A kind of preparation method of thiofuranamide

Abstract

The present invention relates to a preparation method of thiofuranamide, and belongs to the technical field of bactericides. The preparation method of thiofuranamide of the present invention is as follows: (1) a certain proportion of diethylamine and hydrogen sulfide are mixed and reacted, and then 2-chloro-4,4,4-trifluoroacetoacetic acid ethyl ester and triethylamine are added for ring-closure reaction to obtain intermediate product 1; (2) a certain amount of stannous chloride and dichlorodiphenylmethane are added to react to obtain intermediate product 2; (3) 2,6-dibromo-4-(trifluoromethoxy)aniline is added for reflux reaction to obtain thiofuranamide. The thiofuranamide product obtained by the preparation method provided by the present invention has high yield and high purity, simplifies the steps of the traditional method, and does not generate a large amount of saline wastewater in the process to cause post-processing problems, is more suitable for industrial operation, and has high practical value.

Description

Technical Field

[0001] The invention relates to the technical field of fungicides, and in particular to a method for preparing thifluzamide. Background Art

[0002] Thifluzamide belongs to the thiazole amide fungicide, its chemical name is 2',6'-dibromo-2-methyl-4'-trifluoromethoxy-4-trifluoromethyl-1,3-thiazole-5-carboxamide, and its structural formula is as follows (I):

[0003]

[0004] Thifluzamide is active against pathogenic fungi such as Rhizoctonia, Puccinia, Ustilago, Tilletia, Corticotropha, and Pyricularia, and is particularly effective against diseases caused by Basidiomycetes such as sheath blight and damping-off. It has excellent high efficiency, low toxicity, and broad spectrum characteristics.

[0005] Regarding the preparation method of thiofuranamide, the prior art EP0371950A2 discloses a preparation method, the steps of which are: starting from ethyl trifluoroacetoacetate, using DMF as a solvent, reacting with thioacetamide, hydrolyzing to obtain 2-methyl-4-trifluoromethyl-5-thiazolecarboxylic acid, chlorinating with thionyl chloride, and distilling under high vacuum to obtain an intermediate acid chloride, and then reacting the acid chloride with 2,6-dibromo-4-trifluoromethoxyaniline in a xylene solvent to obtain thiofuranamide. This method has many reaction steps, many by-products, and a yield of only 32.3%, which cannot meet the needs of the market and industrial production.

[0006] At present, the domestic industrial process route mainly uses ethyl 2-chloro-4,4,4-trifluoroacetoacetate and thioacetamide as raw materials, acetonitrile as solvent, and triethylamine as acid-binding agent. It is necessary to undergo sodium hydroxide saponification and hydrochloric acid acidification to obtain 2-methyl-4-trifluoromethyl-5-thiazolecarboxylic acid, and then chlorinate with thionyl chloride to obtain the intermediate acid chloride. Finally, the acid chloride is reacted with 2,6-dibromo-4-trifluoromethoxyaniline in xylene solvent to obtain thiofuranamide, as shown in the following route (1). The product content is low, the yield is also low and unstable, the preparation cost is high, and a large amount of salt-containing wastewater is generated, and the industrial operation is not smooth.

[0007] Therefore, developing a method for preparing thiothiocarb which has simpler steps, higher stable yield of the product and is suitable for industrial operation is of great significance to the actual production and application of fungicides. Summary of the invention

[0008] The purpose of the present invention is to overcome the shortcomings of the prior art and provide a method for preparing thiothiocarb. The preparation method provided by the present invention has simple intermediate steps, few by-products, high yield and high product purity, and has a high application prospect in the preparation and production of fungicides.

[0009] To achieve the above object, the technical solution adopted by the present invention is:

[0010] In a first aspect, the present invention provides a method for preparing thiofuranamide, comprising the following steps:

[0011] (1) mixing diethylamine and hydrogen sulfide for reaction, and then sequentially adding ethyl 2-chloro-4,4,4-trifluoroacetoacetate and triethylamine for ring-closing reaction to obtain an intermediate product 1; the mass ratio of diethylamine to hydrogen sulfide is (1.5-2.5):(8.5-9.5);

[0012] (2) adding stannous chloride and dichlorodiphenylmethane to the intermediate product 1 to react and obtain an intermediate product 2; in terms of molar percentage, the amount of the stannous chloride is 2-10% of the amount of the ethyl 2-chloro-4,4,4-trifluoroacetoacetate;

[0013] (3) Adding 2,6-dibromo-4-(trifluoromethoxy)aniline to the intermediate product 2 for reflux reaction to obtain the thiothioamide.

[0014] The preparation method of thiofuran provided by the present invention uses ethyl 2-chloro-4,4,4-trifluoroacetoacetate as a starting point for preparation, firstly synthesizing ethyl 2-methyl-4-trifluoromethyl-5-thiazolecarboxylate (intermediate product 1) by ring-closing: by optimizing the mass ratio of diethylamine to hydrogen sulfide in the reaction, the yield of the intermediate product 1 of the ring-closing reaction is improved, thereby significantly improving the yield of thiofuran obtained; when the mass ratio of diethylamine to hydrogen sulfide is not suitable, the yield and purity of the obtained final product thiofuran are significantly reduced;

[0015] Furthermore, the present invention directly obtains 2-methyl-4-(trifluoromethyl)-1,3-thiazole-5-carbonyl chloride (intermediate product 2) by adding stannous chloride and diphenylmethane dichloride in a specific ratio through an acyl chlorination reaction: the present invention explores and optimizes the relationship between the amount of stannous chloride and the reaction yield, and within the specified range of stannous chloride dosage, the preparation efficiency of intermediate product 2 can be improved; when the amount of stannous chloride is not appropriate, the yield and purity of the final product thiofuranamide are greatly affected;

[0016] Finally, the intermediate product 2 is subjected to a reflux reaction with 2,6-dibromo-4-(trifluoromethoxy)aniline to obtain the thiofuranamide. The preparation of the present invention simplifies the synthesis steps in the traditional synthesis method, greatly reduces the by-products produced in the intermediate steps, and improves the yield and the purity of the product; the purity of thiofuranamide in the final product obtained by the preparation method of the present invention can reach more than 97%, and the yield is more than 81.8%, the raw material utilization rate is high, it simplifies the steps of the traditional method, does not produce a large amount of salt-containing wastewater in the process, is more suitable for industrial operation, and has high practical value in the industrial preparation of fungicides.

[0017] Preferably, in terms of molar percentage, the amount of stannous chloride used is 4-8% of the amount of ethyl 2-chloro-4,4,4-trifluoroacetoacetate used.

[0018] As a preferred embodiment, the amount of stannous chloride used is 4% of the amount of ethyl 2-chloro-4,4,4-trifluoroacetoacetate used.

[0019] According to the preferred embodiment, the preparation method of thiofuranamide of the present invention can achieve a yield of 92.6% through a simple washing and separation step, and the purity of the product can reach up to 98.66%.

[0020] Preferably, the molar ratio of the dichlorodiphenylmethane to the ethyl 2-chloro-4,4,4-trifluoroacetoacetate is (1.2-1.5):1.

[0021] The molar ratio of the dichlorodiphenylmethane to the ethyl 2-chloro-4,4,4-trifluoroacetoacetate also has a certain influence on the yield of the product. Within the preferred molar ratio range, the yield of thiothioamide is above 85%.

[0022] Preferably, the mass ratio of diethylamine to hydrogen sulfide is 2:9.

[0023] Preferably, the mass ratio of diethylamine, ethyl 2-chloro-4,4,4-trifluoroacetoacetate, triethylamine and 2,6-dibromo-4-(trifluoromethoxy)aniline is diethylamine:ethyl 2-chloro-4,4,4-trifluoroacetoacetate:triethylamine:2,6-dibromo-4-(trifluoromethoxy)aniline = (1.5-2.5):(47-48):(47-48):(64-66):.

[0024] Preferably, in step (1), the mixed reaction of diethylamine and hydrogen sulfide is specifically: diethylamine and hydrogen sulfide are mixed in acetonitrile for reaction at a temperature of 45-55° C., and acetonitrile is removed after the reaction is completed.

[0025] Further preferably, the temperature of removing acetonitrile is 50°C-55°C.

[0026] Further preferably, in step (1), the ring-closing reaction is specifically:

[0027] After adding dichloroethane, add ethyl 2-chloro-4,4,4-trifluoroacetoacetate at 15-25°C, and keep warm at 25-30°C for 2.5-3.5 hours; continue to add triethylamine at below 25°C, and then reflux for 2.5-3.5 hours.

[0028] Preferably, in step (2), the reaction temperature is room temperature.

[0029] Preferably, in step (3), the reflux reaction time is 2-4 hours.

[0030] Preferably, in step (3), after the reflux reaction, cooling, centrifugation and drying steps are also included. After reflux, the mixture is cooled to 40°C, a proper amount of water is added for stirring, and then centrifuged to obtain a wet filter cake, which is then dried to obtain the product.

[0031] Compared with the prior art, the present invention has the following beneficial effects:

[0032] The invention provides a new preparation method with high product yield and high product purity by optimizing the traditional preparation method of thiofuranamide, simplifying the synthesis steps, and optimizing the ratio and parameters between the reactants in the synthesis preparation steps: the preparation method of thiofuranamide of the invention has fewer intermediate steps, low by-product yield, and greatly reduces unnecessary loss of raw materials, and can achieve a maximum yield of more than 92%, and a product purity of more than 97%, which is better than the prior art; at the same time, the preparation steps of the invention are more suitable for industrial operation, and a large amount of salt-containing wastewater is not generated during the process, and the invention has high practical value. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 The synthetic route diagram of the preparation method of thiofuranamide of the present invention;

[0034] Figure 2 A comparison diagram of the synthetic routes of the preparation methods of thiofuranamide in the prior art;

[0035] Figure 3 The preparation method of thiofuranamide of the present invention is to obtain thiofuranamide product 1 H-NMR result diagram;

[0036] Figure 4 The preparation method of thiofuranamide of the present invention is to obtain thiofuranamide product 13 C-NMR result diagram;

[0037] Figure 5 This is a diagram showing the mass spectrometry analysis result of the thiofuranamide product obtained by the preparation method of the thiofuranamide of the present invention;

[0038] Figure 6 The figure is a liquid chromatography analysis result diagram of the thiofuranamide product obtained by the preparation method of the thiofuranamide of the present invention. DETAILED DESCRIPTION

[0039] In order to better illustrate the purpose, technical scheme and advantages of the present invention, the present invention will be further described below in conjunction with specific examples. The test methods used in the following examples are conventional methods unless otherwise specified; the materials and reagents used are reagents and materials that can be obtained from commercial channels unless otherwise specified.

[0040] Example 1

[0041] An embodiment of the preparation method of thiofuranamide of the present invention, the specific steps of the preparation method of thiofuranamide described in this embodiment are as follows:

[0042] S1. Put 90g acetonitrile and 2g diethylamine into a pressure autoclave, heat until the temperature rises to 50°C, open the valve of the hydrogen sulfide cylinder, and keep the system temperature at 50°C; introduce a total of 9g hydrogen sulfide, keep warm at 50°C until the pressure in the reactor is negative, and cool to room temperature; transfer to a desolventizing kettle for acetonitrile removal. During the acetonitrile removal process, the temperature is controlled at 50°C-55°C. Stop stirring after the material becomes viscous, continue to vacuum for 30min, and try to remove the acetonitrile;

[0043] S2, after the desolventizing is completed, nitrogen is broken, 110g of dichloroethane is added to the desolventizing kettle, stirred for 0.5h, and the reaction mass is cooled to 10°C; 47.1g of ethyl 2-chloro-4,4,4-trifluoroacetoacetate is added dropwise, and the reaction temperature is maintained at 15-25°C during the addition. After the addition is completed, it is kept warm at 25-30°C for 3h; then 47.5g of triethylamine is added dropwise to the reactor within 2h, and the material temperature is kept below 25°C; after the addition is completed, the reaction mass is heated to reflux, refluxed for 3h, and the intermediate product 1 (ethyl 2-methyl-4-trifluoromethyl-5-thiazolecarboxylate) is obtained;

[0044] S3, adding 0.82 g of stannous chloride and 61.3 g of dichlorodiphenylmethane to the reaction solution containing the intermediate product 1, and reacting at room temperature for 3 h to obtain the intermediate product 2 (2-methyl-4-(trifluoromethyl)1,3-thiazole-5-carbonyl chloride);

[0045] S4. Continue to add 65 g of 2,6-dibromo-4-(trifluoromethoxy)aniline to react, reflux for 15 h, cool to 40° C., add 45 g of water and stir for 30 min, centrifuge to obtain a wet product; dry the wet filter cake to obtain 94.78 g of thiothioamide product.

[0046] The synthetic route diagram of preparing thiofuranamide of the present invention is as follows Figure 1 ; Comparison of the synthesis route of thiofuranamide in the prior art Figure 2It can be seen that the preparation method of the present invention simplifies the synthesis steps.

[0047] The prepared thiofuranamide product was subjected to nuclear magnetic resonance testing, and the hydrogen spectrum of the obtained thiofuranamide product was 1 H-NMR Figure 3 As shown, the carbon spectrum of the obtained thiothioamide product 13 C-NMR Figure 4 As shown;

[0048] The obtained thiothioamide product was subjected to mass spectrometry analysis, and the results were as follows: Figure 5 As shown, Figure 3-5 The comprehensive results demonstrate the successful preparation of the thiothioamide product of the present invention.

[0049] Example 2

[0050] An embodiment of the preparation method of thiofuranamide of the present invention, the preparation method of thiofuranamide described in this embodiment is different from that of Example 1 only in that: in step S3, the amount of stannous chloride used is 4.1g, and 95.14g of thiofuranamide product is prepared.

[0051] Example 3

[0052] An embodiment of the preparation method of thiofuranamide of the present invention, the specific steps of the preparation method of thiofuranamide described in this embodiment are as follows:

[0053] S1. Put 900kg acetonitrile and 20kg diethylamine into a pressure autoclave, heat it to 50°C, open the valve of the hydrogen sulfide cylinder, and keep the system temperature at 50°C; introduce a total of 90kg hydrogen sulfide, keep it at 50°C until the pressure in the reactor is negative, and cool it to room temperature; transfer it to a desolventizing kettle to remove acetonitrile. During the desolventizing process, the temperature is controlled at 50°C-55°C. Stop stirring after the material becomes viscous, continue to apply vacuum for 30 minutes, and try to remove the acetonitrile;

[0054] S2. After the desolventizing is completed, nitrogen is released, 1100 kg of ethylene dichloride is added to the desolventizing kettle, stirred for 0.5 h, and the reaction mass is cooled to 10 ° C; 471 kg of ethyl 2-chloro-4,4,4-trifluoroacetoacetate is added dropwise, and the reaction temperature is maintained at 15-25 ° C during the addition. After the addition is completed, it is kept warm at 25-30 ° C for 3 h; then 475 kg of triethylamine is added dropwise to the reactor within 2 h, and the material temperature is maintained below 25 ° C; after the addition is completed, the reaction mass is heated to reflux, refluxed for 3 h, and the intermediate product 1 (ethyl 2-methyl-4-trifluoromethyl-5-thiazolecarboxylate) is obtained;

[0055] S3, adding 10 kg of stannous chloride and 613 kg of dichlorodiphenylmethane to the reaction solution containing the intermediate product 1, and reacting at room temperature for 3 hours to obtain the intermediate product 2 (2-methyl-4-(trifluoromethyl)1,3-thiazole-5-carbonyl chloride);

[0056] S4. Continue to add 650 kg of 2,6-dibromo-4-(trifluoromethoxy)aniline for reaction, reflux for reaction for 15 hours, cool to 40°C, add 450 kg of water and stir for 30 minutes, centrifuge to obtain a wet product; dry the wet filter cake to obtain 949.3 kg of thiothioamide product.

[0057] Example 4

[0058] An embodiment of the preparation method of thiofuranamide of the present invention, the preparation method of thiofuranamide described in this embodiment is different from that of Example 1 only in that: in step S3, the amount of stannous chloride used is 1.64g, and 106.83g of thiofuranamide product is prepared.

[0059] Example 5

[0060] An embodiment of the preparation method of thiofuranamide of the present invention, the preparation method of thiofuranamide described in this embodiment is different from that of Example 1 only in that: in step S3, the amount of stannous chloride used is 2.46g, and 105.93g of thiofuranamide product is prepared.

[0061] Example 6

[0062] An embodiment of the preparation method of thiofuranamide of the present invention, the preparation method of thiofuranamide described in this embodiment is different from that of Example 1 only in that: in step S3, the amount of stannous chloride used is 3.28g, and 105.31g of thiofuranamide product is prepared.

[0063] Example 7

[0064] An embodiment of the preparation method of thiofuranamide of the present invention, the specific steps of the preparation method of thiofuranamide described in this embodiment are as follows:

[0065] S1. Put 90g acetonitrile and 2g diethylamine into a pressure autoclave, heat until the temperature rises to 50°C, open the valve of the hydrogen sulfide cylinder, and keep the system temperature at 50°C; introduce a total of 9g hydrogen sulfide, keep warm at 50°C until the pressure in the reactor is negative, and cool to room temperature; transfer to a desolventizing kettle for acetonitrile removal. During the acetonitrile removal process, the temperature is controlled at 50°C-55°C. Stop stirring after the material becomes viscous, continue to vacuum for 30min, and try to remove the acetonitrile;

[0066] S2, after the desolventizing is completed, nitrogen is broken, 110g of dichloroethane is added to the desolventizing kettle, stirred for 0.5h, and the reaction mass is cooled to 10°C; 47.1g of ethyl 2-chloro-4,4,4-trifluoroacetoacetate is added dropwise, and the reaction temperature is maintained at 15-25°C during the addition. After the addition is completed, it is kept warm at 25-30°C for 3h; then 47.5g of triethylamine is added dropwise to the reactor within 2h, and the material temperature is kept below 25°C; after the addition is completed, the reaction mass is heated to reflux, refluxed for 3h, and the intermediate product 1 (ethyl 2-methyl-4-trifluoromethyl-5-thiazolecarboxylate) is obtained;

[0067] S3, adding 1.64 g of stannous chloride and 51.1 g of dichlorodiphenylmethane to the reaction solution containing the intermediate product 1, and reacting at room temperature for 3 h to obtain the intermediate product 2 (2-methyl-4-(trifluoromethyl)1,3-thiazole-5-carbonyl chloride);

[0068] S4. Continue to add 65 g of 2,6-dibromo-4-(trifluoromethoxy)aniline to react, reflux for 15 h, cool to 40° C., add 45 g of water and stir for 30 min, centrifuge to obtain a wet product; dry the wet filter cake to obtain 99.98 g of thiofuranamide product.

[0069] Example 8

[0070] An embodiment of the preparation method of thiofuranamide of the present invention, the preparation method of thiofuranamide described in this embodiment is different from that of Example 7 only in that: in step S3, the amount of dichlorodiphenylmethane used is 76.6g, and 105.98g of thiofuranamide product is prepared.

[0071] Comparative Example 1

[0072] A method for preparing thiofuranamide comprises the following steps:

[0073] S1. Add 19.4g of thioacetamide and 90ml of acetonitrile into a three-necked flask. Add ethyl 2-chloro-4,4,4-trifluoroacetoacetate (47.1g, 0.21mol) dropwise into the above solution over 15min, keeping the reaction temperature at 15-25℃ during the addition; after the addition is complete, keep the temperature at 25-30℃ for 3h, and add 47.5g of triethylamine to the reactor within 2h, keeping the material temperature below 25℃; after the addition is complete, heat the reaction mass to reflux and reflux for 3h.

[0074] S2, add 1.64g of stannous chloride and 61.3g of dichlorodiphenylmethane to the above reaction solution and react at room temperature for 3h;

[0075] S3. Then add 65 g of 2,6-dibromo-4-(trifluoromethoxy)aniline, reflux for 15 h, cool to 40°C, add 45 g of water, stir for 30 min, and centrifuge to obtain a wet product; dry the wet filter cake to obtain 78.63 g of thiothioamide product.

[0076] Comparative Example 2

[0077] A method for preparing thiofuranamide comprises the following steps:

[0078] S1. Put 90g acetonitrile and 1g diethylamine into a pressure autoclave, heat until the temperature rises to 50°C, open the valve of the hydrogen sulfide cylinder, and keep the system temperature at 50°C; introduce a total of 10g hydrogen sulfide, keep warm at 50°C until the pressure in the reactor is negative, and cool to room temperature; transfer to a desolventizing kettle for acetonitrile removal. During the acetonitrile removal process, the temperature is controlled at 50°C-55°C. Stop stirring after the material becomes viscous, continue to apply vacuum for 30min, and try to remove the acetonitrile;

[0079] S2, after the desolventizing is completed, nitrogen is broken, 110g of dichloroethane is added to the desolventizing kettle, stirred for 0.5h, and the reaction mass is cooled to 10°C; 47.1g of ethyl 2-chloro-4,4,4-trifluoroacetoacetate is added dropwise, and the reaction temperature is maintained at 15-25°C during the addition. After the addition is completed, it is kept warm at 25-30°C for 3h; then 47.5g of triethylamine is added dropwise to the reactor within 2h, and the material temperature is kept below 25°C; after the addition is completed, the reaction mass is heated to reflux, refluxed for 3h, and the intermediate product 1 (ethyl 2-methyl-4-trifluoromethyl-5-thiazolecarboxylate) is obtained;

[0080] S3, adding 1.64 g of stannous chloride and 61.3 g of dichlorodiphenylmethane to the reaction solution containing the intermediate product 1, and reacting at room temperature for 3 h to obtain the intermediate product 2 (2-methyl-4-(trifluoromethyl)1,3-thiazole-5-carbonyl chloride);

[0081] S4. Continue to add 65 g of 2,6-dibromo-4-(trifluoromethoxy)aniline to react, reflux for 15 h, cool to 40° C., add 45 g of water and stir for 30 min, centrifuge to obtain a wet product; dry the wet filter cake to obtain 89.2 g of thiothioamide product.

[0082] Comparative Example 3

[0083] A method for preparing thiofuranamide, which is different from Comparative Example 2 only in that: in step S1, the amount of diethylamine used is 4g, 8g of hydrogen sulfide is introduced, and 90.28g of thiofuranamide product is prepared.

[0084] Comparative Example 4

[0085] A method for preparing thiofuranamide, which is different from Example 1 only in that: in step S3, the amount of stannous chloride used is 0.41 g, and 87.95 g of thiofuranamide product is prepared.

[0086] Comparative Example 5

[0087] A method for preparing thiofuranamide, which is different from Example 1 only in that: in step S3, the amount of stannous chloride used is 6.15g, and 96.26g of thiofuranamide product is prepared.

[0088] Effect Example 1

[0089] In order to explore the preparation effect of the preparation method of thiofuranamide provided by the present invention, the products prepared by each preparation method in the above embodiments and comparative examples were subjected to liquid chromatography analysis to obtain the purity of thiofuranamide in each product, and the yield of thiofuranamide was calculated and compared. The results are shown in Table 1 below; wherein, the liquid chromatogram of the thiofuranamide product prepared by the preparation method of thiofuranamide in Example 4 is as follows Figure 6 .

[0090] From Table 1, we can see that:

[0091] By using the preparation method of thiofuranamide provided by the present invention in the embodiment, compared with the comparative example and the traditional preparation method, the obtained thiofuranamide product has high purity and high yield; and in Example 3, the preparation method of the present invention is expanded to produce, and a stable high yield and product purity can still be maintained; among them, the preparation effect of the scheme in Example 4 is the best, the yield can reach 92.6%, and the product purity can reach 98.66%, which is a better effect;

[0092] In Comparative Example 1, thioacetamide was used to carry out the first step of the ring-closing reaction, and the preparation yield was significantly reduced; in Comparative Examples 2 and 3, the ratio of diethylamine and hydrogen sulfide was changed to be higher or lower than the protection scope of the present invention, the preparation yield was significantly reduced, the raw material utilization rate was significantly reduced, and the product purity was slightly affected; in Comparative Example 4, the amount of stannous chloride was reduced to be lower than the scope of the present invention, the preparation yield was significantly reduced, the product purity was reduced to only 90.16%, and the preparation effect was poor; in Comparative Example 5, the amount of stannous chloride was increased to be higher than the scope of the present invention, which still resulted in a decrease in yield, and the product purity was also slightly reduced.

[0093] In summary, it can be seen that the present invention optimizes the preparation method of thiothiocarb in the prior art, provides a new preparation strategy with less intermediate by-products, no large amount of salt-containing wastewater, high yield and high product purity, provides a reliable path for industrial operation and production, and has high practical value in the field of fungicide preparation and production.

[0094] Table 1 Comparison of the preparation effects of the thiothioamide preparation method of the embodiment and the comparative example

[0095]

[0096] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing thiofuranamide, characterized in that: The following steps are involved: (1) mixing diethylamine and hydrogen sulfide for reaction, and then sequentially adding ethyl 2-chloro-4,4,4-trifluoroacetoacetate and triethylamine for ring-closing reaction to obtain an intermediate product 1; the mass ratio of diethylamine to hydrogen sulfide is (1.5-2.5):(8.5-9.5); (2) adding stannous chloride and dichlorodiphenylmethane to the intermediate product 1 to react and obtain an intermediate product 2; in terms of molar percentage, the amount of the stannous chloride is 2-10% of the amount of the ethyl 2-chloro-4,4,4-trifluoroacetoacetate; (3) Adding 2,6-dibromo-4-(trifluoromethoxy)aniline to the intermediate product 2 for reflux reaction to obtain the thiothioamide.

2. The method for preparing thiothioamide according to claim 1, characterized in that: In terms of molar percentage, the amount of stannous chloride used is 4-8% of the amount of ethyl 2-chloro-4,4,4-trifluoroacetoacetate used.

3. The method for preparing thiothioamide according to claim 1, characterized in that: The molar ratio of the dichlorodiphenylmethane to the ethyl 2-chloro-4,4,4-trifluoroacetoacetate is (1.2-1.5):

1.

4. The method for preparing thiothioamide according to claim 1, characterized in that: The mass ratio of the diethylamine to hydrogen sulfide is 2:

9.

5. The method for preparing thiothioamide according to claim 1, characterized in that: The mass ratio of diethylamine, ethyl 2-chloro-4,4,4-trifluoroacetoacetate, triethylamine and 2,6-dibromo-4-(trifluoromethoxy)aniline is diethylamine:ethyl 2-chloro-4,4,4-trifluoroacetoacetate:triethylamine:2,6-dibromo-4-(trifluoromethoxy)aniline = (1.5-2.5):(47-48):(47-48):(64-66):.

6. The method for preparing thiofuranamide according to claim 1, characterized in that: In the step (1), the mixed reaction of diethylamine and hydrogen sulfide is specifically: diethylamine and hydrogen sulfide are mixed in acetonitrile for reaction at a temperature of 45-55° C., and acetonitrile is removed after the reaction is completed.

7. The method for preparing thiothioamide according to claim 6, characterized in that: In the step (1), the ring-closing reaction is specifically: After adding dichloroethane, add ethyl 2-chloro-4,4,4-trifluoroacetoacetate at 15-25°C, and keep warm at 25-30°C for 2.5-3.5 hours; continue to add triethylamine at below 25°C, and then reflux for 2.5-3.5 hours.

8. The method for preparing thiofuranamide according to claim 1, characterized in that: In the step (2), the reaction temperature is room temperature.

9. The method for preparing thiofuranamide according to claim 1, characterized in that: In the step (3), the reflux reaction time is 2-4 hours.

10. The method for preparing thiofuranamide according to claim 1, characterized in that: In the step (3), after the reflux reaction, the process further comprises cooling, centrifuging and drying steps.

Images