A method for synthesizing sulfonepyraclostrobin intermediate

Abstract

The invention discloses a synthetic method of a sulfonepyrazol intermediate, using hydrazine hydrate as a raw material, and reacting with BOC anhydride to generate tert-butyloxycarbonyl hydrazine. Under high temperature conditions, tert-butyloxycarbonyl hydrazine and ethyl trifluoroacetoacetate undergo a ring-closing reaction, then undergo a hydroxymethylation reaction with formaldehyde or paraformaldehyde in the presence of a base, and then continue to react with difluoromonochloromethane in the presence of a base, and the resulting product takes off the BOC protecting group, and then undergoes an N-methylation reaction with an N-methylating agent to obtain sulfonepyrazol intermediate 5-difluoromethoxy-4-hydroxymethyl-3-trifluoromethyl-1-methylpyrazole. The present invention uses cheap hydrazine hydrate instead of highly toxic methylhydrazine, adjusts the reaction route, has low cost, low toxicity, high safety, mild reaction conditions, does not require excessive temperature and high pressure, has low equipment requirements, and post-processing is simple and extensive, suitable for industrialized mass production.

Description

Technical Field

[0001] The invention relates to a method for synthesizing a sulfonepyraclostrobin intermediate, and in particular to a method for preparing a sulfonepyraclostrobin intermediate, 5-difluoromethoxy-4-hydroxymethyl-3-trifluoromethyl-1-methylpyrazole, by using ethyl trifluoroacetoacetate and hydrazine with a protecting group. The method belongs to the technical field of sulfonepyraclostrobin preparation. Background Art

[0002] Pyroxasulfone, also known as rockweed sulfone, was developed by Japan Kumamoto Chemical. It is a new type of pyrazole selective herbicide and was launched in 2011. It is a new type of pre-emergence herbicide that can interfere with the elongation of the C18 chain and inhibit the synthesis of very long-chain fatty acids (VLCFA). It is mainly absorbed into the target plant through the plant roots or apical meristems and is mainly effective against annual grass weeds and some broad-leaved weeds.

[0003] 5-Difluoromethoxy-4-hydroxymethyl-3-trifluoromethyl-1-methylpyrazole is an important intermediate in the synthesis of sulfone pyrazoline, and its structure is as follows:

[0004]

[0005] At present, there are several processes for the synthesis of 5-difluoromethoxy-4-hydroxymethyl-3-trifluoromethyl-1-methylpyrazole:

[0006] Patent EP1990336 reports a method for synthesizing 5-hydroxy-1-methyl-3-trifluoromethylpyrazole by reacting ethyl trifluoroacetoacetate with a 35% methylhydrazine aqueous solution. The obtained 5-hydroxy-1-methyl-3-trifluoromethylpyrazole is subjected to a hydroxymethylation reaction with a 37% formaldehyde aqueous solution, and then reacted with difluorochloromethane to prepare 5-difluoromethoxy-4-hydroxymethyl-3-trifluoromethyl-1-methylpyrazole. In the preparation process of 5-hydroxy-1-methyl-3-trifluoromethylpyrazole of this route, a 35% methylhydrazine aqueous solution is required, which is highly dangerous and toxic.

[0007] Patent WO2020 / 240392 reports a method for continuously preparing 5-difluoromethoxy-4-hydroxymethyl-3-trifluoromethyl-1-methylpyrazole. The main process is: 5-hydroxy-1-methyl-3-trifluoromethylpyrazole is subjected to hydroxymethylation reaction with formaldehyde aqueous solution in the presence of potassium hydroxide, and then reacted with acetonitrile solution of difluorochloromethane to prepare 5-difluoromethoxy-4-hydroxymethyl-3-trifluoromethyl-1-methylpyrazole. Although this process realizes continuous operation and improves the raw material conversion rate, it is easy to cause an increase in by-products and a decrease in product selectivity while strengthening the reaction. Summary of the invention

[0008] In view of the shortcomings of the prior art, the present invention provides a method for synthesizing a sulfonepyraclostrobin intermediate suitable for industrialization. The method uses hydrazine hydrate as a raw material, has the advantages of easy purchase of the raw material, low price, simple preparation method, mild reaction conditions and high safety, and solves the problem of high danger of using methylhydrazine as a raw material in the existing process.

[0009] The present invention provides a method for synthesizing a sulfonepyraclostrobin intermediate, which comprises the following steps:

[0010] (1) Using hydrazine hydrate as raw material, it reacts with BOC anhydride (di-tert-butyl dicarbonate) to generate tert-butyloxycarbonylhydrazine;

[0011] (2) Under high temperature conditions, tert-butyloxycarbonylhydrazine and ethyl trifluoroacetoacetate undergo a cyclization reaction to prepare compound I;

[0012] (3) Compound I is subjected to a hydroxymethylation reaction with formaldehyde or paraformaldehyde in the presence of a base. After the reaction, difluorochloromethane is added in the presence of a base to continue the reaction to obtain compound II. Compound II is deprotected from the BOC protecting group to obtain compound III. Compound III is then subjected to an N-methylation reaction with an N-methylating agent to obtain 5-difluoromethoxy-4-hydroxymethyl-3-trifluoromethyl-1-methylpyrazole, i.e., a sulfonepyrazoline intermediate.

[0013] .

[0014] The process route of the present invention is as follows:

[0015]

[0016] Furthermore, in step (1), the present invention selects cheap hydrazine hydrate to replace the highly toxic methylhydrazine, and the hydrazine hydrate is first protected with BOC, which not only avoids the N-difluoromethylation reaction, but also effectively solves the selectivity problem of the subsequent N-methylation.

[0017] Furthermore, in step (1), the molar ratio of hydrazine hydrate to BOC anhydride is 2.2-2.5:1.

[0018] Furthermore, in step (1), the reaction temperature of hydrazine hydrate and BOC anhydride is -10~10°C.

[0019] Furthermore, in step (1), the reaction is carried out in the presence of an organic solvent, and the organic solvent can satisfy the requirements of providing a reaction medium, for example, acetonitrile, isopropanol, tetrahydrofuran, methyl isobutyl ketone, benzene, xylene, N-methylpyrrolidone, etc., and the amount of the organic solvent can be selected as required. During the reaction, it is preferred to dropwise add the organic solvent solution of BOC anhydride into the organic solvent solution of hydrazine hydrate to carry out the reaction.

[0020] Furthermore, in step (2), tert-butyloxycarbonylhydrazine and ethyl trifluoroacetoacetate are heated in an organic solvent and subjected to reflux reaction to obtain compound I. The molar ratio of ethyl trifluoroacetoacetate to tert-butyloxycarbonylhydrazine is 1:1-1.5.

[0021] Furthermore, in step (2), the organic solvent used can meet the requirements of providing a reaction medium, for example, it can be acetonitrile, isopropanol, tetrahydrofuran, methyl isobutyl ketone, benzene, xylene, N-methylpyrrolidone, etc. The amount of the organic solvent can be selected as needed.

[0022] Furthermore, in step (3), the formaldehyde is present in the form of a formaldehyde aqueous solution, and the concentration of the formaldehyde aqueous solution is preferably 35-50 wt %.

[0023] Furthermore, in step (3), the hydroxymethylation reaction is carried out in an alkaline aqueous environment, wherein the alkaline is an inorganic base or an organic base, wherein the inorganic base includes sodium hydroxide, potassium hydroxide, etc., and the organic base includes sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, etc., and the molar ratio of compound I to the alkaline is 1:1.2~1.5.

[0024] Furthermore, in step (3), the molar ratio of compound I to formaldehyde or paraformaldehyde is 1:1.0-1.5, where paraformaldehyde is calculated as formaldehyde.

[0025] Furthermore, in step (3), after the reaction of compound I with formaldehyde or paraformaldehyde is completed, a base and an organic solvent are directly added to the reaction system, and then difluorochloromethane is introduced for reaction. The added base is an inorganic base or an organic base. The inorganic base includes sodium hydroxide, potassium hydroxide, etc., and the organic base includes sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, etc.

[0026] Furthermore, in step (3), after the hydroxymethylation reaction, the molar ratio of the hydroxymethylation reaction product to the added base is 1:2.5-5.0, and the molar ratio of the hydroxymethylation reaction product to difluorochloromethane is 1:2.0-10.0.

[0027] Furthermore, in step (3), the reaction temperature of the hydroxymethylation reaction product and difluorochloromethane is 0° C. to 25° C. The reaction time varies slightly depending on the temperature, and the reaction can be terminated when the raw material content is extremely low.

[0028] Furthermore, in step (3), the organic solvent added serves as a reaction medium and may be acetonitrile, isopropanol, tetrahydrofuran, methyl isobutyl ketone, benzene, xylene, N-methylpyrrolidone, etc. The amount thereof may be selected as required.

[0029] Furthermore, in step (3), the BOC protecting group of compound II is removed in the presence of an acid, and the acid is preferably trifluoroacetic acid, hydrochloric acid, sulfuric acid or phosphoric acid.

[0030] Furthermore, in step (3), when the acid is trifluoroacetic acid, compound II can be reacted in pure trifluoroacetic acid or a mixture of trifluoroacetic acid and an organic solvent to remove the BOC protecting group. In a specific embodiment of the present invention, the volume ratio of trifluoroacetic acid to organic solvent is 1-2:1.

[0031] Furthermore, in step (3), when the acid is hydrochloric acid, sulfuric acid or phosphoric acid, compound II is reacted in a mixture of acid and organic solvent to remove the BOC protecting group. In a specific embodiment of the present invention, the concentration of hydrochloric acid, sulfuric acid or phosphoric acid in the organic solvent is 1-2 mol / L.

[0032] Furthermore, in step (3), the N-methylating agent is dimethyl sulfate or monohalomethane, preferably dimethyl sulfate.

[0033] Furthermore, in step (3), the N-methylation reaction is carried out in the presence of a base, and the base is sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.

[0034] Furthermore, in step (3), the molar ratio of compound III to the N-methylating agent is 1:1.0-1.5; and the molar ratio of compound III to the base is 1:1.0-4.0.

[0035] The advantages of the present invention are:

[0036] (1) Using cheap hydrazine hydrate instead of the highly toxic methylhydrazine is simple and easy to obtain, and has the advantages of low cost, low toxicity and high safety.

[0037] (2) The present invention uses hydrazine hydrate as a raw material and adjusts the reaction route. The reaction conditions of the entire preparation process are relatively mild, and excessively high temperature and high pressure are not required, and the equipment requirements are low.

[0038] (3) The synthesis of the present invention is simple in operation and high in yield, and is suitable for large-scale industrial production.

[0039] Specific example method

[0040] The present invention is further described below in conjunction with specific embodiments. The following description is only exemplary and does not limit its content.

[0041] In the following examples, the concentrations are expressed in mass percentage unless otherwise specified.

[0042] Example 1

[0043] (1) Synthesis of 1-N-Boc-5-hydroxy-3-trifluoromethylpyrazole (I)

[0044] At room temperature, 14.39 g of hydrazine hydrate (80% aqueous solution, 0.23 mol) was weighed and added to 400 mL of isopropanol. After stirring and dissolving, the temperature was lowered to 0°C. 21.82 g of di-tert-butyl dicarbonate was added to 98.0 g of isopropanol and diluted, and then slowly added dropwise to the above solution. After the addition was completed, the mixture was kept warm for 2.0 h, and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 12.80 g of solid (yield based on di-tert-butyl dicarbonate, 97%). The mixture was dissolved in 360 mL of xylene again, 16.57 g of ethyl trifluoroacetoacetate (0.09 mol) was added, and the mixture was heated to reflux for 15 h. The reaction was detected by HPLC after completion. The reactants were concentrated under reduced pressure, and the residue was added to ethyl acetate. The mixture was heated and stirred until dissolved. Petroleum ether was added until the reaction solution became turbid. After stirring for 15 min, the mixture was cooled and solid precipitated. The mixture was cooled to 0-5 °C for crystallization for 2.0 h. The mixture was filtered to obtain 20.04 g of solid with a purity of 94.7% and a yield of 83.6% based on ethyl trifluoroacetoacetate.

[0045] (2) Synthesis of 5-difluoromethoxy-4-hydroxymethyl-3-trifluoromethyl-1-hydrogen-pyrazole (III)

[0046] At 25°C, 13.32 g of compound (I) (0.05 mol) was weighed and added to 80.0 mL of water. 4.20 g of potassium hydroxide (0.075 mol) was added and stirred until dissolved. Then, 1.90 g of paraformaldehyde (0.06 mol) was added and stirred for 1.0 h. After HPLC detection, the reaction was complete. 23.38 g of 30% potassium hydroxide aqueous solution (0.125 mol) was added and 40.0 mL of acetonitrile was added. 0.5 mol of difluorochloromethane was introduced under rapid stirring. After HPLC detection, the reaction was complete for 4.0 h. The reaction solution was separated. The lower aqueous phase was extracted with 20.0 mL of acetonitrile. The organic phases were combined and 60.0 mL of trifluoroacetic acid was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 3.0 h. After HPLC detection, the mixture was concentrated under reduced pressure. The concentrate was washed with 20.0 mL of acetonitrile and concentrated under reduced pressure to obtain 11.78 g of an oily substance with a purity of 90.7%. The yield was 92.1% based on compound I.

[0047] (3) Synthesis of 5-difluoromethoxy-4-hydroxymethyl-3-trifluoromethyl-1-methylpyrazole

[0048] 60.0 mL of 1,4-dioxane was added to the above 11.78 g of compound (III) (0.046 mol) and stirred until dissolved. 12.71 g of potassium carbonate (0.092 mol) and 5.81 g of dimethyl sulfate (0.046 mol) were added and heated under reflux for 7 h. The reaction was completed when detected by HPLC. The temperature was lowered and the reaction solution was poured into water. The mixture was extracted twice with 40.0 mL of dichloromethane. The organic phases were combined and concentrated under reduced pressure to obtain 11.82 g of a crude final product with a purity of 89.7% and a yield of 93.7% based on compound (III).

[0049] Example 2

[0050] (1) Synthesis of 1-N-Boc-5-hydroxy-3-trifluoromethylpyrazole (I)

[0051] At room temperature, 14.39 g of hydrazine hydrate (80% aqueous solution, 0.23 mol) was weighed and added to 400 mL of isopropanol. After stirring and dissolving, the temperature was lowered to -10°C. 21.82 g of di-tert-butyl dicarbonate was added to 98.0 g of isopropanol and diluted, and then slowly added dropwise to the above solution. After the addition was completed, the mixture was kept warm for 2.0 h, and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 12.64 g of solid (yield based on di-tert-butyl dicarbonate, 95.6%). Dissolve again in 360 mL of xylene, add 17.67 g of ethyl trifluoroacetoacetate (0.096 mol), heat to reflux for 15 h, and detect the end of the reaction by HPLC. The reactants are concentrated under reduced pressure, and the residue is added to ethyl acetate, heated and stirred until dissolved. Petroleum ether is added until the reaction solution becomes turbid. After stirring for 15 min, cool and solid precipitates. Cool to 0-5 ° C for crystallization for 2.0 h, and filter to obtain 20.60 g of solid with a purity of 92.9%.

[0052] (2) Synthesis of 5-difluoromethoxy-4-hydroxymethyl-3-trifluoromethyl-1-hydrogen-pyrazole (III)

[0053] Weigh 13.57 g of compound (I) (0.05 mol) and add it to 80.0 mL of water. Add 4.20 g of potassium hydroxide (0.075 mol) and stir until dissolved. Then add 1.90 g of paraformaldehyde (0.06 mol). Stir and react for 1.0 h. After HPLC detection, the reaction is complete. Cool to 15 °C and add 28.00 g of 40.0 mL of tetrahydrofuran was added to a 30% aqueous potassium hydroxide solution, and the temperature was lowered to 0°C. 0.5 mol of difluorochloromethane was introduced under rapid stirring. After stirring for 10.0 h, the reaction was completed by HPLC detection. The reaction liquid was separated, and the lower aqueous phase was extracted with 20.0 mL of tetrahydrofuran. The organic phases were combined, and 60.0 mL of trifluoroacetic acid was added dropwise. After the addition was completed, it was stirred at room temperature for 3.0 h. After the reaction was completed by HPLC detection, it was concentrated under reduced pressure, and 20.0 mL of tetrahydrofuran was added to the concentrate for washing, and concentrated under reduced pressure to obtain 11.59 g of an oily substance with a purity of 90.3% and a yield of 90.2% based on compound I.

[0054] (3) Synthesis of 5-difluoromethoxy-4-hydroxymethyl-3-trifluoromethyl-1-methylpyrazole

[0055] 60.0 mL of 1,4-dioxane was added to the above 11.59 g of compound (III) (0.045 mol) and stirred until dissolved. 6.22 g of potassium carbonate (0.045 mol) and 5.68 g of dimethyl sulfate (0.045 mol) were added and heated under reflux for 7 h. The reaction was completed when detected by HPLC. The temperature was lowered, the reaction solution was poured into water, extracted twice with 40.0 mL of dichloromethane, the organic phases were combined, and concentrated under reduced pressure to obtain 11.63 g of a crude final product with a purity of 88.9% and a yield of 93.4% based on compound (III).

[0056] Example 3

[0057] (1) Synthesis of 1-N-Boc-5-hydroxy-3-trifluoromethylpyrazole (I)

[0058] At room temperature, 14.39 g of hydrazine hydrate (80% aqueous solution, 0.23 mol) was weighed and added to 400 mL of isopropanol. After stirring and dissolving, the temperature was lowered to 10°C. 21.82 g of di-tert-butyl dicarbonate was added to 98.0 g of isopropanol and diluted, and then slowly added dropwise to the above solution. After the addition was completed, the mixture was kept warm for 2.0 h, and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 12.25 g of solid (yield based on di-tert-butyl dicarbonate, 92.7%). Dissolve again in 360 mL of xylene, add 16.57 g of ethyl trifluoroacetoacetate (0.09 mol), heat to reflux for 15 h, and detect the end of the reaction by HPLC. The reactants are concentrated under reduced pressure, and the residue is added to ethyl acetate, heated and stirred until dissolved. Petroleum ether is added until the reaction solution becomes turbid. After stirring for 15 min, cool and solid precipitates. Cool to 0-5 ° C for crystallization for 2.0 h, filter and obtain 20.18 g of solid with a purity of 92.3%.

[0059] (2) Synthesis of 5-difluoromethoxy-4-hydroxymethyl-3-trifluoromethyl-1-hydrogen-pyrazole (III)

[0060] At 25°C, weigh 13.66 g of compound (I) (0.05 mol) and add it to 80.0 mL of water. Add 4.20 g of potassium hydroxide (0.075 mol) and stir until dissolved. Then add 1.90 g of paraformaldehyde (0.06 mol). Stir and react for 1.0 h. HPLC detection shows that the reaction is complete. Add 46.76 g of 40.0 mL of methyl isobutyl ketone was added to a 30% aqueous potassium hydroxide solution (0.25 mol), and 0.5 mol of difluorochloromethane was introduced under rapid stirring. After stirring for 4.0 h, the reaction was completed by HPLC detection. The reaction solution was separated, and the lower aqueous phase was extracted with 20.0 mL of methyl isobutyl ketone. The organic phases were combined, and 60.0 mL of trifluoroacetic acid was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 3.0 h. After the reaction was completed by HPLC detection, it was concentrated under reduced pressure, and 20.0 mL of methyl isobutyl ketone was added to the concentrate for washing, and it was concentrated under reduced pressure to obtain 11.31 g of an oily substance with a purity of 90.5% and a yield of 88.2% based on compound I.

[0061] (3) Synthesis of 5-difluoromethoxy-4-hydroxymethyl-3-trifluoromethyl-1-methylpyrazole

[0062] 60.0 mL of 1,4-dioxane was added to the above 11.31 g of compound (III) (0.044 mol) and stirred until dissolved. 24.32 g of potassium carbonate (0.176 mol) and 5.55 g of dimethyl sulfate (0.044 mol) were added and heated under reflux for 7 h. The reaction was completed after HPLC detection. The temperature was lowered, the reaction solution was poured into water, extracted twice with 40.0 mL of dichloromethane, the organic phases were combined, and concentrated under reduced pressure to obtain 11.37 g of a crude final product with a purity of 88.1% and a yield of 92.5% based on compound (III).

[0063] Example 4

[0064] (1) Synthesis of 1-N-Boc-5-hydroxy-3-trifluoromethylpyrazole (I)

[0065] At room temperature, 14.39 g of hydrazine hydrate (80% aqueous solution, 0.23 mol) was weighed and added to 400 mL of isopropanol. After stirring and dissolving, the temperature was lowered to 0°C. 21.82 g of di-tert-butyl dicarbonate was added to 98.0 g of isopropanol and diluted, and then slowly added dropwise to the above solution. After the addition was completed, the mixture was kept warm for 2.0 h, and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 12.80 g of solid (yield based on di-tert-butyl dicarbonate, 97%). Dissolve again in 360 mL of xylene, add 11.97 g of ethyl trifluoroacetoacetate (0.065 mol), heat to reflux for 15 h, and detect the end of the reaction by HPLC. The reactants are concentrated under reduced pressure, and the residue is added to ethyl acetate, heated and stirred until dissolved. Petroleum ether is added until the reaction solution becomes turbid. After stirring for 15 min, cool and solid precipitates. Cool to 0-5 ° C for crystallization for 2.0 h, and filter to obtain 14.70 g of solid with a purity of 91.3%.

[0066] (2) Synthesis of 5-difluoromethoxy-4-hydroxymethyl-3-trifluoromethyl-1-hydrogen-pyrazole (III)

[0067] At 25°C, 13.39 g of compound (I) (0.05 mol) was weighed and added to 80.0 mL of water. 4.20 g of potassium hydroxide (0.075 mol) was added and stirred until dissolved. Then, 1.90 g of paraformaldehyde (0.06 mol) was added and stirred for 1.0 h. After HPLC detection, the reaction was complete. 28.00 g of 30% potassium hydroxide aqueous solution was added. 40.0 mL of acetonitrile was added and 0.1 mol of difluorochloromethane was introduced under rapid stirring. After HPLC detection, the reaction was complete for 4.0 h. The reaction solution was separated. The lower aqueous phase was extracted with 20.0 mL of acetonitrile. The organic phases were combined and 60.0 mL of trifluoroacetic acid was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 3.0 h. After HPLC detection, the mixture was concentrated under reduced pressure. The concentrate was washed with 20.0 mL of acetonitrile and concentrated under reduced pressure to obtain 11.67 g of an oily substance with a purity of 89.9% and a yield of 90.4% based on compound I.

[0068] (3) Synthesis of 5-difluoromethoxy-4-hydroxymethyl-3-trifluoromethyl-1-methylpyrazole

[0069] 60.0 mL of 1,4-dioxane was added to the above 11.67 g of compound (III) (0.045 mol) and stirred until dissolved. 9.54 g of sodium carbonate (0.09 mol) and 5.68 g of dimethyl sulfate (0.045 mol) were added and heated under reflux for 7 h. The reaction was completed after HPLC detection. The temperature was lowered, the reaction solution was poured into water, extracted twice with 40.0 mL of dichloromethane, the organic phases were combined, and concentrated under reduced pressure to obtain 11.32 g of a crude final product with a purity of 89.3%. The yield was 91.2% based on compound (III).

[0070] Example 5

[0071] (1) Synthesis of 1-N-Boc-5-hydroxy-3-trifluoromethylpyrazole (I)

[0072] Under room temperature, weigh 14.39 g of hydrazine hydrate (80% aqueous solution, 0.23 mol) and add it to 400 mL of isopropanol. After stirring to dissolve, cool to 0°C, add 21.82 g of di-tert-butyl dicarbonate to 98.0 g of isopropanol and dilute it, then slowly add it dropwise to the above solution. After the addition is complete, keep the temperature to react for 2.0 h, evaporate the solvent under reduced pressure, dissolve the residue in dichloromethane, dry over anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain solid Boc-hydrazine. Dissolve again in 360 mL of xylene, add 16.57 g of ethyl trifluoroacetoacetate (0.09 mol), heat to reflux for 15 h, and detect the end of the reaction by HPLC. The reactants are concentrated under reduced pressure, and the residue is added to ethyl acetate, heated and stirred until dissolved. Petroleum ether is added until the reaction solution becomes turbid. After stirring for 15 min, cool and solid precipitates. Cool to 0-5 ° C for crystallization for 2.0 h, and filter to obtain 20.17 g of solid with a purity of 92.5%.

[0073] (2) Synthesis of 5-difluoromethoxy-4-hydroxymethyl-3-trifluoromethyl-1-hydrogen-pyrazole (III)

[0074] At 25°C, compound (I) (0.05 mol) was added to 80.0 mL of water, 3.0 g of sodium hydroxide (0.075 mol) was added, and the mixture was stirred until dissolved. Then, 1.90 g of paraformaldehyde (0.06 mol) was added, and the mixture was stirred for reaction for 1.0 h. After HPLC detection, the reaction was complete. Then, 12.50 g of 40% sodium hydroxide aqueous solution (0.125 mol) was added, 40.0 mL of acetonitrile was added, and 0.25 mol of difluorochloromethane was introduced under rapid stirring. After HPLC detection, the reaction was complete for 4.0 h. The reaction solution was separated, and the lower aqueous phase was extracted with 20.0 mL of acetonitrile. The organic phases were combined, and 60.0 mL of trifluoroacetic acid was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 3.0 h. After HPLC detection, the mixture was concentrated under reduced pressure. The concentrate was washed with 20.0 mL of acetonitrile and concentrated under reduced pressure to obtain 11.75 g of an oily substance with a purity of 90.2%. The yield was 91.3% based on compound I.

[0075] (3) Synthesis of 5-difluoromethoxy-4-hydroxymethyl-3-trifluoromethyl-1-methylpyrazole

[0076] Compound (III) (0.046 mol) was weighed, 60.0 mL of 1,4-dioxane was added and stirred until dissolved, 12.71 g of potassium carbonate (0.092 mol) and 5.81 g of dimethyl sulfate (0.046 mol) were added, and the mixture was heated under reflux for 7 h. The reaction was completed after HPLC detection. The temperature was lowered, the reaction solution was poured into water, and extracted twice with 40.0 mL of dichloromethane. The organic phases were combined and concentrated under reduced pressure to obtain 11.64 g of a crude final product with a purity of 89.3%. The yield was 91.8% based on compound (III).

[0077] Example 6

[0078] (1) Synthesis of 1-N-Boc-5-hydroxy-3-trifluoromethyl-1-methylpyrazole (I)

[0079] Under room temperature, weigh 14.39 g of hydrazine hydrate (80% aqueous solution, 0.23 mol) and add it to 400 mL of isopropanol. After stirring to dissolve, cool to 0°C, add 21.82 g of di-tert-butyl dicarbonate to 98.0 g of isopropanol and dilute it, then slowly add it dropwise to the above solution. After the addition is complete, keep the temperature to react for 2.0 h, evaporate the solvent under reduced pressure, dissolve the residue in dichloromethane, dry over anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain solid Boc-hydrazine. The mixture was dissolved again in 360 mL of xylene, 16.57 g of ethyl trifluoroacetoacetate (0.09 mol) was added, and the mixture was heated to reflux for 15 h. The reaction was detected by HPLC after completion. The reactants were concentrated under reduced pressure, and the residue was added to ethyl acetate. The mixture was heated and stirred until dissolved. Petroleum ether was added until the reaction solution became turbid. After stirring for 15 min, the mixture was cooled and solid precipitated. The mixture was cooled to 0-5 °C for crystallization for 2.0 h. The solid was filtered to obtain 20.03 solid with a purity of 93.1%.

[0080] (2) Synthesis of 5-difluoromethoxy-4-hydroxymethyl-3-trifluoromethyl-1-hydrogen-pyrazole (III)

[0081] At 25°C, compound (I) (0.05 mol) was added to 80.0 mL of water, 3.0 g of sodium hydroxide (0.075 mol) was added, and the mixture was stirred until dissolved. Then, 1.90 g of paraformaldehyde (0.06 mol) was added, and the mixture was stirred for 1.0 h. After that, the reaction was completed as determined by HPLC. Then, 15.00 g of 40% aqueous sodium hydroxide solution was added, 40.0 mL of isopropanol was added, and 0.25 mol of difluorochloromethane was introduced under rapid stirring. After that, the reaction was completed as determined by HPLC for 4.0 h. The reaction solution was separated, and the lower aqueous phase was extracted with 20.0 mL of isopropanol. The organic phases were combined, and 60.0 mL of trifluoroacetic acid was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 3.0 h. After the reaction was completed as determined by HPLC, the mixture was concentrated under reduced pressure. The concentrate was washed with 20.0 mL of isopropanol and concentrated under reduced pressure to obtain 11.63 g of an oily substance with a purity of 89.8% and a yield of 90.0% based on compound I.

[0082] (3) Synthesis of 5-difluoromethoxy-4-hydroxymethyl-3-trifluoromethyl-1-methylpyrazole

[0083] Compound (III) (0.045 mol) was weighed, 60.0 mL of 1,4-dioxane was added and stirred until dissolved, 3.60 g of sodium hydroxide (0.09 mol) and 5.68 g of dimethyl sulfate (0.045 mol) were added, and the mixture was heated under reflux for 7 h. The reaction was completed after HPLC detection. The temperature was lowered, the reaction solution was poured into water, and extracted twice with 40.0 mL of dichloromethane. The organic phases were combined and concentrated under reduced pressure to obtain 10.92 g of a crude final product with a purity of 88.7%. The yield was 87.4% based on compound (III).

[0084] Example 7

[0085] (1) Synthesis of 1-N-Boc-5-hydroxy-3-trifluoromethyl-1-methylpyrazole (I)

[0086] Under room temperature, weigh 14.39 g of hydrazine hydrate (80% aqueous solution, 0.23 mol) and add it to 400 mL of isopropanol. After stirring to dissolve, cool to 0°C, add 21.82 g of di-tert-butyl dicarbonate to 98.0 g of isopropanol and dilute it, then slowly add it dropwise to the above solution. After the addition is complete, keep the temperature to react for 2.0 h, evaporate the solvent under reduced pressure, dissolve the residue in dichloromethane, dry over anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain solid Boc-hydrazine. Dissolve again in 360 mL of xylene, add 16.57 g of ethyl trifluoroacetoacetate (0.09 mol), heat to reflux for 15 h, and then detect the end of the reaction by HPLC. The reactants are concentrated under reduced pressure, and the residue is added to ethyl acetate, heated and stirred until dissolved, and petroleum ether is added until the reaction solution becomes turbid. After stirring for 15 min, cool and solid precipitate. Cool to 0-5 ° C for crystallization for 2.0 h, and filter to obtain 20.07 g of solid with a purity of 93.4%.

[0087] (2) Synthesis of 5-difluoromethoxy-4-hydroxymethyl-3-trifluoromethylpyrazole (III)

[0088] At 25°C, compound (I) (0.05 mol) was added to 80.0 mL of water, 3.0 g of sodium hydroxide (0.075 mol) was added, and the mixture was stirred until dissolved. Then, 4.86 g of 37% formaldehyde aqueous solution (0.06 mol) was added, and the mixture was stirred for 1.0 h. After that, the reaction was detected by HPLC to be complete. Then, 15.00 g of 40% sodium hydroxide aqueous solution was added, 40.0 mL of acetonitrile was added, and 0.5 mol of difluorochloromethane was introduced under rapid stirring. After that, the reaction was detected by HPLC to be complete for 4.0 h. The reaction solution was separated, and the lower aqueous phase was extracted with 20.0 mL of acetonitrile. The organic phases were combined, and 60.0 mL of trifluoroacetic acid was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 3.0 h. After the reaction was detected by HPLC to be complete, the mixture was concentrated under reduced pressure, and the concentrate was washed with 20.0 mL of acetonitrile and concentrated under reduced pressure to obtain 11.65 g of an oily substance with a purity of 90.2%. The yield was 90.5% based on compound I.

[0089] (3) Synthesis of 5-difluoromethoxy-4-hydroxymethyl-3-trifluoromethyl-1-hydrogen-pyrazole

[0090] Compound (III) (0.045 mol) was weighed, 60.0 mL of 1,4-dioxane was added and stirred until dissolved, 5.05 g of potassium hydroxide (0.09 mol) and 5.68 g of dimethyl sulfate (0.045 mol) were added, and the mixture was heated under reflux for 7 h. The reaction was completed after HPLC detection. The temperature was lowered, the reaction solution was poured into water, and extracted twice with 40.0 mL of dichloromethane. The organic phases were combined and concentrated under reduced pressure to obtain 11.58 g of a crude final product with a purity of 89.1%. The yield was 93.1% based on compound (III).

[0091] Example 8

[0092] (1) Synthesis of 1-N-Boc-5-hydroxy-3-trifluoromethylpyrazole (I)

[0093] Under room temperature, weigh 14.39 g of hydrazine hydrate (80% aqueous solution, 0.23 mol) and add it to 400 mL of isopropanol. After stirring to dissolve, cool to 0°C, add 21.82 g of di-tert-butyl dicarbonate to 98.0 g of isopropanol and dilute it, then slowly add it dropwise to the above solution. After the addition is complete, keep the temperature to react for 2.0 h, evaporate the solvent under reduced pressure, dissolve the residue in dichloromethane, dry over anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain solid Boc-hydrazine. Dissolve again in 360 mL of xylene, add 16.57 g of ethyl trifluoroacetoacetate (0.09 mol), heat to reflux for 15 h, and detect the end of the reaction by HPLC. The reactants are concentrated under reduced pressure, and the residue is added to ethyl acetate, heated and stirred until dissolved. Petroleum ether is added until the reaction solution becomes turbid. After stirring for 15 min, cool and solid precipitates. Cool to 0-5 ° C for crystallization for 2.0 h, and filter to obtain 20.03 g of solid with a purity of 93.7%.

[0094] (2) Synthesis of 5-difluoromethoxy-4-hydroxymethyl-3-trifluoromethyl-1-hydrogen-pyrazole (III)

[0095] At 25°C, compound (I) (0.05 mol) was added to 80.0 mL of water, 3.0 g of sodium hydroxide (0.075 mol) was added, and the mixture was stirred until dissolved. Then, 4.86 g of 37% formaldehyde aqueous solution (0.06 mol) was added, and the mixture was stirred for reaction for 1.0 h. The reaction was detected by HPLC after the reaction was completed. Then, 40.0 mL of acetonitrile was added, and 0.5 mol of difluorochloromethane was introduced under rapid stirring. At the same time, 15.00 g of 40% sodium hydroxide aqueous solution was added dropwise. After the addition was completed, the mixture was stirred for reaction for 4.0 h. The reaction was detected by HPLC after the reaction was completed. The reaction solution was separated, and the lower aqueous phase was extracted with 20.0 mL of acetonitrile. The organic phases were combined, and 60.0 mL of trifluoroacetic acid was added dropwise. After the addition was completed, the mixture was stirred for 3.0 h at room temperature. After the reaction was detected by HPLC after the reaction was completed, the mixture was concentrated under reduced pressure. The concentrate was washed with 20.0 mL of acetonitrile and concentrated under reduced pressure to obtain 11.75 g of an oily substance with a purity of 90.3%. The yield was 91.4% based on compound I.

[0096] (3) Synthesis of 5-difluoromethoxy-4-hydroxymethyl-3-trifluoromethyl-1-methylpyrazole

[0097] Compound (III) (0.046 mol) was weighed, 60.0 mL of 1,4-dioxane was added and stirred until dissolved, 12.71 g of potassium carbonate (0.092 mol) and 5.81 g of dimethyl sulfate (0.046 mol) were added, and the mixture was heated under reflux for 7 h. The reaction was completed after HPLC detection. The temperature was lowered, the reaction solution was poured into water, and extracted twice with 40.0 mL of dichloromethane. The organic phases were combined and concentrated under reduced pressure to obtain 10.97 g of a crude final product with a purity of 89.5%. The yield was 86.7% based on compound (III).

[0098] Comparative Example 1

[0099] (1) Synthesis of 5-hydroxy-3-trifluoromethyl-1-hydrogen-pyrazole

[0100] At room temperature, 14.39 g of hydrazine hydrate (80% aqueous solution, 0.23 mol) was weighed and added to 360 mL of xylene, and 16.57 g of ethyl trifluoroacetoacetate (0.09 mol) was added. After heating to reflux for 15 h, the reaction was detected by HPLC to be complete. The reactants were concentrated under reduced pressure, and the residue was added to ethyl acetate. The mixture was heated and stirred until dissolved. Petroleum ether was added until the reaction solution became turbid. After stirring for 15 min, the temperature was lowered and solids precipitated. The temperature was lowered to 0-5 ° C for crystallization for 2.0 h, and 5-hydroxy-3-trifluoromethyl-1 hydrogen-pyrazole was obtained with a yield of 38.4% based on ethyl trifluoroacetoacetate and a purity of 38.2%.

[0101] (2) Synthesis of 5-difluoromethoxy-4-hydroxymethyl-3-trifluoromethyl-1-hydrogen-pyrazole (III)

[0102] 5-Hydroxy-3-trifluoromethyl-1-hydrogen-pyrazole (0.05 mol) was added to 80.0 mL of water, and 4.20 g of potassium hydroxide (0.075 mol) was added. After stirring until dissolved, 1.90 g of paraformaldehyde (0.06 mol) was added. After stirring for 1.0 h, the reaction was detected by HPLC to be complete. 28.00 g of 30% potassium hydroxide aqueous solution was added, and 40.0 mL of acetonitrile was added. 0.5 mol of difluorochloromethane was introduced under rapid stirring. After stirring for 4.0 h, the reaction was detected by HPLC to be complete. The reaction liquid was separated, and the lower aqueous phase was extracted with 20.0 mL of acetonitrile. The organic phases were combined, and 60.0 mL of trifluoroacetic acid was added dropwise. After the addition was completed, it was stirred at room temperature for 3.0 h. After the reaction was detected by HPLC, it was concentrated under reduced pressure, and the concentrate was washed with 20.0 mL of acetonitrile and concentrated under reduced pressure to obtain 10.39 g of an oily substance with a purity of 34.7% and a yield of 45.0%.

[0103] (3) Synthesis of 5-difluoromethoxy-4-hydroxymethyl-3-trifluoromethyl-1-methylpyrazole

[0104] 60.0 mL of 1,4-dioxane was added to the above compound (III) and stirred until dissolved. 12.71 g of potassium carbonate (0.092 mol) and 5.81 g of dimethyl sulfate (0.046 mol) were added and heated under reflux for 7 h. The reaction was completed when detected by HPLC. The temperature was lowered, the reaction solution was poured into water, extracted twice with 40.0 mL of dichloromethane, the organic phases were combined, and concentrated under reduced pressure to obtain 10.83 g of a crude final product with a purity of 31.7%. The yield was 89.9% based on compound (III).

[0105] Comparative Example 2

[0106] (1) Synthesis of 1-N-Fmoc-5-hydroxy-3-trifluoromethylpyrazole

[0107] At room temperature, weigh 14.39 g of hydrazine hydrate (80% aqueous solution, 0.23 mol) and add it to 400 mL of isopropanol. After stirring to dissolve, cool to 0°C, add 25.82 g of fluorenylmethoxycarbonyl chloride to 98.0 g of isopropanol and dilute it, then slowly drop it into the above solution. After the addition is complete, keep the temperature to react for 2.0 h, evaporate the solvent under reduced pressure, dissolve the residue in dichloromethane, dry over anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain solid Fmoc-hydrazine. The mixture was dissolved again in 360 mL of xylene, 16.57 g of ethyl trifluoroacetoacetate (0.09 mol) was added, and the reaction was heated to reflux for 15 h. The reaction was detected by HPLC after completion. The reactants were concentrated under reduced pressure, and the residue was added to ethyl acetate. The mixture was heated and stirred until dissolved. Petroleum ether was added until the reaction solution became turbid. After stirring for 15 min, the mixture was cooled and solid precipitated. The mixture was cooled to 0-5 °C for crystallization for 2.0 h. The mixture was filtered to obtain 1-N-Fmoc-5-hydroxy-3-trifluoromethylpyrazole. The yield was 71.8% based on ethyl trifluoroacetoacetate and the purity was 88.3%.

[0108] (2) Synthesis of 5-difluoromethoxy-4-hydroxymethyl-3-trifluoromethyl-1-hydrogen-pyrazole (III)

[0109] 1-N-Fmoc-5-hydroxy-3-trifluoromethylpyrazole (0.05 mol) was added to 80.0 mL of water, and 4.20 g of potassium hydroxide (0.075 mol) was added. After stirring until dissolved, 1.90 g of paraformaldehyde (0.06 mol) was added. After stirring for 1.0 h, the reaction was detected by HPLC to be complete. 28.00 g of 30% potassium hydroxide aqueous solution was added, and 40.0 mL of acetonitrile was added. 0.5 mol of difluorochloromethane was introduced under rapid stirring. After stirring for 4.0 h, the reaction was detected by HPLC to be complete. The reaction liquid was separated, and the lower aqueous phase was extracted with 20.0 mL of acetonitrile. The organic phases were combined, and 60.0 mL of trifluoroacetic acid was added dropwise. After the addition was completed, it was stirred at room temperature for 3.0 h. After the reaction was detected by HPLC, it was concentrated under reduced pressure, and the concentrate was washed with 20.0 mL of acetonitrile and concentrated under reduced pressure to obtain 10.71 g of an oily substance with a purity of 32.3% and a yield of 29.8%.

[0110] (3) Synthesis of 5-difluoromethoxy-4-hydroxymethyl-3-trifluoromethyl-1-methylpyrazole

[0111] 60.0 mL of 1,4-dioxane was added to the above compound and stirred until dissolved. 12.71 g of potassium carbonate (0.092 mol) and 5.81 g of dimethyl sulfate (0.046 mol) were added and heated under reflux for 7 h. The reaction was completed when detected by HPLC. The temperature was lowered and the reaction solution was poured into water. The mixture was extracted twice with 40.0 mL of dichloromethane. The organic phases were combined and concentrated under reduced pressure to obtain 10.42 g of a crude final product with a purity of 30.1%. The yield was 85.5% based on compound (III).

Claims

1. A method for synthesizing a sulfonepyraclostrobin intermediate, characterized in that The following steps are involved: (1) Using hydrazine hydrate as raw material, it reacts with BOC anhydride to generate tert-butyloxycarbonyl hydrazine; (2) Under high temperature conditions, tert-butyloxycarbonylhydrazine and ethyl trifluoroacetoacetate undergo a cyclization reaction to prepare compound I; (3) Compound I is subjected to a hydroxymethylation reaction with formaldehyde or paraformaldehyde in the presence of a base, and after the reaction, difluorochloromethane is added in the presence of a base to continue the reaction to obtain compound II, and compound II is deprotected from the BOC protecting group to obtain compound III, and then compound III is subjected to an N-methylation reaction with an N-methylating agent to obtain 5-difluoromethoxy-4-hydroxymethyl-3-trifluoromethyl-1-methylpyrazole, i.e., a sulfonepyrazol intermediate; 。 2. The synthesis method according to claim 1, characterized in that: In step (1), the molar ratio of hydrazine hydrate to BOC anhydride is 2.2-2.5:1; in step (2), the molar ratio of ethyl trifluoroacetoacetate to tert-butyloxycarbonylhydrazine is 1:1-1.

5.

3. The synthesis method according to claim 1, characterized in that: In step (1), the reaction temperature of hydrazine hydrate and BOC anhydride is -10 to 10°C; in steps (1) and (2), the reaction is carried out in the presence of an organic solvent, and the organic solvent is acetonitrile, isopropanol, tetrahydrofuran, methyl isobutyl ketone, benzene, xylene or N-methylpyrrolidone.

4. The synthesis method according to claim 1 or 3, characterized in that: In step (1), an organic solvent solution of BOC anhydride is added dropwise to an organic solvent solution of hydrazine hydrate to carry out a reaction; in step (2), tert-butyloxycarbonylhydrazine and ethyl trifluoroacetoacetate are heated in an organic solvent to carry out a reflux reaction to obtain compound I.

5. The synthesis method according to claim 1, characterized in that: In step (3), the hydroxymethylation reaction is carried out in an alkaline water environment, the base is an inorganic base or an organic base, the inorganic base is sodium hydroxide or potassium hydroxide, the organic base is sodium methoxide, potassium methoxide, sodium ethoxide or potassium ethoxide, and the molar ratio of compound I to the base is 1:1.2-1.

5.

6. The synthesis method according to claim 1 or 5, characterized in that: In step (3), the molar ratio of compound I to formaldehyde or paraformaldehyde is 1:1.0-1.5, where paraformaldehyde is calculated as formaldehyde.

7. The synthesis method according to claim 6, characterized in that: In step (3), the formaldehyde is present in the form of a formaldehyde aqueous solution, and the concentration of the formaldehyde aqueous solution is 35-50 wt %.

8. The synthesis method according to claim 1, characterized in that: In step (3), after the reaction of compound I with formaldehyde or paraformaldehyde is completed, a base and an organic solvent are directly added to the reaction system, and then difluorochloromethane is introduced to react.

9. The synthesis method according to claim 8, characterized in that: In step (3), the added base is an inorganic base or an organic base, the inorganic base is sodium hydroxide or potassium hydroxide, and the organic base is sodium methoxide, potassium methoxide, sodium ethoxide or potassium ethoxide.

10. The synthesis method according to claim 8, characterized in that: In step (3), the added organic solvent is acetonitrile, isopropanol, tetrahydrofuran, methyl isobutyl ketone, benzene, xylene or N-methylpyrrolidone.

11. The synthesis method according to claim 8, characterized in that: In step (3), after the hydroxymethylation reaction, the molar ratio of the hydroxymethylation reaction product to the added base is 1:2.5-5.0, and the molar ratio of the hydroxymethylation reaction product to difluoromonochloromethane is 1:2.0-10.0; in step (3), the reaction temperature of the hydroxymethylation reaction product and difluoromonochloromethane is 0°C-25°C.

12. The synthesis method according to claim 1 or 8, characterized in that: In step (3), compound II is subjected to the removal of the BOC protecting group in the presence of an acid, wherein the acid is trifluoroacetic acid, hydrochloric acid, sulfuric acid or phosphoric acid; in step (3), the N-methylating agent is dimethyl sulfate or a halogenated methyl ester.

13. The synthesis method according to claim 12, characterized in that: In step (3), the N-methylating agent is dimethyl sulfate.

14. The synthesis method according to claim 1 or 8, characterized in that: In step (3), the N-methylation reaction is carried out in the presence of a base, and the base is sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide; in step (3), the molar ratio of compound III to the N-methylation agent is 1:1.0-1.5, and the molar ratio of compound III to the base is 1:1.0-4.0.

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