Synthesis method of 2-methyl-1H-1, 2, 4-triazole-3 (2H)-ketone

Abstract

The invention discloses a synthesis method of 2-methyl-1H-1, 2, 4-triazole-3 (2H)-ketone, which comprises the following steps: adding a compound 1, namely 1-methyl-1, 2, 4-triazole into an organic solvent I, integrally cooling to-80 DEG C to-50 DEG C under the protection of inert gas, then dropwise adding an n-butyllithium solution, after dropwise adding, keeping the temperature to-80 DEG C to-50 DEG C, stirring and reacting for 0.5-2 hours, and then cooling to room temperature to obtain the 2-methyl-1H-1, 2, 4-triazole-3 (2H)-ketone. The preparation method comprises the following steps: adding a compound 1 into an organic solvent I, dropwise adding a solution obtained by dissolving iodine into an organic solvent II at-80 DEG C to-50 DEG C, after dropwise adding, naturally heating to room temperature, reacting for 8-20 hours, and after the reaction is finished, carrying out first post-treatment to obtain a compound 2, namely 5-iodine-1-methyl-1H-1, 2, 4-triazole; and adding the crude product of the compound 2 into an alkaline aqueous solution, heating to 50-200 DEG C, reacting for 10-20 hours, and performing secondary post-treatment after the reaction to obtain a compound 3, namely 2-methyl-1H-1, 2, 4-triazole-3 (2H)-ketone.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for synthesizing 2-methyl-1H-1,2,4-triazol-3(2H)-one. Background Technology

[0002] The compound 2-methyl-1H-1,2,4-triazol-3(2H)-one is an important molecular building block. As a key intermediate, it was used in the synthesis of a selective inhibitor of BDII of the BET protein in international patent publication number WO2022 / 261204. This inhibitor has the potential to treat diseases such as cancer, acute kidney disease, and viral infections. In the US patent application number US2017 / 217922, it was used in the synthesis of an activator of Nrf2. This activator can be used to treat autoimmune and inflammatory diseases and disorders, such as psoriasis and multiple sclerosis.

[0003] In existing technologies, 2-(2-methylhydrazone)acetic acid and the azide reagent diphenylphosphohydrazine undergo a Curtiss rearrangement reaction in the presence of a base to synthesize the compound 2-methyl-1H-1,2,4-triazol-3(2H)-one. However, this method has disadvantages such as low yield, incomplete reaction or byproduct formation, difficult post-processing purification, high time and labor costs, and unsuitability for large-scale process development. Summary of the Invention

[0004] To address the above technical problems, this application provides a method for synthesizing 2-methyl-1H-1,2,4-triazol-3(2H)-one, wherein the method for synthesizing 2-methyl-1H-1,2,4-triazol-3(2H)-one includes: S1001, Compound 1, namely 1-methyl-1,2,4-triazole, was added to organic solvent I. Under inert gas protection, the temperature was lowered to -80℃ to -50℃, and then n-butyllithium solution was added dropwise. After the addition was complete, the reaction was stirred at -80℃ to -50℃ for 0.5 to 2 hours. Then, a solution of iodine dissolved in organic solvent II was added dropwise at -80℃ to -50℃. After the addition was complete, the temperature was naturally raised to room temperature and the reaction was carried out for 8 to 20 hours. After the reaction was completed, the first post-treatment was performed to obtain compound 2, namely 5-iodo-1-methyl-1H-1,2,4-triazole. S1002, the crude product of compound 2 is added to an alkaline aqueous solution, heated to 50-200℃, and reacted for 10-20 hours. After the reaction is completed, a second post-treatment is performed to obtain compound 3, which is 2-methyl-1H-1,2,4-triazol-3(2H)-one.

[0005] In a preferred embodiment, in step S1001, the organic solvent I is selected from tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane, cyclohexane, n-hexane, diethyl ether, or methyl tert-butyl ether.

[0006] In a preferred embodiment, in step S1001, the organic solvent II is selected from tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane, cyclohexane, n-hexane, diethyl ether, or methyl tert-butyl ether.

[0007] In a preferred embodiment, in step S1001, the n-butyllithium solution is n-butyllithium dissolved in n-hexane solution, n-butyllithium dissolved in n-ethane solution, or n-butyllithium dissolved in tetrahydrofuran solution.

[0008] In a preferred embodiment, in step S1001, the inert gas is selected from one or more of nitrogen and argon.

[0009] In a preferred embodiment, at least one of the following conditions is satisfied: in step S1001, the mass-to-volume ratio of compound 1 to organic solvent I is 1:5 to 40 (g / mL); In step S1001, the molar ratio of compound 1 to n-butyllithium is 1:1 to 2; In step S1001, the molar ratio of compound 1 to iodine is 1:1 to 2.

[0010] In a preferred embodiment, the first post-processing procedure includes: S10011: After the reaction is complete, saturated sodium thiosulfate aqueous solution is added to the reaction solution to quench the reaction, and the mixture is stirred for 0.5–2 hours. Then, organic solvent III is added, and the mixture is separated. The aqueous phase is extracted again with organic solvent III, and the organic phases are combined. The organic phase is washed, dried, and evaporated to dryness. Organic solvent IV is added to slurry for purification. The mixture is filtered, and the filter cake is washed again with organic solvent IV. The solid on the filter cake is collected, dried, and the crude product of compound 2 is obtained. The crude product does not require further purification.

[0011] In a preferred embodiment, in step S10011; the organic solvent III is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, or dichloroethane; and / or The organic solvent IV is selected from one or more of isooctane, cyclohexane, hexane, petroleum ether, n-pentane, and isopentane.

[0012] In a preferred embodiment, in step S1002, the alkaline aqueous solution is selected from one or more of sodium bicarbonate solution, sodium carbonate solution, potassium carbonate solution, sodium hydroxide solution, or potassium hydroxide solution; and / or The acidic aqueous solution is one or more of hydrochloric acid solution, sulfuric acid solution, nitric acid solution, and acetic acid solution.

[0013] In a preferred embodiment, in step S1002, the post-processing includes: after the reaction is completed, cooling the reaction solution to room temperature, adjusting the pH to 7 with an acidic aqueous solution, precipitating the solid, filtering, rinsing the filter cake with water, collecting the solid on the filter cake, and drying to obtain the target compound, namely 2-methyl-1H-1,2,4-triazol-3(2H)-one; preferably, the acidic aqueous solution is one or more of hydrochloric acid solution, sulfuric acid solution, nitric acid solution, and acetic acid solution.

[0014] Compared with the prior art, the beneficial technical effects of this application are as follows: This invention proposes a method for preparing 2-methyl-1H-1,2,4-triazol-3(2H)-one. Using 1-methyl-1,2,4-triazole as a raw material, intermediate 2 is obtained under the action of n-butyllithium and iodine, and then converted into the target compound 3 (2-methyl-1H-1,2,4-triazol-3(2H)-one).

[0015] This synthetic method yields the compound 2-methyl-1H-1,2,4-triazol-3(2H)-one with a short procedure, simple operation, low cost, and relatively mild reaction conditions.

[0016] Furthermore, the synthesis method of this application has the advantages of low cost, simple and easy operation, and ideal yield. Attached Figure Description

[0017] Figure 1 The flowchart shows the synthesis method of 2-methyl-1H-1,2,4-triazol-3(2H)-one.

[0018] Figure 2 The 1H NMR spectrum of 2-methyl-1H-1,2,4-triazol-3(2H)-one in Example 1 is shown. Detailed Implementation

[0019] The preferred embodiments described below are merely examples, and other obvious variations will be apparent to those skilled in the art. The basic principles of the invention defined in the following description can be applied to other embodiments, modifications, improvements, equivalents, and other technical solutions that do not depart from the spirit and scope of the invention.

[0020] A preferred embodiment of the present invention provides a method for synthesizing 2-methyl-1H-1,2,4-triazol-3(2H)-one, which will be described in detail below. The method involves using 1-methyl-1,2,4-triazol as a starting material, undergoing a halogenation reaction to obtain intermediate 2 (5-iodo-1-methyl-1H-1,2,4-triazol), which is then converted into the target compound 3 (2-methyl-1H-1,2,4-triazol-3(2H)-one). Figure 1 As shown.

[0021] Specifically, the method for synthesizing the 2-methyl-1H-1,2,4-triazol-3(2H)-one includes: S1001, Compound 1, namely 1-methyl-1,2,4-triazole, was added to organic solvent I. Under inert gas protection, the temperature was lowered to -80℃ to -50℃, and then n-butyllithium solution was added dropwise. After the addition was complete, the reaction was stirred at -80℃ to -50℃ for 0.5 to 2 hours. Then, a solution of iodine dissolved in organic solvent II was added dropwise at -80℃ to -50℃. After the addition was complete, the temperature was naturally raised to room temperature and the reaction was carried out for 8 to 20 hours. After the reaction was completed, the first post-treatment was performed to obtain compound 2, namely 5-iodo-1-methyl-1H-1,2,4-triazole. S1002, the crude product of compound 2 is added to an alkaline aqueous solution, heated to 50-200℃, and reacted for 10-20 hours. After the reaction is completed, a second post-treatment is performed to obtain compound 3, which is 2-methyl-1H-1,2,4-triazol-3(2H)-one.

[0022] In a preferred embodiment, in step S1001, the organic solvent I is selected from tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane, cyclohexane, n-hexane, diethyl ether, or methyl tert-butyl ether.

[0023] In a preferred embodiment, in step S1001, the organic solvent II is selected from tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane, cyclohexane, n-hexane, diethyl ether, or methyl tert-butyl ether.

[0024] In a preferred embodiment, in step S1001, the n-butyllithium solution is n-butyllithium dissolved in n-hexane solution, n-butyllithium dissolved in n-ethane solution, or n-butyllithium dissolved in tetrahydrofuran solution.

[0025] In a preferred embodiment, in step S1001, the inert gas is selected from one or more of nitrogen and argon.

[0026] In a preferred embodiment, in step S1001, the mass-to-volume ratio of compound 1 to organic solvent I is 1:5 to 40 (g / mL).

[0027] In a preferred embodiment, in step S1001, the molar ratio of compound 1 to n-butyllithium is 1:1 to 2.

[0028] In a preferred embodiment, in step S1001, the molar ratio of compound 1 to iodine is 1:1 to 2.

[0029] In a preferred embodiment, the first post-processing procedure includes: S10011: After the reaction is complete, saturated sodium thiosulfate aqueous solution is added to the reaction solution to quench the reaction, and the mixture is stirred for 0.5–2 hours. Then, organic solvent III is added, and the mixture is separated. The aqueous phase is extracted again with organic solvent III, and the organic phases are combined. The organic phase is washed, dried, and evaporated to dryness. Organic solvent IV is added to slurry for purification. The mixture is filtered, and the filter cake is washed again with organic solvent IV. The solid on the filter cake is collected, dried, and the crude product of compound 2 is obtained. The crude product does not require further purification.

[0030] In a preferred embodiment, in step S10011, the organic solvent III is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, or dichloroethane.

[0031] In a preferred embodiment, in step S10011, the organic solvent IV is selected from one or more of isooctane, cyclohexane, hexane, petroleum ether, n-pentane, and isopentane.

[0032] In a preferred embodiment, in step S1002, the alkaline aqueous solution is selected from one or more of sodium bicarbonate solution, sodium carbonate solution, potassium carbonate solution, sodium hydroxide solution, or potassium hydroxide solution.

[0033] In a preferred embodiment, in step S1002, the post-processing includes: after the reaction is completed, cooling the reaction solution to room temperature, adjusting the pH to 7 with an acidic aqueous solution, precipitating the solid, filtering, rinsing the filter cake with water, collecting the solid on the filter cake, and drying to obtain the target compound, namely 2-methyl-1H-1,2,4-triazol-3(2H)-one; preferably, the acidic aqueous solution is one or more of hydrochloric acid solution, sulfuric acid solution, nitric acid solution, and acetic acid solution. Example

[0034] In this embodiment, the compound 2-methyl-1H-1,2,4-triazol-3(2H)-one was synthesized using the following steps: (1) Compound 1, namely 1-methyl-1,2,4-triazole (600.00 g, 7.22 mol, 1.00 eq), was added to tetrahydrofuran (12.0 L). Under nitrogen protection, the system was cooled to -60 °C, and a solution of n-butyllithium (2.0 M solution in Hexanes, 4.33 kg mL, 8.66 mol, 1.20 eq) was added dropwise. After the addition was complete, the mixture was stirred at -60 °C for 1 hour. Iodine (2.02 kg, 7.94 mol, 1.10 eq) in tetrahydrofuran (6.0 L) was added dropwise at -60 °C. After the addition was complete, the mixture was allowed to rise naturally to room temperature for 12 hours. After the reaction was complete, a saturated sodium thiosulfate aqueous solution was added to the reaction solution to quench the reaction until the reaction solution was clear and transparent, and the mixture was stirred for 1 hour. Then, ethyl acetate (5.0 L) was added for extraction, and the mixture was separated. The aqueous phase was extracted once more with ethyl acetate (5.0 L), and the organic phases were combined. The organic phase was washed twice with saturated brine (6.0 L × 2), dried, and evaporated to dryness to obtain the crude product. Petroleum ether (6.0 L) was added for slurry purification, and the mixture was filtered. The filter cake was washed with petroleum ether (1.0 L), and the solid on the filter cake was collected and dried to obtain the crude product of compound 2 (weight 1.49 kg, purity 97%, yield 96%). The crude product did not require further purification.

[0035] (2) The crude product of compound 2 (1.40 kg, 6.70 mol, 1.00 eq) was added to an aqueous solution of potassium hydroxide (5.00 M, 6.03 L, 30.14 mol, 4.50 eq), and the temperature was raised to 70 °C. The reaction was allowed to proceed for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and the pH was adjusted to 7 with 12 M hydrochloric acid aqueous solution. The solid precipitated, filtered, and the filter cake was washed with water. The solid on the filter cake was collected and dried to obtain the target compound 2-methyl-1H-1,2,4-triazol-3(2H)-one (weight 658.90 g, purity 98%, yield 97%).

[0036] The 1H NMR spectrum of the obtained compound 3 (2-methyl-1H-1,2,4-triazol-3(2H)-one) is as follows: Figure 2 As shown, the characterization data is as follows: 1 H NMR (400 MHz, DMSO) δ 11.46 (s, 1H), 7.79 (s, 1H), 3.25 (s, 3H).

[0037] Those skilled in the art should understand that the embodiments of the present invention described above are merely examples and do not limit the invention. The objectives of the present invention have been fully and effectively achieved. The functions and structural principles of the present invention have been shown and explained in the embodiments, and any modifications or variations of the implementation of the present invention may be made without departing from the stated principles.

Claims

1. A method for the synthesis of 2-methyl-1 H-1,2,4-triazole-3(2H)-one, characterized in that, The synthesis method of the 2-methyl-1H-1,2,4-triazole-3(2H)-one comprises the following steps: S1001, compound 1, i.e. 1-methyl-1,2,4-triazole, is added to an organic solvent I, the whole is cooled to-80℃ to-50℃ under inert gas protection, and then a n-butyllithium solution is added dropwise, after the dropwise addition is completed, stirring reaction is carried out at-80℃ to-50℃ for 0.5-2 hours, then, a solution of iodine dissolved in an organic solvent II is added dropwise at-80℃ to-50℃, after the dropwise addition is completed, natural temperature rise to room temperature is carried out for 8-20 hours, after the reaction is completed, first post-treatment is carried out, and compound 2, i.e. 5-iodo-1-methyl-1H-1,2,4-triazole, is obtained; S1002, the crude product of compound 2 is added to an alkaline aqueous solution, temperature rise to 50-200℃ is carried out for 10-20 hours, after the reaction is completed, second post-treatment is carried out, and compound 3, i.e. 2-methyl-1H-1,2,4-triazole-3(2H)-one, is obtained.

2. The process for the synthesis of 2-methyl-lH-l,2,4-triazole-3(2H)-one according to claim 1, characterized in that, In step S1001, the organic solvent I is selected from tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane, cyclohexane, n-ethane, diethyl ether or methyl tert-butyl ether.

3. The process for the synthesis of 2-methyl-lH-l,2,4-triazole-3(2H)-one according to claim 1, characterized in that, In step S1001, the organic solvent II is selected from tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane, cyclohexane, n-ethane, diethyl ether or methyl tert-butyl ether.

4. The process for the synthesis of 2-methyl-lH-l,2,4-triazole-3(2H)-one according to claim 1, characterized in that, In step S1001, the n-butyllithium solution is n-butyllithium solution in n-hexane solution, n-butyllithium solution in n-ethane solution or n-butyllithium solution in tetrahydrofuran solution.

5. The process for the synthesis of 2-methyl-lH-l,2,4-triazole-3(2H)-one according to claim 1, characterized by, In step S1001, the inert gas is selected from one or more of nitrogen and argon.

6. The process for the synthesis of 2-methyl-lH-l,2,4-triazole-3(2H)-one according to claim 1, characterized by, It satisfies at least one of the following conditions: In step S1001, the mass-volume ratio g / mL of compound 1 to the organic solvent I is 1:5-40; In step S1001, the molar ratio of compound 1 to n-butyllithium is 1:1-2; In step S1001, the molar ratio of compound 1 to iodine is 1:1-2.

7. The process for the synthesis of 2-methyl-lH-l,2,4-triazole-3(2H)-one according to claim 1, characterized by, The process of the first post-treatment comprises: S10011: after the reaction is completed, saturated sodium thiosulfate aqueous solution is added to the reaction solution to quench the reaction, and stirring is carried out for 0.5-2 hours. Then, an organic solvent III is added, liquid separation is carried out, the aqueous phase is extracted with the organic solvent III again, and the combined organic phase is washed, dried, rotary evaporated, slurried and purified with an organic solvent IV, filtered, the filter cake is eluted with the organic solvent IV, the solid on the filter cake is collected, and dried to obtain the crude product of compound 2, which does not need to be further purified.

8. The process for the synthesis of 2-methyl-lH-l,2,4-triazole-3(2H)-one according to claim 1, characterized by, In step S10011, the organic solvent III is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane or dichloroethane; and / or The organic solvent IV is selected from one or more of isooctane, cyclohexane, hexane, petroleum ether, n-pentane and isopentane.

9. The synthesis method of the 2-methyl-1H-1,2,4-triazole-3(2H)-one according to claim 1, characterized in that, In step S1002, the alkaline aqueous solution is selected from one or more of sodium bicarbonate solution, sodium carbonate solution, potassium carbonate solution, sodium hydroxide solution, or potassium hydroxide solution.

10. The method for synthesizing 2-methyl-1H-1,2,4-triazol-3(2H)-one according to claim 1, characterized in that, In step S1002, the post-processing includes: after the reaction is completed, cooling the reaction solution to room temperature, adjusting the pH to 7 with an acidic aqueous solution, precipitating the solid, filtering, rinsing the filter cake with water, collecting the solid on the filter cake, and drying to obtain the target compound, namely 2-methyl-1H-1,2,4-triazol-3(2H)-one, wherein the acidic aqueous solution is one or more of hydrochloric acid solution, sulfuric acid solution, nitric acid solution, and acetic acid solution.

Images