Synthesis method of pyrazosulfuron intermediate

Abstract

The invention relates to the technical field of preparation of pesticide intermediates, and discloses a synthesis method of a pyrazosulfuron intermediate. The preparation method comprises the following steps: (1) in the presence of a palladium catalyst, alkali and an optional ligand, reacting a compound of formula (1) with carbon monoxide and 1, 3-dimethyl-5-hydroxypyrazole to obtain a compound of formula (2); and (2) reacting the compound shown in the formula (2) with sodium methyl mercaptide, and then carrying out oxidation reaction to obtain a compound shown in a formula (3). The intermediate (1, 3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy)) provided by the invention is used for further preparing the intermediate 1, 3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonyl benzoyloxy) of the sulfonamide, and the method is simple in process, moderate in reaction condition, simple in post-treatment and high in industrial practicability. # imgabs0 #

Description

Technical Field

[0001] The invention relates to the technical field of pesticide intermediate preparation, and in particular to a method for synthesizing a pyrasulfone intermediate. Background Art

[0002] Pyrasulfotole was developed by Bayer and launched on the market in 2007. As the first HPPD-inhibiting highly active systemic herbicide in cereal fields, it is mainly used to control dicotyledonous weeds in cereal crop fields in the late seedling stage.

[0003] At present, the synthesis of the key intermediate 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonylbenzoyloxy) (i.e., compound of formula (3)) of pyrazole is based on 4-trifluoromethyl-2-methylsulfonylbenzonitrile as raw material, which is subjected to hydrolysis reaction to obtain 4-trifluoromethyl-2-methylsulfonylbenzoic acid, which is then subjected to acylation reaction to obtain acyl chloride, and finally subjected to esterification reaction with 1,3-dimethyl-5-hydroxypyrazole to obtain the target intermediate 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonylbenzoyloxy) (i.e., compound of formula (3)). The reaction route is as follows:

[0004]

[0005] The above reaction route involves the following preparation methods:

[0006] Method 1: Prepare 4-trifluoromethyl-2-methylsulfonylbenzoic acid according to the method disclosed in CN112010793B: 4-trifluoromethyl-2-methylthiobenzonitrile is used as raw material, first oxidized and then hydrolyzed, and the two-step yield is about 95%. This method involves the oxidation reaction of nitrile under acidic conditions, and there may be a fatal danger of hydrocyanic acid in the process. Moreover, after the nitrile is hydrolyzed, a large amount of ammonia nitrogen wastewater exists in the reaction mother liquor, which damages the ecological environment, may cause eutrophication of water bodies and imbalance of water ecology, and even produce toxic effects on humans and organisms.

[0007] Method 2: CN105646356A discloses a method for preparing 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonylbenzoyloxy) (i.e., compound of formula (3)) using 4-trifluoromethyl-2-methylsulfonylbenzoic acid as a raw material, and the two-step crude product yield is about 84%. The acyl chloride reagent used in this method is thionyl chloride, which is used in a large amount. The post-reaction treatment requires a strict thionyl chloride removal process, which is not simple and will affect the reaction yield.

[0008] Method 3: CN1187335C discloses a method for preparing a homologue of formula (3): 1-ethyl-3-methyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonylbenzoyloxy) using 4-trifluoromethyl-2-methylsulfonylbenzoic acid as a raw material, with a crude product yield of 95%. This method requires the use of a dichloromethane solvent of about 250 times the mass of the product, and the product requires chromatography purification, which is not conducive to industrial production.

[0009] In summary, the existing preparation method of 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonylbenzoyloxy) (i.e., the compound of formula (3)) has the problems of using unfriendly acyl chloride reagents, long reaction steps, and relatively difficult synthesis and post-treatment processes, which makes it difficult to achieve industrialization. Summary of the invention

[0010] The purpose of the present invention is to overcome the problems existing in the prior art and provide a method for synthesizing a pyrasulfone intermediate.

[0011] In order to achieve the above-mentioned object, the first aspect of the present invention provides a method for synthesizing 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) represented by formula (2), wherein the compound of formula (1) is reacted with carbon monoxide and 1,3-dimethyl-5-hydroxypyrazole in the presence of a palladium catalyst, a base and an optional ligand to obtain a compound of formula (2);

[0012]

[0013] The second aspect of the present invention provides a method for synthesizing a pyrasulfone intermediate represented by formula (3), wherein the method comprises the following steps:

[0014] (1) obtaining a compound of formula (2) by the method described in the first aspect;

[0015] (2) reacting the compound of formula (2) with sodium methyl mercaptan, and then subjecting the compound of formula (3) to oxidation reaction;

[0016]

[0017] Through the above technical solution, the beneficial technical effects achieved by the present invention are as follows:

[0018] (1) The present invention uses 4-halogenated-3-nitro-trifluorotoluene as a raw material to obtain 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) through carbonyl insertion reaction and esterification reaction, thereby improving the carbonyl insertion efficiency with a simplified synthesis process and avoiding the generation of wastewater.

[0019] (2) The intermediate (1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy)) provided by the present invention is further used to prepare the sulfonylurea intermediate 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonylbenzoyloxy). This method has simple process, moderate reaction conditions, simple post-treatment, and strong industrial applicability.

[0020] (3) The present invention completely avoids the use of acyl chloride reagents, and has the advantages of fewer reaction steps, low cost, mild reaction conditions, relatively simple synthesis and post-treatment processes, and higher product yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonylbenzoyloxy) synthesized in Example 8 of the present invention 1 H NMR spectra. DETAILED DESCRIPTION

[0022] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0023] The first aspect of the present invention provides a method for synthesizing 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) represented by formula (2), wherein the compound of formula (1) is reacted with carbon monoxide and 1,3-dimethyl-5-hydroxypyrazole in the presence of a palladium catalyst, a base and an optional ligand to obtain a compound of formula (2);

[0024]

[0025] In the present invention, the compound of formula (1) is commercially available; 1,3-dimethyl-5-hydroxypyrazole can be prepared according to the methods provided in EP0240001 and CN101006092B, and is also commercially available.

[0026] The reaction route is as follows:

[0027]

[0028] In some embodiments of the present invention, in the compound of formula (1), X is chlorine, bromine or iodine, preferably bromine.

[0029] In some embodiments of the present invention, the palladium catalyst is selected from at least one of palladium acetate, bis(triphenylphosphine)palladium dichloride, 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride, trisdibenzylideneacetone dipalladium and tetrakis(triphenylphosphine)palladium.

[0030] In some embodiments of the present invention, the base is selected from at least one of sodium acetate, sodium carbonate, potassium carbonate, triethylamine and n-butylamine.

[0031] In some embodiments of the present invention, the ligand is selected from at least one of triphenylphosphine, 1,2-bis(diphenylphosphine)ethane and 1,3-bis(diphenylphosphine)propane.

[0032] In some embodiments of the present invention, the molar ratio of the 4-halogenated-3-nitro-trifluorotoluene to the palladium catalyst is 1:0.01-0.3, preferably 1:0.03-0.1.

[0033] In some embodiments of the present invention, the molar ratio of the 4-halogeno-3-nitro-trifluorotoluene to the base is 1:1.5-2.

[0034] In some embodiments of the present invention, the molar ratio of the 4-halogenated-3-nitro-trifluorotoluene to the ligand is 1:0.01-0.1.

[0035] In some embodiments of the present invention, the molar ratio of the 4-halogenated-3-nitro-trifluorotoluene to 1,3-dimethyl-5-hydroxypyrazole is 1:1.05-1.2, preferably 1:1.1.

[0036] In some embodiments of the present invention, the reaction temperature is 40-80°C, preferably 60-65°C.

[0037] In some embodiments of the present invention, the reaction time is 3-12 h, preferably 4-8 h, and more preferably 5 h.

[0038] In some embodiments of the present invention, the reaction pressure is 1-4 atm.

[0039] In some embodiments of the present invention, the reaction is carried out in a first solvent.

[0040] In some embodiments of the present invention, the first solvent is selected from at least one of dichloromethane, toluene, acetonitrile and DMF, preferably a mixed solvent of toluene and dichloromethane.

[0041] In some embodiments of the present invention, the ratio of toluene to dichloromethane in the mixed solvent is 8:2.

[0042] The second aspect of the present invention provides a method for synthesizing a pyrasulfone intermediate represented by formula (3), wherein the method comprises the following steps:

[0043] (1) obtaining a compound of formula (2) by the method described in the first aspect;

[0044] (2) reacting the compound of formula (2) with sodium methyl mercaptan, and then subjecting the compound of formula (3) to oxidation reaction;

[0045]

[0046] The reaction route of step (2) is as follows:

[0047]

[0048] The compound of formula (3) is the pyrazole intermediate 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonylbenzoyloxy).

[0049] In some embodiments of the present invention, the sodium methyl mercaptan in step (2) is a 20 wt % sodium methyl mercaptan aqueous solution.

[0050] In some embodiments of the present invention, the oxidant of the oxidation reaction is selected from at least one of hydrogen peroxide, sodium hypochlorite, oxygen and meta-chloroperbenzoic acid, preferably hydrogen peroxide.

[0051] In some embodiments of the present invention, the molar ratio of the compound of formula (2) to sodium methyl mercaptan is 1:1.1-1.5, preferably 1:1.3.

[0052] In some embodiments of the present invention, the molar ratio of the compound of formula (2) to the oxidant in the oxidation reaction is 1:2.5-3.5, preferably 1:3.

[0053] In some embodiments of the present invention, the reaction temperature of the compound of formula (2) and sodium methyl mercaptan is 60-80°C, preferably 70°C.

[0054] In some embodiments of the present invention, the temperature of the oxidation reaction is 70-85°C, preferably 80°C.

[0055] In some embodiments of the present invention, the reaction in step (2) is carried out in a second solvent.

[0056] In some embodiments of the present invention, the second solvent is selected from at least one of DMF, isopropanol, toluene and acetonitrile, preferably acetonitrile.

[0057] The present invention will be described in detail below through examples.

[0058] In the following examples and comparative examples, if no specific conditions are specified, the experiments were carried out under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used, if no manufacturer is specified, are all conventional products that can be obtained through commercial channels.

[0059] In the following examples, unless otherwise specified, all raw materials used are commercially available products.

[0060] In the following examples, unless otherwise specified, the concentrations are all in mass percentage.

[0061] In the following examples, yield = actual mass of product × content / theoretical mass of product.

[0062] Example 1

[0063] This example is used to illustrate the synthesis of 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) using 4-bromo-3-nitro-trifluorotoluene as a raw material.

[0064] At room temperature, 2.70 g (10 mmol) of 4-bromo-3-nitro-trifluorotoluene, 1.30 g (11 mmol, GC purity 95%) of 1,3-dimethyl-5-hydroxypyrazole and 8 g of DMF were added to a reaction steel bottle. After stirring for 10 min, 1.52 g (15 mmol) of triethylamine was added. The air in the reaction steel bottle was replaced with nitrogen three times. A dichloromethane solution (2 g of dichloromethane) of 0.26 g (1 mmol) of ligand triphenylphosphine and 0.67 g (3 mmol) of palladium acetate was added. Then, carbon monoxide was introduced into the reaction steel bottle. The pressure was maintained at 1 atm and the mixture was heated to 60° C. The reaction was carried out for 12 hours. HPLC detection showed that the raw material 4-bromo-3-nitro-trifluorotoluene was <10% (HPLC area %), and the product 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) was >40% (HPLC area %). After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and 7% wt hydrochloric acid was added dropwise to adjust the pH to 3. The mixture was extracted twice with ethyl acetate, separated, and the organic phase was evaporated under reduced pressure to obtain 1.38 g of a yellow solid with a content of 55.5% and a yield of 23.3%.

[0065] Example 2

[0066] This example is used to illustrate the synthesis of 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) using 4-bromo-3-nitro-trifluorotoluene as a raw material.

[0067] At room temperature, 2.70 g (10 mmol) of 4-bromo-3-nitro-trifluorotoluene, 1.30 g (11 mmol, GC purity 95%) of 1,3-dimethyl-5-hydroxypyrazole and 8 g of toluene were added to a reaction steel bottle. After stirring for 10 min, 1.52 g (15 mmol) of triethylamine was added. The air in the reaction steel bottle was replaced with nitrogen three times. A dichloromethane solution (2 g of dichloromethane) of 0.26 g (1 mmol) of ligand triphenylphosphine and 0.70 g (1 mmol) of bis(triphenylphosphine)palladium dichloride was added. Then, carbon monoxide was introduced into the reaction steel bottle. The pressure was maintained at 1 atm and the mixture was heated to 60° C. The reaction was carried out for 8 hours. HPLC detection showed that the raw material 4-bromo-3-nitro-trifluorotoluene was <10% (HPLC area %), and the product 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) was >55% (HPLC area %). After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and 7% wt hydrochloric acid was added dropwise to adjust the pH to 3. The mixture was extracted twice with ethyl acetate, separated, and the organic phase was evaporated under reduced pressure to obtain 1.84 g of a yellow solid with a content of 72.5% and a yield of 40.5%.

[0068] Example 3

[0069] This example is used to illustrate the synthesis of 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) using 4-bromo-3-nitro-trifluorotoluene as a raw material.

[0070] At room temperature, 2.70 g (10 mmol) of 4-bromo-3-nitro-trifluorotoluene, 1.30 g (11 mmol, GC purity 95%) of 1,3-dimethyl-5-hydroxypyrazole and 8 g of toluene were added to a reaction steel bottle. After stirring for 10 min, 1.52 g (15 mmol) of triethylamine was added. The air in the reaction steel bottle was replaced with nitrogen three times. A toluene solution of 0.35 g (0.3 mmol) of tetrakis(triphenylphosphine)palladium (2 g of toluene) was added. Then, carbon monoxide was introduced into the reaction steel bottle. The pressure was maintained at 1 atm and heated to 60° C. The reaction was carried out for 8 hours. HPLC detection showed that the raw material 4-bromo-3-nitro-trifluorotoluene was <5% (HPLC area %), and the product 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) was >50% (HPLC area %). After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and 7% wt hydrochloric acid was added dropwise to adjust the pH to 3. The mixture was extracted twice with ethyl acetate, separated, and the organic phase was evaporated under reduced pressure to obtain 1.92 g of a yellow solid with a content of 73.1% and a yield of 42.6%.

[0071] Example 4

[0072] This example is used to illustrate the synthesis of 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) using 4-bromo-3-nitro-trifluorotoluene as a raw material.

[0073] At room temperature, 2.70 g (10 mmol) of 4-bromo-3-nitro-trifluorotoluene, 1.30 g (11 mmol, GC purity 95%) of 1,3-dimethyl-5-hydroxypyrazole and 8 g of toluene were added to a reaction steel bottle. After stirring for 10 min, 1.52 g (15 mmol) of triethylamine was added. The air in the reaction steel bottle was replaced with nitrogen three times. A toluene solution of 0.35 g (0.3 mmol) of tetrakis(triphenylphosphine)palladium (2 g of toluene) was added. Then, carbon monoxide was introduced into the reaction steel bottle. The pressure was maintained at 4 atm and the temperature was heated to 80° C. The reaction was carried out for 5 hours. HPLC detection showed that the raw material 4-bromo-3-nitro-trifluorotoluene was <5% (HPLC area %), and the product 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) was >60% (HPLC area %). After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and 7% wt hydrochloric acid was added dropwise to adjust the pH to 3. The solution was extracted twice with ethyl acetate, separated, and the organic phase was evaporated under reduced pressure to obtain 2.31 g of a yellow solid with a content of 84.6% and a yield of 59.35%.

[0074] Example 5

[0075] This example is used to illustrate the synthesis of 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) using 4-bromo-3-nitro-trifluorotoluene as a raw material.

[0076] At room temperature, 2.70 g (10 mmol) of 4-bromo-3-nitro-trifluorotoluene, 1.30 g (11 mmol, GC purity 95%) of 1,3-dimethyl-5-hydroxypyrazole and 8 g of toluene were added to a reaction steel bottle. After stirring for 10 min, 1.52 g (15 mmol) of triethylamine was added. The air in the reaction steel bottle was replaced with nitrogen three times. A dichloromethane solution (2 g of dichloromethane) of 0.26 g (1 mmol) of ligand triphenylphosphine and 0.70 g (1 mmol) of bis(triphenylphosphine)palladium dichloride was added. Then, carbon monoxide was introduced into the reaction steel bottle. The pressure was maintained at 4 atm and the mixture was heated to 80° C. The reaction was carried out for 5 hours. HPLC detection showed that the raw material 4-bromo-3-nitro-trifluorotoluene was <1% (HPLC area %), and the product 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) was >85% (HPLC area %). After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and 7% wt hydrochloric acid was added dropwise to adjust the pH to 3. The mixture was extracted twice with ethyl acetate, separated, and the organic phase was evaporated under reduced pressure to obtain 2.49 g of a yellow solid with a content of 82.8% and a yield of 62.6%.

[0077] Example 6

[0078] This example is used to illustrate the synthesis of 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) using 4-bromo-3-nitro-trifluorotoluene as a raw material.

[0079] At room temperature, 2.70 g (10 mmol) of 4-bromo-3-nitro-trifluorotoluene, 1.30 g (11 mmol, GC purity 95%) of 1,3-dimethyl-5-hydroxypyrazole and 8 g of toluene were added to a reaction steel bottle. After stirring for 10 min, 2.76 g (20 mmol) of potassium carbonate was added. The air in the reaction steel bottle was replaced with nitrogen three times. A dichloromethane solution (2 g of dichloromethane) of 0.40 g (1 mmol) of ligand 1,2-bis(diphenylphosphino)ethane and 0.21 g (0.3 mmol) of di(triphenylphosphine)palladium dichloride was added. Then, carbon monoxide was introduced into the reaction steel bottle. The pressure was maintained at 4 atm and the reaction was heated to 80° C. The reaction was carried out for 3 hours. HPLC detection showed that the raw material 4-bromo-3-nitro-trifluorotoluene was <1% (HPLC area %), and the product 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) was >88% (HPLC area %). After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and 7% wt hydrochloric acid was added dropwise to adjust the pH to 3. The mixture was extracted twice with ethyl acetate, separated, and the organic phase was evaporated under reduced pressure to obtain 2.68 g of a yellow solid with a content of 86.8% and a yield of 70.6%.

[0080] Example 7

[0081] This example is used to illustrate the synthesis of 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) using 4-bromo-3-nitro-trifluorotoluene as a raw material.

[0082] At room temperature, 2.70 g (10 mmol) of 4-bromo-3-nitro-trifluorotoluene, 1.30 g (11 mmol, GC purity 95%) of 1,3-dimethyl-5-hydroxypyrazole and 8 g of toluene were added to a reaction steel bottle. After stirring for 10 min, 2.76 g (20 mmol) of potassium carbonate was added. The air in the reaction steel bottle was replaced with nitrogen three times. A dichloromethane solution (2 g of dichloromethane) of 0.40 g (1 mmol) of ligand 1,2-bis(diphenylphosphino)ethane and 0.21 g (0.3 mmol) of di(triphenylphosphine)palladium dichloride was added. Then, carbon monoxide was introduced into the reaction steel bottle. The pressure was maintained at 4 atm and the temperature was heated to 65° C. The reaction was carried out for 4 hours. HPLC detection showed that the raw material 4-bromo-3-nitro-trifluorotoluene was <1% (HPLC area %), and the product 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) was >90% (HPLC area %). After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and 7% wt hydrochloric acid was added dropwise to adjust the pH to 3. The mixture was extracted twice with ethyl acetate, separated, and the organic phase was evaporated under reduced pressure to obtain 2.76 g of a yellow solid with a content of 86.5% and a yield of 72.5%.

[0083] Example 8

[0084] This example is used to illustrate the synthesis of 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonylbenzoyloxy) using 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) as a raw material.

[0085] At room temperature, 2.0 g (5.1 mmol, AR purity 85%) of 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) and 10 g of acetonitrile were added to a four-necked reaction bottle. After stirring for 10 min, 2.32 g (6.6 mmol) of 20 wt% sodium methyl mercaptan aqueous solution was added. The temperature was raised to 70 ° C and the reaction was carried out for 6 h. HPLC detection of raw material 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) was less than 7%. (HPLC area %), the reaction solution was cooled to 50°C, 2.02g (17.85mmol) of 30% hydrogen peroxide was added dropwise, and the temperature was raised to 80°C for 4h. The product 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonylbenzoyloxy) was detected by HPLC>89% (HPLC area %). After the reaction was completed, 50g of water was added to the reaction solution, cooled to 0°C for crystallization, filtered, and dried to obtain 1.63g of yellow crude product, with a content of 90.1% and a yield of 79.5%. After column chromatography with dichloromethane / petroleum ether (v / v=2:1), crystallization was performed to obtain the product 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonylbenzoyloxy) with a content of 99%, as a yellow solid, 1H NMR (400MHz, Chloroform-d) δ8.40(s,1H),8.01-7.93(m,2H),6.00(s,1H),3.66(s,3H),3.32(s,3H),2.21(s,3H).

[0086] Example 9

[0087] This example is used to illustrate the synthesis of 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonylbenzoyloxy) using 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) as a raw material.

[0088] At room temperature, 2.0 g (5.1 mmol, 85% purity) of 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) and 10 g of acetonitrile were added to a four-necked reaction bottle. After stirring for 10 min, 2.32 g (6.6 mmol) of 20 wt% sodium methyl mercaptan aqueous solution and 0.5 g (1.8 mmol) of tetrabutylammonium chloride were added. The temperature was raised to 70 ° C and the reaction was carried out for 6 h. The raw material 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) was detected by HPLC. The reaction mixture was cooled to 50°C, 2.02 g (17.85 mmol) of 30% hydrogen peroxide was added dropwise, and the mixture was heated to 80°C for 4 h. The product 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonylbenzoyloxy) was detected by HPLC to be >95% (HPLC area %). After the reaction was completed, 50 g of water was added to the reaction mixture, which was cooled to 0°C for crystallization, filtered, and dried to obtain 1.75 g of a yellow crude product with a content of 95.2% and a yield of 90.1%.

[0089] Example 10

[0090] This example is used to illustrate the synthesis of 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonylbenzoyloxy) using 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) as a raw material.

[0091] At room temperature, 2.0 g (5.1 mmol, 85% purity) of 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) and 10 g of acetonitrile were added to a four-necked reaction bottle. After stirring for 10 min, 2.32 g (6.6 mmol) of 20 wt% sodium methyl mercaptan aqueous solution was added. The temperature was raised to 70 ° C and reacted for 6 h. HPLC detection of raw material 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) was less than 7% (HPLC purity). C area %), the reaction solution was cooled to 50°C, 2.02 g (17.85 mmol) of 30% hydrogen peroxide was added dropwise and the reaction was carried out for 2 h, the temperature was raised to 80°C and the reaction was carried out for 2 h, HPLC detection of the product 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonylbenzoyloxy)>93% (HPLC area %), the reaction was completed, 50 g of water was added to the reaction solution, cooled to 0°C for crystallization, filtered, and dried to obtain 1.78 g of a yellow crude product with a content of 93.5% and a yield of 90.1%.

[0092] Embodiment 11

[0093] This example is used to illustrate the synthesis of 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonylbenzoyloxy) using 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) as a raw material.

[0094] At room temperature, 2.0 g (5.1 mmol, 85% purity) of 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) and 10 g of acetonitrile were added to a four-necked reaction bottle. After stirring for 10 min, 2.32 g (6.6 mmol) of 20 wt% sodium methyl mercaptan aqueous solution and 0.5 g (1.8 mmol) of tetrabutylammonium chloride were added. The temperature was raised to 70 ° C and the reaction was carried out for 6 h. The raw material 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) was detected by HPLC. The reaction solution was cooled to 50°C, 2.02 g (17.85 mmol) of 30% hydrogen peroxide was added dropwise and the reaction was carried out for 2 h. The temperature was raised to 80°C and the reaction was carried out for 2 h. HPLC detected the product 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonylbenzoyloxy)>98% (HPLC area %). After the reaction was completed, 50 g of water was added to the reaction solution, which was cooled to 0°C for crystallization, filtered and dried to obtain 1.83 g of a yellow crude product with a content of 96.2% and a yield of 95.3%.

[0095] Example 12

[0096] This example is used to illustrate the synthesis of 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonylbenzoyloxy) using 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) as a raw material.

[0097] At room temperature, 2.0 g (5.1 mmol, 85% purity) of 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) and 10 g of acetonitrile were added to a four-necked reaction bottle. After stirring for 10 min, 2.32 g (6.6 mmol) of 20 wt% sodium methyl mercaptan aqueous solution and 0.5 g (1.8 mmol) of tetrabutylammonium chloride were added. The temperature was raised to 70°C and the reaction was carried out for 6 h. HPLC detected that the raw material 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) was <1% (HPLC area %). The reaction The liquid was cooled to 50°C, 1.01 g (8.93 mmol) of 30% hydrogen peroxide was added dropwise, and the mixture was reacted for 1 h. The temperature was then raised to 55°C, 1.01 g (8.93 mmol) of 30% hydrogen peroxide was added dropwise, and the mixture was reacted for 1 h. The temperature was finally raised to 80°C, and the mixture was reacted for 2 h. HPLC detection showed that the product 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonylbenzoyloxy) was >99% (HPLC area %). The reaction was completed. 50 g of water was added to the reaction solution, and the mixture was cooled to 0°C for crystallization. The mixture was filtered and dried to obtain 1.85 g of a yellow crude product with a content of 98% and a yield of 98.1%.

[0098] Embodiment 13

[0099] This example is used to illustrate the synthesis of 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonylbenzoyloxy) using 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) as a raw material.

[0100] At room temperature, 2.0 g (5.1 mmol, 85% purity) of 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) and 10 g of acetonitrile were added to a four-necked reaction bottle. After stirring for 10 min, 2.32 g (6.6 mmol) of 20 wt% sodium methyl mercaptan aqueous solution and 0.5 g (1.8 mmol) of tetrabutylammonium chloride were added. The temperature was raised to 70 ° C and the reaction was carried out for 6 h. The raw material 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) was detected by HPLC. The reaction mixture was cooled to 50°C, 13.28 g (17.85 mmol) of 10% sodium hypochlorite was added dropwise and the mixture was reacted for 2 h. The mixture was heated to 80°C and reacted for 2 h. HPLC detected the product 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonylbenzoyloxy)>92% (HPLC area %). After the reaction was completed, 50 g of water was added to the reaction mixture, which was cooled to 0°C for crystallization, filtered and dried to obtain 1.53 g of a yellow crude product with a content of 85.1% and a yield of 70.5%.

[0101] Comparative Example 1

[0102] The existing synthesis method for preparing 4-trifluoromethyl-2-methylsulfonylbenzoic acid using 4-chloro-3-nitro-trifluorotoluene as raw material is as follows:

[0103] At 0°C, 2.28 g (10 mmol) of 4-chloro-3-nitro-trifluorotoluene, 1.07 g (12 mmol) of cuprous cyanide, 0.48 g (4 mmol) of potassium bromide and 4 g of dimethyl sulfoxide were added to a reaction flask, and the temperature was raised to 150°C under stirring, and the reaction was kept warm for 5 hours. The product 2-nitro-4-trifluoromethylbenzonitrile was detected by HPLC and was >97% (HPLC area %), and dimethyl sulfoxide was removed under reduced pressure, 5 g of toluene was added, and the inorganic salt was recovered by filtration, the mother liquor was collected, and toluene was recovered under reduced pressure. 0.20 g of 2-nitro-4-trifluoromethylbenzonitrile was obtained by rectification under reduced pressure, with a content of 99.2% and a yield of 92.1%.

[0104] At 0°C, 5.0 g (23.13 mmol) of 2-nitro-4-trifluoromethylbenzonitrile and DMF (20 mL) were added to the reaction bottle, and 12.16 g (34.7 mmol) of 20 wt% sodium methyl mercaptan aqueous solution was slowly added dropwise. After the addition was complete, the mixture was reacted at room temperature for 1 h. The reaction was monitored by TLC to be complete. 100 g of water was added to the reaction solution, and 4.85 g of 2-methylthio-4-trifluoromethylbenzonitrile as a yellow solid was obtained by filtration, with a crude yield of 96.0%.

[0105] At room temperature, 5.10 g (23.0 mmol, content 98%) of 2-methylthio-4-trifluoromethylbenzonitrile and 15.4 g of toluene were added to the reaction bottle, 10.48 g (92.52 mmol) of 30% hydrogen peroxide was added dropwise, and the temperature was raised to 75°C for reaction for 3 h. HPLC detection of the raw material 2-methylthio-4-trifluoromethylbenzonitrile was <1% (HPLC area %), and then 6.17 g (4 6.3mmol), kept at 80℃ for 8 hours, the alkaline hydrolysis reaction was completed, then cooled to room temperature and allowed to stand for stratification, 5.62g (55.51mmol) of 36wt% hydrochloric acid was added dropwise to the aqueous phase to precipitate a solid, which was filtered to obtain 4.96g of a crude white solid 4-trifluoromethyl-2-methylsulfonylbenzoic acid with a content of 96%. The yield was 95.4% based on 2-methylthio-4-trifluoromethylbenzonitrile, and the linear yield was 91.6% based on 2-nitro-4-trifluoromethylbenzonitrile.

[0106] It was calculated that the linear yield of 4-trifluoromethyl-2-methylsulfonylbenzoic acid was 84.4% based on 4-chloro-3-nitro-trifluorotoluene as the raw material.

[0107] Comparative Example 2

[0108] At room temperature, 54 g (0.2 mol) of 4-trifluoromethyl-2-methylsulfonylbenzoic acid and 328 g of thionyl chloride (2.76 mol) were added to a reaction flask, heated to reflux, and the reaction was completed in 4 hours. The excess thionyl chloride was evaporated under reduced pressure to obtain 50 g of the product 4-trifluoromethyl-2-methylsulfonylbenzoyl chloride.

[0109] Under ice bath, 50g of 4-trifluoromethyl-2-methylsulfonylbenzoyl chloride was dissolved in 397.5g (4.68mol) of dichloromethane, and then 24.7g (0.21mol, GC purity 95%) of 1,3-dimethyl-5-hydroxypyrazole and 24.2g (0.24mol) of triethylamine were added. The mixture was reacted at room temperature for 2 hours, 50g of water was added, and the mixture was allowed to stand for separation. The aqueous phase was extracted with dichloromethane, and the organic phases were combined, dried, concentrated, and recrystallized to obtain 61g of 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonylbenzoyloxy).

[0110] After calculation, based on 4-trifluoromethyl-2-methylsulfonylbenzoic acid as the raw material, the yield of 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonylbenzoyloxy) was 83.6%.

[0111] Combined with Comparative Example 1, based on 4-chloro-3-nitro-trifluorotoluene as the raw material, the linear yield of 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonylbenzoyloxy) was 70.5%.

[0112] Comparative Example 3

[0113] At room temperature, 2.70 g (10 mmol) of 4-bromo-3-nitro-trifluorotoluene, 1.30 g (11 mmol, GC purity 95%) of 1,3-dimethyl-5-hydroxypyrazole and 8 g of DMF were added to a reaction bottle. After stirring for 10 min, 1.52 g (15 mmol) of triethylamine was added. The air in the reaction bottle was replaced with nitrogen three times. Carbon monoxide was introduced into the reaction bottle. The pressure was maintained at 1 atm and heated to 60° C. The reaction was carried out for 12 hours. HPLC detection showed that the raw material 4-bromo-3-nitro-trifluorotoluene was >80% (HPLC area %), and the product 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) was <3% (HPLC area %).

[0114] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims

1. A method for synthesizing 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) represented by formula (2), characterized in that: In the presence of a palladium catalyst, a base and an optional ligand, reacting the compound of formula (1) with carbon monoxide and 1,3-dimethyl-5-hydroxypyrazole to obtain a compound of formula (2); 2. The synthesis method according to claim 1, characterized in that In the compound of formula (1), X is chlorine, bromine or iodine, preferably bromine; Preferably, the palladium catalyst is selected from at least one of palladium acetate, bis(triphenylphosphine)palladium dichloride, 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride, tris(dibenzylideneacetone)dipalladium and tetrakis(triphenylphosphine)palladium; Preferably, the base is selected from at least one of sodium acetate, sodium carbonate, potassium carbonate, triethylamine and n-butylamine; Preferably, the ligand is selected from at least one of triphenylphosphine, 1,2-bis(diphenylphosphine)ethane and 1,3-bis(diphenylphosphine)propane.

3. The synthesis method according to claim 1 or 2, characterized in that The molar ratio of the 4-halogenated-3-nitro-trifluorotoluene to the palladium catalyst is 1:0.01-0.3, preferably 1:0.03-0.1; Preferably, the molar ratio of the 4-halogenated-3-nitro-trifluorotoluene to the base is 1:1.5-2; Preferably, the molar ratio of the 4-halogenated-3-nitro-trifluorotoluene to the ligand is 1:0.01-0.1; Preferably, the molar ratio of the 4-halogenated-3-nitro-trifluorotoluene to 1,3-dimethyl-5-hydroxypyrazole is 1:1.05-1.2, preferably 1:1.

1.

4. The synthesis method according to any one of claims 1 to 3, characterized in that The reaction temperature is 40-80°C, preferably 60-65°C; Preferably, the reaction time is 3-12 h, preferably 4-8 h, and more preferably 5 h; Preferably, the reaction pressure is 1-4 atm.

5. The synthesis method according to any one of claims 1 to 4, characterized in that The reaction is carried out in a first solvent; Preferably, the first solvent is selected from at least one of dichloromethane, toluene, acetonitrile and DMF, preferably a mixed solvent of toluene and dichloromethane; Preferably, the ratio of toluene to dichloromethane in the mixed solvent is 8:

2.

6. A method for synthesizing a pyrasulfone intermediate represented by formula (3), characterized in that: The method comprises the following steps: (1) obtaining a compound of formula (2) by the method according to any one of claims 1 to 5; (2) reacting the compound of formula (2) with sodium methyl mercaptan, and then subjecting the compound of formula (3) to oxidation reaction; 7. The method according to claim 6, characterized in that The sodium methyl mercaptan described in step (2) is a 20wt% sodium methyl mercaptan aqueous solution; Preferably, the oxidant of the oxidation reaction is selected from at least one of hydrogen peroxide, sodium hypochlorite, oxygen and meta-chloroperbenzoic acid, preferably hydrogen peroxide.

8. The method according to claim 6 or 7, characterized in that: The molar ratio of the compound of formula (2) to sodium methyl mercaptan is 1:1.1-1.5, preferably 1:1.3; Preferably, the molar ratio of the compound of formula (2) to the oxidant in the oxidation reaction is 1:2.5-3.5, preferably 1:

3.

9. The method according to any one of claims 6 to 8, characterized in that: The reaction temperature of the compound of formula (2) and sodium methyl mercaptan is 60-80°C, preferably 70°C; Preferably, the temperature of the oxidation reaction is 70-85°C, preferably 80°C.

10. The method according to any one of claims 6 to 9, characterized in that: The reaction in step (2) is carried out in a second solvent; Preferably, the second solvent is selected from at least one of DMF, isopropanol, toluene and acetonitrile, preferably acetonitrile.

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