Process for the preparation of 3-(2-furyl)-5-amino-1H-1,2,4-triazole

Abstract

The application provides a preparation method of 3-(2-furyl)-5-amino-1H-1,2,4-triazole, comprising the following steps: step S1, providing 2-furoylhydrazine; step S2, making the 2-furoylhydrazine and N,N'-di-Boc-1H-1-guanylpyrazole undergo a nucleophilic substitution reaction to generate N,N'-di-Boc-2-furoylguanidine; step S3, making the N,N'-di-Boc-2-furoylguanidine remove Boc to generate 2-furoylguanidine; and step S4, making the 2-furoylguanidine undergo intramolecular dehydration to obtain 3-(2-furyl)-5-amino-1H-1,2,4-triazole. According to the preparation method of the embodiment of the application, compared with selecting monocyanamide for reaction, the application adopts N,N'-di-Boc-1H-1-guanylpyrazole, and the selectivity is better and safer, unnecessary side reactions are avoided during the nucleophilic substitution, and the operation is simple and easy to implement.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of organic synthesis, and more particularly relates to an alkyl-substituted phosphoric ring anhydride derivative, a synthesis method and application thereof. BACKGROUND

[0002] 3-(2-furyl)-5-amino-1H-1,2,4-triazole is an important heterocyclic compound in agriculture and medicine. 3-(2-furyl)-5-amino-1H-1,2,4-triazole is used as a multifunctional ligand in metal organic chemistry, and is considered to be a main important material for constructing more complex structures, especially fused heterocycles with biological activity.

[0003] At present, the preparation methods of 3-(2-furyl)-5-amino-1H-1,2,4-triazole mainly include:

[0004] 1) amidation of 2-furoyl chloride and amino guanidine hydrochloride under piperidine conditions. However, this route is very slow, and has a large amount of by-products, and piperidine is used as a solvent, which has a strong smell and is not easy to purify.

[0005] 2) 3-(2-furyl)-5-amino-1H-1,2,4-triazole is prepared by nucleophilic substitution of S-methyl isothiourea sulfate and 2-furoyl hydrazine. However, the reaction produces a pungent odor, and the yield is low.

[0006] 3) 2-furoyl hydrazine and monocyamine are prepared. This method requires a large excess of monocyamine for complete reaction, and monocyamine is unstable, and commercially available is a 50% aqueous solution, which increases the difficulty of post-processing, and monocyamine is a toxic product, so its use is limited. SUMMARY

[0007] Therefore, the present application aims to provide a 3-(2-furyl)-5-amino-1H-1,2,4-triazole preparation method with good reaction selectivity, no pungent odor, no difficult-to-handle by-products, simple and easy operation, and high yield.

[0008] To solve the above technical problems, the present application adopts the following technical solutions:

[0009] The 3-(2-furyl)-5-amino-1H-1,2,4-triazole preparation method according to the embodiments of the present application comprises the following steps:

[0010] Step S1, providing 2-furoyl hydrazine;

[0011] Step S2, nucleophilic substitution reaction of the 2-furoyl hydrazine and N,N'-di-Boc-1H-1-guanyl pyrazole to generate N,N'-di-Boc-2-furoyl guanidine;

[0012] Step S3, removing Boc of the N,N'-di-Boc-2-furoylguanidine to generate 2-furoylguanidine;

[0013] Step S4, intramolecular dehydration of the 2-furoylguanidine to obtain 3-(2-furyl)-5-amino-1H-1,2,4-triazole.

[0014] Further, the step S1 comprises:

[0015] Step S11, acylation and esterification of 2-furoic acid to generate 2-furoate;

[0016] Step S12, reaction of the 2-furoate with a hydrazination reagent to generate the 2-furoylhydrazine.

[0017] Further, the acylation and esterification combination is thionyl chloride and methanol, and the molar ratio of 2-furoic acid:thionyl chloride:hydrazine hydrate is 1.0:(1.0-1.2):(0.8-1.0).

[0018] The hydrazination reagent in the step S12 is hydrazine hydrate.

[0019] Further, the acylation and esterification combination is thionyl chloride and methanol, and the molar ratio of 2-furoic acid:thionyl chloride:hydrazine hydrate is 1.0:(1.0-1.2):(0.8-1.0).

[0020] Further, the step S1 comprises:

[0021] The thionyl chloride is added dropwise in the methanol solution of 2-furoic acid to generate 2-furoate, the temperature for adding the thionyl chloride is 35-40℃, and the reaction time is 3-5h;

[0022] After the reaction is completed, the hydrazine hydrate is added therein, and the temperature is raised to 55-60℃, and the reaction time is 5-6h, to generate the 2-furoylhydrazine in one pot.

[0023] Further, the step S2 comprises:

[0024] The N,N'-di-Boc-1H-1-guanylpyrazole is added to the dichloromethane solution of 2-furoylhydrazine to perform the nucleophilic reaction to obtain the N,N'-di-Boc-2-furoylguanidine.

[0025] Further, the molar ratio of the 2-furoylhydrazine and N,N'-di-Boc-1H-1-guanylpyrazole is 1.0:(1.1-1.3), the temperature for adding the N,N'-di-Boc-1H-1-guanylpyrazole is 20-30℃, and the reaction time after the addition is completed is 5-6h.

[0026] Further, in the step S3, the N,N'-di-Boc-2-furoylguanidine is removed Boc by using a Boc removal reagent selected from one or more of hydrogen chloride in methanol, sulfuric acid, trifluoroacetic acid, and hydrochloric acid.

[0027] Still further, in the step S3, the hydrogen chloride in methanol solution is added dropwise to the N,N'-di-Boc-2-furoylguanidine to generate 2-furoylguanidine, the Boc removal reagent is hydrogen chloride in methanol, the molar ratio of the N,N'-di-Boc-2-furoylguanidine to hydrogen chloride is 1.0:(2-3), the temperature for adding the hydrogen chloride in methanol solution is 20-30℃, the reaction temperature after adding is 30-40℃, and the reaction time is 2-3h.

[0028] Further, the step S4 comprises:

[0029] The 2-furoylguanidine is added to water, and solid sodium hydroxide is added portionwise to generate the 3-(2-furyl)-5-amino-1H-1,2,4-triazole, wherein the molar ratio of the 2-furoylguanidine to sodium hydroxide is 1.0:(0.8-1.2), the reaction temperature is 70-80℃, and the reaction time is 3-4h.

[0030] The above technical solution of the present application has at least one of the following beneficial effects:

[0031] According to the preparation method of the present application, compared with the reaction using cyanamide, N,N'-di-Boc-1H-1-guanidinopyrazole is used, which is more selective and safer, unnecessary side reactions are avoided during nucleophilic substitution, and the operation is simple and easy to implement, and the product obtained has high purity.

[0032] Further, the volume of the reaction system is greatly reduced, and the single-pot efficiency can be improved. DETAILED DESCRIPTION

[0033] To make the purpose, technical scheme and advantages of the embodiments of the present application clearer, the technical scheme of the present application will be described clearly and completely below in combination with the embodiments of the present application. Obviously, the described embodiments are part of the embodiments of the present application, rather than all the embodiments. Based on the described embodiments of the present application, all other embodiments obtained by those of ordinary skill in the art belong to the scope of protection of the present application.

[0034] The preparation method of 3-(2-furyl)-5-amino-1H-1,2,4-triazole according to the embodiments of the present application will be described in detail first, which comprises the following steps:

[0035] Step S1, providing 2-furoyl hydrazine;

[0036] Step S2, subjecting the 2-furoyl hydrazine to a nucleophilic substitution reaction with N,N'-di-Boc-1H-1-guanylpyrazole to generate N,N'-di-Boc-2-furoyl guanidine;

[0037] Step S3, subjecting the N,N'-di-Boc-2-furoyl guanidine to Boc removal to generate 2-furoyl guanidine;

[0038] Step S4, subjecting the 2-furoyl guanidine to intramolecular dehydration to obtain 3-(2-furyl)-5-amino-1H-1,2,4-triazole.

[0039] According to the preparation method of the embodiment of the present application, compared with the reaction of selecting monocyanamide, the present application uses N,N'-di-Boc-1H-1-guanylpyrazole, which is safer and has better selectivity, avoids unnecessary side reactions during nucleophilic substitution, and is simple and easy to operate. The product has a good crystal form. Further, the volume of the reaction system is greatly reduced, and the single-pot efficiency can be improved.

[0040] Next, steps S1 to S4 will be described in detail one by one.

[0041] (I) Step S1, providing 2-furoyl hydrazine.

[0042] First, step S1, i.e., providing 2-furoyl hydrazine, is described.

[0043] The present application, in view of the problems of slow reaction, a large amount of by-products, and the use of piperidine as a solvent which has a strong odor and is not easy to purify in the synthesis route of the prior art which uses 2-furoyl chloride as one of the raw materials and acylates with aminoguanidine hydrochloride under piperidine conditions, selects 2-furoyl hydrazine as a raw material, which can overcome the problems of slow reaction and strong odor.

[0044] According to the preparation method of the present application, commercially available chemically pure 2-furoyl hydrazine can be used as a raw material, or the following method can be used to prepare it.

[0045] In some embodiments of the present application, the step S1 comprises:

[0046] Step S11, subjecting 2-furoic acid to acylation and esterification to generate 2-furoate.

[0047] That is, using 2-furoic acid as a starting raw material, first subjecting it to acylation and esterification to obtain 2-furoate.

[0048] As the combination of acylation and esterification, any one of thionyl chloride and methanol, oxalyl chloride and methanol, and phosphorus oxychloride and methanol can be selected.

[0049] That is, acylation is carried out by using thionyl chloride, oxalyl chloride, and phosphorus oxychloride as the acylating agent, respectively, and then esterification is carried out by using methanol to obtain 2-furanformic acid ester.

[0050] Thionyl chloride (SOCl2) is a commonly used acylating agent, which can convert carboxylic acid, acid anhydride, acid chloride and other compounds into the corresponding acyl chloride. In addition, the acyl chloride can be further used as an intermediate for the synthesis of esters.

[0051] In step S12, the 2-furanformic acid ester is reacted with a hydrazidation reagent to generate the 2-furanformic acid hydrazide.

[0052] In some embodiments of the present application, the hydrazidation reagent is hydrazine hydrate.

[0053] Further, the combination of acylation and esterification is thionyl chloride and methanol, and the molar ratio of 2-furanformic acid:thionyl chloride:hydrazine hydrate is 1.0:(1.0-1.2):(0.8-1.0), preferably, the molar ratio is 1.0:1.1:0.9. That is, a slight excess of thionyl chloride is preferably used, and the amount of hydrazine hydrate is slightly less than the stoichiometric amount. In this way, the reaction of hydrazine hydrate can be completed to avoid danger during post-processing, and the excess amount of 2-furanformic acid ester can be easily removed during post-processing.

[0054] Further, the step S1 comprises:

[0055] The thionyl chloride is added dropwise to the methanol solution of 2-furanformic acid to generate 2-furanformic acid ester, the temperature for adding the thionyl chloride is 35-40°C, and the reaction time is 3-5h;

[0056] After the reaction is completed, the hydrazine hydrate is added thereto, and the temperature is raised to 55-60°C, and the reaction time is 5-6h, and the 2-furanformic acid hydrazide is generated by one-pot method.

[0057] Specifically, the reaction formula is shown in the following formula (1):

[0058]

[0059] That is, the present application can use "one-pot method" to prepare 2-furanformic acid hydrazide, in other words, acylation, esterification, and hydrazidation are carried out in the same reaction system, without the need to extract intermediate products, the operation is simple and easy to operate, and the amount of waste is small.

[0060] In addition, the acylating agent and the hydrazidation reagent are added in a dropwise manner, respectively, so that the reaction speed and temperature are controllable, and the reaction is more complete.

[0061] In addition, step S1 can further include:

[0062] The sampling point plate monitors the reaction progress. After the reaction is completed, the reaction solution is concentrated, and 2-furohydrazide is obtained by beating with PE:EA = 3:1.

[0063] That is, after the reaction in step S1 is completed, the remaining 2-furoic acid ester can be removed by PE:EA = 3:1 column chromatography, so that the obtained 2-furohydrazide can be purified.

[0064] (ii) Step S2, making the 2-furohydrazide and N,N'-di-Boc-1H-1-guanylpyrazole undergo a nucleophilic substitution reaction to generate N,N'-di-Boc-2-furoguanidine.

[0065] In some embodiments of the present application, step S2 includes:

[0066] N,N'-di-Boc-1H-1-guanylpyrazole is added to a dichloromethane solution of 2-furohydrazide to perform the nucleophilic reaction to obtain the N,N'-di-Boc-2-furoguanidine.

[0067] Specifically, the reaction is as shown in the following formula (2):

[0068]

[0069] That is, in the present application, 2-furohydrazide is first subjected to a nucleophilic reaction with N,N'-di-Boc-1H-1-guanylpyrazole, and then subsequent Boc removal and intramolecular dehydration are performed to prepare the target product. Compared with the synthesis route in the prior art in which 2-furohydrazide and monocyanamide are used to prepare the target product, not only can the problems of instability, difficult post-treatment, and toxicity of monocyanamide be avoided, but also N,N'-di-Boc-1H-1-guanylpyrazole is more selective and safer, and the volume of the reaction system is greatly reduced, which can improve the single-pot efficiency.

[0070] In the present application, the molar ratio of 2-furohydrazide to N,N'-di-Boc-1H-1-guanylpyrazole is 1.0:(1.1-1.3), preferably 1.0:1.2. In addition, the temperature for adding the N,N'-di-Boc-1H-1-guanylpyrazole is 20-30°C, and the reaction time after the addition is complete is 5-6h. The reaction conditions are mild, the selectivity is high, and no unnecessary by-products are generated.

[0071] Further, step S2 can further include: after the reaction is completed, washing the reaction solution with water to remove by-products pyrazole, separating the liquid, concentrating the organic phase, and slurring with PE:EA = 10:1 to remove excess N,N'-di-Boc-1H-1-guanylpyrazole to obtain N,N'-di-Boc-2-furoylguanidine.

[0072] After the reaction in step S2 is completed, the intermediate is subjected to purification treatment, and the by-products and excess raw materials can be easily removed.

[0073] (Three) In step S3, the N,N'-di-Boc-2-furoylguanidine is subjected to Boc removal to generate 2-furoylguanidine.

[0074] That is, after the intermediate N,N'-di-Boc-2-furoylguanidine is obtained, the Boc removal is performed to obtain the intermediate 2-furoylguanidine.

[0075] In some embodiments of the present application, in step S3, the N,N'-di-Boc-2-furoylguanidine is subjected to Boc removal by using a Boc removal reagent selected from one or more of methanol solution of hydrogen chloride, sulfuric acid, trifluoroacetic acid, and hydrochloric acid.

[0076] More specifically, in step S3, the methanol solution of hydrogen chloride is added dropwise to the N,N'-di-Boc-2-furoylguanidine to generate 2-furoylguanidine, that is, the Boc removal reagent is the methanol solution of hydrogen chloride. Compared with the reaction using hydrochloric acid as the Boc removal reagent, the reaction using the methanol solution of hydrogen chloride is more convenient in post-treatment.

[0077] Specifically, the reaction formula is shown in the following formula (3):

[0078]

[0079] Further, the molar ratio of the N,N'-di-Boc-2-furoylguanidine to hydrogen chloride is 1.0:(2-3), the temperature for dropwise addition of the methanol solution of hydrogen chloride is 20-30°C, the reaction temperature after the addition is completed is 30-40°C, and the reaction time is 2-3h.

[0080] Further, step S3 can further include: after the reaction is completed, concentrating the reaction solution, slurrying the obtained solid with water, filtering, and drying to obtain 2-furoylguanidine.

[0081] That is, after the reaction in step S3 is completed, the crude product has good purity, and a small amount of water can be used for slurring to completely remove a small amount of residual acid.

[0082] Step S4: intramolecular dehydration of the 2-furoyl guanidine to obtain 3-(2-furyl)-5-amino-1H-1,2,4-triazole.

[0083] That is, after obtaining the 2-furoyl guanidine, intramolecular dehydration is performed to obtain the target product 3-(2-furyl)-5-amino-1H-1,2,4-triazole.

[0084] In some embodiments of the present application, the step S4 comprises:

[0085] The 2-furoyl guanidine is added to water, and sodium hydroxide solid is added portionwise to generate the 3-(2-furyl)-5-amino-1H-1,2,4-triazole.

[0086] Specifically, the reaction is as shown in the following formula (4):

[0087]

[0088] Compared with the high-temperature ring closure using hydrogen chloride gas, the temperature is reduced after using sodium hydroxide, and there is no need for inert gas protection, and the operation is more convenient, and only conventional glass instruments are needed.

[0089] The molar ratio of the 2-furoyl guanidine to sodium hydroxide is 1.0: (0.8-1.2), preferably 1.0:1.0, the reaction temperature is 70-80°C, and the reaction time is 3-4h.

[0090] Further, the step S4 can further comprise:

[0091] After the reaction is completed, the reaction solution is added with hydrochloric acid to adjust the pH value to 2, filtered, slurried with EA, filtered, and dried to obtain 3-(2-furyl)-5-amino-1H-1,2,4-triazole.

[0092] The product is slowly precipitated in the form of a crystalline solid by adjusting the pH value, and therefore, compared with the existing synthesis route, the obtained product has a good crystal form.

[0093] In addition, it can be known from the above description that the purification of the intermediates after each step of the present application is simple and easy to operate, safe and reliable, and the purity of the obtained product can be as high as 99.4%.

[0094] In order for the technical researchers in the art to better understand the technical solutions of the present application, the present application will be further described in detail below in combination with examples.

[0095] Experimental Example 1: Preparation of compound 3-(2-furyl)-5-amino-1H-1,2,4-triazole

[0096] First step: take 250ml three-port flask, add methanol (100ml, 4P) and 2-furan carboxylic acid (25g, 0.223mol, 1.0eq), drop chlorosulfoxide (29.2g, 0.245mol, 1.1eq), control temperature 35-40℃, react 4h at room temperature; then add 80% mass fraction hydrazine hydrate (12.6g, 0.201mol, 0.9eq), warm up to 55-60℃, and react for 5h.

[0097] Sample point board monitors the reaction progress. After the reaction is completed, the reaction liquid is concentrated, and PE:EA=3:1 is used to pulp to obtain 2-furan carboxylic acid hydrazide 24g, with a yield of 85.3%.

[0098] Second step: take 250ml three-port flask, add dichloromethane (72ml, 3P) and 2-furan carboxylic acid hydrazide (24g, 0.19mol, 1.0eq), and then add N,N'-di-Boc-1H-1-guanyl pyrazole (70.8g, 0.228mol, 1.2eq) in batches, control temperature 20-30℃, and react 5h at room temperature.

[0099] After the reaction is completed, the reaction liquid is used to remove pyrazole with water, and the organic phase is concentrated. PE:EA=10:1 is used to pulp to remove excess N,N'-di-Boc-1H-1-guanyl pyrazole to obtain N,N'-di-Boc-2-furan carboxylic acid guanidine 64.4g, with a yield of 92%.

[0100] Third step: take 250ml three-port flask, add N,N'-di-Boc-2-furan carboxylic acid guanidine (64.4g, 0.175mol, 1.0eq), and then drop 15% mass fraction hydrogen chloride methanol solution (105.9g, 0.438mol, 2.5eq). The temperature during dropping is 20-30℃, the reaction temperature after dropping is 35℃, and the reaction time is 2-3h.

[0101] After the reaction is completed, the reaction liquid is concentrated, the obtained solid is pulped with water, filtered, and dried to obtain 2-furan carboxylic acid guanidine 25g, with a yield of 85%.

[0102] Fourth step: take 250ml three-port flask, add 2-furan carboxylic acid guanidine (25g, 0.148mol, 1.0eq) to water (100ml, 4P), and then add sodium hydroxide solid (5.92g, 0.148mol, 1.0eq) in batches. The reaction temperature after adding is 70-80℃, and the reaction time is 3-4h.

[0103] After the reaction is completed, the reaction liquid is added with hydrochloric acid to adjust pH=2, filtered, the filter cake is pulped with EA, filtered, and dried to obtain 3-(2-furyl)-5-amino-1H-1,2,4-triazole 20g, with a yield of 90%.

[0104] The structure of the product was confirmed by nuclear magnetic resonance experiment of the reactant, and the data were as follows:

[0105] 1 H NMR (model: AVANCE III HD 400M, d6-DMSO, 400 MHz): 12.13 (s, 1H), 7.69 (s, 1H), 6.69 (dd, 1H), 6.54 (dd, 1H), 6.03 (s, 2H). The detection result was consistent with the structure.

[0106] Experimental Example 2: Preparation of compound 3-(2-furyl)-5-amino-1H-1,2,4-triazole

[0107] First step: 500 ml three-necked flask was added methanol (200 ml, 4P) and 2-furoic acid (50 g, 0.446 mol, 1.0 eq), and dropwise addition of thionyl chloride (58.4 g, 0.49 mol, 1.1 eq) was performed, the temperature was controlled at 35-40 DEG C, and the reaction was performed at room temperature for 4 h; then 80% hydrazine hydrate (25.2 g, 0.402 mol, 0.9 eq) was added, the temperature was increased to 55-60 DEG C, and the reaction time was 5 h.

[0108] The reaction progress was monitored at the sampling point board. After the reaction was completed, the reaction liquid was concentrated, and PE:EA = 3:1 was used for beating to obtain 2-furohydrazide 46.7 g, with a yield of 83%.

[0109] Second step: 500 ml three-necked flask was added dichloromethane (150 ml, 3P) and 2-furohydrazide (46.7 g, 0.37 mol, 1.0 eq), and N,N'-di-Boc-1H-1-guanylpyrazole (137.8 g, 0.444 mol, 1.2 eq) was added in batches, the temperature was controlled at 20-30 DEG C, and the reaction was performed at room temperature for 5 h.

[0110] After the reaction was completed, the reaction liquid was treated with water to remove pyrazole, and the organic phase was concentrated, PE:EA = 10:1 was used for beating to remove excess N,N'-di-Boc-1H-1-guanylpyrazole to obtain N,N'-di-Boc-2-furoylguanidine 122.7 g, with a yield of 90%.

[0111] Third step: 500 ml three-necked flask was added N,N'-di-Boc-2-furoylguanidine (122.7 g, 0.333 mol, 1.0 eq), and 15% hydrogen chloride methanol solution (202.7 g, 0.833 mol, 2.5 eq) was added dropwise, the temperature during dropwise addition was 20-30 DEG C, the reaction temperature after dropwise addition was 35 DEG C, and the reaction time was 2-3 h.

[0112] After the reaction, the reaction solution was concentrated, the obtained solid was slurried with water, filtered and dried to obtain 2-furancarboxylic acid guanidine 46.26 g, with a yield of 84.4%.

[0113] Step 4: 500 ml three-necked flask was taken and 2-furancarboxylic acid guanidine (46.26 g, 0.275 mol, 1.0 eq) was added into water (190 ml, 4P), and sodium hydroxide solid (11 g, 0.275 mol, 1.0 eq) was added in batches. After the addition was completed, the reaction temperature was 70-80°C, and the reaction time was 3-4 hours.

[0114] After the reaction, the reaction solution was added with hydrochloric acid to adjust pH = 2, filtered, slurried with EA, filtered and dried to obtain 3-(2-furanyl)-5-amino-1H-1,2,4-triazole 37.7 g, with a yield of 91.3%.

[0115] The reaction was subjected to nuclear magnetic resonance experiment to confirm the product structure, and the data were as follows:

[0116] 1 H NMR (model: AVANCE III HD 400M, d6-DMSO, 400 MHz): 12.09 (s, 1H), 7.69 (s, 1H), 6.68 (dd, 1H), 6.55 (dd, 1H), 6.03 (s, 2H). The detection result was consistent with the structure.

[0117] The above is the preferred embodiment of the present application, it should be noted that for those skilled in the art, without departing from the principles of the present application, can also make a number of improvements and refinements, these improvements and refinements should also be considered as the protection scope of the present application.

Claims

1. A method for preparing 3-(2-furanyl)-5-amino-1H-1,2,4-triazole, characterized in that, Includes the following steps: Step S1, providing 2-furanoylhydrazine; Step S2 involves reacting the 2-furanoylhydrazine with N,N'-di-Boc-1H-1-guanidinylpyrazole via a nucleophilic substitution reaction to generate N,N'-di-Boc-2-furanoylguanidine; Step S3 involves removing the Boc from the N,N'-bis-Boc-2-furanoylguanidine to generate 2-furanoylguanidine; Step S4 involves intramolecular dehydration of the 2-furanoylguanidine to yield 3-(2-furanyl)-5-amino-1H-1,2,4-triazole. Step S2 includes: N,N'-di-Boc-1H-1-guanidinylpyrazole was added to a dichloromethane solution of 2-furanoylhydrazine to carry out the nucleophilic reaction, yielding N,N'-di-Boc-2-furanoylguanidine.

2. The preparation method according to claim 1, characterized in that, Step S1 includes: Step S11 involves acylation and esterification of 2-furan carboxylic acid to generate 2-furan carboxylate. Step S12 involves reacting the 2-furan carbamate with an acylhydrazine reagent to generate the 2-furan carbamate hydrazine.

3. The preparation method according to claim 2, characterized in that, In step S11, the acylation and esterification combination is thionyl chloride and methanol, or oxalyl chloride and methanol, or phosphorus oxychloride and methanol. In step S12, the acylhydrazide reagent is hydrazine hydrate.

4. The preparation method according to claim 3, characterized in that, The acylation and esterification combination is thionyl chloride and methanol, and the molar ratio of 2-furanic acid: thionyl chloride: hydrazine hydrate is 1.0:(1.0-1.2):(0.8-1.0).

5. The preparation method according to claim 4, characterized in that, Step S1 includes: The thionyl chloride is added dropwise to a methanol solution of 2-furanic acid to generate 2-furanic acid ester. The temperature of the thionyl chloride addition is 35-40℃ and the reaction time is 3-5 h. After the reaction is complete, the hydrazine hydrate is added, the temperature is raised to 55-60℃, and the reaction time is 5-6 hours to produce the 2-furanoylhydrazine in a one-pot process.

6. The preparation method according to claim 1, characterized in that, The molar ratio of 2-furanoylhydrazide to N,N'-di-Boc-1H-1-guanidinylpyrazole is 1.0:(1.1-1.3), the temperature at which the N,N'-di-Boc-1H-1-guanidinylpyrazole is added is 20-30℃, and the reaction time after addition is 5-6 h.

7. The preparation method according to claim 1, characterized in that, In step S3, the Boc in N,N'-bis-Boc-2-furanoylguanidine is removed using a Boc removal reagent, wherein the Boc removal reagent is selected from one or more of the following: methanol solution of hydrogen chloride, sulfuric acid, trifluoroacetic acid, and hydrochloric acid.

8. The preparation method according to claim 7, characterized in that, In step S3, a methanol solution of hydrogen chloride is added dropwise to N,N'-di-Boc-2-furanoylguanidine to generate 2-furanoylguanidine. The deBoc reagent is a methanol solution of hydrogen chloride. The molar ratio of N,N'-di-Boc-2-furanoylguanidine to hydrogen chloride is 1.0:(2-3). The temperature at which the methanol solution of hydrogen chloride is added is 20-30°C. After the addition is complete, the reaction temperature is 30-40°C, and the reaction time is 2-3 h.

9. The preparation method according to claim 1, characterized in that, Step S4 includes: The 2-furanoylguanidine was added to water, and sodium hydroxide solid was added in batches to generate the 3-(2-furanyl)-5-amino-1H-1,2,4-triazole, wherein the molar ratio of the 2-furanoylguanidine to sodium hydroxide was 1.0:(0.8-1.2), the reaction temperature was 70-80℃, and the reaction time was 3-4 h.

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