Preparation method of pyridine triazolone

Abstract

The invention discloses a preparation method of pyridinetriazolone, and belongs to the technical field of organic synthesis, and the preparation method comprises the following steps: taking hydrazine hydrate as a starting raw material, adding urea in batches at the temperature of 80-85 DEG C, carrying out heat preservation reaction to obtain semicarbazide, dropwise adding hydrochloric acid to form salt, and drying under reduced pressure to obtain semicarbazide hydrochloride; adding the semicarbazide hydrochloride obtained in the previous step and 2-chloropyridine into an ethylene glycol monomethyl ether system, heating to 130-135 DEG C, refluxing, adding a catalytic amount of concentrated sulfuric acid, and carrying out heat preservation reaction to obtain pyridine triazolone; and drying the post-treated mother liquor under reduced pressure, weighing, adding quantitative urea, heating to 130-135 DEG C, and reacting to obtain the pyridinium triazolone. The initial raw materials are hydrazine hydrate and urea, are common industrial raw materials, are easy to obtain and low in price, and are beneficial to industrial production; the by-product 2-hydrazinopyridine is recovered and reacts with urea to prepare the pyridintriazolone, so that the raw material utilization rate and the product yield are greatly improved, the total yield reaches more than 80%, and the purity of the pyridintriazolone is more than or equal to 99.0%.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing pyridinetriazolone. Background Art

[0002] Pyridinetriazolone is an important fine chemical. It is a fungicide widely used in agricultural production, a sterol inhibitor and plant growth regulator. As a pharmaceutical raw material, it can also be used to synthesize trazodone.

[0003] There are two main routes for synthesizing pyridinetriazolone, specifically:

[0004] First, the method published in the document Molecules, 2019, vol. 24, #8, art. no. 1609, the synthesis path of which is as follows Figure 1 As shown. Specific implementation method: (1) 2-chloropyridine and hydrazine hydrate are added to DMF, and 2-hydrazinepyridine is generated by microwave irradiation. After the reaction is completed, DMF is removed by desolventizing, water is added, and DCM is used for extraction. The organic layer is desolventized to obtain 2-hydrazinepyridine with a yield of 14%. (2) 2-Hydrazinepyridine and urea are reacted under microwave irradiation for 50 seconds, and water is added and filtered to obtain pyridinetriazolone with a yield of 49%-75%. The purity is only 97.9%, and further purification is required. Obviously, the reaction product of this route has low purity and cannot meet commercial indicators, and further purification is required; and the required equipment is a special reaction device, and the yield of the two reactions is low, which cannot be used for industrial production.

[0005] Second, the method disclosed in the U.S. invention patent application US2009 / 209550,2009,A1, the synthesis path of which is as follows Figure 2 As shown. This route uses hydrazine hydrate as a raw material, which reacts with urea to generate hydrochloric acid semicarbazide. Hydrochloric acid semicarbazide is added with 2-chloropyridine in ethylene glycol monoethyl ether, and heated to reflux reaction for 24 hours under the catalysis of concentrated sulfuric acid, cooled, and filtered with water to obtain pyridine triazole ketone with a yield of 51% and unknown purity. This route has two-step reaction and simple operation, but the yield is low and the reaction time is long.

[0006] Third, the method disclosed in the world invention patent application WO2017 / 46318,2017,A1, the synthesis path of which is as follows Figure 3 Specific implementation method: 2-hydrazine pyridine and N, N'-carbonyl diimidazole are heated to reflux reaction in solvent acetonitrile for 2 hours, cooled to room temperature, and the pyridine triazole obtained by suction filtration has a reported yield of 50%. The raw materials of this route are expensive and the reaction yield is low, resulting in high route costs and is not suitable for industrial production.

[0007] By comparison, it is found that the raw materials of route 2 are cheap and the reaction has low equipment requirements, but the reaction time is long, the yield of the second step reaction is low, and the product purity reported in the literature is low and needs further purification, which is not conducive to industrial production.

[0008] Therefore, it is necessary to develop a preparation method of pyridinetriazolone which is simple to operate, easy to handle, has few by-products, high yield and purity, can meet industrial production and has good economic benefits. Summary of the invention

[0009] The object of the present invention is to provide a method for preparing pyridinetriazolone to at least solve one of the technical problems in the above-mentioned background technology.

[0010] In order to achieve the above object, the present invention provides a method for preparing pyridinetriazolone, comprising the following steps:

[0011] S1. Add hydrazine hydrate to a reaction flask, raise the temperature to 80°C to 85°C, add urea in batches, and continue to raise the temperature to 100°C to 105°C to keep the temperature until solid precipitation and slight mixing are observed in the system, extend the temperature for 0.5h, and cool to room temperature to obtain a white suspension; filter the white suspension, transfer the filtrate to a reaction flask, add hydrochloric acid dropwise to form a salt, cool and filter, and beat the filter cake with a solvent to obtain an intermediate semicarbazide hydrochloride;

[0012] S2. Add semicarbazide hydrochloride and 2-chloropyridine to a reaction flask, add a solvent, heat to 130°C to 135°C, reflux, add a cyclization reagent, and keep the temperature for 9 hours to obtain a yellow suspension 1; add water to the yellow suspension 1, cool and filter, wash the filter cake with water until it is neutral, and obtain the target product pyridinetriazolone with a purity of ≥99.0%;

[0013] S3, filtering the mother liquor and spinning it to dryness, beating with ethanol, cooling and filtering to obtain the recovered 2-hydrazinepyridine;

[0014] S4, adding 2-hydrazinepyridine and urea to a reaction flask, heating to 130°C-135°C, keeping the temperature for 4 hours, and obtaining a yellow suspension II; cooling the yellow suspension II to room temperature, adding water for suction filtration, and washing the filter cake with water until it is neutral to obtain the target product pyridinetriazolone, with a purity of ≥99.0%;

[0015] S5. The target product pyridinetriazolone is combined and dried under reduced pressure, with a total recovery rate of more than 80%.

[0016] Furthermore, step S1 and / or step S2 is equipped with a 50% sulfuric acid aqueous solution tail gas absorption device.

[0017] Furthermore, in step S1, the feed mass ratio of hydrazine hydrate to urea is 1:1.41 to 1:1.92.

[0018] Furthermore, in step S1, urea is added in batches with an interval of 45 minutes, and urea is added in four times, and the weight ratio of urea added in the four times is 4:3:2:1.

[0019] Furthermore, in step S1, the hydrazine hydrate is an 80% hydrazine hydrate solution.

[0020] Furthermore, the amount of hydrochloric acid added dropwise in step S1 is 2.9 to 6.5 times the mass of the hydrazine hydrate fed.

[0021] Furthermore, the hydrochloric acid added dropwise in step S1 is 36% hydrochloric acid or 30% hydrochloric acid.

[0022] Furthermore, the solvent used in step S1 is methanol or ethanol.

[0023] Furthermore, in step S2, the feed mass ratio of 2-chloropyridine to semicarbazide hydrochloride is 1:1.560 to 1:1.964.

[0024] Furthermore, the solvent used in step S2 is ethylene glycol monomethyl ether or ethylene glycol monoethyl ether.

[0025] Furthermore, the cyclization reagent used in step S2 is concentrated sulfuric acid.

[0026] Furthermore, the amount of concentrated sulfuric acid used is 0.066 to 0.086 times the weight of 2-chloropyridine.

[0027] Furthermore, in step S2, semicarbazide hydrochloride is unstable at 130° C. to 135° C., and about 30% of semicarbazide hydrochloride decomposes to form hydrazine. Both hydrazine hydrate and semicarbazide hydrochloride can react with 2-chloropyridine, wherein 70% of 2-chloropyridine reacts with semicarbazide hydrochloride to form the target product pyridinetriazolone, and 30% of 2-chloropyridine reacts with hydrazine to form 2-hydrazinepyridine.

[0028] Furthermore, the yield of pyridinetriazolone in step S4 is about 70%.

[0029] Furthermore, in step S4, 2-hydrazinepyridine generated by the side reaction in step S3 is recovered, and the recovery rate is 100%.

[0030] Furthermore, in step S4, the feed mass ratio of 2-hydrazinepyridine to urea is 1:1.1 to 1:1.3.

[0031] Compared with the prior art, the preparation process of pyridinetriazole in the present application has at least the following beneficial effects:

[0032] (1) In the present application, the starting material of the reaction is hydrazine hydrate, which is a common industrial raw material, easy to obtain and cheap, and is conducive to industrial production;

[0033] (2) After the semicarbazide is generated in step S1, adding suction filtration operation and then adding hydrochloric acid to prepare hydrochloric semicarbazide is beneficial to remove impurities (biurea). The chemical reaction equation for the generation of impurities is as follows: Figure 4 As shown. The impurities are produced by further reaction of the semicarbazide hydrochloride synthesized in step S1 with excess urea;

[0034] (3) Adding a catalytic amount of concentrated sulfuric acid in step S2 greatly shortens the reaction time, improves production efficiency, and increases the reaction yield to more than 50%, and can even be increased to about 70%;

[0035] (4) In step S3, the side reaction product 2-hydrazinepyridine in step S2 is recovered by concentrating the mother liquor, thereby improving the utilization rate of raw materials and reducing costs;

[0036] (5) In step S4, the recovered 2-hydrazinepyridine is re-reacted with urea to still obtain the target product pyridinetriazolone. The total yield of pyridinetriazolone is more than 80%, even as high as about 86%, which is 35% higher than that reported in other literature patents, greatly improving the utilization rate of raw materials and reducing production costs;

[0037] (6) The crude pyridinetriazolone products synthesized in step S2 and step S4 are all qualified products with a purity of more than 99.0%, and no further purification is required, thereby reducing process operations. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 This is the first preparation route in the prior art;

[0039] Figure 2 This is the second preparation route in the prior art;

[0040] Figure 3 This is the third preparation route in the prior art;

[0041] Figure 4 The chemical reaction equation for the impurity generation;

[0042] Figure 5 is the chemical reaction equation of step S1 of this application;

[0043] Figure 6 is the chemical reaction equation of step S2 of this application;

[0044] Figure 7 The chemical reaction equation for the decomposition of semicarbazide hydrochloride in step S2 of the present application;

[0045] Figure 8 is the chemical reaction equation of step S4 of this application. DETAILED DESCRIPTION

[0046] In the present invention, the final target product pyridinetriazolone is obtained through two-step reaction, and the side reaction product of step (2) is recovered and further synthesized to obtain the target product pyridinetriazolone.

[0047] A method for preparing pyridinetriazolone comprises the following steps:

[0048] S1. Synthesis of semicarbazide hydrochloride. Hydrazine hydrate is used as the starting material and reacts with urea to obtain semicarbazide hydrochloride. The chemical reaction equation is as follows: Figure 5 As shown. The feed mass ratio of hydrazine hydrate to urea is 1:1.41 to 1:1.92. The hydrazine hydrate is a hydrazine hydrate solution with a concentration of 80%.

[0049] S2, synthesizing pyridine triazole. In an ethylene glycol monomethyl ether system, add the hydrochloric acid semicarbazide obtained in step S1, 2-chloropyridine, and concentrated sulfuric acid to react to obtain pyridine triazole; the chemical reaction equation is as follows: Figure 6 shown.

[0050] S3, recovering the 2-hydrazinepyridine in step S2: concentrating the filtered mother liquor in step S2, dispersing it with water, filtering it with suction, and beating the filter cake with ethanol to obtain the byproduct 2-hydrazinepyridine in step S2.

[0051] S4 Synthesis of pyridine triazole: Add urea to the 2-hydrazine pyridine recovered in step S3 for reflux reaction to obtain pyridine triazole; the chemical reaction equation is as follows: Figure 8 shown.

[0052] In step S1, urea is added in batches to avoid prolonged contact between the semicarbazide hydrochloride synthesized in step S1 and excess urea to further generate impurities (biurea).

[0053] The urea was added in four times with an interval of 45 minutes, and the urea addition ratio was 4:3:2:1. The experiment found that adding urea in batches was more conducive to avoiding the generation of impurities (biurea).

[0054] Meanwhile, during the reaction process of step S1, a tail gas absorption device with 50% sulfuric acid aqueous solution is provided, which can be used to absorb volatile gases generated during the reaction process, such as volatile ammonia.

[0055] After the reaction in step S1, the first post-treatment is performed: the reaction solution is cooled to 35°C to 40°C, filtered, the mother liquor obtained after filtration is heated to 65°C to 70°C, and concentrated hydrochloric acid is added dropwise. The amount of hydrochloric acid added dropwise is 2.9 to 6.5 times the mass of the hydrazine hydrate fed. The hydrochloric acid is 36% hydrochloric acid or 30% hydrochloric acid. After the dripping is completed, the temperature is lowered to 0°C to 5°C, and the filter cake is filtered; the filter cake is added to a solvent such as anhydrous ethanol or methanol, slurried at room temperature for 2 hours, filtered to obtain a centrifugal wet product, and the centrifugal wet product is vacuum dried under reduced pressure.

[0056] During the reaction process of step S2, a tail gas absorption device with 50% sulfuric acid aqueous solution is provided, which can be used to absorb volatile gases generated during the reaction process, such as volatile ammonia.

[0057] During the reaction of step S2, add hydrochloric acid semicarbazide, 2-chloropyridine, and ethylene glycol monomethyl ether to the reaction bottle, heat to 130°C to 135°C for reflux, and then control the temperature to add a cyclization reagent for reaction. The feed mass ratio of 2-chloropyridine to hydrochloric acid semicarbazide is 1:1.560 to 1:1.964. The added ethylene glycol monomethyl ether can also be replaced by ethylene glycol monoethyl ether. The cyclization reagent is a catalytic amount of concentrated sulfuric acid. The amount of concentrated sulfuric acid is 0.066 to 0.086 times the weight of 2-chloropyridine.

[0058] After the reaction in step S2, a second post-treatment is performed: water is added to the reaction system, and suction filtration is performed to obtain pyridinetriazolone.

[0059] In the above step S2, the raw material semicarbazide hydrochloride is unstable under high temperature conditions and will produce hydrazine, which can react with another main raw material fragment of step S2 to generate 2-hydrazinepyridine.

[0060] 2-Hydrazinylpyridine can be used to concentrate and pulp the mother liquor of step S2, and then react with urea in water to obtain pyridine triazole. The feed mass ratio of 2-hydrazine pyridine to urea is 1:1.1 to 1:1.3.

[0061] The embodiments of the present invention will be described in detail below in conjunction with specific examples. The following examples are only used to illustrate the present invention and should not be construed as limiting the scope of the present invention. If no specific conditions are specified in the examples, the conditions are carried out according to conventional conditions or the conditions recommended by the manufacturer.

[0062] Example 1

[0063] (1) Synthesis of hydrochloric acid semicarbazide. A 250mL four-necked bottle was equipped with a 50% sulfuric acid aqueous solution tail gas absorption device and an ice-water bath condenser. 30.00g of 80% hydrazine hydrate solution was added thereto and the temperature was raised to 80℃~85℃; the temperature was controlled at 80℃~85℃ and 17.3g, 13g, 8.64g and 4.32g of urea were added four times with an interval of 45min respectively, the temperature was raised to 100℃~105℃ and the reaction was kept warm for 3h. A small amount of solid precipitated and the system was slightly turbid. The reaction was kept warm for 0.5h. Sampling was performed and HPLC detection was performed. Hydrazine hydrate ≤2.0% and semicarbazide ≥95.0%; the reaction was completed. Then, the first post-treatment was carried out. The reaction system was cooled to 30°C to 35°C, filtered, and the filtrate was transferred to a 500mL four-necked bottle, heated to 65°C to 70°C, and 195g of concentrated hydrochloric acid was added dropwise. There was heat release during the addition, and the dropping was completed in about 1h. The mixture was kept at 65°C to 70°C and stirred for 15min. The filter cake was obtained, 71.1g of ethanol was added, the temperature was raised to 75°C to 80°C and stirred for 1h, the temperature was slowly lowered to 15°C, and filtered to obtain a wet product (wet hydrochloride semicarbazide). The wet product was placed in a reduced pressure vacuum oven and dried at 35°C to 40°C under reduced pressure (-0.01MPa) until the loss on drying was ≤0.5%, to obtain a dried semicarbazide hydrochloride product. The purity was 95.15% as determined by HPLC, and the yield was 79.1%.

[0064] (2) Synthesis of pyridine triazole. Add 10 g of 2-chloropyridine, 22.04 g of ethylene glycol monoethyl ether, and 19.64 g of hydrochloric acid semicarbazide into a 100 mL four-necked flask, heat to 130°C to 135°C, reflux, add 0.66 g of concentrated sulfuric acid at 130°C to 135°C, and keep the temperature to react for 7 hours. Take a sample, and HPLC test 2-chloropyridine ≤1.0%, pyridine triazole ≥84.0%, and the reaction is complete.

[0065] Finally, the second post-treatment was performed. The reaction system was cooled to 60°C to 65°C, 30g of water was added, stirred for 15min, cooled to 0°C to 5°C, and filtered. The filter cake was washed with 20g*2 water until neutral to obtain a wet product. The wet product was placed in a reduced pressure vacuum oven and dried at 35°C to 40°C under reduced pressure (-0.01MPa) until the moisture content was ≤0.3%, and a dried product of pyridinetriazole was obtained. The purity of the dried product was 99.34% by HPLC, and the yield was 50.82%.

[0066] (3) Recovering 2-hydrazinepyridine. The mother liquor from step (2) was desolventized at 60°C to 65°C until there was no fraction, 5 mL of water was added and stirred for 30 min, and then filtered. 5 mL of ethanol was added to the filter cake for pulping, and filtered. The wet filtered product was placed in a reduced pressure vacuum oven and dried at 30°C to 35°C under reduced pressure (-0.01 MPa) until the loss on drying was ≤0.5%, to obtain a dried 2-hydrazinepyridine product, with a purity of 98.99% as determined by HPLC.

[0067] (4) Add 5.28 g of 2-hydrazinepyridine and 6.86 g of urea to a 50 mL four-necked bottle, raise the temperature to 130°C, and keep the temperature for 3 hours. Take a sample, and test HPLC to determine if 2-hydrazinepyridine is ≤1.0% and pyridinetriazolone is ≥95.0%. The reaction is complete.

[0068] Finally, the second step post-treatment is carried out. The reaction system is cooled to 60°C to 65°C, 15g of water is added, stirred for 15min, cooled to 0°C to 5°C, and filtered. The filter cake is washed with 10g*2 water until neutral to obtain a wet product. The wet product is placed in a reduced pressure vacuum oven and dried at 35°C to 40°C under reduced pressure (-0.01MPa) until the moisture content is ≤0.3% to obtain a dried product of pyridine triazole. The purity detected by HPLC is 98.75%, and the yield is 57.21%, accounting for 31.46% of the molar yield of 2-chloropyridine in step (2), and the total yield of pyridine triazole synthesis is 82.28% (calculated based on the amount of 2-chloropyridine fed).

[0069] Example 2

[0070] (1) Synthesis of hydrochloric acid semicarbazide. A 250mL four-necked bottle was equipped with a 50% sulfuric acid aqueous solution tail gas absorption device and an ice-water bath condenser. 30.00g of 80% hydrazine hydrate solution was added thereto and the temperature was raised to 80℃~85℃; the temperature was controlled at 80℃~85℃ and 17.3g, 13g, 8.64g and 4.32g of urea were added four times with an interval of 45min respectively, the temperature was raised to 100℃~105℃ and the reaction was kept warm for 3h. A small amount of solid precipitated and the system was slightly turbid. The reaction was kept warm for 0.5h. Sampling was performed and HPLC detection was performed. Hydrazine hydrate ≤2.0% and semicarbazide ≥95.0%; the reaction was completed. Then, the first post-treatment was carried out. The reaction system was cooled to 30°C to 35°C, filtered, and the filtrate was transferred to a 500mL four-necked bottle, heated to 65°C to 70°C, and 195g of concentrated hydrochloric acid was added dropwise. There was heat release during the addition, and the dropping was completed in about 1h. The mixture was kept at 65°C to 70°C and stirred for 15min. The filter cake was obtained, 71.1g of ethanol was added, the temperature was raised to 75°C to 80°C and stirred for 1h, the temperature was slowly lowered to 15°C, and filtered to obtain a wet product (wet hydrochloride semicarbazide). The wet product was placed in a reduced pressure vacuum oven and dried at 35°C to 40°C under reduced pressure (-0.01MPa) until the loss on drying was ≤0.5%, to obtain a dried semicarbazide hydrochloride product. The purity was 95.15% as determined by HPLC, and the yield was 79.1%.

[0071] (2) Synthesis of pyridine triazole. Add 10 g of 2-chloropyridine, 22.04 g of ethylene glycol monoethyl ether, and 15.72 g of hydrochloric acid semicarbazide into a 100 mL four-necked flask, heat to 130°C to 135°C, reflux, add 0.66 g of concentrated sulfuric acid at 130°C to 135°C, and keep the temperature to react for 7 hours. Take a sample, and HPLC test 2-chloropyridine ≤1.0%, pyridine triazole ≥84.0%, and the reaction is complete.

[0072] Finally, the second post-treatment was performed. The reaction system was cooled to 60°C to 65°C, 30g of water was added, stirred for 15min, cooled to 0°C to 5°C, and filtered. The filter cake was washed with 20g*2 water until neutral to obtain a wet product. The wet product was placed in a reduced pressure vacuum oven and dried at 35°C to 40°C under reduced pressure (-0.01MPa) until the moisture content was ≤0.3%, and a dried product of pyridinetriazole was obtained. The purity of the dried product was 99.22% according to HPLC, and the yield was 57.32%.

[0073] (3) Recovering 2-hydrazinepyridine. The mother liquor from step (2) was desolventized at 60°C to 65°C until there was no fraction, 5 mL of water was added and stirred for 30 min, and then filtered. 5 mL of ethanol was added to the filter cake for pulping, and filtered. The wet filtered product was placed in a reduced pressure vacuum oven and dried at 30°C to 35°C under reduced pressure (-0.01 MPa) until the loss on drying was ≤0.5%, to obtain a dried 2-hydrazinepyridine product, with a purity of 99.25% as determined by HPLC.

[0074] (4) Add 3.84 g of 2-hydrazinepyridine and 4.61 g of urea to a 50 mL four-necked bottle, raise the temperature to 130°C, and keep the temperature for 3 hours. Take a sample, and test HPLC to determine if 2-hydrazinepyridine is ≤1.0% and pyridinetriazolone is ≥95.0%. The reaction is complete.

[0075] Finally, the second step post-treatment is carried out. The reaction system is cooled to 60°C to 65°C, 12g of water is added, stirred for 15min, cooled to 0°C to 5°C, and filtered. The filter cake is washed with 8g*2 water until neutral to obtain a wet product. The wet product is placed in a reduced pressure vacuum oven and dried at 35°C to 40°C under reduced pressure (-0.01MPa) until the moisture content is ≤0.3% to obtain a dried product of pyridine triazole. The purity of the product detected by HPLC is 99.38%, and the yield is 60.44%, accounting for 24% of the molar yield of 2-chloropyridine in step (2), and 81% of the total yield of pyridine triazole synthesis (calculated based on the amount of 2-chloropyridine fed).

[0076] Example 3

[0077] (1) Synthesis of hydrochloric acid semicarbazide. A 250mL four-necked bottle was equipped with a 50% sulfuric acid aqueous solution tail gas absorption device and an ice-water bath condenser. 30.00g of 80% hydrazine hydrate solution was added thereto and the temperature was raised to 80℃~85℃; the temperature was controlled at 80℃~85℃ and 17.3g, 13g, 8.64g and 4.32g of urea were added four times with an interval of 45min respectively, the temperature was raised to 100℃~105℃ and the reaction was kept warm for 3h. A small amount of solid precipitated and the system was slightly turbid. The reaction was kept warm for 0.5h. Sampling was performed and HPLC detection was performed. Hydrazine hydrate ≤2.0% and semicarbazide ≥95.0%; the reaction was completed. Then, the first post-treatment was carried out. The reaction system was cooled to 30°C to 35°C, filtered, and the filtrate was transferred to a 500mL four-necked bottle, heated to 65°C to 70°C, and 195g of concentrated hydrochloric acid was added dropwise. There was heat release during the addition, and the dropping was completed in about 1h. The mixture was kept at 65°C to 70°C and stirred for 15min. The filter cake was obtained, 71.1g of ethanol was added, the temperature was raised to 75°C to 80°C and stirred for 1h, the temperature was slowly lowered to 15°C, and filtered to obtain a wet product (wet hydrochloride semicarbazide). The wet product was placed in a reduced pressure vacuum oven and dried at 35°C to 40°C under reduced pressure (-0.01MPa) until the loss on drying was ≤0.5%, to obtain a dried semicarbazide hydrochloride product. The purity was 95.15% as determined by HPLC, and the yield was 79.1%.

[0078] (2) Synthesis of pyridine triazole. Add 10 g of 2-chloropyridine, 21.13 g of ethylene glycol monomethyl ether, and 15.72 g of hydrochloric acid semicarbazide into a 100 mL four-necked flask, heat to 130°C to 135°C, reflux, add 0.66 g of concentrated sulfuric acid at 130°C to 135°C, and keep the temperature to react for 7 hours. Take a sample, and HPLC test 2-chloropyridine ≤1.0%, pyridine triazole ≥84.0%, and the reaction is complete.

[0079] Finally, the second post-treatment was performed. The reaction system was cooled to 60°C to 65°C, 30g of water was added, stirred for 15min, cooled to 0°C to 5°C, and filtered. The filter cake was washed with 20g*2 water until neutral to obtain a wet product. The wet product was placed in a reduced pressure vacuum oven and dried at 35°C to 40°C under reduced pressure (-0.01MPa) until the moisture content was ≤0.3%, and a dried product of pyridinetriazole was obtained. The purity of the dried product was 99.78% and the yield was 63.24% according to HPLC.

[0080] (3) Recovering 2-hydrazinepyridine. The mother liquor from step (2) was desolventized at 60°C to 65°C until there was no fraction, 5 mL of water was added and stirred for 30 min, and then filtered. 5 mL of ethanol was added to the filter cake for pulping, and filtered. The wet filtered product was placed in a reduced pressure vacuum oven and dried at 30°C to 35°C under reduced pressure (-0.01 MPa) until the loss on drying was ≤0.5%, to obtain a dried 2-hydrazinepyridine product, with a purity of 99.33% as determined by HPLC.

[0081] (4) Add 3.36 g of 2-hydrazinepyridine and 3.70 g of urea to a 50 mL four-necked bottle, raise the temperature to 130°C, and keep the temperature for 3 hours. Take a sample, and test HPLC to determine if 2-hydrazinepyridine is ≤1.0% and pyridinetriazolone is ≥95.0%. The reaction is complete.

[0082] Finally, the second step post-treatment is performed. The reaction system is cooled to 60°C to 65°C, 10g of water is added, stirred for 15min, cooled to 0°C to 5°C, and filtered. The filter cake is washed with 6.7g*2 water until neutral to obtain a wet product. The wet product is placed in a reduced pressure vacuum oven and dried at 35°C to 40°C under reduced pressure (-0.01MPa) until the moisture content is ≤0.3% to obtain a dried product of pyridine triazole. The purity of the product detected by HPLC is 99.62%, and the yield is 59.33%, accounting for 20.76% of the molar yield of 2-chloropyridine in step (2), and the total yield of pyridine triazole synthesis is 84% ​​(calculated based on the amount of 2-chloropyridine fed).

[0083] Example 4

[0084] (1) Synthesis of hydrochloric acid semicarbazide. A 250mL four-necked bottle was equipped with a 50% sulfuric acid aqueous solution tail gas absorption device and an ice-water bath condenser. 30.00g of 80% hydrazine hydrate solution was added thereto and the temperature was raised to 80℃~85℃; the temperature was controlled at 80℃~85℃ and 17.3g, 13g, 8.64g and 4.32g of urea were added four times with an interval of 45min respectively, the temperature was raised to 100℃~105℃ and the reaction was kept warm for 3h. A small amount of solid precipitated and the system was slightly turbid. The reaction was kept warm for 0.5h. Sampling was performed and HPLC detection was performed. Hydrazine hydrate ≤2.0% and semicarbazide ≥95.0%; the reaction was completed. Then, the first post-treatment was carried out. The reaction system was cooled to 30°C to 35°C, filtered, and the filtrate was transferred to a 500mL four-necked bottle, heated to 65°C to 70°C, and 195g of concentrated hydrochloric acid was added dropwise. There was heat release during the addition, and the dropping was completed in about 1h. The mixture was kept at 65°C to 70°C and stirred for 15min. The filter cake was obtained, 71.1g of ethanol was added, the temperature was raised to 75°C to 80°C and stirred for 1h, the temperature was slowly lowered to 15°C, and filtered to obtain a wet product (wet hydrochloride semicarbazide). The wet product was placed in a reduced pressure vacuum oven and dried at 35°C to 40°C under reduced pressure (-0.01MPa) until the loss on drying was ≤0.5%, to obtain a dried semicarbazide hydrochloride product. The purity was 95.15% as determined by HPLC, and the yield was 79.1%.

[0085] (2) Synthesis of pyridine triazole. Add 10 g of 2-chloropyridine, 21.13 g of ethylene glycol monomethyl ether, and 15.72 g of hydrochloric acid semicarbazide into a 100 mL four-necked flask, heat to 130°C to 135°C, reflux, add 0.86 g of concentrated sulfuric acid at 130°C to 135°C, and keep the temperature to react for 7 hours. Take a sample, and HPLC test 2-chloropyridine ≤1.0%, pyridine triazole ≥84.0%, and the reaction is complete.

[0086] Finally, the second post-treatment was performed. The reaction system was cooled to 60°C to 65°C, 30g of water was added, stirred for 15min, cooled to 0°C to 5°C, and filtered. The filter cake was washed with 20g*2 water until neutral to obtain a wet product. The wet product was placed in a reduced pressure vacuum oven and dried at 35°C to 40°C under reduced pressure (-0.01MPa) until the moisture content was ≤0.3%, and a dried product of pyridinetriazole was obtained. The purity of the dried product was 99.85% by HPLC, and the yield was 70.22%.

[0087] (3) Recovering 2-hydrazinepyridine. The mother liquor from step (2) was desolventized at 60°C to 65°C until there was no fraction, 5 mL of water was added and stirred for 30 min, and then filtered. 5 mL of ethanol was added to the filter cake for pulping, and filtered. The wet filtered product was placed in a reduced pressure vacuum oven and dried at 30°C to 35°C under reduced pressure (-0.01 MPa) until the loss on drying was ≤0.5%, to obtain a dried 2-hydrazinepyridine product, with a purity of 99.13% as determined by HPLC.

[0088] (4) Add 2.88 g of 2-hydrazinepyridine and 3.17 g of urea to a 50 mL four-necked bottle, raise the temperature to 130°C, and keep the temperature for 3 hours. Take a sample, and test HPLC to determine if 2-hydrazinepyridine is ≤1.0% and pyridinetriazolone is ≥95.0%. The reaction is complete.

[0089] Finally, the second step post-treatment is performed. The reaction system is cooled to 60°C to 65°C, 9g of water is added, stirred for 15min, cooled to 0°C to 5°C, and filtered. The filter cake is washed with 6g*2 water until neutral to obtain a wet product. The wet product is placed in a reduced pressure vacuum oven and dried at 35°C to 40°C under reduced pressure (-0.01MPa) until the moisture content is ≤0.3% to obtain a dried product of pyridine triazole. The purity of the product detected by HPLC is 99.72%, and the yield is 60.09%, accounting for 18% of the molar yield of 2-chloropyridine in step (2) and 88% of the total yield of pyridine triazole synthesis (calculated based on the amount of 2-chloropyridine fed).

[0090] Comparative Example

[0091] (1) Synthesis of hydrochloric acid semicarbazide. A 250mL four-necked bottle was equipped with a 50% sulfuric acid aqueous solution tail gas absorption device and an ice-water bath condenser. 30.00g of 80% hydrazine hydrate solution was added thereto and the temperature was raised to 80℃~85℃; 17.3g, 13g, 8.64g, and 4.32g of urea were added four times at an interval of 45min at a temperature of 80℃~85℃ respectively, and the temperature was raised to 100℃~105℃ for 3h of heat preservation reaction. A small amount of solid precipitated and the system was slightly turbid. The heat preservation reaction was continued for 0.5h. Sampling was performed and HPLC detection was performed. Hydrazine hydrate ≤2.0%, semicarbazide ≥95.0%; the reaction was completed. Then, post-treatment was performed. The reaction system was cooled to 65°C-70°C, and 195 g of concentrated hydrochloric acid was added dropwise. There was heat release during the addition process, and the addition was completed in about 1 h. The temperature was kept at 65°C-70°C and stirred for 15 min. The filter cake was obtained by suction filtration. 71.1 g of ethanol was added, the temperature was raised to 75°C-80°C and stirred for 1 h. The temperature was slowly lowered to 15°C, and the filter cake was obtained by suction filtration (wet semicarbazide hydrochloride). The wet product was placed in a reduced pressure vacuum oven and dried at 35°C-40°C under reduced pressure (-0.01 MPa) until the loss on drying was ≤0.5%, to obtain a dried semicarbazide hydrochloride product. The purity was 78.54% by HPLC detection, and the yield was 67.24%.

[0092] (2) Synthesis of pyridine triazole. Add 10 g of 2-chloropyridine, 22.04 g of ethylene glycol monoethyl ether, and 19.64 g of hydrochloric acid semicarbazide into a 100 mL four-necked flask, heat to 130°C to 135°C, reflux, add 0.66 g of concentrated sulfuric acid at 130°C to 135°C, and keep the temperature to react for 7 hours. Take a sample, and HPLC test 2-chloropyridine ≤1.0%, pyridine triazole ≥84.0%, and the reaction is complete.

[0093] Finally, the second post-treatment was performed. The reaction system was cooled to 60°C to 65°C, 30g of water was added, stirred for 15min, cooled to 0°C to 5°C, and filtered. The filter cake was washed with 20g*2 water until neutral to obtain a wet product. The wet product was placed in a reduced pressure vacuum oven and dried at 35°C to 40°C under reduced pressure (-0.01MPa) until the moisture content was ≤0.3%, and a dried product of pyridinetriazole was obtained. The purity of the product was 98.22% according to HPLC, the yield was 59.42%, and the nominal content was 35.15%.

[0094] Compared with Examples 1-4, it can be seen that the purity of the pyridinetriazolone obtained in the comparative example is lower, while the purity of the pyridinetriazolone prepared in Examples 1-4 is higher, and both are higher than 99%.

[0095] The above description is only a preferred embodiment of the present invention and is not intended to limit the invention. Any modifications, equivalent substitutions, improvements, etc. made within the design concept of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing pyridinetriazolone, characterized in that: It includes the following steps: S1. Add hydrazine hydrate to a reaction flask, raise the temperature to 80°C to 85°C, add urea in batches, and continue to raise the temperature to 100°C to 105°C for heat preservation and reaction until solid precipitation is observed in the system, extend the heat preservation reaction for 0.5h, cool to room temperature, and obtain a white suspension; filter the white suspension, transfer the filtrate to a reaction flask, add hydrochloric acid dropwise to form a salt, cool and filter, and slurry the filter cake with a solvent to obtain an intermediate hydrochloric acid semicarbazide; S2, add semicarbazide hydrochloride and 2-chloropyridine to a reaction flask, add a solvent, heat to 130°C to 135°C, reflux, add a cyclization reagent, keep warm for 9 hours, and obtain a yellow suspension 1; add water to the yellow suspension 1, cool and filter, wash the filter cake with water until it is neutral, and obtain the target product pyridine triazole; S3, filtering the mother liquor and spinning it to dryness, beating with ethanol, cooling and filtering to obtain the recovered 2-hydrazinepyridine; S4, adding 2-hydrazinepyridine and urea to a reaction flask, heating to 130°C-135°C, keeping the temperature for 4 hours to obtain a yellow suspension II; cooling the yellow suspension II to room temperature, adding water for suction filtration, washing the filter cake with water until it is neutral, and obtaining the target product pyridinetriazolone; S5. Combine the target product pyridinetriazolone and dry it under reduced pressure.

2. The method for preparing pyridinetriazolone according to claim 1, wherein: Step S1 and / or step S2 is equipped with a 50% sulfuric acid aqueous solution tail gas absorption device.

3. The method for preparing pyridinetriazolone according to claim 1, wherein: In step S1, the mass ratio of hydrazine hydrate to urea is 1:1.41 to 1:1.

92.

4. The method for preparing pyridinetriazolone according to claim 1, wherein: In step S1, the interval time for adding urea in batches is 45 minutes, and urea is added in four times, and the weight ratio of urea added in the four times is 4:3:2:

1.

5. The method for preparing pyridinetriazolone according to claim 1, wherein: The hydrazine hydrate in step S1 is a hydrazine hydrate solution with a concentration of 80%.

6. The method for preparing pyridinetriazolone according to claim 1, characterized in that: The amount of hydrochloric acid added dropwise in step S1 is 2.9 to 6.5 times the mass of hydrazine hydrate fed; and / or The hydrochloric acid added dropwise in step S1 is 36% hydrochloric acid or 30% hydrochloric acid.

7. The method for preparing pyridinetriazolone according to claim 1, characterized in that: The solvent used in step S1 is methanol or ethanol; and / or The solvent used in step S2 is ethylene glycol monomethyl ether or ethylene glycol monoethyl ether.

8. The method for preparing pyridinetriazolone according to claim 1, characterized in that: The mass ratio of 2-chloropyridine to semicarbazide hydrochloride in step S2 is 1:1.560 to 1:1.964; and / or In step S4, the feed mass ratio of 2-hydrazinepyridine to urea is 1:1.1 to 1:1.

3.

9. The method for preparing pyridinetriazolone according to claim 1, wherein The cyclization reagent used in step S2 is concentrated sulfuric acid.

10. The method for preparing pyridinetriazolone according to claim 9, characterized in that: The amount of concentrated sulfuric acid used is 0.066 to 0.086 times the weight of 2-chloropyridine.

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