A method for synthesizing 1,2,4-triazoles

Abstract

The application provides a synthesis method of 1,2,4-triazole, which comprises the following steps: firstly, reacting part of formamide with hydrazine monohydrate hydrochloride to prepare monoacylhydrazine; and then, adding the monoacylhydrazine into another part of formamide by reverse titration to perform a dehydration reaction. The raw material formamide is added in a step-by-step manner, so that the conversion rate of the formamide is improved, and the yield of 1,2,4-triazole is improved. The generated monoacylhydrazine is added into the formamide by reverse titration, so that the process is optimized, and the yield of 1,2,4-triazole is further improved. By using the method, the yield of the final product 1,2,4-triazole can reach 95.4%, and the content is greater than 98%.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, and relates to the synthesis of 1,2,4-triazole, specifically to a method for synthesizing 1,2,4-triazole. Background Technology

[0002] 1,2,4-Triazole (abbreviated as triazole) is mainly used in the production of highly effective and low-toxicity agricultural fungicides, plant growth regulators, and pharmaceutical intermediates such as triadimefon, paclobutrazol, uniconazole, and triadimefon. It is widely used in the production of pharmaceuticals, pesticides, dyes, and rubber additives. It is also used as a photoconductor in replication systems and is a very important chemical intermediate. It is also used in the antifungal drug fluconazole. Its chemical structure is shown below:

[0003]

[0004] In the prior art, the main methods for synthesizing 1,2,4-triazole are as follows:

[0005] (1) European Patent EP44438 discloses a method for preparing 1,2,4-triazole. Specifically, formamide is first heated to 175–185°C, then 80% hydrazine hydrate is slowly added dropwise while heating to remove water. After the addition is complete, the mixture is kept at 180–185°C for 30 minutes to obtain triazole with a yield of 91%. This synthetic route is one of the commonly used methods for producing triazole, with advantages such as readily available raw materials, simple production process, low equipment requirements, and high product yield. However, compared to the formic acid method, formamide is more expensive than ammonium formate, and unreacted formamide in the product is difficult to separate from the product. The reaction formula for this method is as follows:

[0006]

[0007] (2) Chinese patent CN86100564 discloses a method for preparing 1,2,4-triazole. Specifically, ammonia gas is passed into formic acid, and the ammonia flow is stopped when the reactant temperature reaches 130℃ and pH = 7-8. The temperature is then raised to 155℃, and 80% hydrazine hydrate is added dropwise while simultaneously dehydrating the reactants. After the addition is complete, the temperature is maintained for 3 hours, and then raised to 210℃ to obtain triazole with a yield of 91.08%. However, the formic acid method is more complex than the formamide method. Formic acid is highly corrosive to equipment, resulting in high equipment maintenance costs. Furthermore, after the ammonia gas is passed through the formic acid, the temperature must be raised to 155℃ for dehydration, requiring a large amount of dehydration and consuming significant energy. Therefore, the overall cost of the formic acid method is not significantly lower than that of the formamide method. The reaction formula for this method is as follows:

[0008]

[0009] In summary, the existing technologies for synthesizing 1,2,4-triazole mainly include the formamide method and the formic acid method. Although both methods have mature and stable production processes, they each have their drawbacks. The formic acid method is more complex than the formamide method. Formic acid is highly corrosive to equipment, resulting in high equipment maintenance costs. Furthermore, after the formic acid is passed through ammonia gas, it must be heated to 155°C for dehydration, which involves a large amount of dehydration and consumes more energy. Compared to the formic acid method, formamide is more expensive than ammonium formate, and unreacted formamide in the product is difficult to separate from the product, resulting in a lower yield. Summary of the Invention

[0010] In view of the defects and deficiencies of the existing technology, the purpose of this invention is to provide a method for synthesizing 1,2,4-triazole, which solves the technical problems of the existing technology, such as the complexity of the formic acid method, the high corrosiveness of formic acid to equipment, the high equipment maintenance cost, the large amount of dehydration, and the high energy consumption; and the high raw material cost of the formamide method, the difficulty in separating unreacted formamide from the product, and the low yield.

[0011] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0012] A method for synthesizing 1,2,4-triazole, comprising first reacting a portion of formamide with hydrazine hydrochloride to obtain monohydrazide; then back-dropping the monohydrazide onto another portion of formamide for a dehydration reaction.

[0013] The method specifically includes the following steps:

[0014] Step 1, Preparation of monohydrazides:

[0015] A portion of formamide was added to the reaction vessel, and the temperature was raised to 60°C. Then, an aqueous solution of hydrazine hydrochloride was slowly added dropwise. After the addition was complete, the temperature was raised to 90–110°C and the reaction was maintained for 1–2 hours to obtain monohydrazide.

[0016] Step 2, Preparation of crude product:

[0017] Add another portion of formamide to another reaction vessel, heat to 90-110°C, and slowly add the monohydrazide prepared in step one. After the addition is complete, gradually increase the temperature to 150-185°C while dehydrating, and the dehydration time is 2-6 hours.

[0018] The present invention also has the following technical features:

[0019] Preferably, in step two, the monohydrazide prepared in step one is slowly added dropwise, and while dehydrating, the temperature is gradually raised to 175-185°C for 3-5 hours.

[0020] Specifically, the molar ratio of the total amount of hydrazine hydrochloride to formamide is 1:(2-2.5).

[0021] Specifically, the molar ratio of hydrazine hydrochloride, a portion of formamide, and another portion of formamide is 1:(0.88~1.32):(0.88~1.32).

[0022] Specifically, in step two, after the dehydration reaction is complete, the temperature is lowered to 50°C.

[0023] Specifically, the method also includes the following steps:

[0024] Step 3, Product purification:

[0025] Ethanol was added to the reaction flask of step two and heated under reflux. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure and recrystallized to obtain the purified product of 1,2,4-triazole.

[0026] Specifically, the heating reflux temperature is 75°C and the time is 2 hours.

[0027] The beneficial technical effects of this invention compared to the prior art are as follows:

[0028] (I) This invention employs a stepwise method to add formamide, thereby improving the conversion rate of formamide and consequently increasing the yield of 1,2,4-triazole. The generated monohydrazide is added to the formamide via a back-dropping method, optimizing the process and further improving the yield of 1,2,4-triazole. Using the method of this invention, the final product yield of 1,2,4-triazole can reach 95.4%, with a content greater than 98%.

[0029] (II) The synthesis process of the present invention is simple to operate, the reaction conditions are easy to control, and the production cost is low. It is suitable for manufacturers with hydrazine hydrochloride by-products to turn waste into treasure and produce 1,2,4-triazole in batches for industrial production.

[0030] The specific content of the present invention will be further explained in detail below with reference to the embodiments. Detailed Implementation

[0031] It should be noted that, unless otherwise specified, all raw materials used in this invention are those known in the art.

[0032] In this invention, the synthetic route for 1,2,4-triazole is as follows:

[0033]

[0034] Following the above technical solutions, specific embodiments of the present invention are given below. It should be noted that the present invention is not limited to the following specific embodiments, and all equivalent modifications made based on the technical solutions of this application fall within the protection scope of the present invention.

[0035] Example 1:

[0036] This embodiment provides a method for synthesizing 1,2,4-triazole, which specifically includes the following steps:

[0037] Step 1, Preparation of monohydrazides:

[0038] Add 49.5 g (1.1 mol) of formamide to a 250 mL three-necked round-bottom flask, heat to 60 °C, and then slowly add 100 mL of an aqueous solution containing 68.5 g (1 mol) of hydrazine hydrochloride. After the addition is complete, heat to 100 °C and keep the reaction at this temperature for 1 h to prepare monohydrazide.

[0039] Step 2, Preparation of crude product:

[0040] Add 49.5 g (1.1 mol) of formamide to another 250 mL three-necked round-bottom flask, heat to 110 °C, and slowly add the monohydrazide prepared in step one. After the addition is complete, gradually increase the temperature to 180 °C while dehydrating. The time from the start of the addition to the completion of the dehydration is about 3 to 5 hours. After the dehydration reaction is complete, cool down to 50 °C.

[0041] Step 3, Product purification:

[0042] Ethanol was added to the reaction flask of step two, the mixture was heated to 75°C and refluxed for 2 hours, cooled to room temperature and filtered, the filtrate was concentrated under reduced pressure and recrystallized to obtain 65.8 g of product.

[0043] The above products were identified, and the results are as follows: 1 1H NMR (δppm, D2O): 8.26 (s, 2H). The 1H NMR spectrum indicates that the target product, 1,2,4-triazole, was successfully synthesized in this invention, with a yield of 95.4% and a purity of 98.7%.

[0044] Example 2:

[0045] This embodiment provides a method for synthesizing 1,2,4-triazole, which specifically includes the following steps:

[0046] Step 1, Preparation of monohydrazides:

[0047] Add 56.3 g (1.25 mol) of formamide to a 250 mL three-necked round-bottom flask, heat to 60 °C, and then slowly add 100 mL of an aqueous solution containing 68.5 g (1 mol) of hydrazine hydrochloride. After the addition is complete, heat to 100 °C and keep the reaction at this temperature for 1 h to prepare monohydrazide.

[0048] Step 2, Preparation of 1,2,4-triazole:

[0049] Add 56.3 g (1.25 mol) of formamide to another 250 mL three-necked round-bottom flask, heat to 110 °C, and slowly add the monohydrazide prepared in step one. After the addition is complete, gradually increase the temperature to 180 °C while dehydrating. The time from the start of the addition to the completion of the dehydration is about 3 to 5 hours. After the dehydration reaction is complete, cool down to 50 °C.

[0050] Step 3, Product purification:

[0051] Ethanol was added to the reaction flask from step two, and the mixture was heated to 75°C and refluxed for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure and recrystallized to obtain 65.2 g of 1,2,4-triazole, with a product yield of 94.5% and a purity of 98.5%.

[0052] Example 3:

[0053] This embodiment provides a method for synthesizing 1,2,4-triazole, which specifically includes the following steps:

[0054] Step 1, Preparation of monohydrazides:

[0055] Add 45g (1.0mol) of formamide to a 250mL three-necked round-bottom flask, heat to 60℃, and then slowly add 100mL of aqueous solution containing 68.5g (1mol) of hydrazine hydrochloride. After the addition is complete, heat to 100℃ and keep the reaction at this temperature for 1h to obtain monohydrazide.

[0056] Step 2, Preparation of 1,2,4-triazole:

[0057] Add 45g (1mol) of formamide to another 250mL three-necked round-bottom flask, heat to 110℃, slowly add the monohydrazide prepared in step one, and gradually raise the temperature to 175-185℃ while dehydrating. The time from the start of the addition to the completion of the dehydration is about 3-5 hours. After the dehydration reaction is completed, cool down to 50℃.

[0058] Step 3, Product purification:

[0059] Ethanol was added to the reaction flask from step two, and the mixture was heated to 75°C and refluxed for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure and recrystallized to obtain 60.7 g of 1,2,4-triazole, with a product yield of 88.0% and a purity of 98.3%.

[0060] Example 4:

[0061] This embodiment provides a method for synthesizing 1,2,4-triazole, which specifically includes the following steps:

[0062] Step 1, Preparation of monohydrazides:

[0063] Add 39.6 g (0.88 mol) of formamide to a 250 mL three-necked round-bottom flask, heat to 60 °C, and then slowly add 100 mL of an aqueous solution containing 68.5 g (1 mol) of hydrazine hydrochloride. After the addition is complete, heat to 100 °C and keep the reaction at this temperature for 1 h to prepare monohydrazide.

[0064] Step 2, Preparation of 1,2,4-triazole:

[0065] Add 59.4 g (1.32 mol) of formamide to another 250 mL three-necked round-bottom flask, heat to 110 °C, and slowly add the monohydrazide prepared in step one. After the addition is complete, gradually increase the temperature to 175–185 °C while dehydrating. The time from the start of the addition to the completion of the dehydration is about 3–5 h. After the dehydration reaction is complete, cool down to 50 °C.

[0066] Step 3, Product purification:

[0067] Ethanol was added to the reaction flask from step two, and the mixture was heated to 75°C and refluxed for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure and recrystallized to obtain 54.6 g of 1,2,4-triazole, with a product yield of 79.1% and a purity of 99.1%.

[0068] Example 5:

[0069] This embodiment provides a method for synthesizing 1,2,4-triazole, which specifically includes the following steps:

[0070] Step 1, Preparation of monohydrazides:

[0071] Add 59.4 g (1.32 mol) of formamide to a 250 mL three-necked round-bottom flask, heat to 60 °C, and then slowly add 100 mL of an aqueous solution containing 68.5 g (1 mol) of hydrazine hydrochloride. After the addition is complete, heat to 100 °C and keep the reaction at this temperature for 1 h to prepare monohydrazide.

[0072] Step 2, Preparation of 1,2,4-triazole:

[0073] Add 39.6 g (0.88 mol) of formamide to another 250 mL three-necked round-bottom flask, heat to 110 °C, and slowly add the monohydrazide prepared in step one. After the addition is complete, gradually increase the temperature to 175–185 °C while dehydrating. The time from the start of the addition to the completion of the dehydration is about 3–5 h. After the dehydration reaction is complete, cool down to 50 °C.

[0074] Step 3, Product purification:

[0075] Ethanol was added to the reaction flask from step two, and the mixture was heated to 75°C and refluxed for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure and recrystallized to obtain 56.9 g of 1,2,4-triazole, with a product yield of 82.5% and a purity of 99.0%.

[0076] Example 6:

[0077] This embodiment provides a method for synthesizing 1,2,4-triazole, which is basically the same as that in Example 1, except that the reaction time in step one is different, being 2 hours.

[0078] In this embodiment, step one specifically involves adding 49.5g (1.1mol) of formamide to a 250mL three-necked round-bottom flask, heating to 60°C, and then slowly adding 100mL of an aqueous solution containing 68.5g (1mol) of hydrazine hydrochloride. After the addition is complete, the temperature is raised to 100°C and kept at that temperature for 2 hours to obtain monohydrazide.

[0079] In this embodiment, 65.5 g of 1,2,4-triazole was finally synthesized, with a product yield of 94.9% and a purity of 99.0%.

[0080] Example 7:

[0081] This embodiment provides a method for synthesizing 1,2,4-triazole, which is basically the same as that in Example 1, except that the reaction temperature in step one is different, being 90-110℃.

[0082] In this embodiment, step one specifically involves adding 49.5g (1.1mol) of formamide to a 250mL three-necked round-bottom flask, heating to 60°C, and then slowly adding 100mL of an aqueous solution containing 68.5g (1mol) of hydrazine hydrochloride. After the addition is complete, the temperature is raised to 90-110°C and kept at this temperature for 1 hour to obtain monohydrazide.

[0083] In this embodiment, the yield and content of the finally synthesized 1,2,4-triazole are shown in Table 1:

[0084] Table 1. Effect of different reaction temperatures on the reaction

[0085]

[0086] As can be seen from Table 1, the yield of 1,2,4-triazole does not change much with the increase of reaction temperature during the preparation of monohydrazide, and a high yield can be achieved in the temperature range of 90 to 110 °C.

[0087] Example 8:

[0088] This embodiment provides a method for synthesizing 1,2,4-triazole, which is basically the same as that in Example 1, except that the reaction temperature in step two is different, ranging from 150 to 185°C.

[0089] In this embodiment, step two specifically involves: adding 49.5g (1.1mol) of formamide to another 250mL three-necked round-bottom flask, heating to 110°C, and slowly adding the monohydrazide prepared in step one. After the addition is complete, the temperature is gradually increased to 150-185°C while dehydrating. The time from the start of the addition to the completion of the dehydration is approximately 3-5 hours. After the dehydration reaction is complete, the temperature is lowered to 50°C.

[0090] In this embodiment, the yield and content of the finally synthesized 1,2,4-triazole are shown in Table 2:

[0091] Table 2. Effect of different reaction temperatures on the reaction

[0092]

[0093] As can be seen from Table 2, when the reaction temperature is less than or equal to 180℃, the yield of 1,2,4-triazole gradually increases with the increase of reaction temperature. However, when the temperature exceeds 180℃, the yield decreases due to the decomposition of formamide.

Claims

1. A method for synthesizing 1,2,4-triazole, characterized in that, The method first reacts a portion of formamide with hydrazine hydrochloride to prepare monohydrazide; then the monohydrazide is back-dropped into another portion of formamide to carry out a dehydration reaction. The method specifically includes the following steps: Step 1, Preparation of monohydrazides: A portion of formamide was added to the reaction vessel, and the temperature was raised to 60°C. Then, an aqueous solution containing hydrazine hydrochloride was slowly added dropwise. After the addition was completed, the temperature was raised to 90–110°C and the reaction was maintained for 1–2 hours to obtain monohydrazide. Step 2, Preparation of crude product: Add another portion of formamide to another reaction vessel, heat to 90-110°C, and slowly add the monohydrazide prepared in step one. After the addition is complete, gradually increase the temperature to 175-185°C while dehydrating. The dehydration time is 3-5 hours. The molar ratio of hydrazine hydrochloride, a portion of formamide, and the remaining portion of formamide is 1:(0.88–1.32):(0.88–1.32). In step two, after the dehydration reaction is complete, the temperature is lowered to 50°C; The method also includes the following steps: Step 3, Product purification: Ethanol was added to the reaction flask of step two and heated under reflux. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure and recrystallized to obtain the purified product of 1,2,4-triazole. The heating reflux temperature is 75°C and the time is 2 hours.

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