Synthetic method of 1, 2, 4-triazole-3-carboxylic acid methyl ester

Abstract

The invention discloses a synthetic method of 1, 2, 4-triazole-3-carboxylic acid methyl ester, and belongs to the field of organic synthesis. The preparation method comprises the following steps: by taking formamidine acetate, hydrazine hydrate and dimethyl oxalate as raw materials, carrying out one-pot reaction to obtain the 1, 2, 4-triazole-3-carboxylic acid methyl ester. Compared with the prior art, the method has the advantages of short synthesis process route, short reaction time and simplicity in operation; and the synthesis process is few in three wastes, environment-friendly and green. Meanwhile, the synthesis process is safe and reliable, reaction conditions are mild, and dangerous processes such as diazotization and desulfurization are not involved.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing methyl 1,2,4-triazole-3-carboxylate. Background Art

[0002] Methyl 1,2,4-triazole-3-carboxylate, with the molecular formula C4H5N3O2, molecular weight 127.101, English name Methyl 1,2,4-triazole-3-carboxylate, CAS registration number 4928-88-5, is a colorless or light yellow liquid. Due to its high chemical reactivity, it is an important organic synthesis intermediate. In the field of medicinal chemistry, as an important derivative of nitrogen-containing heterocyclic compounds, the triazole ring structure in its molecule, due to its unique electronic effect and spatial configuration, is a key group for constructing the active center of anti-infective drugs. This compound can effectively regulate the lipophilicity and bioavailability of drug molecules through structural modification, and has currently been widely used in the synthesis processes of clinical drugs such as ribavirin (broad-spectrum antiviral), fluconazole (antifungal), letrozole (antitumor), etc. Its market demand is also continuously increasing with the research and development of such drugs.

[0003] There are many literature or patent reports on the synthesis of methyl 1,2,4-triazole-3-carboxylate, but they all have problems such as cumbersome routes, dangerous processes, and a large amount of "three wastes".

[0004] The traditional industrial production method of methyl 1,2,4-triazole-3-carboxylate uses calcium cyanamide as the raw material, and the product is obtained through hydrazinolysis, oxalylation, cyclization, esterification, and diazotization and denitrogenation; Chemical Reagents, 2006, 28(8), 503-504 reported that using diethyl oxalate as the raw material, through ammonolysis, methyl ether acetate, hydrazinolysis, then cyclization, and methylation to obtain the product. Such methods have relatively inexpensive and easily available raw materials, but the reaction steps are long, a large amount of concentrated sulfuric acid is required as a catalyst in the esterification reaction, and a large amount of three wastes are generated. In addition, in the diazotization reaction, due to the explosiveness of diazonium salts, there is a high industrial risk.

[0005] Patent CN101830858A reported that using dimethyl oxalate as the raw material, the product is obtained through steps such as hydrazinolysis, cyclization, thiation, and esterification; CN103145632A / CN105037284A reported that using thiosemicarbazide as the raw material, first cyclizing with oxalic acid / oxalate / acyl chloride, etc., and then through steps such as desulfurization and esterification to obtain the product. Such methods avoid the diazotization reaction by introducing a thiol group on the triazole ring, but on the one hand, ammonium thiocyanate is required as a sulfurizing reagent in the thiation reaction, and on the other hand, strong acidic substances such as sulfur dioxide and sulfuric acid are generated during the desulfurization reaction, which is easy to corrode pipelines and reactors, resulting in a large environmental pollution and high post-treatment costs. Summary of the Invention

[0006] Based on the disadvantages of the existing synthesis routes of methyl 1,2,4-triazole-3-carboxylate, such as long steps, complex operations, and high "three wastes", which lead to high production costs and safety risks, the present invention aims to solve the above problems and provides a synthesis method of methyl 1,2,4-triazole-3-carboxylate with simplicity, economy, and environmental friendliness.

[0007] The synthesis method of methyl 1,2,4-triazole-3-carboxylate of the present invention innovatively uses formamidine acetate (FAAc), hydrazine hydrate, and dimethyl oxalate as raw materials, and obtains methyl 1,2,4-triazole-3-carboxylate through a one-pot reaction.

[0008] The chemical reaction formula of the present invention is:

[0009]

[0010] Further, in the above technical solution, the specific operation steps are as follows: using formamidine acetate as a raw material, mixing it evenly with a solvent, dropping hydrazine hydrate under stirring to obtain an aminomethylenehydrazine intermediate, and then dropping the reaction solution into a mixed solution of dimethyl oxalate, a catalyst, and a solvent, reacting at room temperature until no dimethyl oxalate raw material remains, then heating up to continue the reaction, and after the reaction is completed, the obtained crude product is purified by recrystallization to obtain methyl 1,2,4-triazole-3-carboxylate.

[0011] Further, in the above technical solution, the solvent is one or a mixture of two or more of water, methanol, and ethanol in any proportion.

[0012] Further, in the above technical solution, the reaction temperature is 10 - 80 °C.

[0013] Further, in the above technical solution, the reaction time is 5 - 8 h.

[0014] Further, in the above technical solution, the catalyst is selected from tris(pentafluorophenyl)borane catalyst.

[0015] Further, in the above technical solution, the molar ratio of the catalyst to formamidine acetate is 0.001 - 0.05:1.

[0016] Further, in the above technical solution, the molar ratio of the reactants formamidine acetate, hydrazine hydrate, and dimethyl oxalate is 1.25 - 2:1.25 - 2:1.

[0017] Further, in the above technical solution, the recrystallization solvent is dichloromethane.

[0018] Compared with the prior art, the present invention has the following advantages:

[0019] A. The synthetic process route is short, the reaction time is short, and the operation is simple; the "three wastes" of the synthetic process are less, environmentally friendly, and green.

[0020] B. The synthetic process is safe and reliable, the reaction conditions are mild, and it does not involve dangerous processes such as diazotization and desulfurization. Specific embodiments

[0021] The present invention will be further described in detail below in conjunction with specific embodiments.

[0022] Example 1

[0023] Add 20 g of formamidine acetate and 200 mL of methanol to the reaction flask, stir at room temperature and slowly dropwise add 12 g of 80% hydrazine hydrate. After 10 minutes, dropwise add a mixed solution prepared by dissolving 18 g of dimethyl oxalate and 3.8 g of tris(pentafluorophenyl)borane in 200 mL of anhydrous methanol. Stir at room temperature until there is no signal of dimethyl oxalate. Then transfer the reaction solution into a water bath at 60 °C and reflux for 6 h. By liquid phase detection, the external standard yield of methyl triazole is 82%. Cool the reaction solution to room temperature, filter, concentrate, stir the concentrated mother liquor at 5 °C for 1 h to crystallize, filter, wash the filter cake with petroleum ether to obtain the crude product, and recrystallize with dichloromethane to obtain 14.7 g of pure methyl 1,2,4-triazole-3-carboxylate, with a yield of 77%.

[0024] Example 2

[0025] Add 23.4 g of formamidine acetate and 200 mL of methanol to the reaction flask, stir at room temperature and slowly dropwise add 12 g of 80% hydrazine hydrate. After 10 minutes, dropwise add a mixed solution prepared by dissolving 18 g of dimethyl oxalate and 3.8 g of tris(pentafluorophenyl)borane in 200 mL of anhydrous methanol. Stir at room temperature until there is no signal of dimethyl oxalate. Then transfer the reaction solution into a water bath at 60 °C and reflux for 6 h. By liquid phase detection, the external standard yield of methyl triazole is 88%. Cool the reaction solution to room temperature, filter, concentrate, stir the concentrated mother liquor at 5 °C for 1 h to crystallize, filter, wash the filter cake with petroleum ether to obtain the crude product, and recrystallize with methanol to obtain 14.9 g of pure methyl 1,2,4-triazole-3-carboxylate, with a yield of 78.2%.

[0026] Example 3

[0027] Add 31.2 g of formamidine acetate and 200 mL of methanol to the reaction flask. Stir at room temperature and slowly add dropwise 14.1 g of 80% hydrazine hydrate. After 10 minutes, add dropwise the mixed solution prepared by dissolving 18 g of dimethyl oxalate and 2.3 g of tris(pentafluorophenyl)borane in 200 mL of anhydrous methanol. Stir at room temperature until there is no signal of dimethyl oxalate. Then transfer the reaction solution into a water bath at 60 °C and reflux for 6 h. By liquid phase detection, the external standard yield of methyl triazole carboxylate is 80.5%. Cool the reaction solution to room temperature, filter, concentrate, stir the concentrated mother liquor for crystallization at 5 °C for 1 h, filter, wash the filter cake with petroleum ether to obtain the crude product, and recrystallize with methanol to obtain 14.5 g of pure methyl 1,2,4-triazole-3-carboxylate, with a yield of 76.2%.

[0028] Example 4

[0029] Add 23.4 g of formamidine acetate and 200 mL of methanol to the reaction flask. Stir at room temperature and slowly add dropwise 12 g of 80% hydrazine hydrate. After 10 minutes, add dropwise the mixed solution prepared by dissolving 18 g of dimethyl oxalate and 3.8 g of tris(pentafluorophenyl)borane in 200 mL of anhydrous methanol. Stir at room temperature until there is no signal of dimethyl oxalate. Then transfer the reaction solution into a water bath at 70 °C and reflux for 7 h. By liquid phase detection, the external standard yield of methyl triazole carboxylate is 85.2%. Cool the reaction solution to room temperature, filter, concentrate, stir the concentrated mother liquor for crystallization at 0 °C for 1 h, filter, wash the filter cake with petroleum ether to obtain the crude product, and recrystallize with methanol to obtain 14.4 g of pure methyl 1,2,4-triazole-3-carboxylate, with a yield of 75.6%.

[0030] Comparative Example 1

[0031] Add 23.4 g of formamidine acetate and 200 mL of methanol to the reaction flask. Stir at room temperature and slowly add dropwise 12 g of 80% hydrazine hydrate. After 10 minutes, add dropwise the solution of 18 g of dimethyl oxalate dissolved in 200 mL of methanol. Stir at room temperature until there is no signal of dimethyl oxalate. Then transfer the reaction solution into a water bath at 60 °C and reflux for 6 h. By liquid phase detection, the external standard yield of methyl triazole carboxylate is 48%. Cool the reaction solution to room temperature, filter, concentrate, stir the concentrated mother liquor for crystallization at 5 °C for 1 h, filter, wash the filter cake with petroleum ether to obtain the crude product, and recrystallize with methanol to obtain 7.3 g of pure methyl 1,2,4-triazole-3-carboxylate, with a yield of 38.2%.

[0032] The above examples describe the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above examples. The content described in the above examples and the specification only illustrates the principle of the present invention. Without departing from the principle of the present invention, the present invention will have various changes and improvements, and these changes and improvements all fall within the scope of protection of the present invention.

Claims

1. A method for synthesizing 1,2,4-triazole-3-carboxylic acid methyl ester, characterized in that: The steps include: Using 4-formamidine acetate, hydrazine hydrate and dimethyl oxalate as raw materials, 1,2,4-triazole-3-carboxylic acid methyl ester was obtained by one-pot reaction.

2. The method for preparing 1,2,4-triazole-3-carboxylic acid methyl ester according to claim 1, characterized in that: Take formamidine acetate as the raw material, mix it with the solvent evenly, add hydrazine hydrate dropwise under stirring to obtain aminomethylhydrazine intermediate, then add dimethyl oxalate, a mixed solution of the catalyst and the solvent dropwise to the reaction solution, react at room temperature until no dimethyl oxalate raw material remains, then raise the temperature to continue the reaction, and the reaction is completed. The obtained crude product is purified by recrystallization to obtain 1,2,4-triazole-3-carboxylic acid methyl ester.

3. The method for preparing 1,2,4-triazole-3-carboxylic acid methyl ester according to claim 2, characterized in that: The solvent is selected from at least one of water, methanol and ethanol.

4. The method for preparing 1,2,4-triazole-3-carboxylic acid methyl ester according to claim 2, characterized in that: The reaction temperature is 60-80°C.

5. The method for preparing 1,2,4-triazole-3-carboxylic acid methyl ester according to claim 2, characterized in that: The reaction time is 5 to 8 hours.

6. The method for preparing 1,2,4-triazole-3-carboxylic acid methyl ester according to claim 2, characterized in that: The catalyst is selected from tris(pentafluorophenyl)borane.

7. The method for preparing 1,2,4-triazole-3-carboxylic acid methyl ester according to claim 2, characterized in that: The molar ratio of the catalyst to formamidine acetate is 0.001-0.05:

1.

8. The method for preparing 1,2,4-triazole-3-carboxylic acid methyl ester according to claim 2, characterized in that: The molar ratio of formamidine acetate, hydrazine hydrate and dimethyl oxalate is 1.25-2:1.25-2:

1.

9. The method for preparing 1,2,4-triazole-3-carboxylic acid methyl ester according to claim 1, characterized in that: The recrystallization solvent was dichloromethane.

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