Preparation method of hydroxypyrazole derivative under action of alkali

Abstract

The invention relates to a preparation method of a hydroxypyrazole derivative under the action of alkali, and belongs to the technical field of pesticides. The reaction formula is as follows: # imgabs0 #; mixing the compound shown in the formula III with alkaline inorganic matter and water, adding the compound shown in the formula II, and reacting at 20-50 DEG C to obtain the compound shown in the formula I; according to the method, water is used as a solvent, so that the recovery cost of an organic solvent is reduced, and the emission of three wastes such as organic tail gas is reduced; alkaline inorganic matters such as sodium hydroxide are used as reactants, the reaction is carried out at a lower temperature, the reaction time is short, the energy consumption is reduced, and meanwhile, the raw material cost is reduced; compared with an acid catalyst, an alkaline inorganic matter is adopted as a reactant, water is adopted as a solvent, and corrosion loss to equipment is small.

Description

Technical Field

[0001] The invention relates to the technical field of pesticides, and in particular to a method for preparing a hydroxypyrazole derivative under the action of a base. Background Art

[0002] Hydroxypyrazole derivatives are key intermediates for the synthesis of herbicides such as pyraclostrobin. Among them, pyraclostrobin has been widely valued and applied worldwide due to its excellent characteristics such as broad herbicidal spectrum, high activity, low dosage and good safety. Under the current situation where the EU has banned acetochlor and isopropylamine, it can be considered that pyraclostrobin will gradually replace widely used chloroacetamide herbicides such as acetochlor and isopropylamine, and become a new mainstream herbicide variety with more application prospects. Therefore, it is particularly important to produce this intermediate simply, economically and environmentally friendly.

[0003] The existing technical document EP1990336A1 discloses the preparation of 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole, and the preparation route is as follows: ; The specific method is: dissolve ethyl 4,4,4-trifluoroacetoacetate (compound A) in 2 equivalents of acetic acid, add 40% methylhydrazine aqueous solution (compound B) at 10°C, then stir the solution at room temperature for 1 hour, and finally stir at 80°C for 5 hours to obtain the target product (compound C) with a yield of 86.5%. Patent CN108026051A repeats the operating steps of Example 1 in the above patent (EP1990336A1) to obtain a ratio of 96:4 between the target product and the isomer (compound D). The technology of patent CN108026051A has the following disadvantages in process production: 1. When acetic acid is used as a reaction solvent, it is highly corrosive to the equipment; 2. It is difficult to separate the three components of acetic acid, ethanol and water, which increases the solvent recovery cost and the discharge of three wastes; 3. The proportion of useless isomer by-products is relatively large, resulting in the loss of some raw materials.

[0004] Patent CN114605326A discloses the key intermediate of sulfonepyraclostrobin, 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole, and the preparation route is as follows: ; The specific method is: add ethanol to the reactor, then add 40% methylhydrazine aqueous solution (compound B), cool in an ice bath, slowly add ethyl 4,4,4-trifluoroacetoacetate (compound A), and heat to 80°C after the addition is complete. The reaction is then terminated after 9 hours. Then the reaction solution is decompressed and desolventized to recover ethanol, and then the product is concentrated by vacuum distillation to precipitate, and the product is filtered while hot to obtain the product 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole (compound C) with a yield of 83% and a content of 98.1%. Although patent CN114605326A avoids the drawbacks of patent CN108026051A, it increases the reaction time and energy consumption. Therefore, in order to facilitate industrial production, it is necessary to develop a simpler and less energy-consuming preparation method. Summary of the invention

[0005] In view of the problems existing in the existing acid-catalyzed preparation of hydroxypyrazole derivatives, such as serious equipment corrosion, high energy consumption, high product isomer content and difficult separation, severe reaction conditions, and long reaction time, the present invention provides a method for preparing hydroxypyrazole derivatives under the action of a base to solve the above problems. The present invention uses acyl acetate compounds and hydrazine compounds as raw materials, uses alkaline inorganic substances as reactants, and uses water as a solvent to prepare a series of hydroxypyrazole derivatives. Compared with the existing preparation method, the present invention has mild reaction conditions, reduces the corrosion of the existing process to the equipment, and at the same time, the isomer content in the prepared product is low, which has a good application prospect.

[0006] The technical solution of the present invention is as follows: A method for preparing a hydroxypyrazole derivative under the action of a base, the reaction formula is as follows: ; in, R1 is selected from trihalomethyl, dihalomethyl, halomethyl, C1-C4 alkyl or C2-C4 haloalkyl; R2 is selected from hydrogen or C1-C4 alkyl; R3 is selected from C1-C4 alkyl, C3-C6 cycloalkyl or C3-C6 cycloalkyl having C1-C4 alkyl substituent; R4 is selected from C1-C4 alkyl, C3-C6 cycloalkyl, C4-C7 cycloalkyl having alkyl substituents, phenyl, naphthyl, C1-C4 alkyl-substituted phenyl or C1-C4 alkyl-substituted naphthyl; The specific method is: The compound of formula III is mixed with an alkaline inorganic substance and water, and then the compound of formula II is added and reacted at 20-50° C. to obtain a compound of formula I; the alkaline inorganic substance is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, aluminum hydroxide, magnesium hydroxide, zinc hydroxide, ammonia water, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, disodium hydrogen phosphate, dipotassium hydrogen phosphate or sodium phosphate.

[0007] Furthermore, the alkaline inorganic substance is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, disodium hydrogen phosphate, dipotassium hydrogen phosphate or sodium phosphate.

[0008] Further, R1 is selected from trifluoromethyl, trichloromethyl, tribromomethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, chloromethyl, bromomethyl, fluoroethyl, fluoropropyl, fluorobutyl, chloroethyl, chloropropyl, chlorobutyl, bromoethyl, bromopropyl, bromobutyl or isopropyl; R2 is selected from hydrogen, methyl, ethyl, propyl, isopropyl or tert-butyl; R3 is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl; R4 is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, phenyl, naphthyl, benzyl, phenethyl, phenpropyl, phenbutyl, naphthylmethyl or naphthylethyl.

[0009] Furthermore, R1 is selected from trifluoromethyl, chloromethyl or isopropyl; R2 is selected from hydrogen or methyl; R3 is selected from ethyl; R4 is selected from methyl.

[0010] Furthermore, the feed ratio of the compound of formula II, the compound of formula III and the alkaline inorganic substance is 1:1.0~1.1:1.1~1.3.

[0011] Furthermore, after the reaction is completed, a post-treatment step is also included, including concentrating the reaction solution, adding acid to adjust the pH of the reaction system to 1-6, filtering and drying to obtain the compound of formula I.

[0012] Furthermore, the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or hydrobromic acid.

[0013] Furthermore, the concentration of the acid is 10% to 40%, more preferably 20% to 30%.

[0014] Furthermore, the reaction time is 1 to 10 hours.

[0015] The beneficial effects of the present invention are: The preparation method provided by the present invention has the following advantages: (1) The present invention uses alkaline inorganic substances such as sodium hydroxide as reactants. Compared with acidic catalysts, the present invention can be carried out at a lower temperature and the reaction time is significantly shortened, thereby reducing production energy consumption. The isomer content in the prepared product is significantly reduced, and in the reaction of certain structures, it can be ensured that no isomers are produced, thereby improving the conversion rate of the target product and reducing the cost of raw materials.

[0016] (2) The present invention uses water as a solvent, which reduces the recovery cost of the organic solvent and reduces the emission of three wastes such as organic tail gas.

[0017] (3) Compared with acidic catalysts, the present invention uses alkaline inorganic substances as reactants and water as solvent, which causes less corrosion loss to the equipment. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, for ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0019] Figure 1 It is the HPLC spectrum of the product prepared in Example 1 of the present invention.

[0020] Figure 2 It is the HPLC spectrum of the product prepared in Comparative Example 1 of the present invention.

[0021] Figure 3 It is the HPLC spectrum of the product prepared in Comparative Example 2 of the present invention. DETAILED DESCRIPTION

[0022] In order to enable those skilled in the art to better understand the technical solutions in the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. 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 should fall within the scope of protection of the present invention.

[0023] Example 1 Preparation of 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole

[0024] 2.37 kg of water and 473.6 g of sodium hydroxide (1.1 eq, 11.84 mol) were added to the reactor. After stirring and dissolving, 1.24 kg of 40% methylhydrazine aqueous solution (1.0 eq, 10.76 mol) was added dropwise. After reacting at room temperature for 0.5 hours, 1.98 kg of ethyl 4,4,4-trifluoroacetoacetate (1.0 eq, 10.76 mol) was added dropwise. The reaction was terminated after 2 hours of reaction at room temperature. The reaction solution was decompressed and desolventized to recover the by-product ethanol. The pH was adjusted to 2-3 with 30% concentrated hydrochloric acid. The product was precipitated, filtered, and the filter cake was washed with water and dried to obtain 1.73 kg of white solid product. The purity of HPLC detection was 99.0% (area normalization method), and the yield was 94.8%, wherein the ratio of product to isomer was 100:0. See the detection spectrum for details. Figure 1 .

[0025] Example 2 Preparation of 5-Hydroxy-1,4-dimethyl-3-trifluoromethyl-1H-pyrazole

[0026] 2.58 kg of water and 516.48 g of sodium hydroxide (1.2 eq, 12.91 mol) were added to the reactor, and 1.24 kg of 40% methylhydrazine aqueous solution (1.0 eq, 10.76 mol) was added dropwise after stirring and dissolving. After reacting at room temperature for 0.5 hours, 2.13 kg of ethyl 2-methyl-4,4,4-trifluoroacetoacetate (1.0 eq, 10.76 mol) was added dropwise. The temperature was raised to 40°C and the reaction was terminated after 2.5 hours. The reaction liquid was decompressed and desolventized to recover the byproduct ethanol, and then the pH was adjusted to 3-4 with 30% concentrated hydrochloric acid to precipitate the product, filter, wash the filter cake with water, and dry to obtain 1.84 kg of white solid product. The purity was 97.3% (area normalization method) by HPLC, and the yield was 92.0%, wherein the ratio of product to isomer was 98.6:1.4.

[0027] Example 3 Preparation of 5-Hydroxy-1-methyl-3-chloromethyl-1H-pyrazole

[0028] 8.2 kg of water and 1.64 kg of potassium carbonate (1.1 eq, 11.84 mol) were added to the reactor, and 1.24 kg of 40% methylhydrazine aqueous solution (1.0 eq, 10.76 mol) was added dropwise after stirring and dissolving. After reacting at room temperature for 1 hour, 1.77 kg of ethyl 4-chloroacetoacetate (1.0 eq, 10.76 mol) was added dropwise, and the temperature was raised to 50°C for 3 hours before the reaction ended; the reaction liquid was decompressed and desolventized to recover the byproduct ethanol, and then the pH was adjusted to 3-4 with 30% concentrated hydrochloric acid to precipitate the product, filter, wash the filter cake with water, and dry to obtain 1.38 kg of white solid product. HPLC detection purity was 95.1% (area normalization method), and the yield was 83.6%, wherein the ratio of product to isomer was 97.2:2.8.

[0029] Example 4 Preparation of 5-hydroxy-1-methyl-3-isopropyl-1H-pyrazole

[0030] 3.32 kg of water and 664.3 g of potassium hydroxide (1.1 eq, 11.84 mol) were added to the reactor, and 1.24 kg of 40% methylhydrazine aqueous solution (1.0 eq, 10.76 mol) was added dropwise after stirring and dissolving. After reacting at room temperature for 1 hour, 1.7 kg of ethyl isobutyryl acetate (1.0 eq, 10.76 mol) was added dropwise, and the temperature was raised to 55°C for 3.5 hours before the reaction ended; the reaction liquid was decompressed and desolventized to recover the by-product ethanol, and then the pH was adjusted to 4-5 with 30% concentrated hydrochloric acid to precipitate the product, filter, wash the filter cake with water, and dry to obtain 1.39 kg of white solid product. HPLC detected the purity of 95.6% (area normalization method), the yield was 88.1%, and the ratio of product to isomer was 98.2:1.8.

[0031] Example 5 Synthesis of 5-Hydroxy-1,4-dimethyl-3-isopropyl-1H-pyrazole

[0032] 3.32 kg of water and 664.3 g of potassium hydroxide (1.1 eq, 11.84 mol) were added to the reactor, stirred and dissolved, and then 1.24 kg of 40% methylhydrazine aqueous solution (1.0 eq, 10.76 mol) was added dropwise. After reacting at room temperature for 1 hour, 1.85 kg of ethyl isobutyryl propionate (1.0 eq, 10.76 mol) was added dropwise, and the temperature was raised to 55 ° C for 4 hours to end the reaction. Then, the reaction solution was decompressed and desolventized to recover ethanol, and then the pH was adjusted to 5-6 with 30% concentrated hydrochloric acid. After the product was precipitated, filtered, the filter cake was washed with water, and dried to obtain 1.39 kg of a white solid product. The purity was 96.2% (area normalization method) by HPLC, and the yield was 80.7%, of which the ratio of product to isomer was 98.0:2.0.

[0033] Comparative Example 1 Preparation of 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole

[0034] 1.62kg of acetic acid (2.5eq, 26.9mol) and 1.98kg of ethyl 4,4,4-trifluoroacetoacetate (1.0eq, 10.76mol) were added to the reactor, and then 1.24kg of 40% methylhydrazine aqueous solution (1.0eq, 10.76mol) was added dropwise. The temperature was controlled below 40°C. After the addition was completed, the temperature was raised to 80°C and the reaction was terminated after 4 hours. The reaction solution was then decompressed and desolventized to recover ethanol and acetic acid, and then decompressed and concentrated to precipitate the product. The product was filtered while hot, and the filter cake was washed with water to obtain 1.60kg of a white solid product. The purity was 87.7% (area normalization method) according to HPLC, and the yield was 78.5%, of which the ratio of product to isomer was 96.9:3.1. See the detection spectrum for details. Figure 2 .

[0035] Comparative Example 2 Preparation of 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole

[0036] 1.24 kg of ethanol (2.5 eq, 26.9 mol) and 1.98 kg of ethyl 4,4,4-trifluoroacetoacetate (1.0 eq, 10.76 mol) were added to the reactor, and then 1.24 kg of 40% methylhydrazine aqueous solution (1.0 eq, 10.76 mol) was added dropwise. The temperature was controlled below 40°C. After the addition was completed, the temperature was raised to 80°C and the reaction was terminated after 8 hours. The reaction solution was then decompressed and desolventized to recover ethanol, and then the product was concentrated by decompression distillation to precipitate. The product was filtered while hot, and the filter cake was washed with water to obtain 1.59 kg of a white solid product. The purity of the product was 80.2% (area normalization method) according to HPLC, and the yield was 71.4%, of which the ratio of the product to the isomer was 87.6:12.4. See the detection spectrum for details. Figure 3 .

[0037] Although the present invention has been described in detail with reference to the accompanying drawings and in combination with the preferred embodiments, the present invention is not limited thereto. Without departing from the spirit and essence of the present invention, a person of ordinary skill in the art may make various equivalent modifications or substitutions to the embodiments of the present invention, and these modifications or substitutions shall be within the scope of the present invention. Any person of ordinary skill in the art may easily think of changes or substitutions within the technical scope disclosed by the present invention, and these shall be within the scope of protection of the present invention.

Claims

1. A method for preparing a hydroxypyrazole derivative under the action of a base, characterized in that: The reaction formula is as follows: ； in, R1 is selected from trihalomethyl, dihalomethyl, halomethyl, C1-C4 alkyl or C2-C4 haloalkyl; R2 is selected from hydrogen or C1-C4 alkyl; R3 is selected from C1-C4 alkyl, C3-C6 cycloalkyl or C3-C6 cycloalkyl having C1-C4 alkyl substituent; R4 is selected from C1-C4 alkyl, C3-C6 cycloalkyl, C4-C7 cycloalkyl having alkyl substituents, phenyl, naphthyl, C1-C4 alkyl-substituted phenyl or C1-C4 alkyl-substituted naphthyl; The specific method is: The compound of formula III is mixed with an alkaline inorganic substance and water, and then the compound of formula II is added and reacted at 20-50° C. to obtain a compound of formula I; the alkaline inorganic substance is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, aluminum hydroxide, magnesium hydroxide, zinc hydroxide, ammonia water, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, disodium hydrogen phosphate, dipotassium hydrogen phosphate or sodium phosphate.

2. The preparation method according to claim 1, characterized in that The alkaline inorganic substance is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, disodium hydrogen phosphate, dipotassium hydrogen phosphate or sodium phosphate.

3. The preparation method according to claim 1, characterized in that: R1 is selected from trifluoromethyl, trichloromethyl, tribromomethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, chloromethyl, bromomethyl, fluoroethyl, fluoropropyl, fluorobutyl, chloroethyl, chloropropyl, chlorobutyl, bromoethyl, bromopropyl, bromobutyl or isopropyl; R2 is selected from hydrogen, methyl, ethyl, propyl, isopropyl or tert-butyl; R3 is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl; R4 is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, phenyl, naphthyl, benzyl, phenethyl, phenpropyl, phenbutyl, naphthylmethyl or naphthylethyl.

4. The preparation method according to claim 1, characterized in that: R1 is selected from trifluoromethyl, chloromethyl or isopropyl; R2 is selected from hydrogen or methyl; R3 is selected from ethyl; R4 is selected from methyl.

5. The preparation method according to claim 1, characterized in that: The molar ratio of the compound of formula II, the compound of formula III and the alkaline inorganic substance is 1:1.0-1.1:1.1-1.

3.

6. The preparation method according to claim 1, characterized in that: After the reaction is completed, a post-treatment step is further included, including concentrating the reaction solution, adding acid to adjust the pH of the reaction system to 1-6, filtering and drying to obtain the compound of formula I.

7. The preparation method according to claim 6, characterized in that: The acid is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or hydrobromic acid.

8. The preparation method according to claim 6, characterized in that: The acid concentration is 10%~40%.

9. The preparation method according to claim 6, characterized in that: The acid concentration is 20%~30%.

10. The preparation method according to claim 1, characterized in that: The reaction time is 1~10h.

Images