Synthesis method of 1, 2, 3-triazole-4, 5-dicarboxylic acid

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a synthetic method of a chemical intermediate 1, 2, 3-triazole-4, 5-dicarboxylic acid, which comprises the following steps: introducing O3 gas into a benzotriazole acidic aqueous solution with the pH value of not more than 1 and lower than room temperature to carry out addition reaction, and directly carrying out oxidation reaction on an addition reaction product and hydrogen peroxide to prepare the 1, 2, 3-triazole-4, 5-dicarboxylic acid. The invention discloses 1, 2, 3-triazole-4, 5-dicarboxylic acid. The preparation method disclosed by the invention is low in production cost, relatively high in yield and purity, green and environment-friendly in process and suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and relates to a preparation method of fine chemical products, in particular to a synthesis method of a chemical intermediate 1,2,3-triazole-4,5-dicarboxylic acid. Background Art

[0002] 1,2,3-Triazole-4,5-dicarboxylic acid can be used to synthesize many complex compounds. As an important pharmaceutical and pesticide intermediate, it is indispensable in the synthesis of many antibiotics such as β-lactam antibiotics.

[0003] In the prior art, the process routes for preparing 1,2,3-triazole-4,5-dicarboxylic acid mainly include the following:

[0004] 1) Using benzotriazole as raw material, it is obtained by oxidation with potassium permanganate. The synthetic route is as follows:

[0005] Among them, CN 101104607A uses potassium permanganate for oxidation under acidic conditions, which not only has high reaction temperature and high energy consumption, increasing the risk of process operation, but also has a dark color of the reaction product and low product purity. It requires a large amount of highly polar solvent for refining and produces a large amount of organic waste liquid, which has high environmental protection treatment costs.

[0006] CN 106946803A reports that triazole dicarboxylic acid is obtained by oxidation with potassium permanganate using tetrabutylammonium bromide as a catalyst in a mixed acidic solution of water and chloroform. On the one hand, chloroform is toxic and carcinogenic, which harms the environment; on the other hand, the use of a catalyst increases the cost of raw materials, and the purification process of the product is cumbersome, requiring multiple extractions and pH adjustments to obtain the product.

[0007] Different from the above documents, CN 109096213A obtains the target product by oxidation with potassium permanganate under alkaline conditions, so the product has low purity and is a complex salt of triazoledicarboxylic acid and benzotriazole. It needs to be refined to obtain a product with higher purity, which increases the difficulty of operation and production cost.

[0008] In addition, the above process route has a strong oxidizing property, the reaction is violent and difficult to control, and the reaction will produce a large amount of solid waste manganese dioxide, which is difficult to handle and causes serious environmental pollution.

[0009] 2) By adding a special catalyst, the oxidation of benzotriazole using hydrogen peroxide can be successfully achieved.

[0010] The catalysts used in this type of process route include transition metal oxides or salts (CN 109651273A), heavy metals or heavy metal salts (US 005917049A), etc. However, the catalysts are expensive to prepare, difficult to recycle and difficult to handle, and it is difficult to achieve industrial production.

[0011] 3) CN 116947769A proposes that concentrated sulfuric acid is used as a solvent and catalyst, and hydrogen peroxide can be directly used to oxidize benzotriazole to synthesize triazole dicarboxylic acid. The hydrogen peroxide raw material used in this method is easy to source, and the process is environmentally friendly and green, but the amount of concentrated sulfuric acid and hydrogen peroxide required for the synthesis is large, which not only increases the cost of raw materials, but also produces a large amount of acid-containing wastewater. In particular, this process route directly uses hydrogen peroxide to oxidize the relatively stable benzene ring, and the oxidation effect is very poor. Summary of the invention

[0012] The purpose of the invention is to solve the problems existing in the prior art and provide a green and environmentally friendly method for synthesizing 1,2,3-triazole-4,5-dicarboxylic acid.

[0013] Ozone is an excellent strong oxidant. Under acidic conditions, it can react with aromatic hydrocarbon compounds containing double bonds to generate ozone cyclization adducts, peroxide compounds or aldehyde compounds. It has a fast reaction speed, mild conditions, and no secondary pollution. It has been widely used in the organic synthesis industry. After a lot of exploration and research, the present invention proposes a synthesis method of synthesizing 1,2,3-triazole-4,5-dicarboxylic acid by first using ozone and benzotriazole for addition reaction and then oxidizing with hydrogen peroxide to solve the problems of high material cost and serious pollution in the preparation of 1,2,3-triazole-4,5-dicarboxylic acid in the prior art.

[0014] The 1,2,3-triazole-4,5-dicarboxylic acid synthesis method of the present invention comprises firstly introducing O3 gas into an acidic aqueous solution of benzotriazole having a pH value lower than room temperature and not greater than 1 to carry out an addition reaction, and then directly carrying out an oxidation reaction with hydrogen peroxide on the addition reaction product to prepare 1,2,3-triazole-4,5-dicarboxylic acid.

[0015] Furthermore, the present invention provides a more detailed synthesis method of the 1,2,3-triazole-4,5-dicarboxylic acid, comprising:

[0016] 1) Using benzotriazole as raw material and water as solvent, stirring and dissolving under acidic conditions with a pH value of no more than 1 to obtain a reaction solution;

[0017] 2) Controlling the temperature at 0-15°C, introducing O3 gas into the reaction solution to perform an addition reaction to oxidize benzotriazole to benzotriazole ozonide;

[0018] 3) Directly add hydrogen peroxide as an oxidant to the addition reaction product, control the reaction temperature at 40-70° C. to carry out oxidation reaction, and prepare a 1,2,3-triazole-4,5-dicarboxylic acid reaction solution.

[0019] Furthermore, the present invention adjusts the pH value of the prepared 1,2,3-triazole-4,5-dicarboxylic acid reaction solution to 2.5-3.0 for crystallization to precipitate 1,2,3-triazole-4,5-dicarboxylic acid.

[0020] More specifically, the crystallization process is preferably carried out at a temperature of 0 to 10°C.

[0021] Preferably, the molar ratio of the raw material benzotriazole to O3 in the present invention is 1:(2-4).

[0022] Preferably, the amount of hydrogen peroxide used for the oxidation reaction in the present invention is 2 to 3.5 times the molar amount of the raw material benzotriazole, calculated as hydrogen peroxide.

[0023] More specifically, the concentration of hydrogen peroxide in the present invention is 25 to 50 wt.%.

[0024] Preferably, the oxidation reaction time is 10 to 60 hours, more preferably 10 to 25 hours.

[0025] The invention provides a method for preparing 1,2,3-triazole-4,5-dicarboxylic acid, wherein the raw material benzotriazole is first subjected to addition reaction with O3 under acidic conditions and low temperature to obtain a mixture containing a triazole structure, and then oxidized with hydrogen peroxide to obtain 1,2,3-triazole-4,5-dicarboxylic acid. The reaction can be carried out in solvent water, the raw materials used are cheap and easily available, and no toxic reagents are used.

[0026] The ozone used in the present invention is a green oxidant, the amount of hydrogen peroxide used is small, the oxidation reaction is carried out at a relatively low temperature, the production process has low energy consumption, a simple process, and is safe and reliable.

[0027] The product purity and yield of the synthesis method of the present invention are high, no toxic or harmful substances are generated during the reaction, no solid waste is generated, the method is environmentally friendly, conforms to the concept of green production, and is suitable for industrial scale-up production. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 This is the HPLC spectrum of the raw material benzotriazole.

[0029] Figure 2 This is the HPLC spectrum of the intermediate product of the reaction between benzotriazole and ozone.

[0030] Figure 3 This is the HPLC spectrum of the final product 1,2,3-triazole-4,5-dicarboxylic acid. Implementation

[0031] The specific implementation of the present invention is further described in detail below in conjunction with the accompanying drawings and examples. The following examples are only used to more clearly illustrate the technical solution of the present invention so that those skilled in the art can well understand and utilize the present invention, rather than limiting the scope of protection of the present invention.

[0032] The production processes, experimental methods or detection methods involved in the embodiments and comparative examples of the present invention are all conventional methods in the prior art unless otherwise specified, and their names and / or abbreviations are all conventional names in the field and are very clear and unambiguous in the relevant application fields. Those skilled in the art can understand the conventional process steps based on the names and apply the corresponding equipment to implement them according to conventional conditions or the conditions recommended by the manufacturer.

[0033] The various instruments, equipment, raw materials or reagents used in the embodiments of the present invention are not particularly limited in terms of their sources, and are all conventional products that can be purchased through regular commercial channels, or can be prepared according to conventional methods well known to those skilled in the art.

[0034] The present invention still uses benzotriazole as a starting material, but adopts a step-by-step oxidation method to synthesize 1,2,3-triazole-4,5-dicarboxylic acid.

[0035] The first step is to introduce a certain amount of O3 gas into the benzotriazole aqueous solution for addition reaction to oxidize the benzotriazole into benzotriazole ozonide.

[0036] The above reaction is carried out with water as the solvent system. In order to increase the solubility of O3 in water and the addition reaction rate with aromatic hydrocarbons, the reaction of the present invention is carried out under acidic conditions and low temperature. The reaction obtains a complex mixture containing a triazole structure. The possible structures of the reaction products include: , , , .

[0037] Specifically, the low temperature condition is to control the reaction solution at 0-15°C.

[0038] Preferably, the acid used to adjust the pH value of the benzotriazole aqueous solution of the present invention is a conventional inorganic or organic acid that does not react with the reaction raw materials, including but not limited to sulfuric acid, nitric acid, acetic acid, phosphoric acid, or a mixture of any proportion of any of the above, as long as the pH value is less than 1.

[0039] Preferably, the molar ratio of benzotriazole to O3 in the addition reaction is 1:(2-4).

[0040] The second step is to continue to oxidize the addition reaction product with hydrogen peroxide to prepare a 1,2,3-triazole-4,5-dicarboxylic acid reaction solution.

[0041] Preferably, the oxidation reaction is carried out at a temperature of 40 to 70°C.

[0042] Preferably, the oxidation reaction time is 10 to 60 hours, more preferably 10 to 25 hours.

[0043] Preferably, the amount of hydrogen peroxide used for the oxidation reaction in the present invention is 2 to 3.5 times the molar amount of the raw material benzotriazole, calculated as hydrogen peroxide.

[0044] More specifically, the concentration of hydrogen peroxide in the present invention is 25 to 50 wt.%.

[0045] The third step is to adjust the pH value of the prepared 1,2,3-triazole-4,5-dicarboxylic acid reaction solution to 2.5-3.0 for crystallization to precipitate the 1,2,3-triazole-4,5-dicarboxylic acid product.

[0046] Specifically, the crystallization process is preferably carried out at a temperature of 0 to 10°C.

[0047] Preferably, the crystallization time is 1 to 3 hours.

[0048] Preferably, in the present invention, any alkaline solution such as NaOH solution, KOH solution or ammonia solution can be used to adjust the pH value of the reaction solution. Example

[0049] Example 1

[0050] Weigh 60 g of benzotriazole and add it to 500 mL of 20% sulfuric acid solution. After stirring to dissolve, cool to 0°C and introduce O3 gas for addition reaction.

[0051] After 6 hours of ventilation, the HPLC spectrum of the reaction solution was as follows: Figure 2 , multiple chromatographic peaks of the intermediate products of the reaction between benzotriazole and ozone appeared around the retention time of 3 min, and no peak appeared around the retention time of 5.5 min ( Figure 1 The retention time of the raw material benzotriazole is 5.304min), which proves that the raw material benzotriazole has been completely consumed, and the residual amount is less than 1%, so the reaction is stopped.

[0052] A total of 351 g of O was absorbed during the reaction.

[0053] The reaction solution was heated to 45°C, 76 g of 50% hydrogen peroxide was added, and the mixture was kept warm for 25 h. HPLC tracking detected that there was only one chromatographic peak with a retention time of 2.737 min in the reaction solution ( Figure 3), indicating that the intermediate product has been completely converted into 1,2,3-triazole-4,5-dicarboxylic acid.

[0054] The reaction solution was cooled to 0°C, the pH value was adjusted to 2.5-3.0 with 25% ammonia water, and crystallized at 0°C for 1 hour. The solution was filtered, washed with deionized water, and dried to obtain 70.7 g of dry 1,2,3-triazole-4,5-dicarboxylic acid with a molar yield of 89.4% and a detected product content of 97.3%.

[0055] Example 2

[0056] Weigh 60g of benzotriazole and add it to 500mL of 25% nitric acid solution. After stirring and dissolving, cool to 5℃ and introduce O3 gas for addition reaction. Stop the reaction after 9h of ventilation. A total of 60g of O3 is absorbed during the reaction.

[0057] The reaction solution was heated to 50°C, 115 g of 45% hydrogen peroxide was added, the reaction was kept warm for 21 h, the temperature was lowered to 3°C, the pH value was adjusted to 2.5-3.0 with 30% NaOH solution, crystallization was maintained at 3°C ​​for 1 h, filtered, washed with deionized water and dried to obtain 71.4 g of dry 1,2,3-triazole-4,5-dicarboxylic acid with a molar yield of 90.2%. The product content was detected to be 96.8%.

[0058] Example 3

[0059] A mixed acid solution was prepared with 85 g of 70% concentrated nitric acid, 50 g of glacial acetic acid and 380 mL of deionized water.

[0060] Weigh 60g of benzotriazole and add it to the mixed acid solution. After stirring and dissolving, cool to 8°C and introduce O3 gas for addition reaction. Stop the reaction after 11.5h of ventilation. A total of 60g of O3 is absorbed during the reaction.

[0061] The reaction solution was heated to 60°C, 160 g of 30% hydrogen peroxide was added, the reaction was kept warm for 16 h, the temperature was lowered to 5°C, the pH value was adjusted to 2.5-3.0 with 25% ammonia water, the crystallization was maintained at 5°C for 2.5 h, the solution was filtered, washed with deionized water and dried to obtain 71.9 g of dry 1,2,3-triazole-4,5-dicarboxylic acid with a molar yield of 90.9% and a detected product content of 97.8%.

[0062] Example 4

[0063] A mixed acid solution was prepared with 80 g of 98% concentrated sulfuric acid, 80 g of glacial acetic acid and 360 mL of deionized water.

[0064] Weigh 60g of benzotriazole and add it to the mixed acid solution. After stirring and dissolving, cool to 10°C and introduce O3 gas for addition reaction. Stop the reaction after 12.5h of ventilation. A total of 68g of O3 is absorbed during the reaction.

[0065] The reaction solution was heated to 55°C, 150 g of 40% hydrogen peroxide was added, the reaction was kept warm for 18.5 h, the temperature was lowered to 2°C, the pH value was adjusted to 2.5-3.0 with 30% KOH solution, crystallization was maintained at 2°C for 1 h, filtered, washed with deionized water and dried to obtain 72.2 g of dry 1,2,3-triazole-4,5-dicarboxylic acid with a molar yield of 91.2%. The detected product content was 96.2%.

[0066] Example 5

[0067] A mixed acid solution was prepared with 60 g of 98% concentrated sulfuric acid, 70 g of 85% phosphoric acid and 390 mL of deionized water.

[0068] Weigh 60g of benzotriazole and add it to the mixed acid solution. After stirring and dissolving, cool to 12°C and introduce O3 gas for addition reaction. Stop the reaction after 15.5h of ventilation. A total of 85g of O3 is absorbed during the reaction.

[0069] The reaction solution was heated to 65°C, 206 g of 25% hydrogen peroxide was added, the reaction was kept warm for 14 h, the temperature was lowered to 8°C, the pH value was adjusted to 2.5-3.0 with 30% NaOH solution, crystallization was maintained at 8°C for 2.5 h, filtered, washed with deionized water and dried to obtain 72.6 g of dry 1,2,3-triazole-4,5-dicarboxylic acid with a molar yield of 91.8% and a detected product content of 97.4%.

[0070] Example 6

[0071] A mixed acid solution was prepared with 65 g of 98% concentrated sulfuric acid, 20 g of glacial acetic acid, 25 g of 85% phosphoric acid and 400 mL of deionized water.

[0072] Weigh 60g of benzotriazole and add it to the mixed acid solution. After stirring and dissolving, cool to 15°C and introduce O3 gas for addition reaction. Stop the reaction after 18h of ventilation. A total of 96g of O3 is absorbed during the reaction.

[0073] The reaction solution was heated to 70°C, 90 g of 50% hydrogen peroxide was added, the reaction was kept warm for 10 h, the temperature was lowered to 10°C, the pH value was adjusted to 2.5-3.0 with 30% KOH solution, and crystallization was maintained at 10°C for 3 h. The reaction solution was filtered, washed with deionized water, and dried to obtain 72.8 g of dry 1,2,3-triazole-4,5-dicarboxylic acid with a molar yield of 92.0%. The product content was detected to be 96.5%.

[0074] Comparative Example 1

[0075] Weigh 60 g of benzotriazole and add it to 500 mL of 20% sulfuric acid solution. After stirring to dissolve, introduce O3 gas at 35-40°C for addition reaction.

[0076] The reaction process was detected by HPLC, and no intermediate product chromatographic peak appeared near the retention time of 3min. Figure 1 The chromatographic peak of raw material benzotriazole with a retention time of 5.304 min showed almost no change.

[0077] On the one hand, O3 gas is unstable at high temperatures and decomposes quickly. On the other hand, the higher the temperature, the lower the solubility of O3 gas in water, so the addition reaction hardly occurs.

[0078] Comparative Example 2

[0079] Weigh 60g of benzotriazole and add it to 500mL of 0.3% sulfuric acid solution (pH=1.2). After stirring and dissolving, cool to 0℃ and introduce O3 gas for addition reaction. Stop the reaction after 15h of ventilation. A total of 39g of O3 is absorbed during the reaction. The residual amount of raw material benzotriazole in the reaction solution is about 18%.

[0080] The reaction solution was heated to 45°C, 76 g of 50% hydrogen peroxide was added, the reaction was kept warm for 25 h, the temperature was lowered to 0°C, the pH value was adjusted to 2.5-3.0 with 25% ammonia water, the crystallization was kept at 0°C for 1 h, the solution was filtered, washed with deionized water and dried to obtain 48.3 g of dry 1,2,3-triazole-4,5-dicarboxylic acid with a molar yield of 61.1% and a detected product content of 74.4%.

[0081] Compared with Example 1, although the time for passing O3 gas in this comparative example is greatly extended, the yield and content of 1,2,3-triazole-4,5-dicarboxylic acid are still significantly reduced. This is because the solubility of O3 gas in water is related to the pH value. The lower the pH value, the higher the solubility. The pH value in this comparative example is higher than the actual reaction requirement, and the O3 gas absorption rate is reduced, resulting in incomplete addition reaction.

[0082] Comparative Example 3

[0083] Weigh 60g of benzotriazole and add it to 500mL of 20% sulfuric acid solution. After stirring and dissolving, cool to 0℃ and introduce O3 gas for addition reaction. After 6h of ventilation, stop the reaction. A total of 51g of O3 is absorbed during the reaction.

[0084] The reaction solution was heated to 85°C, 105 g of 50% hydrogen peroxide was added, and the reaction was kept warm for 25 hours. The temperature was then lowered to 0°C, and the pH value was adjusted to 2.5-3.0 with 25% ammonia water. The solution was kept at 0°C for crystallization for 1 hour. The solution was filtered, washed with deionized water, and dried to obtain 64.6 g of dry 1,2,3-triazole-4,5-dicarboxylic acid with a molar yield of 81.7%. The product content was detected to be 87.8%.

[0085] Compared with Example 1, the oxidation reaction temperature in this comparative example was increased, resulting in the decomposition of hydrogen peroxide. Although more hydrogen peroxide was added, the amount of hydrogen peroxide actually participating in the reaction was reduced, resulting in incomplete oxidation reaction.

[0086] The above embodiments of the present invention do not describe all the details in detail, nor limit the present invention to the above embodiments. Various changes, modifications, substitutions and variations made by ordinary technicians in this field without departing from the principles and purpose of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for synthesizing 1,2,3-triazole-4,5-dicarboxylic acid, comprising firstly introducing O3 gas into an acidic aqueous solution of benzotriazole having a pH value of not more than 1 and below room temperature for an addition reaction, and then directly subjecting the addition reaction product to an oxidation reaction with hydrogen peroxide to prepare 1,2,3-triazole-4,5-dicarboxylic acid.

2. The method for synthesizing 1,2,3-triazole-4,5-dicarboxylic acid according to claim 1, comprising: 1) Using benzotriazole as raw material and water as solvent, stirring and dissolving under acidic conditions with a pH value of no more than 1 to obtain a reaction solution; 2) Controlling the temperature at 0-15°C, introducing O3 gas into the reaction solution to perform an addition reaction to oxidize benzotriazole to benzotriazole ozonide; 3) Directly add hydrogen peroxide as an oxidant to the addition reaction product, control the reaction temperature at 40-70° C. to carry out oxidation reaction, and prepare a 1,2,3-triazole-4,5-dicarboxylic acid reaction solution.

3. The method for synthesizing 1,2,3-triazole-4,5-dicarboxylic acid according to claim 2, further comprising adjusting the pH value of the reaction solution of the prepared 1,2,3-triazole-4,5-dicarboxylic acid to 2.5 to 3.0 for crystallization to precipitate 1,2,3-triazole-4,5-dicarboxylic acid.

4. The method for synthesizing 1,2,3-triazole-4,5-dicarboxylic acid according to claim 3, characterized in that The crystallization is carried out at 0-10°C.

5. The method for synthesizing 1,2,3-triazole-4,5-dicarboxylic acid according to claim 3, characterized in that The crystallization time is 1 to 3 hours.

6. The method for synthesizing 1,2,3-triazole-4,5-dicarboxylic acid according to claim 1 or 2, characterized in that The molar ratio of benzotriazole to O3 is 1:(2-4).

7. The method for synthesizing 1,2,3-triazole-4,5-dicarboxylic acid according to claim 1 or 2, characterized in that The amount of hydrogen peroxide used is 2 to 3.5 times the molar amount of benzotriazole calculated on the basis of hydrogen peroxide.

8. The method for synthesizing 1,2,3-triazole-4,5-dicarboxylic acid according to claim 1 or 2, characterized in that The concentration of hydrogen peroxide is 25-50wt.%.

9. The method for synthesizing 1,2,3-triazole-4,5-dicarboxylic acid according to claim 1 or 2, characterized in that The oxidation reaction time is 10 to 60 hours.

10. The method for synthesizing 1,2,3-triazole-4,5-dicarboxylic acid according to claim 1 or 2, characterized in that The oxidation reaction time is 10 to 25 hours.

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