Preparation method of 1-methyl-5-hydroxypyrazole

Abstract

The invention relates to a preparation method of 1-methyl-5-hydroxypyrazole, which comprises the following steps: (a) methylation reaction: fully dissolving pyrazole in a reaction solvent a, dropwise adding a methylation reagent into the reaction solvent a to carry out methylation reaction, adding water into the reaction solvent a to carry out quenching reaction after the reaction is completed, fully washing and concentrating to generate 1-methylpyrazole; (b) bromination hydrolysis reaction: fully dispersing 1-methylpyrazole in a reaction solvent b, dropwise adding bromine into the reaction solvent b to perform bromination reaction, dropwise adding liquid caustic soda and a sodium thiosulfate solution into the reaction solvent b to perform quenching reaction after the reaction is completed, adding the liquid caustic soda into the reaction solvent b after extraction and concentration, and performing heating hydrolysis and cooling crystallization to obtain the 1-methyl-5-hydroxypyrazole. The preparation method of the 1-methyl-5-hydroxypyrazole is reasonable in design, not only reduces the isomer 1-methyl-3-hydroxypyrazole, but also avoids the use of liquid with pungent smell, such as ethylenediamine, and precursor reagents, such as methylhydrazine, improves the operation safety, is environment-friendly, and is beneficial to industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of preparation of pyrazole herbicide intermediates and relates to a preparation method of 1-methyl-5-hydroxypyrazole, in particular to a preparation method of 1-methyl-5-hydroxypyrazole, a pyrazole herbicide intermediate. Background Art

[0002] Benpyrazone is a very effective herbicide. It is the first benzoyl pyrazolone herbicide developed by BASF and also belongs to the class of hydroxyphenylpyruvate dioxidase inhibitors. Benpyrazone has a good control effect on weeds resistant to glyphosate, triazines, acetolactate synthase inhibitors and acetyl-CoA carboxylase, and can effectively control the main grass weeds and broadleaf weeds on corn crops.

[0003] Among them, 1-methyl-5-hydroxypyrazole is an important intermediate of benzylpyrazone. In the prior art, the main synthesis methods of 1-methyl-5-hydroxypyrazole are as follows: Route 1: Patents IN201611027903 and CN112480008 both propose using diethyl ethoxymethylenemalonate as a starting material to first react with diethylamine or tetrahydropyrrole to form an amide, and then cyclize with methylhydrazine to form 1-methyl-5-hydroxypyrrole-4-carboxylic acid ethyl ester, and then decarboxylate under the action of an acid to form the target intermediate 1-methyl-5-hydroxypyrazole, as shown in the following formula: .

[0004] Route 2: Patent CN112574111 proposes that diethyl ethoxymethylenemalonate first reacts with hydrazine hydrate to form 3-hydroxypyrrole-4-carboxylic acid ethyl ester, then reacts with a methylating agent to form 1-methyl-5-hydroxypyrrole-4-carboxylic acid ethyl ester, and finally decarboxylates to form the target product 1-methyl-5-hydroxypyrazole, as shown in the following formula: .

[0005] The purpose of the above two process routes is to reduce the formation of the isomer 1-methyl-3-hydroxypyrazole, thereby improving the conversion rate.

[0006] The above two process routes have certain improvements in reducing the formation of isomers, but increase the use of tetrahydropyrrole and ethylenediamine, which have pungent odors and increase the discharge of waste liquid, which is unfriendly to production personnel and the environment. In addition, the above two process routes both require the use of easy-to-make drug reagents such as methylhydrazine and hydrazine hydrate, which take a long time to purchase, and the raw material supply may be untimely during continuous production.

[0007] Therefore, it is urgent to develop a new process route for the preparation of 1-methyl-5-hydroxypyrazole, an intermediate of pyrazole herbicides. The process route avoids the use of pungent odor liquids such as ethylenediamine and tetrahydropyrrole and easily-made drug reagents such as methylhydrazine and hydrazine hydrate while ensuring high yield, thereby improving operational safety, being suitable for industrial production, facilitating the large-scale production of pyrazole herbicides, and having great social and economic benefits. Summary of the invention

[0008] Purpose of the invention: In order to overcome the above shortcomings, the purpose of the present invention is to provide a method for preparing 1-methyl-5-hydroxypyrazole, which is used to prepare 1-methyl-5-hydroxypyrazole, an intermediate of pyrazole herbicides. The preparation method is reasonably designed, which not only reduces the isomer 1-methyl-3-hydroxypyrazole, but also avoids the use of pungent odor liquids such as ethylenediamine and tetrahydropyrrole and easily-made drug reagents such as methylhydrazine and hydrazine hydrate, thereby improving the operation safety, being environmentally friendly, being conducive to process realization and industrial production, and having broad application prospects.

[0009] The objective of the present invention is achieved through the following technical solutions: A method for preparing 1-methyl-5-hydroxypyrazole comprises the following steps: (a) Methylation reaction: Pyrazole is fully dissolved in a reaction solvent a, and a methylation reagent is added dropwise thereto to carry out a methylation reaction. After the reaction is completed, water is added thereto to quench the reaction, and the mixture is fully washed and concentrated to produce an intermediate 1-methylpyrazole, as shown in the following formula: ; (b) Bromine hydrolysis reaction: The above intermediate 1-methylpyrazole is fully dispersed in the reaction solvent b, bromine is added dropwise thereto for bromination reaction, and after the reaction is completed, liquid alkali and sodium thiosulfate solution are added dropwise thereto for quenching the reaction, and after extraction and concentration, liquid alkali is added thereto, the temperature is raised for hydrolysis, and the temperature is lowered for crystallization to obtain the target product 1-methyl-5-hydroxypyrazole, as shown in the following formula: .

[0010] The preparation method of 1-methyl-5-hydroxypyrazole described in the present application is to use pyrazole as a starting material, first react with a methylating agent to generate an intermediate 1-methylpyrazole, and then undergo bromination and hydrolysis reactions to generate the target product 1-methyl-5-hydroxypyrazole. The reaction conditions are relatively mild, the operation is simple, the raw materials are easily available, and a very high yield can be obtained, which is conducive to process implementation and industrial production.

[0011] Among them, the preparation of 1-methyl-5-hydroxypyrazole through the above reaction can reduce the production of the isomer 1-methyl-3-hydroxypyrazole, and avoids the use of pungent odor liquids such as ethylenediamine and tetrahydropyrrole and easily-made drug reagents such as methylhydrazine and hydrazine hydrate. Compared with the preparation method of 1-methyl-5-hydroxypyrazole in the prior art, the operation is safer and more environmentally friendly.

[0012] Preferably, in the above-mentioned method for preparing 1-methyl-5-hydroxypyrazole, in the step (a), the reaction solvent a is dichloromethane or dichloroethane, and the methylating agent is one or a combination of dimethyl sulfate, dimethyl carbonate, methyl iodide, and trimethyl orthoformate.

[0013] More preferably, in the above-mentioned method for preparing 1-methyl-5-hydroxypyrazole, the reaction solvent is dichloromethane, and the methylating agent is iodomethane.

[0014] Preferably, in the above-mentioned method for preparing 1-methyl-5-hydroxypyrazole, in the step (a), the molar ratio of the methylating agent to pyrazole is 1.1 to 1.2.

[0015] Preferably, in the above-mentioned method for preparing 1-methyl-5-hydroxypyrazole, in the step (a), the methylation reaction temperature is 0-40° C. and the reaction time is 1-4 h.

[0016] More preferably, in the above-mentioned method for preparing 1-methyl-5-hydroxypyrazole, in the step (a), the methylation reaction is first stirred at room temperature for 0-1 hour and then heated to 30-40° C. and stirred for 1-3 hours at this temperature until the pyrazole reaction is complete.

[0017] Preferably, in the above-mentioned method for preparing 1-methyl-5-hydroxypyrazole, in the step (b), the reaction solvent b is 48% HBr.

[0018] Preferably, in the above-mentioned method for preparing 1-methyl-5-hydroxypyrazole, in the step (b), the molar ratio of bromine to 1-methylpyrazole is 1.05-1.1 times.

[0019] Preferably, in the above-mentioned method for preparing 1-methyl-5-hydroxypyrazole, in the step (b), the bromination reaction temperature is 30-70°C.

[0020] More preferably, in the above-mentioned method for preparing 1-methyl-5-hydroxypyrazole, in the step (b), the bromination reaction temperature is 50-70°C.

[0021] Preferably, in the above-mentioned method for preparing 1-methyl-5-hydroxypyrazole, in the step (b), the bromination reaction time is 5 to 12 hours.

[0022] More preferably, in the above-mentioned method for preparing 1-methyl-5-hydroxypyrazole, the bromination reaction time is 5 to 7 hours.

[0023] Compared with the prior art, the present invention has the following beneficial effects: (1) The preparation method of 1-methyl-5-hydroxypyrazole of the present invention has a reasonable preparation step design. Pyrazole is used as a starting material, first reacts with a methylating agent to generate an intermediate 1-methylpyrazole, and then undergoes bromination and hydrolysis to generate the target product 1-methyl-5-hydroxypyrazole. The reaction yield is high, the reaction is safe and simple, and it is suitable for industrial production. It provides convenience for the large-scale production of pyrazole herbicides and has great social and economic benefits. (2) The method for preparing 1-methyl-5-hydroxypyrazole of the present invention not only reduces the production of the isomer 1-methyl-3-hydroxypyrazole, but also avoids the use of pungent odor liquids such as ethylenediamine and tetrahydropyrrole and easily produced drug-making reagents such as methylhydrazine and hydrazine hydrate, thereby improving operational safety, being environmentally friendly, and having broad application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 HPLC chart of the white solid obtained in the embodiment of the present invention; Figure 2 HPLC peak table of the white solid obtained in the embodiment of the present invention; Figure 3 This is the HNMR graph of the white solid obtained in the embodiment of the present invention. DETAILED DESCRIPTION

[0025] The following will be attached Figure 1 , 2 3. In combination with Example 1, Example 2 and specific experimental data, the technical solutions in the embodiments of the present invention are clearly and completely described. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work belong to the protection scope of the present invention. If the specific conditions are not specified in the embodiments, they are carried out according to conventional conditions or the conditions recommended by the manufacturer, and the instruments and reagents used can be purchased. The following Examples 1 and 2 both provide a method for preparing 1-methyl-5-hydroxypyrazole.

[0026] Example 1 The preparation method of 1-methyl-5-hydroxypyrazole of Example 1 comprises the following steps: (a) Preparation of 1-methylpyrazole: Add 34 ml of dichloromethane and 6.8 g of pyrazole to a 250 ml three-necked flask. After fully dissolving, add 17 g of iodomethane dropwise. Stir at room temperature for 0.5 h, then heat to 30-40 °C and keep stirring for 1-3 h until the pyrazole reacts completely. Then add 34 ml of water to quench the reaction, add 34 ml of dichloromethane to extract once, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to obtain the intermediate 1-methylpyrazole.

[0027] (b) Preparation of 1-methyl-5-hydroxypyrazole: 68 ml of 48% HBr was added to the concentrated 1-methylpyrazole obtained in step (a), and after thorough mixing, 17.6 g of bromine was added dropwise thereto while maintaining the temperature at 10-30°C. After the addition was completed, the temperature was raised to 50-70°C and stirred for 5-7 hours until the intermediate 1-methylpyrazole reacted completely. After cooling to room temperature, liquid alkali and sodium thiosulfate solution were slowly added dropwise thereto, and the pH was adjusted to neutral. The solution was detected as colorless by starch potassium iodide test paper. Then 34 ml × 2 dichloroethane was added thereto for extraction twice, and after the organic phases were combined, 40 ml of liquid alkali was added thereto, and the temperature was raised to 70-80°C and stirred for reaction for 2-5 hours until the bromide reacted completely. After separation, the solution was washed once with water, dried over anhydrous sodium sulfate, and cooled for crystallization to obtain 8.1 g of a white solid with a yield of 82.6%.

[0028] Example 2 The preparation method of 1-methyl-5-hydroxypyrazole of Example 2 comprises the following steps: (a) Preparation of 1-methylpyrazole: Add 225 kg of dichloromethane and 34 kg of pyrazole to a 1000 L reactor, stir at room temperature for 1 hour, then drop 85 kg of iodomethane, and continue stirring at room temperature for 1 hour. Then heat to 30-40 °C and keep stirring for 1-3 hours until the pyrazole reacts completely, then add 170 kg of water to quench the reaction, add 110 kg of dichloromethane to extract the aqueous phase once, combine the organic phases and wash once with 170 kg of water, and concentrate at 40-45 °C until the distillate is in the form of drops to obtain the intermediate 1-methylpyrazole.

[0029] (b) Preparation of 1-methyl-5-hydroxypyrazole: 510 kg of 48% HBr was added to the concentrated dry 1-methylpyrazole obtained in step (a), and after thorough mixing, 88 kg of bromine was added dropwise thereto while maintaining the temperature at 10-30°C. After the addition was completed, the temperature was raised to 50-70°C and stirred for 5-7 hours until the intermediate 1-methylpyrazole was completely reacted. After cooling to room temperature, liquid alkali and sodium thiosulfate solution were slowly added dropwise thereto, and the pH was adjusted to neutral. The starch potassium iodide test paper detected that it was colorless. Then, 212 kg of dichloroethane and 106 kg were added thereto for extraction twice, and after the organic phase was combined, 200 kg of liquid alkali was added thereto, and the temperature was raised to 70-80°C and stirred for reaction for 2-5 hours until the bromide was completely reacted. After separation, it was washed twice with 340 kg of water, and the temperature was lowered and crystallized to obtain 40.2 kg of white solid, with a yield of 81.9%.

[0030] The white solids obtained in Example 1 and Example 2 were subjected to HPLC determination. The HPLC test results are as follows: Figure 1 , 2 shown.

[0031] The white solids obtained in Examples 1 and 2 were subjected to HNMR measurement.

[0032] 1 H-NMR (400M, DMSO) δ7.27 (s, 1H), 5.52 (d, J=1.2Hz, 1H), 3.69 (s, 3H). Figure 3 shown.

[0033] It can be seen from the above that 1-methyl-5-hydroxypyrazole can be prepared by the preparation method of the present invention, and the preparation method has higher operation safety, is environmentally friendly and is suitable for industrial production, has a high reaction yield, is safe and simple to react, provides convenience for the large-scale production of pyrazole herbicides, has greater social and economic benefits, and has broad application prospects.

[0034] The present invention has many specific application paths, and the above is only a preferred embodiment of the present invention. It should be pointed out that the above embodiments are only used to illustrate the present invention, and are not used to limit the protection scope of the present invention. For those of ordinary skill in the art, several improvements can be made without departing from the principle of the present invention, and these improvements should also be regarded as the protection scope of the present invention.

Claims

1. A method for preparing 1-methyl-5-hydroxypyrazole, characterized in that: The steps include: (a) Methylation reaction: Pyrazole is fully dissolved in a reaction solvent a, and a methylation reagent is added dropwise thereto to carry out a methylation reaction. After the reaction is completed, water is added thereto to quench the reaction, and the mixture is fully washed and concentrated to produce an intermediate 1-methylpyrazole, as shown in the following formula: ； (b) Bromohydrolysis reaction: The above intermediate 1-methylpyrazole is fully dispersed in the reaction solvent b, bromine is added dropwise thereto for bromination reaction, and after the reaction is completed, liquid alkali and sodium thiosulfate solution are added dropwise thereto for quenching the reaction, and after extraction and concentration, liquid alkali is added thereto, the temperature is raised for hydrolysis, and the temperature is lowered for crystallization to obtain the target product 1-methyl-5-hydroxypyrazole. 。 2. The method for preparing 1-methyl-5-hydroxypyrazole according to claim 1, characterized in that: In the step (a), the reaction solvent a is dichloromethane or dichloroethane, and the methylating agent is one or a combination of dimethyl sulfate, dimethyl carbonate, methyl iodide, and trimethyl orthoformate.

3. The method for preparing 1-methyl-5-hydroxypyrazole according to claim 1, characterized in that: In the step (a), the molar ratio of the methylating agent to pyrazole is 1.1-1.

2.

4. The method for preparing 1-methyl-5-hydroxypyrazole according to claim 1, characterized in that: In the step (a), the methylation reaction temperature is 0-40° C. and the reaction time is 1-4 hours.

5. The method for preparing 1-methyl-5-hydroxypyrazole according to claim 4, characterized in that: In the step (a), the methylation reaction is first stirred at room temperature for 0-1 hour and then heated to 30-40° C. and stirred for 1-3 hours until the pyrazole reaction is complete.

6. The method for preparing 1-methyl-5-hydroxypyrazole according to claim 1, characterized in that: In the step (b), the reaction solvent b is 48% HBr.

7. The method for preparing 1-methyl-5-hydroxypyrazole according to claim 1, characterized in that: In the step (b), the molar ratio of bromine to 1-methylpyrazole is 1.05-1.

10.

8. The method for preparing 1-methyl-5-hydroxypyrazole according to claim 1, characterized in that: In the step (b), the bromination reaction temperature is 30-70°C.

9. The method for preparing 1-methyl-5-hydroxypyrazole according to claim 8, characterized in that: In the step (b), the bromination reaction temperature is 50-70°C.

10. The method for preparing 1-methyl-5-hydroxypyrazole according to claim 1, characterized in that: In the step (b), the bromination reaction time is 5 to 12 hours.

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