Synthesis method of 5-bromo-1H-1, 2, 4-triazole
The synthesis of 5-bromo-1H-1,2,4-triazole via diazotization solves the problems of unsatisfactory yield and difficult purification in existing technologies, achieving an efficient and simple preparation process.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-12-22
- Publication Date
- 2026-04-07
AI Technical Summary
Existing methods for preparing 5-bromo-1H-1,2,4-triazole have drawbacks such as unsatisfactory yields, byproduct formation, and difficulties in post-processing and purification.
Using 3-amino-1H-1,2,4-triazole-5-carboxylic acid as a raw material, a diazonium salt solution was generated through a diazotization reaction, and 5-bromo-1H-1,2,4-triazole was synthesized under the action of cuprous bromide. The reaction involved the dropwise addition of sodium nitrite solution and cuprous bromide solution at low temperature, followed by stirring and heating under mild conditions.
This approach achieves high yields, simple operation, and concise post-processing, providing a potential route for the large-scale production of 5-bromo-1H-1,2,4-triazole.
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Figure CN121800733A_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The embodiments of the present application belong to the technical field of chemical synthesis, and particularly relate to a synthesis method of 5-bromo-1H-1,2,4-triazole. BACKGROUND
[0002] 5-bromo-1H-1,2,4-triazole is an important bromine-containing triazole heterocyclic compound, and its bromine atom and heterocyclic structure endow it with high reactivity. It is mainly used as an organic synthesis intermediate in the fields of medicine and pesticide. In the field of medicine, 5-bromo-1H-1,2,4-triazole can be used for the synthesis of antitumor drugs, as a key building block for the synthesis of inhibitors targeting vascular endothelial growth factor receptor (VEGFR-2) kinase, and through structural modification, candidate drugs with significant cytotoxicity to cell lines such as colon cancer and lung cancer can be developed, for example, a derivative with IC 50 0.08 μM; it can also be used as an intermediate for antifungal drugs to synthesize Fluconazole analogs, enhance the penetration ability of the drug to the fungal cell membrane, and improve the antifungal activity; it can also be used as an antiviral drug building block to participate in the synthesis of nucleoside antiviral drugs (such as structural analogs of ribavirin), and through modification of the triazole ring, the drug stability is enhanced. In the field of pesticides, 5-bromo-1H-1,2,4-triazole can be used for the synthesis of high-efficiency fungicides, as a core structure to synthesize triazole fungicides (such as myclobutanil, uniconazole, and tebuconazole), and the introduction of bromine atoms can enhance the binding force of the molecule to the target enzyme, and improve the control effect (inhibition rate > 90%) on wheat sharp eyespot and vegetable gray mold; it can also be used for resistance pest management agents, and new insecticides can be developed through derivatization, for example, a compound spliced with oxadiazole thiol has an EC 50 as low as 1.7 μg / mL, which is significantly better than traditional pesticides. In other fields, it can be used as an intermediate in material science to synthesize photoconductors, and its heterocyclic structure can regulate the electronic transport performance; it can also be used as a bioactive molecule probe to replace carboxyl or amide groups as a bioisosteric body, for the design of enzyme inhibitors or receptor antagonists.
[0003] In the prior art, there are mainly three routes for the preparation of 5-bromo-1H-1,2,4-triazole, namely using 3-amino-1,2,4-triazole as a raw material, using 3-nitro-1,2,4-triazole as a raw material, and using 3,5-dibromo-1H-1,2,4-triazole as a raw material, and the 5-bromo-1H-1,2,4-triazole is prepared through reactions, but there are defects such as unsatisfactory yield, by-product generation, and difficult post-treatment and purification. Therefore, it is of certain significance to further study the synthesis method of 5-bromo-1H-1,2,4-triazole. SUMMARY
[0004] In view of the deficiencies of the prior art, the application provides a synthesis method of 5-bromo-1H-1,2,4-triazole, which has low cost, mild reaction conditions, simple and efficient operation, simple post-treatment and purification, and ideal yield.
[0005] A first object of the application is to provide a synthesis method of 5-bromo-1H-1,2,4-triazole, and the synthesis route of the method is as follows:
[0006]
[0007] (1) Compound 1, i.e., 3-amino-1H-1,2,4-triazole-5-carboxylic acid, is added into an aqueous hydrogen bromide solution, the system is cooled to -10-5 ℃, and stirring is performed for 20-50 minutes. The temperature is maintained at -10-5 ℃, and an aqueous sodium nitrite solution is further added dropwise. After the dropwise addition is completed, the reaction is performed at -10-5 ℃ for 20-50 minutes to obtain a diazonium salt solution, i.e., a compound 2 solution, which is ready for use in the next step.
[0008] (2) Copper bromide is dissolved in an aqueous hydrogen bromide solution, and the mixed solution is slowly added into the diazonium salt solution obtained in step (1). After the dropwise addition is completed, stirring is performed at room temperature for 20-50 minutes, and then the temperature is increased to 50-100 ℃ for continuous stirring for 6-12 hours. After the reaction is completed, the reaction solution is subjected to post-treatment to obtain the target compound 3, i.e., 5-bromo-1H-1,2,4-triazole.
[0009] Preferably, in step (1), the mass fraction of hydrogen bromide in the aqueous hydrogen bromide solution is 48%-10%.
[0010] Preferably, in step (1), the mass-volume ratio of the compound 1 to the aqueous hydrogen bromide solution is 1:2-20 g / mL.
[0011] Preferably, in step (1), the molar ratio of the compound 1 to sodium nitrite is 1:1-3.
[0012] Preferably, in step (1), the concentration of the aqueous sodium nitrite solution is 1.00 mol / L-5.00 mol / L.
[0013] Preferably, in step (2), the molar ratio of the compound 1 to copper bromide is 1:1-3.
[0014] Preferably, in step (2), the mass-volume ratio of the copper bromide to the aqueous hydrogen bromide solution is 1:0.5-10 g / mL.
[0015] Preferably, in step (2), the post-treatment is as follows: after the reaction is completed, water is added for dilution, organic solvent I is used for extraction, the organic phases are combined, the organic phases are washed, dried, filtered, and evaporated to obtain the target compound 3, namely 5-bromo-1H-1,2,4-triazole.
[0016] Preferably, in step (2), the organic solvent I is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane or dichloroethane.
[0017] The beneficial technical effects of this application are as follows:
[0018] This application provides a method for preparing 5-bromo-1H-1,2,4-triazole, using 3-amino-1H-1,2,4-triazole-5-carboxylic acid as a raw material. The mixture undergoes a diazotization reaction to obtain a corresponding diazonium salt solution, which is then reacted with cuprous bromide to yield 5-bromo-1H-1,2,4-triazole. This method ultimately yields 5-bromo-1H-1,2,4-triazole in high yield with low cost, concise steps, simple operation, and relatively mild reaction conditions, providing a potential route for the large-scale production of 5-bromo-1H-1,2,4-triazole. Attached Figure Description
[0019] The accompanying drawings, which are included to provide a further understanding of this application and form part of this application, illustrate exemplary embodiments and are used to explain this application, but do not constitute an undue limitation of this application. Some specific embodiments of this application will be described in detail below with reference to the accompanying drawings in an exemplary and non-limiting manner. The same reference numerals in the drawings designate the same or similar parts or components. Those skilled in the art should understand that these drawings are not necessarily drawn to scale. In the drawings:
[0020] Figure 1 This is the 1H NMR spectrum of compound 3 prepared in the embodiments of this application. Detailed Implementation
[0021] To enable those skilled in the art to better understand the present application, the technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are merely some, not all, of the embodiments of the present application. All other embodiments obtained by those skilled in the art based on the embodiments of the present application without creative effort should fall within the scope of protection of the present application.
[0022] This application provides a method for synthesizing 5-bromo-1H-1,2,4-triazole, and the synthetic route is as follows:
[0023]
[0024] The specific steps are as follows:
[0025] (1) Compound 1, namely 3-amino-1H-1,2,4-triazol-5-carboxylic acid (100.00 g, 780.69 mmol, 1.00 eq), was added to an aqueous solution of hydrogen bromide obtained by diluting 48% hydrobromic acid (100 mL) with water (200 mL). The system was cooled to 0 °C and stirred for 30 minutes. While maintaining 0 °C, an aqueous solution of sodium nitrite (2.00 M in H2O, 394.25 mL, 788.50 mmol, 1.01 eq) was added dropwise with stirring. After the addition was complete, the reaction was carried out at 0 °C for 30 minutes to obtain a diazonium salt solution, namely the solution of compound 2, for use in the next step.
[0026] (2) At 0°C, cuprous bromide (145.59 g, 1.01 mol, 1.30 eq) was dissolved in an aqueous solution of hydrogen bromide obtained by diluting 48% hydrobromic acid (100 mL) with water (200 mL). This mixed solution was then slowly added dropwise to the diazonium salt solution obtained in step (1). After the addition was complete, the mixture was stirred at room temperature for 30 minutes, and then heated to 60°C and stirred for 8 hours. After the reaction was completed, water (2.0 L) was added for dilution, and the mixture was extracted three times with ethyl acetate (1.5 L × 3). The organic phases were combined, washed twice with water (2.0 L × 2), washed once with saturated brine (3.0 L), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the target compound 3, namely 5-bromo-1H-1,2,4-triazole (CAS No.: 7343-33-1, pale yellow powder, weight 113.10 g, purity 98%, yield 96%).
[0027] The 1H NMR spectrum of 5-bromo-1H-1,2,4-triazole is as follows: Figure 1 As shown, the obtained characterization data are as follows:
[0028] 1 H NMR(400MHz,dmso)δ14.46(s,1H),8.56(s,1H).
[0029] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of this application, and are not intended to limit them. Although this application has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of this application.
Claims
1. A method for synthesizing 5-bromo-1H-1,2,4-triazole, characterized in that, The synthetic route of the method is as follows: Specifically, the steps include the following: Compound 1 was added to an aqueous solution of hydrogen bromide. After cooling the system to a preset temperature, an aqueous solution of sodium nitrite was added, and the reaction was carried out at the preset temperature to obtain a solution of compound 2, which was then used in the next step. While maintaining the preset temperature, cuprous bromide is dissolved in an aqueous solution of hydrogen bromide, and this mixed solution is added to the solution of compound 2. After reacting at room temperature for a preset time, the temperature is increased and the reaction continues. After post-processing, the target compound 3 is obtained.
2. The synthesis method according to claim 1, characterized in that, The hydrogen bromide aqueous solution has a hydrogen bromide mass fraction of 48% to 10%; The mass-to-volume ratio of compound 1 to the aqueous solution of hydrogen bromide is 1:2 to 20 g / mL. The molar ratio of compound 1 to sodium nitrite is 1:1 to 3; The concentration of the sodium nitrite aqueous solution is 1.00 mol / L to 5.00 mol / L.
3. The synthesis method according to claim 1, characterized in that, The molar ratio of compound 1 to cuprous bromide is 1:1 to 3; The mass-to-volume ratio of cuprous bromide to hydrogen bromide aqueous solution is 1:0.5-10 g / mL.
4. The synthesis method according to claim 1, characterized in that, The post-processing includes: diluting with water, extracting with an organic solvent, combining the organic phases, washing, drying, filtering, and evaporating the organic phases to obtain target compound 3.
5. The synthesis method according to claim 4, characterized in that, The organic solvent is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, and dichloroethane.