A process for the synthesis of metalaxyl-m

Abstract

The application provides a synthesis process of metrafenone, in which inorganic alkali KOH is used as a catalyst, a key intermediate 4-(((5,5-dimethyl-dihydroisoxazole-4-yl)thio)methyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol can be obtained at low production cost and high yield, metrafenone is prepared through substitution reaction and oxidation reaction, the reaction yield is high, raw materials are simple and easy to obtain, three-waste emissions are small, and the process is beneficial to industrial mass production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of herbicides, in particular to a synthesis process of metrafenone. BACKGROUND

[0002] Metrafenone is a pre-emergence soil treatment herbicide that can be used in most crop fields. It has the characteristics of broad-spectrum, high efficiency and environmental friendliness, and has received extensive attention. At present, there are few patent literatures on the synthesis of metrafenone in China. The main strategy in the reported synthesis process is to first synthesize the pyrazole ring intermediate and the dihydroisoxazole ring intermediate, then dock the two heterocycles to form a thioether compound, and finally oxidize the thioether to obtain the target product.

[0003] Patent document (WO2007071900A1) discloses a method for preparing metrafenone. The method uses glyoxylic acid as the starting material, and goes through the steps of oximation, [3+2] cyclization, substitution with sodium methyl mercaptide and oxidation, reduction, substitution with a pyrazole intermediate, and oxidation of the thioether to obtain metrafenone. The reaction route is as follows:

[0004] .

[0005] Patent document (CN113754647A) improves the above synthesis steps by replacing the intermediate 5,5-dimethyl-4,5-dihydroisoxazole thiosemicarbazide hydrochloride with S-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl) ethyl ethyl sulfate.

[0006] Patent document (CN111393427A) discloses a synthesis process of metrafenone. Compound I is used as the starting material, and intermediate II is synthesized through cyclization reaction. Intermediate II is subjected to chlorination reaction in the presence of a chlorinating agent to obtain intermediate III. Intermediate III is reacted with thiourea to obtain hydrochloride intermediate IV. Hydrochloride intermediate IV and compound VI are reacted with formaldehyde to obtain intermediate VII, which is then subjected to difluoromethoxylation reaction to obtain intermediate VIII. Finally, metrafenone IX is obtained by oxidation of intermediate VIII using hydrogen peroxide in the presence of a catalyst. The reaction route is as follows:

[0007]

[0008] The above reaction routes are relatively long and the operation process is complex, and chlorination steps are required. Patent document (CN113754648A) discloses a preparation method of metrafenone intermediate A. The intermediate is prepared by Mannich reaction, and then substituted and oxidized to obtain metrafenone. The reaction route is as follows:

[0009] .

[0010] This patent uses cyclic secondary amines and hydrochloric acid as a catalytic system to carry out the Mannich reaction in the presence of a solvent. Cyclic secondary amines are more expensive than general inorganic bases, which increases production costs; in addition, as an organic base, cyclic secondary amines undergo an acid-base neutralization reaction with hydrochloric acid to form cyclic ammonium chloride salts, which is detrimental to the reaction.

[0011] Therefore, this invention provides a synthesis process for sulfonylpyrazole, which uses inorganic base KOH as a catalyst to obtain the key intermediate 4-(((5,5-dimethyl-dihydroisoxazole-4-yl)thio)methyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol with low production cost and high yield. Then, through substitution and oxidation reactions, sulfonylpyrazole is obtained. Summary of the Invention

[0012] The purpose of this invention is to provide a synthesis process for sulfonylpyrazole to solve the technical problems of high production cost, excessively long steps, low yield and low purity in the prior art.

[0013] This invention provides a process for synthesizing sulfonylpyrazole, comprising the following steps:

[0014] 1) In aqueous solution, in the presence of an inorganic base, 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole, formaldehyde, and 5,5-dimethyl-4,5-dihydroisoxazole-3-thiol are reacted to prepare 4-(((5,5-dimethyl-dihydroisoxazole-4-yl)thio)methyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol;

[0015] 2) In the presence of a solvent, a base, and a phase transfer catalyst, 4-(((5,5-dimethyl-dihydroisoxazole-4-yl)thio)methyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol was reacted with dichlorofluoromethane to prepare [(methoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylthio]-5,5-dimethyl-dihydroisoxazole;

[0016] 3) In the presence of hydrogen peroxide, solvent, acid and sodium tungstate, [(methoxy-1-methyl-3-trifluoromethylpyrazol-4-yl)methylthio]-5,5-dimethyl-dihydroisoxazole was oxidized to obtain sulfopyrazol.

[0017] The reaction formula is as follows:

[0018] ;

[0019] Wherein: the inorganic base in step 1) is selected from potassium hydroxide and sodium hydroxide;

[0020] In step 1), the molar ratio of 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole, formaldehyde, and inorganic base is 1:1.1-1.3:2.5-3.5, and the reaction temperature is 30-50℃.

[0021] Preferably, the inorganic base in step 1) is selected from potassium hydroxide;

[0022] Preferably, in step 1), the molar ratio of 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole, formaldehyde, and inorganic base is 1:1.2:3.

[0023] Preferably, in step 1), the mass ratio of 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole to the solvent is 1:1-10, more preferably 1:3-5, especially 1:3;

[0024] Preferably, the reaction temperature in step 1) is 40°C.

[0025] Preferably, the solvent in step 2) is selected from chlorinated aromatic hydrocarbons or chlorinated aliphatic hydrocarbons, esters, ethers, amides, nitriles, or mixtures of these solvents. More preferably, one or more of dichloromethane, trichloromethane, and 1,2-dichloroethane are used.

[0026] Preferably, in step 2), the molar ratio of 4-(((5,5-dimethyl-dihydroisoxazol-4-yl)thio)methyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol to the solvent is 1:1-10, preferably 1:3-5, especially 1:3;

[0027] Preferably, the alkali in step 2) is selected from organic or inorganic alkalis, more preferably, the alkali is an inorganic alkali, especially sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate.

[0028] Preferably, the phase transfer catalyst in step 2) is selected from quaternary ammonium salts, especially tetrabutylammonium bromide, dodecyltrimethylammonium bromide, and hexadecyltrimethylammonium bromide.

[0029] Preferably, in step 2), the molar ratio of 4-(((5,5-dimethyl-dihydroisoxazol-4-yl)thio)methyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol, dichlorofluoromethane, and phase transfer catalyst is 1:2-4:0.05-0.2, more preferably 1:3:0.1.

[0030] Preferably, the reaction temperature in step 2) is 50-70°C.

[0031] Preferably, the solvent in step 3) is selected from alcohols, chlorinated aromatic hydrocarbons or chlorinated aliphatic hydrocarbons, esters, ethers, amides, nitriles or mixtures of these solvents, more preferably alcohol solvents, especially one or more of methanol, ethanol, isopropanol and tert-butanol;

[0032] Preferably, in step 3, the mass ratio of [(methoxy-1-methyl-3-trifluoromethylpyrazol-4-yl)methylthio]-5,5-dimethyl-dihydroisoxazole to the solvent is 1:1-7, more preferably 1:2-6, and especially 1:5;

[0033] Preferably, the acid in step 3) is an inorganic acid, more preferably one or more of sulfuric acid and hydrochloric acid.

[0034] Preferably, in step 3, the molar ratio of [(methoxy-1-methyl-3-trifluoromethylpyrazol-4-yl)methylthio]-5,5-dimethyl-dihydroisoxazole, hydrogen peroxide, acid, and sodium tungstate is 1:3-5:0.05-0.2:0.05-0.2; more preferably, it is 1:3:0.1:0.15.

[0035] Preferably, the reaction temperature in step 3 is 20-80°C, more preferably 50-70°C, and especially 65°C.

[0036] In another embodiment, the present invention also provides a method for preparing 4-(((5,5-dimethyl-dihydroisoxazol-4-yl)thio)methyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol, comprising the following steps:

[0037] In aqueous solution and in the presence of an inorganic base, 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole, formaldehyde, and 5,5-dimethyl-4,5-dihydroisoxazole-3-thiol are reacted to prepare 4-(((5,5-dimethyl-dihydroisoxazole-4-yl)thio)methyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol;

[0038] The reaction formula is as follows:

[0039]

[0040] Wherein: the inorganic base in step 1) is selected from potassium hydroxide and sodium hydroxide;

[0041] In step 1), the molar ratio of 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole, formaldehyde, and inorganic base is 1:1.1-1.3:2.5-3.5, and the reaction temperature is 30-50℃.

[0042] Preferably, the inorganic base in step 1) is selected from potassium hydroxide;

[0043] Preferably, in step 1), the molar ratio of 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole, formaldehyde, and inorganic base is 1:1.2:3.

[0044] Preferably, in step 1), the mass ratio of 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole to the solvent is 1:1-10, more preferably 1:3-5, especially 1:3;

[0045] Preferably, the reaction temperature in step 1) is 40°C.

[0046] Compared with the prior art, the present invention has the following beneficial effects:

[0047] 1) In step 1), the present invention uses an inorganic base (especially potassium hydroxide) as a reaction catalyst. The raw materials are simple, readily available, and inexpensive, resulting in low production costs and facilitating industrial production.

[0048] 2) The Mannich reaction in CN113754648A is carried out under acidic conditions with cyclic secondary amines, which is different from the reaction system of this invention. Furthermore, cyclic secondary amines are prone to forming quaternary ammonium salts under acidic conditions, which wastes reaction raw materials and causes the reaction to not proceed well.

[0049] 3) In step 1) of this invention, water is used as the reaction solvent, eliminating the need to add other organic solvents, which saves costs and is more environmentally friendly, in line with the national initiative to promote the development of green industry;

[0050] 4) The reaction temperature in step 1) of this invention is lower, with the optimal reaction temperature being 40°C, thereby reducing reaction energy consumption and saving costs;

[0051] 5) The post-processing of the present invention is simple and the reaction yield is high. The highest yield of step 1) can reach 93.0%. Detailed Implementation

[0052] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments. 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.

[0053] The present invention will be further explained below with reference to specific embodiments.

[0054] Example 1 Effect of different bases on the yield of 4-(((5,5-dimethyl-dihydroisoxazol-4-yl)thio)methyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol

[0055]

[0056] Add 50g (99%), 0.30mol, 150g, and alkali to a reaction flask, followed by an aqueous solution (37%) containing 0.36mol of formaldehyde. Stir at room temperature. HPLC analysis showed that the 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole had reacted completely. Then add 41.5g (95%), 0.30mol, and stir at approximately 40°C. HPLC analysis showed that the 5,5-dimethyl-4,5-dihydroisoxazole-3-thiol had reacted completely. Stop the reaction, add hydrochloric acid and water to the reaction solution to adjust the pH to 4-6. Filter the solution and wash the filter cake twice with water. Dry the filter cake in a 45°C oven. After drying, weigh the cake and calculate the yield for the next reaction step.

[0057]

[0058] Example 2 Effect of different reaction parameters on the yield of 4-(((5,5-dimethyl-dihydroisoxazol-4-yl)thio)methyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol

[0059]

[0060] 5-Hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole (50 g, 99%, 0.30 mol) was added to a 20% potassium hydroxide aqueous solution. After dissolving, formaldehyde aqueous solution (37%) was added dropwise. The mixture was stirred at room temperature for 1.5 h. HPLC analysis showed that the 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole had reacted completely. Then, 5,5-dimethyl-4,5-dihydroisoxazole-3-thiol (41.5 g, 95%, 0.30 mol) was added and stirred for 16 h. HPLC analysis showed that the 5,5-dimethyl-4,5-dihydroisoxazole-3-thiol had reacted completely. The reaction was stopped, and hydrochloric acid and water were added to the reaction solution to adjust the pH to 4-6. The mixture was then filtered, and the filter cake was washed twice with water. The filter cake was dried in a 45°C oven for 2 h. After drying, the cake was weighed and its content was determined for the next reaction step.

[0061]

[0062] Example 3 Preparation of [(methoxy-1-methyl-3-trifluoromethylpyrazol-4-yl)methylthio]-5,5-dimethyl-dihydroisoxazole

[0063]

[0064] 4-(((5,5-dimethyl-dihydroisoxazol-4-yl)thio)methyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol (80 g, 95%, 0.25 mol) was added to 140 g of 20% potassium hydroxide aqueous solution, followed by the sequential addition of tetrabutylammonium bromide and 1,2-dichloroethane. Dichlorofluoromethane was slowly introduced under normal pressure for 2 hours. The reaction was confirmed to be complete by HPLC. The phases were separated, the aqueous phase was extracted with dichloroethane, and the organic phase was collected, rotary evaporated under reduced pressure, and weighed to determine its content for the next reaction step.

[0065]

[0066] Example 4 Preparation of sulfonylpyrazole

[0067]

[0068] Add [(methoxy-1-methyl-3-trifluoromethylpyrazol-4-yl)methylthio]-5,5-dimethyl-dihydroisoxazole (100g, 90%, 0.25mol), 350 mL methanol, sulfuric acid, and sodium tungstate to a reaction flask. Stir at room temperature for 1 hour, then heat to reflux. Add hydrogen peroxide dropwise, and keep warm for 30 minutes after the addition is complete. The reaction is considered complete by HPLC. Add water, cool to 0-5℃, filter, and the filter cake is sulfopyrazol. Dry and weigh to determine the content.

[0069]

[0070] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A process for synthesizing sulfonylpyrazole, comprising the following steps: 1) In aqueous solution, in the presence of an inorganic base, 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole, formaldehyde, and 5,5-dimethyl-4,5-dihydroisoxazole-3-thiol are reacted to prepare 4-(((5,5-dimethyl-dihydroisoxazole-4-yl)thio)methyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol; 2) In the presence of a solvent, an inorganic base, and a phase transfer catalyst, 4-(((5,5-dimethyl-dihydroisoxazole-4-yl)thio)methyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol was reacted with dichlorofluoromethane to prepare [(methoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylthio]-5,5-dimethyl-dihydroisoxazole; 3) In the presence of hydrogen peroxide, solvent, acid and sodium tungstate, [(methoxy-1-methyl-3-trifluoromethylpyrazol-4-yl)methylthio]-5,5-dimethyl-dihydroisoxazole was oxidized to obtain sulfopyrazol. The reaction formula is as follows: ； in: The inorganic base in step 1) is selected from potassium hydroxide; In step 1), the molar ratio of 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole, formaldehyde, and inorganic base is 1:1.2:3, and the reaction temperature is 40℃.

2. The synthesis process according to claim 1, characterized in that, In step 1), the mass ratio of 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole to water is 1:1-10.

3. The synthesis process according to claim 1, characterized in that, The solvent in step 2) is selected from one or more of dichloromethane, trichloromethane, and 1,2-dichloroethane; In step 2), the molar ratio of 4-(((5,5-dimethyl-dihydroisoxazole-4-yl)thio)methyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol to the solvent is 1:1-10.

4. The synthesis process according to any one of claims 1-3, characterized in that, The inorganic base in step 2) is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate; The phase transfer catalyst in step 2) is selected from quaternary ammonium salts.

5. The synthesis process according to claim 4, characterized in that, The phase transfer catalyst in step 2) is selected from tetrabutylammonium bromide, dodecyltrimethylammonium bromide, and hexadecyltrimethylammonium bromide.

6. The synthesis process according to claim 5, characterized in that: In step 2), the molar ratio of 4-(((5,5-dimethyl-dihydroisoxazol-4-yl)thio)methyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol, dichlorofluoromethane, and the phase transfer catalyst is 1 : 2-4 : 0.05-0.

2. The reaction temperature for step 2) is 50-70℃.

7. The synthesis process according to claim 6, characterized in that: In step 2), the molar ratio of 4-(((5,5-dimethyl-dihydroisoxazole-4-yl)thio)methyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol, difluoromethane, and phase transfer catalyst is 1 : 3 : 0.

1.

8. The synthesis process according to claim 1, characterized in that: The solvent in step 3) is selected from one or more of methanol, ethanol, isopropanol, and tert-butanol; In step 3, the mass ratio of [(methoxy-1-methyl-3-trifluoromethylpyrazol-4-yl)methylthio]-5,5-dimethyl-dihydroisoxazole to the solvent is 1:1-7; The acid in step 3) is one or more of sulfuric acid and hydrochloric acid.

9. The synthesis process according to claim 8, characterized in that: In step 3), the mass ratio of [(methoxy-1-methyl-3-trifluoromethylpyrazol-4-yl)methylthio]-5,5-dimethyl-dihydroisoxazole to the solvent is 1:2-6.

10. The synthesis process according to claim 8, characterized in that: In step 3), the mass ratio of [(methoxy-1-methyl-3-trifluoromethylpyrazol-4-yl)methylthio]-5,5-dimethyl-dihydroisoxazole to the solvent is 1:

5.

11. The synthesis process according to any one of claims 8-10, characterized in that: In step 3), the molar ratio of [(methoxy-1-methyl-3-trifluoromethylpyrazol-4-yl)methylthio]-5,5-dimethyl-dihydroisoxazole, hydrogen peroxide, acid, and sodium tungstate is 1 : 3-5 : 0.05-0.2 : 0.05-0.2; The reaction temperature in step 3 is 50-70℃.

12. A method for preparing 4-(((5,5-dimethyl-dihydroisoxazol-4-yl)thio)methyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol, comprising the following steps: In aqueous solution and in the presence of an inorganic base, 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole, formaldehyde, and 5,5-dimethyl-4,5-dihydroisoxazole-3-thiol are reacted to prepare 4-(((5,5-dimethyl-dihydroisoxazole-4-yl)thio)methyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol; The reaction formula is as follows: in, The inorganic base is selected from potassium hydroxide; The molar ratio of 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole, formaldehyde, and inorganic base is 1:1.2:3, and the reaction temperature is 40℃.

13. The method according to claim 12, characterized in that: The mass ratio of 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole to water is 1:3-5.

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