Process for the synthesis of sulfonyl pyrazole intermediates

Abstract

The application relates to the technical field of pesticide intermediate preparation, and discloses a synthesis method of a sulfonyl pyrazole intermediate.(1) A compound shown as formula (1) is reacted with carbon monoxide, 1,3-dimethyl-5-hydroxypyrazole in the presence of a palladium catalyst, a base and an optional ligand to obtain a compound shown as formula (2); (2) the compound shown as formula (2) is reacted with sodium thiomethoxide, and then subjected to an oxidation reaction to obtain a compound shown as formula (3). The intermediate (1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy)) provided by the application is further used to prepare a sulfonyl pyrazole intermediate 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonylbenzoyloxy), and the method has the advantages of simple process, moderate reaction condition, simple post-treatment and strong industrial practicability.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pesticide intermediate preparation, and particularly relates to a synthesis method of a pyrasulfotole intermediate. BACKGROUND

[0002] Pyrasulfotole is developed by Bayer and listed in 2007, which is the first HPPD inhibitor with high activity in cereal fields, and is mainly used for controlling dicotyledonous weeds in the post-emergence stage of cereal crops.

[0003] At present, the synthesis of the key intermediate 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonylbenzoyloxy) (i.e., the compound of formula (3)) of pyrasulfotole is as follows: 4-trifluoromethyl-2-methylsulfonylbenzonitrile is used as a raw material, 4-trifluoromethyl-2-methylsulfonylbenzoic acid is obtained through a hydrolysis reaction, acyl chloride is obtained through an acylation reaction, and finally the esterification reaction of 1,3-dimethyl-5-hydroxypyrazole occurs to obtain the target intermediate 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonylbenzoyloxy) (i.e., the compound of formula (3)), and the reaction route is as follows:

[0004]

[0005] The preparation method involved in the above reaction route mainly includes the following methods:

[0006] Method one: 4-trifluoromethyl-2-methylsulfonylbenzoic acid is prepared according to the method disclosed in CN112010793B: 4-trifluoromethyl-2-methylsulfonylbenzonitrile is used as a raw material, and then oxidation and hydrolysis are carried out, and the two-step yield is about 95%. The method involves the oxidation reaction of nitrile under acidic conditions, and there is a fatal danger of hydrogen cyanide in the process. In addition, after the hydrolysis of nitrile, there is a large amount of ammonia-nitrogen wastewater in the reaction mother liquor, which destroys the ecological environment, may cause eutrophication and ecological imbalance of water, and even has toxic effects on humans and organisms.

[0007] Method two: CN105646356A discloses a method for preparing 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonylbenzoyloxy) (i.e., the 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 the method is thionyl chloride, the usage amount is large, and a strict thionyl chloride removal process is required after the reaction, which is not simple to operate and also affects the reaction yield.

[0008] Method three: CN1187335C discloses a method for preparing the homolog of formula (3) 1-ethyl-3-methyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonyl benzoyloxy) using 4-trifluoromethyl-2-methylsulfonylbenzoic acid as raw material, and the yield of the crude product is 95%. The method needs to use about 250 times of product mass of dichloromethane solvent, and the product needs to be purified by chromatography, which is not conducive to industrial production.

[0009] In summary, in the existing preparation method of 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonyl benzoyloxy) (i.e. the compound of formula (3)), there are problems such as the use of an unfriendly acyl chloride reagent, a long reaction step, and relatively difficult synthesis and post-processing process, and the industrialization is difficult to realize. SUMMARY

[0010] The purpose of the present application is to overcome the problems existing in the prior art, and to provide a synthesis method of a sulfonyl grass pyrazole intermediate.

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

[0012]

[0013] The second aspect of the present application provides a synthesis method of a sulfonyl grass pyrazole intermediate shown in formula (3), wherein the method comprises the following steps:

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

[0015] (2) reacting the compound of formula (2) with sodium methyl mercaptide, and then performing an oxidation reaction to obtain the compound of formula (3);

[0016]

[0017] Through the above technical solutions, the present application has the following beneficial technical effects:

[0018] (1) The present application uses 4-halogen-3-nitro-trifluorotoluene as raw material to obtain 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) through carbonyl insertion reaction and esterification reaction, which simplifies the synthesis process, improves the carbonyl insertion efficiency, and avoids the generation of waste water.

[0019] (2) The intermediate (1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy)) provided by the application is further used to prepare the sulfonamide pyrazole intermediate 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonylbenzoyloxy), which has the advantages of simple process, moderate reaction condition, simple post-treatment, strong industrial practicability, and the like.

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

[0021] Figure 1 H NMR chart of 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonylbenzoyloxy) synthesized for Example 8 of the application. 1 H NMR chart. DETAILED DESCRIPTION

[0022] The endpoints of the ranges and any values disclosed herein are not limited to the precise values stated. The endpoints of the ranges and the values are approximate values and should be understood to include values approximately the same as the stated values. For ranges, the endpoints are included in the ranges, and the ranges are inclusive of the single values therein. For values, the value is inclusive of the single value.

[0023] The first aspect of the application provides a synthesis method of 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) shown in formula (2), wherein a 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 application, the compound of formula (1) can be commercially available; the 1,3-dimethyl-5-hydroxypyrazole can be prepared according to the method provided in EP0240001 and CN101006092B, and can also be commercially available.

[0026] The reaction route is as follows:

[0027]

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

[0029] In some embodiments of the present application, the palladium catalyst is selected from at least one of palladium acetate, dichlorobis(triphenylphosphine)palladium, 1,1'- bis(diphenylphosphino)ferrocene dichloropalladium, tris(dibenzylideneacetone)dipalladium and tetrakis(triphenylphosphine)palladium.

[0030] In some embodiments of the present application, 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 application, the ligand is selected from at least one of triphenylphosphine, 1,2-bis(diphenylphosphino)ethane and 1,3- bis(diphenylphosphino)propane.

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

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

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

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

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

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

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

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

[0040] In some embodiments of the present application, 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 application, the ratio of toluene and dichloromethane in the mixed solvent is 8:2.

[0042] The second aspect of the present application provides a method for synthesizing a sulfonyl pyrazole intermediate of formula (3), wherein the method comprises the following steps:

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

[0044] (2) reacting the compound of formula (2) with sodium thiomethoxide, and then performing an oxidation reaction to obtain a compound of formula (3);

[0045]

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

[0047]

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

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

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

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

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

[0053] In some embodiments of the present application, the reaction temperature of the compound of formula (2) and sodium thiomethoxide is 60-80℃, and is preferably 70℃.

[0054] In some embodiments of the present application, the temperature of the oxidation reaction is 70-85℃, and is preferably 80℃.

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

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

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

[0058] The following examples and comparative examples were carried out under ordinary conditions or under conditions recommended by the manufacturer unless otherwise specified. The reagents or instruments used were all conventional products available on the market unless otherwise specified.

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

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

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

[0062] Example 1

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

[0064] Into a reaction cylinder, 4-bromo-3-nitro-trifluoromethylbenzene 2.70 g (10 mmol), 1,3-dimethyl-5-hydroxypyrazole 1.30 g (11 mmol, GC purity 95%) and 8 g of DMF were added at room temperature, and stirred for 10 min. Then, triethylamine 1.52 g (15 mmol) was added, and the reaction cylinder was replaced with nitrogen three times. A solution of ligand triphenylphosphine 0.26 g (1 mmol) and palladium acetate 0.67 g (3 mmol) in dichloromethane (2 g) was added, and then carbon monoxide was introduced into the reaction cylinder. The pressure was maintained at 1 atm, and the temperature was raised to 60°C. The reaction was carried out for 12 hours. HPLC analysis showed that the raw material 4-bromo-3-nitro-trifluoromethylbenzene 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 adjusted to pH = 3 by dropwise addition of 7% wt hydrochloric acid. The organic phase was extracted twice with ethyl acetate, and then distilled off under reduced pressure. A yellow solid 1.38 g was obtained, which had a content of 55.5% and a yield of 23.3%.

[0065] Example 2

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

[0067] Into a reaction bomb was added 4-bromo-3-nitro-trifluorotoluene 2.70 g (10 mmol), 1,3-dimethyl-5-hydroxypyrazole 1.30 g (11 mmol, GC purity 95%) and 8 g of toluene at room temperature, after stirring for 10 min was added triethylamine 1.52 g (15 mmol), the reaction bomb was purged with nitrogen three times with air, a solution of ligand triphenylphosphine 0.26 g (1 mmol) and palladium bis(triphenylphosphine) dichloride 0.70 g (1 mmol) in dichloromethane (2 g of dichloromethane) was added, then the reaction bomb was purged with carbon monoxide, the pressure was maintained at 1 atm, heating to 60°C, the reaction was carried out for 8 hours, HPLC detection of starting material 4-bromo-3-nitro-trifluorotoluene <10% (HPLC area %), product 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) > 55% (HPLC area %). At the end of the reaction, the reaction liquid was cooled to room temperature, filtered, pH = 3 was adjusted by dropwise addition of 7% wt hydrochloric acid, extracted twice with ethyl acetate, separated, the organic phase was removed under reduced pressure, obtaining a yellow solid 1.84 g, content 72.5%, yield 40.5%.

[0068] Example 3

[0069] This example is intended to illustrate the synthesis of 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) starting from 4-bromo-3-nitro-trifluorotoluene.

[0070] Into a reaction bomb was added 4-bromo-3-nitro-trifluorotoluene 2.70 g (10 mmol), 1,3-dimethyl-5-hydroxypyrazole 1.30 g (11 mmol, GC purity 95%) and 8 g of toluene at room temperature, after stirring for 10 min was added triethylamine 1.52 g (15 mmol), the reaction bomb was purged with nitrogen three times with air, a solution of ligand triphenylphosphine 0.26 g (1 mmol) and palladium bis(triphenylphosphine) dichloride 0.70 g (1 mmol) in dichloromethane (2 g of dichloromethane) was added, then the reaction bomb was purged with carbon monoxide, the pressure was maintained at 1 atm, heating to 60°C, the reaction was carried out for 8 hours, HPLC detection of starting material 4-bromo-3-nitro-trifluorotoluene <10% (HPLC area %), product 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) > 55% (HPLC area %). At the end of the reaction, the reaction liquid was cooled to room temperature, filtered, pH = 3 was adjusted by dropwise addition of 7% wt hydrochloric acid, extracted twice with ethyl acetate, separated, the organic phase was removed under reduced pressure, obtaining a yellow solid 1.84 g, content 72.5%, yield 40.5%.

[0071] Example 4

[0072] This example is intended to illustrate the synthesis of 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) starting from 4-bromo-3-nitro-trifluorotoluene.

[0073] At room temperature, in a reaction bomb was added 4-bromo-3-nitro-trifluorotoluene 2.70 g (10 mmol), 1,3-dimethyl-5-hydroxypyrazole 1.30 g (11 mmol, GC purity 95%) and 8 g of toluene, after stirring for 10 min was added triethylamine 1.52 g (15 mmol), the reaction bomb was replaced with nitrogen three times with air, was added a solution of ligand triphenylphosphine 0.26 g (1 mmol) and palladium dichloride bis(triphenylphosphine) 0.70 g (1 mmol) in dichloromethane (2 g of dichloromethane), then the reaction bomb was connected to a carbon monoxide cylinder, the pressure was kept at 4 atm, heating to 80°C, the reaction was carried out for 5 hours, HPLC detection of starting material 4-bromo-3-nitro-trifluorotoluene < 1% (HPLC area %), product 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) > 85% (HPLC area %). At the end of the reaction, the reaction liquid was cooled to room temperature, filtered, pH was adjusted to 3 by dropwise addition of 7% wt hydrochloric acid, extracted twice with ethyl acetate, separated, the organic phase was removed under reduced pressure, obtaining a yellow solid 2.49 g, content 82.8%, yield 62.6%.

[0074] Example 5

[0075] This example is intended to illustrate the synthesis of 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) starting from 4-bromo-3-nitro-trifluorotoluene.

[0076] At room temperature, in a reaction bomb was added 4-bromo-3-nitro-trifluorotoluene 2.70 g (10 mmol), 1,3-dimethyl-5-hydroxypyrazole 1.30 g (11 mmol, GC purity 95%) and 8 g of toluene, after stirring for 10 min was added triethylamine 1.52 g (15 mmol), the reaction bomb was replaced with nitrogen three times with air, was added a solution of ligand triphenylphosphine 0.26 g (1 mmol) and palladium dichloride bis(triphenylphosphine) 0.70 g (1 mmol) in dichloromethane (2 g of dichloromethane), then the reaction bomb was connected to a carbon monoxide cylinder, the pressure was kept at 4 atm, heating to 80°C, the reaction was carried out for 5 hours, HPLC detection of starting material 4-bromo-3-nitro-trifluorotoluene < 1% (HPLC area %), product 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) > 85% (HPLC area %). At the end of the reaction, the reaction liquid was cooled to room temperature, filtered, pH was adjusted to 3 by dropwise addition of 7% wt hydrochloric acid, extracted twice with ethyl acetate, separated, the organic phase was removed under reduced pressure, obtaining a yellow solid 2.49 g, content 82.8%, yield 62.6%.

[0077] Example 6

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

[0079] Into a reaction bomb was added 4-bromo-3-nitro-trifluoromethylbenzene 2.70 g (10 mmol), 1,3-dimethyl-5-hydroxypyrazole 1.30 g (11 mmol, GC purity 95%) and 8 g of toluene at room temperature, after stirring for 10 min, potassium carbonate 2.76 g (20 mmol) was added, the reaction bomb was purged with nitrogen three times with air, ligand 1,2-bis(diphenylphosphino)ethane 0.40 g (1 mmol) and palladium bis(triphenylphosphine) dichloride 0.21 g (0.3 mmol) in dichloromethane 2 g were added, then carbon monoxide was bubbled into the reaction bomb, the pressure was maintained at 4 atm, the temperature was raised to 80°C, the reaction was carried out for 3 hours, HPLC analysis showed that the starting material 4-bromo-3-nitro-trifluoromethylbenzene was <1% (HPLC area %), the product 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) was >88% (HPLC area %). At the end of the reaction, the reaction mixture was cooled to room temperature, filtered, the pH was adjusted to 3 by dropwise addition of 7% wt hydrochloric acid, extracted twice with ethyl acetate, separated, the organic phase was removed under reduced pressure, obtaining 2.68 g of yellow solid, content 86.8%, yield 70.6%.

[0080] Example 7

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

[0082] Into a reaction flask, 4-bromo-3-nitro-benzotrifluoride 2.70 g (10 mmol), 1,3-dimethyl-5-hydroxypyrazole 1.30 g (11 mmol, GC purity 95%) and 8 g of toluene were added at room temperature, after stirring for 10 min, potassium carbonate 2.76 g (20 mmol) was added, the reaction flask was purged with nitrogen three times, a solution of ligand 1,2-bis(diphenylphosphino)ethane 0.40 g (1 mmol) and palladium tetrakis(triphenylphosphine) 0.21 g (0.3 mmol) in dichloromethane (2 g of dichloromethane) was added, then carbon monoxide was introduced into the reaction flask, the pressure was maintained at 4 atm, heating was carried out at 65 °C, the reaction was carried out for 4 h, HPLC detection of the starting material 4-bromo-3-nitro-benzotrifluoride <1% (HPLC area %), product 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) > 90% (HPLC area %). At the end of the reaction, the reaction liquid was cooled to room temperature, filtered, pH = 3 was adjusted by dropwise addition of 7% wt hydrochloric acid, extracted twice with ethyl acetate, separated, the organic phase was removed under reduced pressure, obtaining 2.76 g of yellow solid, content 86.5%, yield 72.5%.

[0083] Example 8

[0084] This example is intended to illustrate the synthesis of 1,3-dimethyl-1H-pyrazole-5-(4- trifluoromethyl-2-methylsulfonylbenzoyloxy) starting from 1,3-dimethyl-1H-pyrazole-5-(4- trifluoromethyl-2-nitrobenzoyloxy).

[0085] Into a four-necked flask, 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2- nitrobenzoyloxy) 2.0 g (5.1 mmol, AR purity 85%) and 10 g of acetonitrile were added at room temperature, after stirring for 10 min, 20% wt aqueous sodium methanethiolate 2.32 g (6.6 mmol) was added, heating was carried out at 70 °C for 6 h, HPLC detection of the starting material 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) <7% (HPLC area %), the reaction liquid was cooled to 50 °C, 30% hydrogen peroxide 2.02 g (17.85 mmol) was added dropwise, heating was carried out at 80 °C for 4 h, HPLC detection of the product 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonylbenzoyloxy) > 89% (HPLC area %), at the end of the reaction, 50 g of water were added to the reaction liquid, which was cooled to 0 °C, the crystals were filtered and dried, obtaining 1.63 g of yellow crude product, content 90.1%, yield 79.5%. After column chromatography using dichloromethane / petroleum ether (v / v = 2:1), the product 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonylbenzoyloxy) was obtained in a content of 99%, yellow solid, 1H NMR (400 MHz, Chloroform-d) δ 8.40 (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 the starting material.

[0088] Into a four-necked flask was placed 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2- nitrobenzoyloxy) 2.0 g (5.1 mmol, 85% purity) and 10 g acetonitrile, stirred for 10 min, then added 20 wt% sodium thiomethoxide aqueous solution 2.32 g (6.6 mmol) and tetrabutylammonium chloride 0.5 g (1.8 mmol), warmed to 70 °C for 6 h, HPLC detection of starting material 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2- nitrobenzoyloxy) <1% (HPLC area %), the reaction solution was cooled to 50 °C, dropwise added 30% hydrogen peroxide 2.02 g (17.85 mmol), warmed to 80 °C for 4 h, HPLC detection of product 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonylbenzoyloxy) >95% (HPLC area %), the reaction was completed, 50 g water was added to the reaction solution, cooled to 0 °C to crystallize, filtered, and dried to obtain yellow crude product 1.75 g, content 95.2%, yield 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 the starting material.

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

[0092] Example 11

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

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

[0095] Example 12

[0096] This example is 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 the starting material.

[0097] Into a four-necked flask, was placed 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2- nitrobenzoyloxy) 2.0 g (5.1 mmol, 85% purity) and 10 g acetonitrile, stirred for 10 min, then added 20 wt% sodium thiomethoxide aqueous solution 2.32 g (6.6 mmol) and tetrabutylammonium chloride 0.5 g (1.8 mmol), heated to 70 °C for 6 h, HPLC detection of starting material 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) <1% (HPLC area %), the reaction solution was cooled to 50 °C, then added 30% hydrogen peroxide 1.01 g (8.93 mmol) dropwise and reacted for 1 h, then heated to 55 °C, added 30% hydrogen peroxide 1.01 g (8.93 mmol) dropwise and reacted for 1 h, finally heated to 80 °C for 2 h, HPLC detection of product 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonylbenzoyloxy) >99% (HPLC area %), the reaction was completed, 50 g water was added to the reaction solution, cooled to 0 °C to precipitate, filtered and dried to obtain yellow crude product 1.85 g, content 98%, yield 98.1%.

[0098] Example 13

[0099] This example is 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 the starting material.

[0100] In a four-necked flask, 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) 2.0 g (5.1 mmol, 85% purity) and 10 g acetonitrile were added at room temperature, 20 wt% sodium thiomethoxide aqueous solution 2.32 g (6.6 mmol) and tetrabutylammonium chloride 0.5 g (1.8 mmol) were added after stirring for 10 min, 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) <1% (HPLC area %), the reaction solution was cooled to 50 °C, 10% sodium hypochlorite 13.28 g (17.85 mmol) was added dropwise after cooling to 0 °C, and reacted for 2 h, the temperature was raised to 80 °C and reacted for 2 h, HPLC detection of product 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonylbenzoyloxy) >92% (HPLC area %), the reaction was completed, 50 g of water was added to the reaction solution, cooled to 0 °C, crystallized, filtered, and dried to obtain yellow crude product 1.53 g, content 85.1%, yield 70.5%.

[0101] Comparative Example 1

[0102] The existing synthesis method for preparing 4-trifluoromethyl-2-methylsulfonylbenzoic acid from 4-chloro-3-nitro-trifluoromethylbenzene is as follows:

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

[0104] At 0 °C, 2-nitro-4-trifluoromethylbenzonitrile 5.0 g (23.13 mmol) and DMF (20 mL) were added to a reaction flask, 20 wt% sodium thiomethoxide aqueous solution 12.16 g (34.7 mmol) was slowly added dropwise, and the reaction was carried out at room temperature for 1 h. TLC monitoring showed that the reaction was complete. Water 100 g was added to the reaction solution, and yellow solid 2-methylthio-4-trifluoromethylbenzonitrile 4.85 g was obtained by filtration, crude product yield 96.0%.

[0105] Reaction flask was charged with 2-methylthio-4-trifluoromethylbenzonitrile 5.10 g (23.0 mmol, 98% purity) and 15.4 g of toluene at room temperature, 30% hydrogen peroxide 10.48 g (92.52 mmol) was added dropwise, the temperature was raised to 75°C for 3h, HPLC assay of starting material 2-methylthio-4-trifluoromethylbenzonitrile <1% (HPLC area %), then 30 wt% aqueous sodium hydroxide 6.17 g (46.3 mmol) was added directly to the reaction system, 80°C for 8h, the base reaction was completed, then cooled to room temperature and separated into two layers, the aqueous phase was added 36 wt% hydrochloric acid 5.62 g (55.51 mmol) to precipitate solid, filtration to obtain crude white solid 4-trifluoromethyl-2-methylsulfonylbenzoic acid 4.96 g, purity 96%, yield 95.4% based on 2-methylthio-4-trifluoromethylbenzonitrile, linear yield 91.6% based on 2-nitro-4-trifluoromethylbenzonitrile.

[0106] Calculated, the linear yield of 4-trifluoromethyl-2-methylsulfonylbenzoic acid was 84.4% based on 4-chloro-3-nitro-trifluoromethylbenzene.

[0107] Comparative Example 2

[0108] Reaction flask was charged with 4-trifluoromethyl-2-methylsulfonylbenzoic acid 54 g (0.2 mol) and 328 g of thionyl chloride (2.76 mol) at room temperature, heated to reflux, 4h reaction was complete, excess thionyl chloride was distilled off under reduced pressure to obtain the product 4-trifluoromethyl-2-methylsulfonylbenzoyl chloride 50 g.

[0109] Dichloromethane 397.5 g (4.68 mol) was dissolved in 50 g of 4-trifluoromethyl-2-methylsulfonylbenzoyl chloride under ice bath, then 1,3-dimethyl-5-hydroxypyrazole 24.7 g (0.21 mol, GC purity 95%) and triethylamine 24.2 g (0.24 mol) were added. Reaction at room temperature for 2h, added 50g water, separated into two layers, the aqueous phase was extracted with dichloromethane, the combined organic phase was dried, concentrated, recrystallized to obtain 61g 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-methylsulfonylbenzoyloxy).

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

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

[0112] Comparative Example 3

[0113] Into a reaction flask was added 4-bromo-3-nitro-benzotrifluoride 2.70 g (10 mmol), 1,3-dimethyl-5-hydroxypyrazole 1.30 g (11 mmol, GC purity 95%) and 8 g DMF at room temperature, stirred for 10 min, then added triethylamine 1.52 g (15 mmol), the reaction flask was purged with nitrogen three times with air, carbon monoxide was introduced into the reaction flask, the pressure was maintained at 1 atm, heated to 60 °C, and the reaction was carried out for 12 hours. HPLC detection showed that the starting material 4-bromo-3-nitro-benzotrifluoride was > 80% (HPLC area %), and the product 1,3-dimethyl-1H-pyrazol-5-(4-trifluoromethyl-2-nitrobenzoyloxy) was < 3% (HPLC area %).

[0114] The above describes the preferred embodiments of the present application, but the present application is not limited thereto. Within the technical concept of the present application, various simple modifications can be made to the technical solutions of the present application, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be considered as disclosed by the present application and fall within the protection scope of the present application.

Claims

1. A method for synthesizing 1,3-dimethyl-1H-pyrazole-5-(4-trifluoromethyl-2-nitrobenzoyloxy) as shown in formula (2), characterized in that, Compound (1) was reacted with carbon monoxide and 1,3-dimethyl-5-hydroxypyrazole in the presence of a palladium catalyst, a base and an optional ligand to give compound (2). ； In the compound of formula (1), X is chlorine, bromine or iodine; The palladium catalyst is selected from at least one of palladium acetate, bis(triphenylphosphine)dichloride palladium, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride, tris(benzyleneacetone)dipalladium, and tetra(triphenylphosphine)palladium; The ligand is selected from at least one of triphenylphosphine, 1,2-bis(diphenylphosphine)ethane and 1,3-bis(diphenylphosphine)propane.

2. The synthesis method according to claim 1, characterized in that, In the compound of formula (1), X is bromine; And / or, the base is selected from at least one of sodium acetate, sodium carbonate, potassium carbonate, triethylamine, and n-butylamine.

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

2.

4. The synthesis method according to claim 3, characterized in that, The molar ratio of 4-halo-3-nitro-trifluorotoluene to palladium catalyst is 1:0.03-0.1; And / or, the molar ratio of the 4-halo-3-nitro-trifluorotoluene to 1,3-dimethyl-5-hydroxypyrazole is 1:1.

1.

5. The synthesis method according to any one of claims 1-4, characterized in that, The reaction temperature is 40-80℃; And / or, the reaction time is 3-12 hours; And / or, the pressure of the reaction is 1-4 atm.

6. The synthesis method according to claim 5, characterized in that, The reaction temperature is 60-65℃; And / or, the reaction time is 4-8 hours.

7. The synthesis method according to claim 6, characterized in that, The reaction time is 5 hours.

8. The synthesis method according to any one of claims 1-4, characterized in that, The reaction is carried out in the first solvent.

9. The synthesis method according to claim 8, characterized in that, The first solvent is selected from at least one of dichloromethane, toluene, acetonitrile, and DMF.

10. The synthesis method according to claim 9, characterized in that, The first solvent is a mixture of toluene and dichloromethane.

11. The synthesis method according to claim 10, characterized in that, The ratio of toluene to dichloromethane in the mixed solvent is 8:

2.

12. A method for synthesizing the sulfonylpyrazol intermediate shown in formula (3), characterized in that, The method includes the following steps: (1) The compound of formula (2) is obtained by the method of any one of claims 1-11; (2) React the compound of formula (2) with sodium methanethiol, and then oxidize it to obtain the compound of formula (3); 。 13. The method according to claim 12, characterized in that, The sodium methanethiol mentioned in step (2) is a 20 wt% aqueous solution of sodium methanethiol; And / or, the oxidant in the oxidation reaction is selected from at least one of hydrogen peroxide, sodium hypochlorite, oxygen, and m-chloroperoxybenzoic acid.

14. The method according to claim 13, characterized in that, The oxidizing agent in the oxidation reaction is hydrogen peroxide.

15. The method according to claim 12, characterized in that, The molar ratio of the compound of formula (2) to sodium methanethiol is 1:1.1-1.5; And / or, the molar ratio of the compound of formula (2) to the oxidant of the oxidation reaction is 1:2.5-3.

5.

16. The method according to claim 15, characterized in that, The molar ratio of the compound of formula (2) to sodium methanethiol is 1:1.3; And / or, the molar ratio of the compound of formula (2) to the oxidant of the oxidation reaction is 1:

3.

17. The method according to any one of claims 12-16, characterized in that, The reaction temperature of the compound of formula (2) with sodium methanethiol is 60-80℃; And / or, the oxidation reaction is carried out at a temperature of 70-85°C.

18. The method according to claim 17, characterized in that, The reaction temperature of the compound of formula (2) with sodium methanethiol is 70°C; And / or, the oxidation reaction is carried out at a temperature of 80°C.

19. The method according to any one of claims 12-16, characterized in that, The reaction in step (2) is carried out in the second solvent.

20. The method according to claim 19, characterized in that, The second solvent is selected from at least one of DMF, isopropanol, toluene, and acetonitrile.

21. The method according to claim 20, characterized in that, The second solvent is acetonitrile.

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