Synthesis method for 1-methyl-5-hydroxypyrazole

Abstract

Disclosed in the present invention is a synthesis method for 1-methyl-5-hydroxypyrazole. The synthesis route comprises the following steps: step S1: using a methylhydrazine aqueous solution as a raw material, adding a water-soluble solvent, and reacting same with N,N-dimethylamino acrylate to obtain a crude product; and step S2: concentrating the crude product to a solid content of 60-65%, adding a crystallization solvent, and crystallizing and centrifuging same to obtain the target product, i.e., 1-methyl-5-hydroxypyrazole. Provided in the present invention is the synthesis method for 1-methyl-5-hydroxypyrazole. The synthesis method is simple, the equipment requirements are low, the raw material is low in price and easy to obtain, the post-treatment is simple, the reaction yield is high, and high-purity solid 1-methyl-5-hydroxypyrazole can be obtained.

Description

A method for synthesizing 1-methyl-5-hydroxypyrazole Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for synthesizing 1-methyl-5-hydroxypyrazole. Background Technology

[0002] 1-Methyl-5-hydroxypyrazole is a very important organic synthesis intermediate and a key raw material for the production of benzoylpyrazole pesticides, such as the herbicide benzoylpyrazole. These pesticides have advantages such as high selectivity, low toxicity, and high efficiency, and are widely used globally. Therefore, 1-methyl-5-hydroxypyrazole has a very large market potential, which is continuing to expand.

[0003] Currently, 1-methyl-5-hydroxypyrazole can be synthesized mainly through the following methods:

[0004] 1) Redox method: 1-Methyl-5-aminopyrazole and excess hydrogen peroxide are reacted in benzene or dimethylformamide for several hours to obtain 1-methyl-5-hydroxypyrazole. The raw materials used in this method are very expensive and involve dangerous reactions, making it difficult to industrialize.

[0005] 2) Cyclic synthesis with 1,3-electrophilic compounds and hydrazine followed by decarboxylation, as described in patent CN112480008A, involves adding tetrahydropyrrole dropwise to diethyl ethoxymethylene malonate at room temperature. After the reaction is complete, an aqueous solution of methylhydrazine is added dropwise. After the reaction is complete, an alkali is added to adjust the pH to neutral. The mixture is then filtered, distilled, and filtered again after adding a poor solvent to obtain the target compound. This method involves two or more steps, and the post-processing is complex, resulting in low product purity.

[0006] 3) Cyclic synthesis using α,β-unsaturated carbonyl compounds and hydrazine compounds, such as in patent CN109320457, methyl 3-methoxyacrylate is used as the main raw material and reacted with methylhydrazine to prepare 1-methyl-5-hydroxypyrazole. In this patent, the hydroxyl position selectivity is poor. In addition to 1-methyl-5-hydroxypyrazole, 1-methyl-3-hydroxypyrazole is often generated, which is difficult to separate, resulting in low reaction yield and poor product purity.

[0007] 4) Preparation of 1-methyl-5-hydroxypyrazole using a microchannel reactor. For example, patent CN112979550A reports a method for preparing 1-methyl-5-hydroxypyrazole using a microchannel reactor. This method requires advanced equipment and is difficult for personnel to operate.

[0008] Therefore, developing a synthetic route for 1-methyl-5-hydroxypyrazole that is based on conventional equipment, uses inexpensive and readily available raw materials, and has simple post-processing is of great significance for improving the economic efficiency and safety of the process. Summary of the Invention

[0009] In view of the above-mentioned shortcomings of the prior art, the present invention provides a method for synthesizing 1-methyl-5-hydroxypyrazole. The synthesis method is simple, requires low equipment, uses inexpensive and readily available raw materials, has simple post-processing, and has a high reaction yield, which can obtain high-purity solid 1-methyl-5-hydroxypyrazole.

[0010] To achieve the above objectives, the embodiments of the present invention adopt the following technical solutions:

[0011] A method for synthesizing 1-methyl-5-hydroxypyrazole, the synthetic route is as follows:

[0012]

[0013] The synthetic route includes the following steps:

[0014] Step S1: Using methylhydrazine aqueous solution as raw material, add water-soluble solvent and react with N,N-dimethylaminoacrylate to obtain crude product;

[0015] Step S2: Concentrate the crude product to a solid content of 60-65%, add crystallization solvent, crystallize, and centrifuge to obtain the target product 1-methyl-5-hydroxypyrazole.

[0016] According to one aspect of the present invention, the crystallization solvent includes, but is not limited to, one or more of dichloromethane, dichloroethane, ethyl acetate, acetonitrile, or dimethyl carbonate.

[0017] According to one aspect of the invention, the amount of the crystallization solvent is 1 to 3 times the mass of N,N-dimethyl acrylate.

[0018] According to one aspect of the invention, the concentration of crude product includes concentrating the crude product under reduced pressure to a solid content of 60-65%.

[0019] According to one aspect of the present invention, the temperature of the vacuum concentration is 60~130°C and the vacuum degree is 100~1000Pa.

[0020] According to one aspect of the present invention, in step S1, the reaction temperature is 20-30°C.

[0021] According to one aspect of the present invention, the N,N-dimethacrylate is one or a combination of N,N-dimethacrylate, N,N-dimethacrylate, and / or N,N-dimethacrylate.

[0022] According to one aspect of the invention, the water-soluble solvent includes, but is not limited to, one or more of alcohols, tetrahydrofuran, or acetonitrile.

[0023] According to one aspect of the invention, the amount of the water-soluble solvent is 1 to 5 times the mass of N,N-dimethyl acrylate.

[0024] According to one aspect of the invention, the amount of the methylhydrazine aqueous solution is 1 to 1.5 times the molar mass of N,N-dimethacrylate.

[0025] According to one aspect of the present invention, the concentration of the methylhydrazine aqueous solution is 20% to 40%.

[0026] Advantages of this invention: This invention discloses a method for synthesizing 1-methyl-5-hydroxypyrazole. Using an aqueous solution of methylhydrazine as a raw material, a water-soluble solvent is added, and the mixture reacts with N,N-dimethylaminoacrylate to obtain a crude product. The crude product is concentrated under reduced pressure, a crystallization solvent is added, crystallization is performed, and centrifugation yields the target product, 1-methyl-5-hydroxypyrazole. The synthesis method is simple, uses inexpensive and readily available raw materials, requires minimal equipment, involves simple post-processing, and has a high reaction yield, producing high-purity solid 1-methyl-5-hydroxypyrazole. Attached Figure Description

[0027] To more clearly illustrate the technical solutions in the embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0028] Figure 1 is a synthetic route diagram of the method for synthesizing 1-methyl-5-hydroxypyrazole according to the present invention;

[0029] Figure 2 is a high-performance liquid chromatogram of the crude product in Example 1 of this application;

[0030] Figure 3 is a high-performance liquid chromatogram of the target product 1-methyl-5-hydroxypyrazole in Example 1 of this application. Detailed Implementation

[0031] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0032] A method for synthesizing 1-methyl-5-hydroxypyrazole, the synthetic route is as follows:

[0033] The synthetic route includes the following steps:

[0034] Step S1: Using methylhydrazine aqueous solution as raw material, add water-soluble solvent and react with N,N-dimethylaminoacrylate to obtain crude product;

[0035] Step S2: Concentrate the crude product under reduced pressure to a solid content of 60-65%, add crystallization solvent, crystallize, and centrifuge to obtain the target product 1-methyl-5-hydroxypyrazole.

[0036] Example 1

[0037] S1: At room temperature, 125 g (0.543 mol) of a 20% aqueous solution of methylhydrazine and 250 g of acetonitrile (a water-soluble solvent) were added to a reaction vessel. The temperature was controlled at 20-30°C, and 50 g (0.387 mol) of N,N-dimethylaminoacrylate was added dropwise. After the addition was complete, the reaction was maintained at this temperature for 5 hours, yielding 415 g of crude product containing solvent and water, with a yield of 97.6%. As shown in Figure 2, the HPLC purity was 94.84%.

[0038] S2: The crude product was concentrated under reduced pressure at a vacuum of 100 Pa and a temperature of 60 °C until it reached a viscous state with a solid content of 62%. Then, 150 g of dichloromethane was added as a crystallization solvent, and the mixture was cooled to 20 °C for crystallization. After centrifugation and drying, 34.9 g of the target product, 1-methyl-5-hydroxypyrazole, was obtained, with a molar yield of 92%. As shown in Figure 3, the HPLC purity of the target product, 1-methyl-5-hydroxypyrazole, was 99.86%.

[0039] Example 2

[0040] S1: At room temperature, 135 g (0.879 mol) of a 30% aqueous solution of methylhydrazine and 150 g of water-soluble solvent ethanol were added to a reaction vessel. The temperature was controlled at 20-30℃, and 114 g (0.796 mol) of N,N-dimethylaminoacrylate was added dropwise. After the addition was complete, the reaction was maintained at this temperature for 2 hours to obtain 391 g of crude product containing solvent and water, with a yield of 98% and an HPLC purity of 94.47%.

[0041] S2: The crude product was concentrated under reduced pressure at a vacuum of 700 Pa and a temperature of 130 °C until it reached a viscous state with a solid content of 65%. 120 g of ethyl acetate, the crystallization solvent, was added, and the mixture was cooled to 20 °C to crystallize. After centrifugation and drying, 69.5 g of the target product 1-methyl-5-hydroxypyrazole was obtained. The purity of the target product was 99.78%, and the molar yield was 89%.

[0042] Example 3

[0043] S1: At room temperature, 150 g (0.977 mol) of a 30% aqueous solution of methylhydrazine and 340 g of water-soluble solvent ethanol were added to a reaction vessel. The temperature was controlled at 20-30℃, and 114 g (0.796 mol) of N,N-dimethylaminoacrylate was added dropwise. After the addition was completed, the reaction was kept at the temperature for 2 hours to obtain 595 g of crude product containing solvent and water, with a yield of 98.5% and an HPLC purity of 94.56%.

[0044] S2: The crude product was concentrated under reduced pressure at a vacuum of 400 Pa and a temperature of 85 °C until it reached a viscous state with a solid content of 60%. 230 g of ethyl acetate, the crystallization solvent, was added, and the mixture was cooled to 20 °C to crystallize. After centrifugation and drying, 70.3 g of the target product 1-methyl-5-hydroxypyrazole was obtained. The purity of the target product was 99.79%, and the molar yield was 90%.

[0045] Comparative Example 1

[0046] S1: At room temperature, 150 g (0.977 mol) of a 30% aqueous solution of methylhydrazine and 340 g of water-soluble solvent ethanol were added to a reaction vessel. The temperature was controlled at 20-30℃, and 114 g (0.796 mol) of N,N-dimethylaminoacrylate was added dropwise. After the addition was complete, the reaction was maintained at this temperature for 2 hours to obtain 587 g of crude product containing solvent and water, with a yield of 97.2% and an HPLC purity of 94.23%.

[0047] S2: The crude product was concentrated under reduced pressure at a vacuum of 1400 Pa and a temperature of 135 °C until it reached a viscous state with a solid content of 60%. 230 g of ethyl acetate, the crystallization solvent, was added, and the mixture was cooled to 20 °C to crystallize. After centrifugation and drying, 35.1 g of the target product 1-methyl-5-hydroxypyrazole was obtained. The purity of the target product was 91.5%, and the molar yield was 45%.

[0048] Comparative Example 2

[0049] S1: At room temperature, 250 g (1.628 mol) of a 30% aqueous solution of methylhydrazine and 340 g of water-soluble solvent ethanol were added to a reaction vessel. The temperature was controlled at 20-30℃, and 114 g (0.796 mol) of N,N-dimethylaminoacrylate was added dropwise. After the addition was complete, the reaction was maintained at this temperature for 2 hours to obtain 589 g of crude product containing solvent and water, with a yield of 97.5% and an HPLC purity of 94.37%.

[0050] S2: The crude product was concentrated under reduced pressure at a vacuum of 400 Pa and a concentration temperature of 85 °C until it reached a viscous state with a solid content of 60%. 230 g of ethyl acetate, the crystallization solvent, was added, and the mixture was cooled to 20 °C to crystallize. After centrifugation and drying, 59.4 g of the target product 1-methyl-5-hydroxypyrazole was obtained. The purity of the target product was 98.38%, and the molar yield was 76%.

[0051] Analysis of the synthesis methods of 1-methyl-5-hydroxypyrazole in Examples 1-3 and Comparative Examples 1-2 of this application reveals that: in Examples 1-3, the molar yield of 1-methyl-5-hydroxypyrazole reached 89-92%, while the molar yield of 1-methyl-5-hydroxypyrazole in Comparative Example 1 was 45%, and the molar yield of 1-methyl-5-hydroxypyrazole in Comparative Example 2 was 76%. It is evident that the molar yield of 1-methyl-5-hydroxypyrazole in Examples 1-3 is significantly higher than that in Comparative Examples 1-2. Therefore, using N,N-dimethylaminoacrylate and methylhydrazine aqueous solution as raw materials, and undergoing reaction, vacuum concentration, crystallization, and other post-processing, yields 1-methyl-5-hydroxypyrazole. This method is simple to operate, requires minimal post-processing, and yields a high reaction rate. Furthermore, the ratio of reactants and the reaction conditions at each step significantly affect the yield of the target product.

[0052] Advantages of this invention: This invention discloses a method for synthesizing 1-methyl-5-hydroxypyrazole. Using an aqueous solution of methylhydrazine as a raw material, a water-soluble solvent is added, and the mixture reacts with N,N-dimethylaminoacrylate to obtain a crude product. The crude product is concentrated to a viscous state, a crystallization solvent is added, crystallization is performed, and centrifugation yields the target product, 1-methyl-5-hydroxypyrazole. The synthesis method is simple, uses inexpensive and readily available raw materials, requires minimal equipment, involves simple post-processing, and has a high reaction yield, producing high-purity solid 1-methyl-5-hydroxypyrazole.

[0053] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A method for synthesizing 1-methyl-5-hydroxypyrazole, characterized in that, The synthetic route includes the following steps: Step S1: Using methylhydrazine aqueous solution as raw material, add water-soluble solvent and react with N,N-dimethylaminoacrylate to obtain crude product; Step S2: Concentrate, crystallize, and centrifuge the crude product to obtain the target product 1-methyl-5-hydroxypyrazole.

2. The method for synthesizing 1-methyl-5-hydroxypyrazole according to claim 1, characterized in that, The crystallization is carried out by adding a crystallization solvent, which includes, but is not limited to, one or more of dichloromethane, dichloroethane, ethyl acetate, acetonitrile, or dimethyl carbonate.

3. The method for synthesizing 1-methyl-5-hydroxypyrazole according to claim 2, characterized in that, The amount of the crystallization solvent used is 1 to 3 times the mass of N,N-dimethyl acrylate.

4. The method for synthesizing 1-methyl-5-hydroxypyrazole according to claim 1, characterized in that, The concentration of crude product includes concentrating the crude product under reduced pressure to a solid content of 60-65%, wherein the reduced pressure concentration temperature is 60-130°C and the vacuum degree is 100-1000 Pa.

5. The method for synthesizing 1-methyl-5-hydroxypyrazole according to claim 1, characterized in that, In step S1, the reaction temperature is 20-30℃.

6. The method for synthesizing 1-methyl-5-hydroxypyrazole according to claim 1, characterized in that, The N,N-dimethacrylate is one or a combination of N,N-dimethacrylate, N,N-dimethacrylate, and / or N,N-dimethacrylate.

7. The method for synthesizing 1-methyl-5-hydroxypyrazole according to claim 1, characterized in that, The water-soluble solvent includes, but is not limited to, one or more of alcohols, tetrahydrofuran, or acetonitrile.

8. The method for synthesizing 1-methyl-5-hydroxypyrazole according to claim 1, characterized in that, The amount of the water-soluble solvent used is 1 to 5 times the mass of N,N-dimethyl acrylate.

9. The method for synthesizing 1-methyl-5-hydroxypyrazole according to claim 1, characterized in that, The amount of the methylhydrazine aqueous solution used is 1 to 1.5 times the molar mass of N,N-dimethyl acrylate.

10. The method for synthesizing 1-methyl-5-hydroxypyrazole according to claim 1, characterized in that, The concentration of the methylhydrazine aqueous solution is 20%~40%.

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