A preparation method and application of pyrazole mercaptomethyl derivatives

Abstract

The invention discloses a preparation method and application of a pyrazole mercaptomethylated derivative, wherein 5-difluoromethoxy-4-halomethyl-3-trifluoromethyl-1-methylpyrazole is used as a raw material and reacted with 3-mercaptopropionic acid ester under alkaline conditions to obtain the pyrazole mercaptomethylated derivative. The invention has fast reaction speed, mild reaction conditions, high yield, less three wastes, easy recycling of by-products, low cost, and is suitable for industrial production.

Description

Technical Field

[0001] The invention relates to a method for preparing a pyrazole mercaptomethyl derivative and also relates to a method for preparing sulfonepyraclostrobin using the pyrazole mercaptomethyl derivative as an intermediate, belonging 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] Pyrazole mercaptomethyl derivatives (structural formula I) are important intermediates for the synthesis of sulfone pyraclostrobin, and their structure is as follows:

[0004]

[0005] At present, there are several processes for the synthesis of pyrazole mercaptomethyl derivatives:

[0006] Patent CN114450270A reports the preparation of pyrazole thiomethyl derivatives by reacting 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol with S-bromomethylthioacetate or S-(1-piperidinylmethyl)thioacetate hydrochloride. The raw materials S-bromomethylthioacetate or S-(1-piperidinylmethyl)thioacetate hydrochloride of this method are not easy to obtain, and the required solvent needs to be dried. The reaction process is protected by nitrogen, resulting in high cost and shortcomings.

[0007] Patent EP1541561A1 reports the preparation of pyrazole mercaptomethyl derivatives by reacting 5-difluoromethoxy-4-bromomethyl-3-trifluoromethyl-1-methylpyrazole with sodium hydrosulfide. This method has many by-products, low product purity and yield, and has great shortcomings.

[0008] Patents EP1541561A1, US2010 / 285958, and CN114716379 report the preparation of pyrazole thiomethyl derivatives by reacting 5-difluoromethoxy-4-bromomethyl-3-trifluoromethyl-1-methylpyrazole with thiourea. This method uses thiourea, which is easily oxidized to disulfide byproducts under acidic conditions and requires refining treatment. The post-treatment is cumbersome and has shortcomings. Summary of the invention

[0009] Aiming at the shortcomings of existing pyrazole thiomethyl derivatives in the preparation process, the present invention provides a method for preparing pyrazole thiomethyl derivatives. The method has readily available raw materials, mild reaction conditions, high reaction conversion rate, simple post-treatment, and is suitable for industrial production.

[0010] The specific technical solutions of the present invention are as follows:

[0011] The present invention provides a method for preparing a pyrazole mercaptomethyl derivative suitable for industrialization. The pyrazole mercaptomethyl derivative has a structural formula shown in the following formula (I), wherein R is a C1-C4 alkyl group, such as methyl, ethyl, propyl, butyl, etc., preferably methyl or ethyl.

[0012]

[0013] Furthermore, the preparation method of the pyrazole thiomethyl derivative comprises the following steps: using 5-difluoromethoxy-4-halomethyl-3-trifluoromethyl-1-methylpyrazole as a raw material and reacting it with 3-mercaptopropionic acid ester under alkaline conditions to obtain the pyrazole thiomethyl derivative.

[0014] Further, the structural formula of the 5-difluoromethoxy-4-halomethyl-3-trifluoromethyl-1-methylpyrazole is shown in the following formula (II), wherein X refers to a halogen, and the halogen can be a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, preferably a chlorine atom or a bromine atom. When the halogen is a chlorine atom or a bromine atom, the 5-difluoromethoxy-4-halomethyl-3-trifluoromethyl-1-methylpyrazole is 5-difluoromethoxy-4-chloromethyl-3-trifluoromethyl-1-methylpyrazole or 5-difluoromethoxy-4-bromomethyl-3-trifluoromethyl-1-methylpyrazole.

[0015]

[0016] Furthermore, the structural formula of the 3-mercaptopropionic acid ester is shown below, wherein the definition of R is consistent with that in formula (I), and R is a C1-C4 alkyl group, such as methyl, ethyl, propyl, butyl, etc., preferably methyl or ethyl. When R is methyl or ethyl, the 3-mercaptopropionic acid ester is ethyl 3-mercaptopropionate or methyl 3-mercaptopropionate.

[0017]

[0018] Further, the reaction formula of 5-difluoromethoxy-4-halomethyl-3-trifluoromethyl-1-methylpyrazole and 3-mercaptopropionic acid ester is as follows:

[0019]

[0020] Among them, 5-difluoromethoxy-4-halomethyl-3-trifluoromethyl-1-methylpyrazole shown in formula (II) can be prepared by referring to the methods disclosed in patents such as EP1541561A1 and WO2021002484A2, and 3-mercaptopropionic acid ester is a commercial reagent and is relatively easy to obtain.

[0021] Further, the molar ratio of 5-difluoromethoxy-4-halomethyl-3-trifluoromethyl-1-methylpyrazole to 3-mercaptopropionic acid ester is 1:1.1-1.3, preferably 1:1.1.

[0022] Further, the alkaline condition is provided by an alkaline substance, and the alkaline substance is at least one of triethylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, potassium bicarbonate and sodium bicarbonate, preferably at least one of triethylamine, sodium carbonate and potassium carbonate, and most preferably a mixture of triethylamine and potassium carbonate in a mass ratio of 1:0.2-0.5.

[0023] Furthermore, the molar ratio of 5-difluoromethoxy-4-halomethyl-3-trifluoromethyl-1-methylpyrazole to the alkaline substance is 1:1.07-1.2, preferably 1:1.2.

[0024] Further, the reaction temperature of 5-difluoromethoxy-4-halomethyl-3-trifluoromethyl-1-methylpyrazole and 3-mercaptopropionic acid ester is 25° C. to 60° C., for example, 25° C., 30° C., 35° C., 40° C., 45° C., 50° C., 55° C., 60° C. The reaction time varies slightly depending on the temperature. When the raw material content is extremely low, the reaction can be terminated. In the temperature range of 25° C. to 60° C., the time to reach the reaction endpoint is generally 2.0 h to 3.5 h.

[0025] Further, the reaction of 5-difluoromethoxy-4-halomethyl-3-trifluoromethyl-1-methylpyrazole and 3-mercaptopropionic acid ester is carried out in the presence of a reaction medium, and the reaction medium is an organic solvent. The organic solvent can meet the requirements of the reaction medium, and the range of options is relatively wide, for example, it can be at least one of dichloromethane, chloroform, dichloroethane, N,N-dimethylformamide, tetrahydrofuran, methyl isobutyl ketone, acetonitrile, N-methylpyrrolidone, etc. The amount of the organic solvent can be selected as needed.

[0026] Further, it has been found through experiments that some organic solvents can not only act as reaction media, but also improve the yield of the reaction, reduce the occurrence of side reactions, and show unexpected technical effects. Preferably, the organic solvent used is at least one of dichloromethane, dichloroethane, chloroform, N,N-dimethylformamide, etc. More preferably, the organic solvent is a mixture of dichloroethane and N,N-dimethylformamide in a mass ratio of 8-10:1.

[0027] Furthermore, during the reaction, there is no special requirement for the mixing order of the raw materials. Preferably, 5-difluoromethoxy-4-halomethyl-3-trifluoromethyl-1-methylpyrazole, an organic solvent and an alkaline substance can be mixed first, and then 3-mercaptopropionic acid ester is slowly added, and the temperature is controlled to the reaction temperature for reaction. The advantage of such a mixing order is that the temperature is stable and controllable, and the side reactions are reduced.

[0028] Furthermore, after the reaction is completed, the post-treatment process is as follows: when the organic solvent is a high-boiling point solvent miscible with water such as N,N-dimethylformamide and N-methylpyrrolidone, the reaction solution is added with an appropriate amount of saline to wash with water, and then the pH is adjusted to neutral with hydrochloric acid, and ethyl acetate is added for extraction, and the organic phase obtained by extraction is removed from the solvent to obtain a pyrazole thiomethyl derivative; when the organic solvent is other solvents that are not miscible with water, the reaction solution is added with an appropriate amount of water to wash with water, and then the pH is adjusted to neutral with hydrochloric acid, the liquids are separated, and the obtained organic phase is concentrated under reduced pressure to obtain a pyrazole thiomethyl derivative.

[0029] Furthermore, the present invention also provides a method for preparing sulfonepyrazoline using the pyrazole thiomethyl derivative shown in formula (I) as an intermediate, and the preparation process route is: the pyrazole thiomethyl derivative is hydrolyzed in a reaction system of sodium alcohol and the corresponding alcohol to obtain pyrazole thiosulfate sodium salt, and then the pyrazole thiosulfate sodium salt is substituted with 3-halogenated-5,5-dimethyl-4,5-dihydroisoxazole, and the reaction product is oxidized under the action of hydrogen peroxide to obtain sulfonepyrazoline; the reaction formula is as follows:

[0030]

[0031] Furthermore, when preparing sulfonepyraclostrobin, the hydrolysis of the thiomethylated pyrazole derivative into a sodium salt needs to be carried out in a metal alkoxide and a corresponding alcohol solution. The sodium alkoxide and alcohol used can be a sodium methoxide-methanol system, a sodium ethoxide-ethanol system, etc. The specific reaction conditions can be operated according to the disclosure of the prior art.

[0032] Furthermore, when preparing sulfonepyraclostrobin, the substitution reaction of pyrazole thiol sodium salt and 3-halo-5,5-dimethyl-4,5-dihydroisoxazole and the oxidation reaction of the reaction product with hydrogen peroxide can be carried out according to the disclosure of the prior art.

[0033] The present invention has the following beneficial effects:

[0034] 1. The method for preparing the thiomethylated pyrazole derivative of the present invention has readily available raw materials, fast reaction speed, short reaction time, mild reaction conditions, no need for excessively high temperature and high pressure, low equipment requirements, and low production cost. It further reduces the components of preparing sulfonepyraclostrobin using the thiomethylated pyrazole derivative as an intermediate, and is more suitable for large-scale industrial production.

[0035] 2. The reaction conversion rate of the present invention is high, the reaction selectivity is good, and the yield and purity of the obtained pyrazole mercaptomethylated derivatives are high.

[0036] 3. The post-processing of the present invention is simple, the three wastes are less, the by-products are easy to recycle, and it is more environmentally friendly. DETAILED DESCRIPTION

[0037] The present invention is further explained and illustrated below in conjunction with specific embodiments. The following description is only exemplary and does not limit the scope of protection thereof.

[0038] In the following examples, unless otherwise specified, the concentrations are all mass percentage concentrations.

[0039] Example 1

[0040] At room temperature, 13.93 g of 5-difluoromethoxy-4-chloromethyl-3-trifluoromethyl-1-methylpyrazole (purity 95%, 0.05 mol) was weighed and added to 60.0 mL of dichloroethane, 5.41 g of triethylamine was added, and then 6.61 g of methyl 3-mercaptopropionate (0.055 mol) was slowly added dropwise. After the addition was completed, the temperature was raised to 60°C and kept for reaction for 2.0 h. After HPLC detection, the reaction was completed. 36.00 g of water was added to the reaction solution for washing, and then the pH was adjusted to neutral with 36% concentrated hydrochloric acid. The liquids were separated and the obtained organic phase was concentrated under reduced pressure to obtain 15.87 g of pyrazole mercaptomethyl derivative with a purity of 88.5% and a yield of 80.7%.

[0041] LC-MS (ESI+): M+1=349.

[0042] Example 2

[0043] At room temperature, 16.40 g of 5-difluoromethoxy-4-bromomethyl-3-trifluoromethyl-1-methylpyrazole (purity 94.2%, 0.05 mol) was weighed and added to 60.00 mL of dichloroethane, 6.07 g of triethylamine was added, and then 6.61 g of methyl 3-mercaptopropionate (0.055 mol) was slowly added dropwise. After the addition was completed, the temperature was raised to 60°C and the reaction was kept for 2.0 h. After HPLC detection, the reaction was completed. 36.00 g of water was added to the reaction solution for washing, and then the pH was adjusted to neutral with 36% concentrated hydrochloric acid. The liquids were separated and the obtained organic phase was concentrated under reduced pressure to obtain 16.48 g of pyrazole thiomethyl derivative with a purity of 90.7% and a yield of 85.9%.

[0044] Example 3

[0045] At room temperature, 13.93 g of 5-difluoromethoxy-4-chloromethyl-3-trifluoromethyl-1-methylpyrazole (purity 95%, 0.05 mol) was weighed and added to 60.0 mL of tetrahydrofuran, 6.91 g of N,N-diisopropylethylamine was added, and then 6.61 g of methyl 3-mercaptopropionate (0.055 mol) was slowly added dropwise. After the addition was completed, the mixture was kept at 25°C for 3.5 h. After HPLC detection, the reaction was completed. 36.00 g of water was added to the reaction solution for washing, and then the pH was adjusted to neutral with 36% concentrated hydrochloric acid. The liquids were separated, and the obtained organic phase was concentrated under reduced pressure to obtain 14.92 g of pyrazole mercaptomethyl derivative with a purity of 85.8% and a yield of 73.5%.

[0046] Example 4

[0047] At room temperature, 13.93 g of 5-difluoromethoxy-4-chloromethyl-3-trifluoromethyl-1-methylpyrazole (purity 95%, 0.05 mol) was weighed and added to 60.0 mL of dichloromethane, 6.07 g of triethylamine was added, and then 6.61 g of methyl 3-mercaptopropionate (0.055 mol) was slowly added dropwise. After the addition was completed, the mixture was kept at 25°C for 3.5 h. After HPLC detection, the reaction was completed. 36.00 g of water was added to the reaction solution for washing, and then the pH was adjusted to neutral with 36% concentrated hydrochloric acid. The liquids were separated and the obtained organic phase was concentrated under reduced pressure to obtain 15.79 g of pyrazole mercaptomethyl derivative with a purity of 89.1% and a yield of 80.8%.

[0048] Example 5

[0049] At room temperature, 13.93 g of 5-difluoromethoxy-4-chloromethyl-3-trifluoromethyl-1-methylpyrazole (purity 95%, 0.05 mol) was weighed and added to 60.0 mL of dichloroethane, 5.41 g of triethylamine was added, and then 7.81 g of methyl 3-mercaptopropionate (0.065 mol) was slowly added dropwise. After the addition was completed, the temperature was raised to 60°C and the reaction was kept for 2.0 h. After HPLC detection, the reaction was completed. 36.00 g of water was added to the reaction solution for washing, and then the pH was adjusted to neutral with 36% concentrated hydrochloric acid. The liquids were separated and the obtained organic phase was concentrated under reduced pressure to obtain 15.34 g of pyrazole mercaptomethyl derivative with a purity of 87.3% and a yield of 76.9%.

[0050] Example 6

[0051] At room temperature, 13.93 g of 5-difluoromethoxy-4-chloromethyl-3-trifluoromethyl-1-methylpyrazole (purity 95%, 0.05 mol) was weighed and added to 60.0 mL of chloroform, 5.41 g of triethylamine was added, and then 6.61 g of methyl 3-mercaptopropionate (0.055 mol) was slowly added dropwise. After the addition was completed, the temperature was raised to 45°C and the reaction was kept for 2.0 h. After HPLC detection, the reaction was completed. 36.00 g of water was added to the reaction solution for washing, and then the pH was adjusted to neutral with 36% concentrated hydrochloric acid. The liquids were separated and the obtained organic phase was concentrated under reduced pressure to obtain 15.89 g of pyrazole mercaptomethyl derivative with a purity of 88.2% and a yield of 80.5%.

[0052] Example 7

[0053] At room temperature, 13.93 g of 5-difluoromethoxy-4-chloromethyl-3-trifluoromethyl-1-methylpyrazole (purity 95%, 0.05 mol) was weighed and added to 60.0 mL of N,N-dimethylformamide, 7.60 g of potassium carbonate was added, and then 6.61 g of methyl 3-mercaptopropionate (0.055 mol) was slowly added dropwise. After the addition was completed, the temperature was raised to 60°C and the reaction was kept for 2.0 h. After HPLC detection, the reaction was completed. 150.0 g of saturated salt was added to the reaction solution for washing with water, and then the pH was adjusted to neutral with 36% concentrated hydrochloric acid, 40.00 g of ethyl acetate was added for extraction, separation, and then 20.00 g of ethyl acetate was added for extraction and washing, separation, and the organic phases were combined. The obtained organic phase was concentrated under reduced pressure to obtain 15.77 g of pyrazole mercaptomethyl derivative with a purity of 87.9% and a yield of 79.6%.

[0054] Example 8

[0055] At room temperature, 13.93 g of 5-difluoromethoxy-4-chloromethyl-3-trifluoromethyl-1-methylpyrazole (purity 95%, 0.05 mol) was weighed and added to 60.0 mL of dichloromethane, 5.36 g of potassium bicarbonate was added, and then 7.38 g of ethyl 3-mercaptopropionate (0.055 mol) was slowly added dropwise. After the addition was completed, the temperature was raised to 35°C and kept for reaction for 2.0 h. After HPLC detection, the reaction was completed. 36.00 g of water was added to the reaction solution for washing, and then the pH was adjusted to neutral with 36% concentrated hydrochloric acid. The liquids were separated, and the obtained organic phase was concentrated under reduced pressure to obtain 16.10 g of pyrazole mercaptomethyl derivative with a purity of 88.0% and a yield of 78.2%.

[0056] LC-MS (ESI+): M+1=363.

[0057] Example 9

[0058] Under room temperature, 16.40 g of 5-difluoromethoxy-4-bromomethyl-3-trifluoromethyl-1-methylpyrazole (purity 94.2%, 0.05 mol) was weighed and added to 60.00 g of a mixed solution of dichloroethane and N,N-dimethylformamide in a mass ratio of 9:1, 6.36 g of a mixture of triethylamine and potassium carbonate in a mass ratio of 1:0.2 was added, and then 6.61 g of methyl 3-mercaptopropionate (0.055 mol) was slowly added dropwise. After the addition was completed, the temperature was raised to 60°C and the reaction was kept warm for 2.0 h. After HPLC detection, the reaction was completed, 36.00 g of water was added to the reaction solution for washing, and then the pH was adjusted to neutral with 36% concentrated hydrochloric acid, and the liquids were separated. The obtained organic phase was concentrated under reduced pressure to obtain 16.95 g of pyrazole thiomethyl derivative with a purity of 93.2% and a yield of 90.8%.

[0059] Example 10

[0060] At room temperature, 11.51 g of the thiomethylated pyrazole derivative prepared in Example 2 (purity 90.7%, 0.03 mol) was added to 60 mL of methanol and stirred to dissolve. Then, 10.80 g (0.06 mol) of a 30% sodium methoxide methanol solution was slowly added dropwise. After the addition was completed, the mixture was stirred at room temperature for 1 h before the HPLC control reaction was completed. 7.01 g of bromooxazole (purity 76.2%, 0.03 mol) was added dropwise. After the addition was completed, the temperature was raised to 40 ° C and the reaction was continued for 1.5 h before the HPLC control reaction was completed. The reaction solution was poured into ice water, stirred for 30 min, and concentrated under reduced pressure at 45 ° C until no fraction flowed out. Dichloromethane was added for extraction, the liquids were separated, the organic phases were combined, and concentrated under reduced pressure to obtain 10.92 g of a residue with a purity of 83.7% and a yield of 84.9%.

[0061] 8.59 g of the residue (purity 83.7%, 0.02 mol) was added to 30 mL of acetic acid, and 9.07 g of hydrogen peroxide (content 30%, 0.08 mol) was added. The mixture was heated to 80 ° C for 4.0 h. The reaction was controlled to be complete by HPLC. The reaction solution was cooled to -5~0 ° C for crystallization for 2.0 h and filtered to obtain 7.30 g of a white solid (pyraclostrobin) with a purity of 97.3% and a yield of 90.7%.

[0062] LC-MS (ESI+): M+1=392.

Claims

1. A method for preparing a pyrazole mercaptomethyl derivative, characterized in that: 5-difluoromethoxy-4-halomethyl-3-trifluoromethyl-1-methylpyrazole is used as a raw material and reacted with 3-mercaptopropionic acid ester under alkaline conditions to obtain a pyrazole mercaptomethyl derivative, the structural formula of the pyrazole mercaptomethyl derivative is shown in the following formula (I); ； In formula (I), R is a C1-C4 alkyl group.

2. The preparation method according to claim 1, characterized in that: In formula (I), R is a methyl group or an ethyl group.

3. The preparation method according to claim 1, characterized in that: 5-Difluoromethoxy-4-halomethyl-3-trifluoromethyl-1-methylpyrazole is 5-difluoromethoxy-4-chloromethyl-3-trifluoromethyl-1-methylpyrazole or 5-difluoromethoxy-4-bromomethyl-3-trifluoromethyl-1-methylpyrazole.

4. The preparation method according to claim 1, 2 or 3, characterized in that: The molar ratio of 5-difluoromethoxy-4-halomethyl-3-trifluoromethyl-1-methylpyrazole to 3-mercaptopropionic acid ester is 1:1.1-1.

3.

5. The preparation method according to claim 1, characterized in that: The alkaline condition is provided by an alkaline substance, and the alkaline substance is at least one of triethylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, potassium bicarbonate and sodium bicarbonate.

6. The preparation method according to claim 5, characterized in that: The alkaline substance is a mixture of triethylamine and potassium carbonate in a mass ratio of 1:0.2-0.

5.

7. The preparation method according to claim 5, characterized in that: The molar ratio of 5-difluoromethoxy-4-halomethyl-3-trifluoromethyl-1-methylpyrazole to the alkaline substance is 1:1.07-1.

2.

8. The preparation method according to claim 1, characterized in that: The reaction temperature of 5-difluoromethoxy-4-halomethyl-3-trifluoromethyl-1-methylpyrazole and 3-mercaptopropionic acid ester is 25°C to 60°C.

9. The preparation method according to claim 1, characterized in that: The reaction is carried out in the presence of an organic solvent.

10. The preparation method according to claim 9, characterized in that: The organic solvent is at least one of dichloromethane, chloroform, dichloroethane, N,N-dimethylformamide, tetrahydrofuran, methyl isobutyl ketone, acetonitrile and N-methylpyrrolidone.

11. The preparation method according to claim 10, characterized in that: The organic solvent is a mixture of ethylene dichloride and N,N-dimethylformamide in a mass ratio of 8-10:

1.

12. A method for preparing sulfonepyraclostrobin, characterized in that: The pyrazole thiomethyl derivative is prepared using the pyrazole thiomethyl derivative represented by formula (I) as an intermediate, and the pyrazole thiomethyl derivative is prepared according to the preparation method of the pyrazole thiomethyl derivative according to any one of claims 1 to 11; 。 13. The preparation method according to claim 12, characterized in that: The pyrazole thiomethyl derivative shown in formula (I) is hydrolyzed in a reaction system of sodium alcohol and alcohol to obtain pyrazole thiosodium salt, and then the pyrazole thiosodium salt undergoes a substitution reaction with 3-halogenated-5,5-dimethyl-4,5-dihydroisoxazole, and the reaction product is oxidized under the action of hydrogen peroxide to obtain sulfonepyraclostrobin.

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