Synthesis method of 1, 2, 4-triazole

Abstract

The invention provides a synthesis method of 1, 2, 4-triazole, which comprises the following steps: reacting a part of formamide with hydrazine hydrate hydrochloride to prepare monohydrazide; and then dropwise adding the monohydrazide into the other part of formamide to carry out dehydration reaction. According to the method, the raw material formamide is added by adopting a fractional step method, so that the conversion rate of the formamide is improved, and the yield of the 1, 2, 4-triazole is further improved. And the generated monohydrazide is added into formamide in a reverse dripping manner, so that the process is optimized, and the yield of the 1, 2, 4-triazole is further improved. The 1, 2, 4-triazole is synthesized by adopting the method disclosed by the invention, the yield of the final product can reach 95.4%, and the content is greater than 98%.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, relates to the synthesis of 1,2,4-triazole, and specifically relates to a synthesis method of 1,2,4-triazole. Background Art

[0002] 1,2,4-triazole (abbreviated as triazole) is mainly used for the production of high-efficiency and low-toxic agricultural fungicides, plant production regulators, and the synthesis of pharmaceutical intermediates such as triadimefon, paclobutrazol, uniconazole, triadimefon, etc. It is widely used in the production of pharmaceuticals, pesticides, dyes, rubber additives and other industries. It is also used for photoconductors of replication systems. It is a very important chemical intermediate and can be used for the antifungal drug fluconazole. Its chemical structure is shown below:

[0003]

[0004] In the prior art, there are mainly the following methods for synthesizing 1,2,4-triazole:

[0005] (1) European Patent EP44438 discloses a method for preparing 1,2,4-triazole, which specifically comprises the following steps: firstly heat formamide to 175-185°C, then slowly drip 80% hydrazine hydrate, and heat and dehydrate while dripping. After the dripping, 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 at present, and its advantages are simple and easy-to-obtain raw materials, simple production process, low equipment requirements, and high product yield. However, compared with the formic acid method, the price of formamide is higher than that of ammonium formate, and the unreacted formamide in the product is not easy to separate from the product. The reaction formula of this method is as follows:

[0006]

[0007] (2) Chinese patent CN86100564 discloses a method for preparing 1,2,4-triazole. The method is specifically as follows: ammonia is passed into formic acid, and the ammonia is stopped when the temperature of the reactants rises to 130°C and the pH is 7-8. The temperature is raised to 155°C, and 80% hydrazine hydrate is added dropwise, while dehydration is performed dropwise. After the addition is completed, the temperature is kept for 3 hours, and then the temperature is raised to 210 degrees Celsius to obtain triazole with a yield of 91.08%. However, the production process of the formic acid method is more complicated than that of the formamide method, and formic acid is highly corrosive to equipment, resulting in high equipment maintenance costs. At the same time, after the formic acid is passed through ammonia, the temperature must be raised to 155°C for dehydration, and the dehydration amount is large, consuming more energy. Therefore, the comprehensive cost of the formic acid method is not significantly superior to that of the formamide method. The reaction formula of this method is as follows:

[0008]

[0009] In summary, in the prior art, the synthesis methods of 1,2,4-triazole mainly include the formamide method and the formic acid method. Although the production processes of these two methods are mature and stable, they each have their own defects. The production process of the formic acid method is more complicated than that of the formamide method. Formic acid is highly corrosive to equipment, resulting in high equipment maintenance costs. At the same time, after the formic acid is passed through ammonia, it must be heated to 155°C for dehydration. The dehydration amount is large and consumes more energy. Compared with the formic acid method, the price of formamide is higher than that of ammonium formate. The unreacted formamide in the product is not easy to separate from the product, and the yield is low. Summary of the invention

[0010] In view of the defects and shortcomings of the prior art, the purpose of the present invention is to provide a method for synthesizing 1,2,4-triazole, so as to solve the technical problems in the prior art that the formic acid method has a complex route, formic acid has a large corrosion to equipment, the equipment maintenance cost is high, the dehydration amount is large, and the energy consumption is high; the formamide method has a high raw material cost, the unreacted formamide is not easy to separate from the product, and the yield is low.

[0011] In order to solve the above technical problems, the present invention adopts the following technical solutions to achieve the above problems:

[0012] A method for synthesizing 1,2,4-triazole comprises the following steps: firstly reacting a portion of formamide with hydrazine hydrochloride to obtain monohydrazide; and then dripping the monohydrazide into another portion of formamide to perform a dehydration reaction.

[0013] The method specifically comprises the following steps:

[0014] Step 1, preparation of monohydrazide:

[0015] Add a portion of formamide to the reaction container, heat it to 60°C and slowly drop an aqueous solution containing hydrated hydrazine hydrochloride, heat it to 90-110°C and keep it warm for 1-2 hours to obtain monohydrazide.

[0016] Step 2, preparing crude product:

[0017] Add another portion of formamide to another reaction container, raise the temperature to 90-110°C, and slowly drop the monohydrazide prepared in step 1. After the dropwise addition, gradually raise the temperature to 150-185°C while dehydrating. The dehydration time is 2-6 hours.

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

[0019] Preferably, in step 2, the monohydrazide prepared in step 1 is slowly added dropwise, and the temperature is gradually raised to 175-185° C. while dehydrating the mixture, and the dehydration time is 3-5 h.

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

[0021] Specifically, the molar ratio of hydrazine hydrate hydrochloride, a part of formamide, and the other part of formamide is 1:(0.88-1.32):(0.88-1.32).

[0022] Specifically, in step 2, after the dehydration reaction is completed, the temperature is lowered to 50°C.

[0023] Specifically, the method further comprises the following steps:

[0024] Step 3, product purification:

[0025] Add ethanol to the reaction bottle in step 2 and heat to reflux, cool to room temperature and filter, concentrate the filtrate under reduced pressure and recrystallize to obtain a 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 the present invention compared with the prior art are as follows:

[0028] (I) The present invention adopts a step-by-step method to add the raw material formamide, thereby improving the conversion rate of formamide and thus improving the yield of 1,2,4-triazole. The generated monohydrazide is added to formamide by reverse addition, which optimizes the process and further improves the yield of 1,2,4-triazole. The method of the present invention is used to synthesize 1,2,4-triazole, and the final product yield can reach 95.4%, and the content is 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 hydrate hydrochloride by-products to turn waste into wealth and mass-produce 1,2,4-triazole on an industrial scale.

[0030] The specific contents of the present invention are further explained in detail below in conjunction with embodiments. DETAILED DESCRIPTION

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

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

[0033]

[0034] In accordance with the above technical scheme, 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 changes made on the basis of the technical scheme of this application fall within the protection scope of the present invention.

[0035] Embodiment 1:

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

[0037] Step 1, preparation of monohydrazide:

[0038] Add 49.5 g (1.1 mol) of formamide to a 250 mL three-necked round-bottom flask, heat to 60 °C, then slowly drop 100 mL of an aqueous solution containing 68.5 g (1 mol) of hydrazine hydrochloride, heat to 100 °C and keep warm for 1 h to obtain monohydrazide.

[0039] Step 2, preparing crude product:

[0040] Add 49.5 g (1.1 mol) of formamide to another 250 mL three-necked round-bottom flask, raise the temperature to 110°C, slowly drop the monohydrazide prepared in step 1, and gradually raise the temperature to 180°C while dehydrating. The time from the start of dropwise addition to the completion of dehydration is about 3 to 5 h. After the dehydration reaction is completed, cool to 50°C.

[0041] Step 3, product purification:

[0042] Add ethanol to the reaction bottle in step 2, heat to 75°C and reflux for 2h, cool to room temperature and filter, concentrate the filtrate under reduced pressure and recrystallize to obtain 65.8g of product.

[0043] The above product was identified and the results are as follows: 1 H NMR (δppm, D2O): 8.26 (s, 2H). It can be seen from the hydrogen nuclear magnetic resonance spectrum that the present invention finally synthesizes the target product 1,2,4-triazole, with a product yield of 95.4% and a content of 98.7%.

[0044] Embodiment 2:

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

[0046] Step 1, preparation of monohydrazide:

[0047] Add 56.3 g (1.25 mol) of formamide to a 250 mL three-necked round-bottom flask, heat to 60 °C, then slowly drop 100 mL of an aqueous solution containing 68.5 g (1 mol) of hydrazine hydrochloride, heat to 100 °C and keep warm for 1 h to obtain 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, raise the temperature to 110°C, slowly drop the monohydrazide prepared in step 1, and gradually raise the temperature to 180°C while dehydrating. The time from the start of dropwise addition to the completion of dehydration is about 3 to 5 h. After the dehydration reaction is completed, cool to 50°C.

[0050] Step 3, product purification:

[0051] Add ethanol to the reaction bottle in step 2, heat to 75°C and reflux for 2h. Cool to room temperature and filter, concentrate the filtrate under reduced pressure and recrystallize to obtain 65.2g of 1,2,4-triazole, with a product yield of 94.5% and a content of 98.5%.

[0052] Embodiment 3:

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

[0054] Step 1, preparation of monohydrazide:

[0055] Add 45 g (1.0 mol) of formamide to a 250 mL three-necked round-bottom flask, heat to 60 °C, then slowly drop 100 mL of an aqueous solution containing 68.5 g (1 mol) of hydrazine hydrochloride, heat to 100 °C and keep warm for 1 h to obtain monohydrazide.

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

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

[0058] Step 3, product purification:

[0059] Add ethanol to the reaction bottle in step 2, heat to 75°C and reflux for 2h. Cool to room temperature and filter, concentrate the filtrate under reduced pressure and recrystallize to obtain 60.7g of 1,2,4-triazole, with a product yield of 88.0% and a content of 98.3%.

[0060] Embodiment 4:

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

[0062] Step 1, preparation of monohydrazide:

[0063] Add 39.6 g (0.88 mol) of formamide to a 250 mL three-necked round-bottom flask, heat to 60 °C, then slowly drop 100 mL of an aqueous solution containing 68.5 g (1 mol) of hydrazine hydrochloride, heat to 100 °C and keep the mixture for 1 h to obtain 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, raise the temperature to 110°C, slowly drop the monohydrazide prepared in step 1, and gradually raise the temperature to 175-185°C while dehydrating. The time from the start of dropwise addition to the completion of dehydration is about 3-5 h. After the dehydration reaction is completed, cool to 50°C.

[0066] Step 3, product purification:

[0067] Add ethanol to the reaction bottle in step 2, heat to 75°C and reflux for 2h. Cool to room temperature and filter, concentrate the filtrate under reduced pressure and recrystallize to obtain 54.6g of 1,2,4-triazole, with a product yield of 79.1% and a content of 99.1%.

[0068] Embodiment 5:

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

[0070] Step 1, preparation of monohydrazide:

[0071] Add 59.4 g (1.32 mol) of formamide to a 250 mL three-necked round-bottom flask, heat to 60 °C, then slowly drop 100 mL of an aqueous solution containing 68.5 g (1 mol) of hydrazine hydrochloride, heat to 100 °C and keep warm for 1 h to obtain 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, raise the temperature to 110°C, slowly drop the monohydrazide prepared in step 1, and gradually raise the temperature to 175-185°C while dehydrating. The time from the start of dropwise addition to the completion of dehydration is about 3-5 h. After the dehydration reaction is completed, cool to 50°C.

[0074] Step 3, product purification:

[0075] Add ethanol to the reaction bottle in step 2, heat to 75°C and reflux for 2h. Cool to room temperature and filter, concentrate the filtrate under reduced pressure and recrystallize to obtain 56.9g of 1,2,4-triazole, with a product yield of 82.5% and a content of 99.0%.

[0076] Embodiment 6:

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

[0078] In this embodiment, step 1 is specifically as follows: 49.5 g (1.1 mol) of formamide is added to a 250 mL three-necked round-bottom flask, the temperature is raised to 60° C., and then 100 mL of an aqueous solution containing 68.5 g (1 mol) of hydrazine hydrochloride is slowly added dropwise, and the temperature is raised to 100° C. and kept for 2 h to obtain a 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 content of 99.0%.

[0080] Embodiment 7:

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

[0082] In this embodiment, step 1 is specifically as follows: 49.5 g (1.1 mol) of formamide is added to a 250 mL three-necked round-bottom flask, the temperature is raised to 60° C., and then 100 mL of an aqueous solution containing 68.5 g (1 mol) of hydrazine hydrochloride is slowly added dropwise, and the temperature is raised to 90-110° C. and the reaction is kept warm for 1 h to obtain a 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] It can be seen from Table 1 that when preparing monohydrazide, the yield of 1,2,4-triazole does not change much with the increase of reaction temperature, and a high yield can be achieved within the temperature range of 90 to 110°C.

[0087] Embodiment 8:

[0088] This embodiment provides a method for synthesizing 1,2,4-triazole, which is basically the same as that of Embodiment 1, except that the reaction temperature of step 2 is different, being 150-185°C.

[0089] In this embodiment, step 2 is specifically as follows: add 49.5 g (1.1 mol) of formamide to another 250 mL three-necked round-bottom flask, heat to 110 ° C, slowly dropwise add the monohydrazide prepared in step 1, gradually increase the temperature to 150-185 ° C while dehydrating, and the time from the start of dropwise addition to the completion of dehydration is about 3-5 h; after the dehydration reaction is completed, cool 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] It can be seen from Table 2 that when the reaction temperature is less than or equal to 180°C, the yield of 1,2,4-triazole gradually increases with the increase of the reaction temperature, but after exceeding 180°C, the yield decreases due to the decomposition of formamide.

Claims

1. A method for synthesizing 1,2,4-triazole, characterized in that: The method firstly reacts a part of formamide with hydrazine hydrochloride to obtain monohydrazide; then the monohydrazide is dripped into another part of formamide to perform a dehydration reaction; The method specifically comprises the following steps: Step 1, preparation of monohydrazide: Add a portion of formamide to the reaction container, heat it to 60°C, then slowly drop an aqueous solution containing hydrated hydrazine hydrochloride, heat it to 90-110°C after the dropwise addition, and keep the temperature to react for 1-2 hours to obtain monohydrazide; Step 2, preparing crude product: Add another portion of formamide to another reaction container, raise the temperature to 90-110°C, and slowly drop the monohydrazide prepared in step 1. After the dropwise addition, gradually raise the temperature to 150-185°C while dehydrating. The dehydration time is 2-6 hours.

2. The method for synthesizing 1,2,4-triazole according to claim 1, characterized in that: In step 2, the monohydrazide prepared in step 1 is slowly added dropwise, and the temperature is gradually raised to 175-185° C. while dehydrating the mixture. The dehydration time is 3-5 h.

3. The method for synthesizing 1,2,4-triazole as claimed in claim 1, characterized in that: The molar ratio of the total amount of hydrazine hydrate hydrochloride added to formamide is 1:(2-2.5).

4. The method for synthesizing 1,2,4-triazole as claimed in claim 1, characterized in that: The molar ratio of hydrazine hydrate hydrochloride, a part of formamide, and another part of formamide is 1:(0.88-1.32):(0.88-1.32).

5. The method for synthesizing 1,2,4-triazole as claimed in claim 1, characterized in that: In step 2, after the dehydration reaction is completed, the temperature is lowered to 50°C.

6. The method for synthesizing 1,2,4-triazole according to claim 1, characterized in that: The method further comprises the steps of: Step 3, product purification: Add ethanol to the reaction bottle in step 2 and heat to reflux, cool to room temperature and filter, concentrate the filtrate under reduced pressure and recrystallize to obtain a purified product of 1,2,4-triazole.

7. The method for synthesizing 1,2,4-triazole according to claim 6, characterized in that: The heating reflux temperature is 75° C. and the time is 2 h.

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