A preparation method of 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol

Abstract

The invention discloses a method for preparing 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-alcohol, wherein methylhydrazine and ethyl trifluoroacetoacetate undergo hydrazine decyclization reaction to obtain 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-alcohol under the action of a catalyst; the catalyst is a nitrogen-containing organic compound; alternatively, the catalyst is a nitrogen-containing heterocyclic compound; alternatively, the catalyst is a cyclic secondary amine. The reaction conditions of the present invention are mild, the reaction selectivity is high under the action of a specific catalyst, the isomers produced during the reaction are few, the reaction yield is relatively high, the separation yield is more than 90%, and even more than 95%, the post-processing is simple and extensive, the purity can reach more than 98%, and it can be directly used in subsequent reactions, and is suitable for large-scale production.

Description

Technical Field

[0001] The invention relates to the field of pesticides, and in particular to a method for preparing 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol. Background Art

[0002] 1-Methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol is an important intermediate in the synthesis of sulfonepyrazoline. In addition, pyrazole compounds are very valuable organic compounds. Many pyrazole compounds have high biological activity and are widely used in many fields. For example, in medical applications, pyrazole compounds are effective for many diseases; in pesticide applications, pyrazole compounds have insecticidal, bactericidal and herbicidal activities, and show high efficiency, low toxicity and structural diversity; at the same time, this type of compound is also found in chemicals in various fields such as dyes, coatings, fragrances, detergents, surfactants, etc. Therefore, it is of great significance to study and develop pyrazole compounds. In addition, this intermediate is an important intermediate in the synthesis of sulfonepyrazoline, and its structure is as shown in formula (III):

[0003]

[0004] The synthesis of formula III currently has the following process:

[0005] J. Heterocyclic Chem. 27, 243 (1990). discloses a preparation method: methylhydrazine is added to a mixture of ethyl trifluoroacetoacetate and water at room temperature. After the reaction subsides, the mixture is kept under reflux for 2 hours. The yield is 24.2 g (49%) of 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol (III) and 4.2 g (8%) of 2-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol (IV), and the selectivity is 6:1. The method has a violent reaction process, a low yield of the obtained product, and poor selectivity, and is not suitable for industrial production.

[0006] ACS Chemical Neuroscience.8,2746-2758(2017). A method is reported in which ammonia is introduced into ethyl trifluoroacetoacetate (I) to react at 85°C for 3 hours to form an intermediate product, and then methyl hydrazine (II) is added and stirred for 1 hour and reacted at 85°C overnight to obtain 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol (III) and 2-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol (IV) in a ratio of 85:15. This method requires additional introduction of ammonia, which is cumbersome to operate, and has a long reaction time and low selectivity. The above methods basically have the problem of low yield or low selectivity and are not suitable for industrial production.

[0007] CN 113979944 A. discloses a preparation method: 4,4,4-trifluoroacetoacetic acid ethyl ester and methylhydrazine aqueous solution are used as raw materials, and condensation cyclization reaction is carried out in the presence of an organic solvent and a molecular sieve catalyst. After the reaction is completed, the reaction system is filtered, washed and dried to obtain the target product 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol. The catalyst used in this method is a modified molecular sieve, which is insoluble in both organic solvents and water. After the reaction is completed, the molecular sieve and the intermediate (III) cannot be separated, which is not suitable for industrial production. In addition, the molecular sieve is accompanied by wear and tear during the actual production process, generating solid waste that is difficult to handle, and the environmental protection pressure is large.

[0008] CN 111393427 A. discloses a preparation method: adding ethyl trifluoroacetoacetate to an acetic acid solution at 0°C, adding methylhydrazine dropwise, and reacting at 80°C after the addition is complete. After the reaction is complete, water is added for crystallization and filtration is performed, and the filter cake is washed three times with 150 mL of water, and the yield is 90%. Although the yield of the method is improved, the problem of low selectivity is still not solved. The method has the problem of low selectivity and the amount of solvent acetic acid used is too large. The energy consumption of recovering acetic acid in production is high, the time is long, and the yield is low, which is not suitable for industrial production.

[0009] Therefore, how to improve the yield and selectivity of 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol is a technical problem that needs to be solved urgently. Summary of the invention

[0010] Purpose of the Invention

[0011] In order to overcome the above-mentioned shortcomings, the purpose of the present invention is to provide a method for preparing 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol. The present invention has high reaction selectivity under the action of a specific catalyst, and few isomers are produced during the reaction. The reaction yield is relatively high, and the separation yield is above 90%, and can even reach above 95%. The post-treatment is simple and extensive, and the purity can reach above 98%. It can be directly used in subsequent reactions and is suitable for large-scale production.

[0012] Solution

[0013] To achieve the purpose of the present invention, the technical solution adopted by the present invention is as follows:

[0014] In a first aspect, the present invention provides a method for preparing 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol. In the presence of a catalyst, methylhydrazine and ethyl trifluoroacetoacetate undergo a hydrazine cyclization reaction to obtain 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol; the catalyst is a nitrogen-containing organic compound.

[0015] Further, the catalyst is a nitrogen-containing heterocyclic compound; optionally, the catalyst is a cyclic secondary amine, and optionally, the number of carbon atoms on the ring of the cyclic secondary amine is 4-6.

[0016] Optionally, the catalyst is selected from one or more of 2,2,6,6-tetramethylpiperidine, 2-methylpiperidine, piperidine, 2,6-dimethylpiperidine, proline, and morpholine.

[0017] Furthermore, the catalyst is piperidine, 2,6-dimethylpiperidine or D-proline.

[0018] Furthermore, the molar ratio of ethyl trifluoroacetoacetate to the catalyst is 1:0.04-0.2, optionally 1:0.04-0.06.

[0019] Furthermore, the temperature of the hydrazine cyclization reaction is 60°C to 80°C.

[0020] Furthermore, the hydrazine cyclization reaction is carried out in a solvent, and the optional solvent is one or more of water, methanol, ethanol, acetic acid and butanol.

[0021] Furthermore, the mass ratio of the solvent to ethyl trifluoroacetoacetate is 1:1-6, and optionally 1:2-6.

[0022] Furthermore, the hydrazine cyclization reaction method is: in a solution containing methylhydrazine and a catalyst, ethyl trifluoroacetoacetate is added dropwise to carry out a hydrazine cyclization reaction;

[0023] Furthermore, in the solution containing methylhydrazine and a catalyst, the solvent includes water and one or more of methanol, ethanol, acetic acid and butanol.

[0024] Further, water accounts for 40% to 80% of the weight of the solvent; optionally, water accounts for 50% to 66% of the weight of the solvent.

[0025] Furthermore, after the hydrazine cyclization reaction, post-treatment is also included: cooling and stirring to crystallize, filtering to obtain a white solid precipitate, and drying to obtain 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol.

[0026] Beneficial Effects

[0027] The reaction conditions of the present invention are mild, the reaction selectivity is high under the action of a specific catalyst, less isomers are produced during the reaction, the reaction yield is high, the separation yield is above 90%, and can even reach above 95%, the post-treatment is simple and extensive, the purity can reach above 98%, and the product can be directly used for subsequent reactions, and is suitable for large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] One or more embodiments are exemplarily described by the pictures in the accompanying drawings, and these exemplary descriptions do not constitute limitations on the embodiments. The special word "exemplary" here means "used as an example, embodiment or illustrative". Any embodiment described as "exemplary" here is not necessarily interpreted as being superior or better than other embodiments.

[0029] Figure 1 This is a liquid phase analysis diagram of the analysis sample of Example 1 of the present invention. Among them, the product (compound of formula III) is at 7.827 min, and the isomer (compound of formula IV) is at a retention time of 8.347 min.

[0030] Figure 2 This is a liquid phase analysis diagram of the analysis sample of comparative example 1 of the present invention, wherein the product (compound of formula III) is present at 7.390 min, and the isomer is present at 8.093 min. DETAILED DESCRIPTION

[0031] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be described clearly and completely below. Obviously, the described embodiments are 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 are within the scope of protection of the present invention.

[0032] In addition, in order to better illustrate the present invention, numerous specific details are provided in the specific embodiments below. It should be understood by those skilled in the art that the present invention can be implemented without certain specific details. In certain embodiments, raw materials, schemes, methods, means, etc. well known to those skilled in the art are not described in detail to highlight the gist of the present invention.

[0033] Unless explicitly stated otherwise, throughout the specification and claims, the term “comprise” or variations such as “include” or “comprising”, etc., will be understood to include the stated elements or components but not to exclude other elements or components.

[0034] The product contents in the following examples were confirmed by liquid or gas chromatography, and the purity and yield of the products after the reaction were calculated using the external standard method.

[0035] The raw materials such as methylhydrazine, acetic acid, piperidine, ethyl trifluoroacetoacetate in the following examples are commercially available.

[0036] The route of the reaction of methylhydrazine (II) with ethyl trifluoroacetoacetate (I) to generate 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol (III):

[0037]

[0038] The catalyst is selected from one or more of 2,2,6,6-tetramethylpiperidine, 2-methylpiperidine, piperidine, 2,6-dimethylpiperidine, proline and morpholine.

[0039] Example 1

[0040] 20.0 g of acetic acid was added to 63.2 g of methylhydrazine aqueous solution (40%), the temperature was controlled at 15°C, 2.1 g of piperidine was added and stirred for 1 hour, and 92.2 g of ethyl trifluoroacetoacetate was added dropwise. After the addition was completed, the temperature was raised to 80°C for reaction. After 3.5 hours, the reaction was detected by HPLC. The temperature was lowered and stirred for crystallization, and a white solid precipitate was obtained by suction filtration. After drying, 81.2 g of 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol was obtained, with a yield of 96.4% and a content of 98.5%. The product was subjected to liquid phase analysis, as shown in FIG. Figure 1 As shown, the product (Formula III compound) is obtained at a retention time of 7.827 min, and the isomer (Formula IV compound) is obtained at a retention time of 8.347 min. The selectivity is 99.95:0.05. The product obtained by filtration in this example can be directly used in subsequent reactions after drying without further purification.

[0041] Example 2

[0042] 16 g of ethanol was added to 63.2 g of methylhydrazine aqueous solution (40%), the temperature was controlled at 10 ° C, 2.48 g of 2-methylpiperidine was added and stirred for 1 hour, 92.2 g of ethyl trifluoroacetoacetate was added dropwise, the temperature was raised to 80 ° C for reaction after the addition was completed, HPLC detection reaction was completed after 3.5 hours, the temperature was lowered and stirred for crystallization, and white solid precipitation was obtained by suction filtration. After drying, 78.9 g of 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol was obtained, with a yield of 93.6% and a content of 98.5%. The product obtained by suction filtration in this embodiment can be directly used in subsequent reactions after drying without further purification.

[0043] Example 3

[0044] 16 g of methanol was added to 63.2 g of methylhydrazine aqueous solution (40%), the temperature was controlled at 25 ° C, 3.51 g of 2,2,6,6-tetramethylpiperidine was added and stirred for 1 hour, 92.2 g of ethyl trifluoroacetoacetate was added dropwise, and the temperature was raised to 60 ° C for reflux reaction after the addition was completed. After 3.5 hours, the reaction was detected by HPLC and the reaction was completed. The temperature was lowered and stirred for crystallization, and a white solid precipitate was obtained by suction filtration. After drying, 78.1 g of 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol was obtained, with a yield of 92.4% and a content of 98.2%. The product obtained by suction filtration in this embodiment can be directly used for subsequent reactions after drying without further purification.

[0045] Example 4

[0046] 36g of butanol was added to 63.2g of methylhydrazine aqueous solution (40%), the temperature was controlled at 15°C, 2.83g of 2,6-dimethylpiperidine was added and stirred for 1hr, 92.2g of ethyl trifluoroacetoacetate was added dropwise, the temperature was raised to 75°C for reaction after the addition was completed, HPLC detection reaction was completed after 3.5hr, the temperature was lowered and stirred for crystallization, and white solid precipitation was obtained by suction filtration, and 81.2g of 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol was obtained after drying, with a yield of 96.4%, a content of 98.5%, and a selectivity of 99%. The product obtained by suction filtration in this embodiment can be directly used for subsequent reactions after drying without further purification.

[0047] Example 5

[0048] 54.1g of acetic acid was added to 63.2g of methylhydrazine aqueous solution (40%), the temperature was controlled at 10°C, 2.18g of morpholine was added and stirred for 1hr, 92.2g of ethyl trifluoroacetoacetate was added dropwise, the temperature was raised to 80°C for reaction after the addition was completed, and the reaction was detected by HPLC after 3.5hr, the temperature was lowered and stirred for crystallization, and a white solid precipitate was obtained by suction filtration. After drying, 78.3g of 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol was obtained, with a yield of 92.5%, a content of 98.1%, and a selectivity of 99%. The product obtained by suction filtration in this embodiment can be directly used in subsequent reactions after drying without further purification.

[0049] Example 6

[0050] 36g of butanol was added to 63.2g of methylhydrazine aqueous solution (40%), the temperature was controlled at 15°C, 2.88g of L-proline was added and stirred for 1hr, 92.2g of ethyl trifluoroacetoacetate was added dropwise, the temperature was raised to 70°C for reaction after the addition was completed, HPLC detection reaction was completed after 3.5hr, the temperature was lowered and stirred for crystallization, and white solid precipitation was obtained by suction filtration, and 78.1g of 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol was obtained after drying, with a yield of 92.2%, a content of 98.0%, and a selectivity of 99%. The product obtained by suction filtration in this embodiment can be directly used for subsequent reactions after drying without further purification.

[0051] Embodiment 7:

[0052] To 63.2 g of methylhydrazine aqueous solution (40%) was added 36 g of butanol, the temperature was controlled at 15 ° C, 2.88 g of D-proline was added and stirred for 1 hour, and then 92.2 g of ethyl trifluoroacetoacetate was added dropwise. After the addition was completed, the temperature was raised to 70 ° C for reaction. After 3.5 hours, HPLC detected that the reaction was complete, the temperature was lowered and stirred for crystallization, and a white solid precipitate was obtained by suction filtration. After drying, 80.3 g of 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol was obtained, with a yield of 95.1%, a content of 98.3%, and a selectivity of 99%. The product obtained by suction filtration in this example can be directly used in subsequent reactions after drying without further purification.

[0053] Comparative Example 1

[0054] Example 1 of WO2005 / 095352 was repeated

[0055] Dissolve 46.1 g (0.25 mol) of ethyl trifluoroacetoacetate in 30.0 g (0.5 mol) of acetic acid. Cool the solution to below 10°C while stirring. Then drop 32.8 g (0.25 mol) of 35% methylhydrazine aqueous solution within 1 hour. After dropping, stir at room temperature for 1 hour, and then stir at 80°C for 5 hours. After the reaction is completed, cool the system to room temperature, add 75 ml of toluene, 300 ml of water and 24 g (0.6 mol) of sodium hydroxide. Separate the liquids, add 77 g (0.8 mol) of 35% hydrochloric acid to the water layer, collect the solid by filtration, wash twice with 25 ml of water, and dry to obtain 36.7 g of the target product, with a yield of 86.5% and a purity of 97.8%. The yield is low. The product was subjected to liquid phase analysis, as shown Figure 2 As shown, the product (compound of formula III) is obtained at a retention time of 7.390 min, and the isomer (compound of formula IV) is obtained at a retention time of 8.093 min. The selectivity of compound of formula III is 93%, and that of compound of formula IV is as high as 3.5%.

[0056] The catalyst used in the route of the present invention can obtain the target product (III) with high yield and high purity. The product after filtration and drying can be directly used in subsequent reactions without further purification, thus solving the problems of low yield, low purity and difficulty in removing or recovering the catalyst in the prior art.

[0057] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol, characterized in that: In the presence of a catalyst, methylhydrazine and ethyl trifluoroacetoacetate undergo a hydrazine cyclization reaction to obtain 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol; The catalyst is selected from one or more of 2,2,6,6-tetramethylpiperidine, 2-methylpiperidine, piperidine, 2,6-dimethylpiperidine, proline and morpholine.

2. The preparation method according to claim 1, characterized in that: The catalyst is piperidine, 2,6-dimethylpiperidine or D-proline.

3. The preparation method according to claim 1, characterized in that: The molar ratio of ethyl trifluoroacetoacetate to the catalyst is 1:0.04-0.

2.

4. The preparation method according to claim 1, characterized in that: The molar ratio of ethyl trifluoroacetoacetate to the catalyst is 1:0.04-0.

06.

5. The preparation method according to claim 1, characterized in that: The temperature of the hydrazine cyclization reaction is 60°C~80°C.

6. The preparation method according to any one of claims 1 to 5, characterized in that: The hydrazine cyclization reaction is carried out in a solvent.

7. The preparation method according to claim 6, characterized in that: The solvent is one or more of water, methanol, ethanol, acetic acid and butanol.

8. The preparation method according to claim 6, characterized in that: The mass ratio of the solvent to ethyl trifluoroacetoacetate is 1:1-6.

9. The preparation method according to claim 6, characterized in that: The mass ratio of the solvent to ethyl trifluoroacetoacetate is 1:2-6.

10. The preparation method according to any one of claims 1 to 5, characterized in that: The hydrazine cyclization reaction method is as follows: ethyl trifluoroacetoacetate is added dropwise to a solution containing methylhydrazine and a catalyst to carry out a hydrazine cyclization reaction.

11. The preparation method according to claim 10, characterized in that: In the solution containing methylhydrazine and a catalyst, the solvent includes water, and the solvent also includes one or more of methanol, ethanol, acetic acid and butanol.

12. The preparation method according to claim 11, characterized in that: Water accounts for 40% to 80% of the solvent weight.

13. The preparation method according to claim 11, characterized in that: Water accounts for 50% to 66% of the solvent weight.

14. The preparation method according to any one of claims 1 to 5, characterized in that: After the hydrazine cyclization reaction, post-treatment is also included: cooling and stirring to crystallize, filtering to obtain a white solid precipitate, and drying to obtain 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol.

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