The amount of dimethyl disulfide used is 1.5 times the molar amount of 4,6-dichloropyrimidine-2-amine.

[0063] Step 2, 120.7g (1.03mol) of isoamyl nitrite is added dropwise to the above system, the molar ratio of 4,6-dichloropyrimidine-2-amine to isoamyl nitrite is 1:1.03. Stir and react for 4 hours, the reaction is completed, and the excess dimethyl disulfide is concentrated and recovered for the next use, and then the temperature is lowered and filtered to remove the copper powder, which is directly used for the next batch, and the filtrate is obtained as a dark oily crude product, and the crude product is distilled to obtain 193.2g of 4,6-dichloropyrimidine-2-ethyl sulfide product.

[0064] After testing, the product yield can reach 92.5%, and the GC purity must reach 99.5%. Figure 2 The test results.

[0065] Example 8

[0066] The specific synthesis steps are as follows:

[0067] Step 1, add 121.18g (1 mol) of 4,6-dichloropyrimidine-2-amine and 348.5g (1.56 mol) of copper bromide to 141.3g (1.5 mol) of dimethyl disulfide, heat to 51-52°C, and stir to mix. The molar ratio of 4,6-dichloropyrimidine-2-amine to copper bromide is 1:1.56. The amount of dimethyl disulfide used is 1.5 times the molar amount of 4,6-dichloropyrimidine-2-amine.

[0068] Step 2, 106.2g (1.03mol) of tert-butyl nitrite is added dropwise to the above system, and the molar ratio of 4,6-dichloropyrimidine-2-amine to tert-butyl nitrite is 1:1.03. Stir the reaction for 6 hours, and when the reaction is finished, concentrate and recover the excess dimethyl disulfide for the next use, and then cool and filter out the copper powder, which is directly used for the next batch, and obtain a dark oily crude product from the filtrate, and the crude product is distilled to obtain 192.6g of 4,6-dichloropyrimidine-2-ethyl sulfide product, with a GC purity of 99.1% and a yield of 92.2%.

[0069] Take the production of 4-chloro-5-iodopyridine-2-methyl sulfide as an example

[0070] Example 9

[0071] The specific synthesis steps are as follows:

[0072] Step 1, add 254.3g (1mol) 4-chloro-5-iodopyridin-2-amine and 100g (1.56mol) copper powder to 183.4g (1.5mol) diethyl disulfide, heat to 51-52°C, and stir to mix. The molar ratio of 4-chloro-5-iodopyridin-2-amine to copper powder is 1:1.56. The amount of diethyl disulfide used is 1.5 times that of 4-chloro-5-iodopyridin-2-amine.

[0073] Step 2, 106.2g (1.03mol) of tert-butyl nitrite is added dropwise to the above mixed system, and the molar ratio of 4-chloro-5-iodopyridin-2-amine to tert-butyl nitrite is 1:1.03. Stir the reaction for 4 hours, and when the reaction is finished, concentrate and recover the excess dimethyl disulfide for the next use, then cool and filter out the copper powder, which is directly used for the next batch, and obtain a dark oily crude product from the filtrate, and the crude product is distilled to obtain 262.8g of 4-chloro-5-iodopyridine-2-methyl sulfide product, with a GC purity of 99.6% and a yield of 92.1%.

[0074] Example 10

[0075] The specific synthesis steps are as follows:

[0076] Step 1, add 254.3g (1mol) 4-chloro-5-iodopyridin-2-amine and 110g (1.72mol) copper powder to 244.5g (2mol) diethyl disulfide, heat to 50-52°C, and stir to mix. The molar ratio of 4-chloro-5-iodopyridin-2-amine to copper powder is 1:1.72. The amount of diethyl disulfide used is twice the molar amount of 4-chloro-5-iodopyridin-2-amine.

[0077] Step 2, 107.2g (1.04mol) of tert-butyl nitrite is added dropwise to the above system, and the molar ratio of 4-chloro-5-iodopyridin-2-amine to tert-butyl nitrite is 1:1.04. Stir the reaction for 4 hours, and when the reaction is finished, concentrate and recover the excess dimethyl disulfide for the next use, and then cool and filter out the copper powder, which is directly used for the next batch, and the filtrate is obtained as a dark oily crude product, and the crude product is distilled to obtain 263.3g of 4-chloro-5-iodopyridine-2-methyl sulfide product, with a GC purity of 99.4% and a yield of 92.3%.

[0078] Embodiment 11

[0079] The specific synthesis steps are as follows:

[0080] Step 1, add 254.3g (1 mol) of 4-chloro-5-iodopyridin-2-amine and 100g (1.56 mol) of copper powder to 183.4g (1.5 mol) of diethyl disulfide, heat to 51-52°C, and stir to mix. The molar ratio of 4-chloro-5-iodopyridin-2-amine to copper powder is 1:1.56. The amount of diethyl disulfide used is 1.5 times the molar amount of 4-chloro-5-iodopyridin-2-amine.

[0081] Step 2, 120.7g (1.03mol) of isoamyl nitrite is added dropwise to the above system, and the molar ratio of 4-chloro-5-iodopyridin-2-amine to isoamyl nitrite is 1:1.03. Stir the reaction for 4 hours, and when the reaction is finished, concentrate and recover the excess dimethyl disulfide for the next use, then cool and filter out the copper powder, which is directly used for the next batch, and obtain a dark oily crude product from the filtrate, and distill the crude product to obtain 264.5g of 4-chloro-5-iodopyridine-2-methyl sulfide product.

[0082] After testing, the product yield can reach 92.7%, and the GC purity must reach 99.2%. Figure 3 The test results.

[0083] Example 12

[0084] The specific synthesis steps are as follows:

[0085] Step 1, add 254.3g (1 mol) of 4-chloro-5-iodopyridin-2-amine and 266g (1.56 mol) of cupric chloride to 183.4g (1.5 mol) of diethyl disulfide, heat to 51-52°C, and stir to mix. The molar ratio of 4-chloro-5-iodopyridin-2-amine to cupric chloride is 1:1.56. The amount of diethyl disulfide used is 1.5 times the molar amount of 4-chloro-5-iodopyridin-2-amine.

[0086] Step 2, 106.2g (1.03mol) of tert-butyl nitrite is added dropwise to the above system, and the molar ratio of 4-chloro-5-iodopyridin-2-amine to tert-butyl nitrite is 1:1.03. Stir the reaction for 4 hours, and when the reaction is finished, concentrate and recover the excess dimethyl disulfide for the next use, and then cool and filter out the copper powder, which is directly used for the next batch, and the filtrate is obtained as a dark oily crude product, and the crude product is distilled to obtain 263.9g of 4-chloro-5-iodopyridine-2-methyl sulfide product, with a GC purity of 99.1% and a yield of 92.5%.

[0087] Take the production of 4-chloro-5-iodopyridine-2-ethyl sulfide as an example

[0088] Embodiment 13

[0089] The specific synthesis steps are as follows:

[0090] Step 1, add 254.3g (1mol) 4-chloro-5-iodopyridin-2-amine and 70.4g (1.1mol) copper powder to 183.4g (1.5mol) diethyl disulfide, heat to 51-52°C, and stir to mix. The molar ratio of 4-chloro-5-iodopyridin-2-amine to copper powder is 1:1.1. The amount of diethyl disulfide used is 1.5 times the molar amount of 4-chloro-5-iodopyridin-2-amine.

[0091] Step 2, 106.2g (1.03mol) of tert-butyl nitrite is added dropwise to the above mixed system, and the molar ratio of 4-chloro-5-iodopyridin-2-amine to tert-butyl nitrite is 1:1.03. Stir the reaction for 4 hours, and when the reaction is finished, concentrate and recover the excess dimethyl disulfide for the next use, then cool and filter out the copper powder, which is directly used for the next batch, and obtain a dark oily crude product from the filtrate, and the crude product is distilled to obtain 275.9g of 4-chloro-5-iodopyridine-2-ethyl sulfide product, with a GC purity of 99.6% and a yield of 92.2%.

[0092] Embodiment 14

[0093] The specific synthesis steps are as follows:

[0094] Step 1, add 254.3g (1mol) 4-chloro-5-iodopyridin-2-amine and 110g (1.72mol) copper powder to 244.5g (2mol) diethyl disulfide, heat to 50-52°C, and stir to mix. The molar ratio of 4-chloro-5-iodopyridin-2-amine to copper powder is 1:1.72. The amount of diethyl disulfide used is twice the molar amount of 4-chloro-5-iodopyridin-2-amine.

[0095] Step 2, 107.2g (1.04mol) of tert-butyl nitrite is added dropwise to the above system, and the molar ratio of 4-chloro-5-iodopyridin-2-amine to tert-butyl nitrite is 1:1.04. Stir the reaction for 4 hours, and when the reaction is finished, concentrate and recover the excess dimethyl disulfide for the next use, then cool and filter out the copper powder, which is directly used for the next batch, and obtain a dark oily crude product from the filtrate, and the crude product is distilled to obtain 276.2g of 4-chloro-5-iodopyridine-2-ethyl sulfide product, with a GC purity of 99.5% and a yield of 92.3%.

[0096] Embodiment 15

[0097] The specific synthesis steps are as follows:

[0098] Step 1, add 254.3g (1 mol) of 4-chloro-5-iodopyridin-2-amine and 121.6g (1.9 mol) of copper powder to 183.4g (1.5 mol) of diethyl disulfide, heat to 51-52°C, and stir to mix. The molar ratio of 4-chloro-5-iodopyridin-2-amine to copper powder is 1:1.9. The amount of diethyl disulfide used is 1.5 times the molar amount of 4-chloro-5-iodopyridin-2-amine.

[0099] Step 2, 120.7g (1.03mol) of isoamyl nitrite is added dropwise to the above system, the molar ratio of 4-chloro-5-iodopyridin-2-amine to isoamyl nitrite is 1:1.03. Stir the reaction for 4 hours, and when the reaction is finished, concentrate and recover the excess dimethyl disulfide for the next use, then cool and filter out the copper powder, which is directly used for the next batch, and obtain a dark oily crude product from the filtrate, and distill the crude product to obtain 276.8g of 4-chloro-5-iodopyridine-2-ethyl sulfide product.

[0100] After testing, the product yield can reach 92.5%, and the GC purity must reach 99.2%. Figure 4 The test results.

[0101] Example 16

[0102] The specific synthesis steps are as follows:

[0103] Step 1, add 254.3g (1 mol) of 4-chloro-5-iodopyridin-2-amine and 266g (1.56 mol) of cupric chloride to 183.4g (1.5 mol) of diethyl disulfide, heat to 53-55°C, and stir to mix. The molar ratio of 4-chloro-5-iodopyridin-2-amine to cupric chloride is 1:1.56. The amount of diethyl disulfide used is 1.5 times the molar amount of 4-chloro-5-iodopyridin-2-amine.

[0104] Step 2, 78.8g (1.05mol) of ethyl nitrite is added dropwise to the above system, and the molar ratio of 4-chloro-5-iodopyridin-2-amine to ethyl nitrite is 1:1.05. Stir the reaction for 4 hours, and when the reaction is finished, concentrate and recover the excess dimethyl disulfide for the next use, then cool and filter out the copper powder, which is directly used for the next batch, and obtain a dark oily crude product from the filtrate, and distill the crude product to obtain 276.5g of 4-chloro-5-iodopyridine-2-ethyl sulfide product, with a GC purity of 99.1% and a yield of 92.4%.

[0105] The embodiments of the present invention are described in detail above, but the contents described are only preferred embodiments of the present invention and cannot be considered to limit the scope of implementation of the present invention. All equivalent changes and improvements made within the scope of the present invention should still fall within the scope of the present invention.

Claims

1. A method for preparing a heterocyclic sulfide compound, characterized in that: The synthesis process is: Wherein, the substituents are defined as follows: R1 is H or C1-C6-alkyl or halogen; R2 is H or C1-C6-alkyl or halogen; R3 is C1-C6-alkyl; R4 is an organic inert group that has no effect on the actual reaction; The specific steps include: Step 1, adding a heterocyclic amine and a copper catalyst into dialkyl disulfide, and stirring to form a mixed system; Step 2: adding an organic nitrite dropwise to the mixed system formed in step 1, and then stirring to react. After the reaction is completed, the reaction solvent is concentrated, the copper catalyst is filtered to separate, and the filtrate is concentrated to recover excess dialkyl disulfide to obtain a dark oily crude product. The crude product is distilled to obtain a heterocyclic sulfide compound product.

2. The method for preparing a heterocyclic thioether compound according to claim 1, characterized in that: The copper catalyst is copper element or copper salt, the physical form of the copper element is one or more combinations of copper turnings, copper rods, copper wires, copper balls, copper particles, and copper powder; the copper salt is copper chloride or copper bromide.

3. The method for preparing a heterocyclic thioether compound according to claim 1, characterized in that: In step 1, the molar ratio of the heterocyclic amine to the copper catalyst is 1:1.9-1:1.

1.

4. The method for preparing a heterocyclic thioether compound according to claim 1, characterized in that: The R4 substituent in the organic nitrite is a C1-C6 alkyl or a C2-C6 alkenyl.

5. The method for preparing a heterocyclic sulfide compound according to claim 1, characterized in that: The organic nitrite is ethyl nitrite, tert-butyl nitrite, isoamyl nitrite or n-butyl nitrite.

6. The method for preparing a heterocyclic sulfide compound according to claim 1, characterized in that: In step 1, the molar ratio of the heterocyclic amine to the organic nitrite is 1:1.1-1:1.

0.

7. The method for preparing heterocyclic thioether compounds according to claim 1, characterized in that: In step 1, the amount of the dialkyl disulfide used is 1.5-2 times the molar amount of the heterocyclic amine.

8. The method for preparing heterocyclic sulfide compounds according to claim 1, characterized in that: In step 2, the stirring reaction time is 2-6 hours.

9. The method for preparing a heterocyclic thioether compound according to claim 1, characterized in that: In step 2, the reaction temperature is 50°C-55°C.

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