Preparation method of pyrazosulfuron intermediate

Abstract

The invention relates to the technical field of synthesis of fine organic chemicals, and discloses a preparation method of a pyrazol intermediate. The method comprises the following steps: by taking 4-trifluoromethyl-2-methylsulfonylbenzoic acid shown in a formula I as a starting material, carrying out acylation reaction and esterification reaction to obtain the sulfonyl pyrazole intermediate 1, 3-dimethyl-1H-pyrazol-5-yl-2-(methylsulfonyl)-4-(trifluoromethyl) benzoate shown in a formula IV. The method provided by the invention solves the problems of excessive consumption of thionyl chloride in an acylation reaction and reduced acyl chloride selectivity in a desolventizing process in the prior art, can significantly reduce the consumption of an acylating chlorination reagent (such as thionyl chloride), avoids the occurrence of side reactions, improves the reaction yield, and is suitable for industrial production. The large-scale production of the pyrazosulfuron intermediate is easy.

Description

Technical Field

[0001] The invention relates to the technical field of fine organic chemical synthesis, and in particular to a method for preparing 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 of pyrazole sulfonyl grass 1,3-dimethyl-1H-pyrazol-5-yl-2-(methylsulfonyl)-4-(trifluoromethyl) benzoate (IV) is based on 4-trifluoromethyl-2-methylsulfonylbenzoic acid (intermediate I) as a raw material, and then undergoes an acylation reaction to obtain an acyl chloride, and then removes the solvent, and then undergoes an esterification reaction with 1,3-dimethyl-5-hydroxypyrazole (intermediate III) under the action of an acid binding agent to obtain intermediate IV. The main preparation methods are as follows:

[0004] Method 1: CN105646356A discloses a method for preparing intermediate IV using 4-trifluoromethyl-2-methylsulfonylbenzoic acid (intermediate I) as a raw material, and the two-step crude product yield is 84.5%. This method uses thionyl chloride as a solvent (13.7 equivalents), and the amount used is too large, resulting in more by-products in the process of removing the solvent, resulting in a low two-step reaction yield.

[0005] Method 2: Synthesis and biological activity study of sulfonylurea. Modern Pesticides, 2020, 19(4), 19 reported a method for synthesizing intermediate IV, with a two-step crude yield of 69.8%. This method used an excess of thionyl chloride (4 equivalents), and the solvent removal process made it difficult to remove thionyl chloride and increased side reactions, resulting in a very low overall yield.

[0006] In summary, the current method for preparing pyrazole sulfonyl intermediate 1,3-dimethyl-1H-pyrazol-5-yl-2-(methylsulfonyl)-4-(trifluoromethyl)benzoate from 4-trifluoromethyl-2-methylsulfonylbenzoic acid generally has the problem of excessive use of dichloride, which obviously leads to too low yield, making the treatment of three wastes and the purification of intermediates difficult, which is not conducive to large-scale industrial production. Summary of the invention

[0007] The purpose of the present invention is to overcome the problems existing in the prior art and provide a method for preparing a pyrasulfone intermediate.

[0008] In order to achieve the above-mentioned object, the present invention provides a method for preparing a pyrazole sulfonate intermediate shown in formula IV, characterized in that the method comprises: using 4-trifluoromethyl-2-methylsulfonylbenzoic acid shown in formula I as a starting material, and obtaining a pyrazole sulfonate intermediate 1,3-dimethyl-1H-pyrazol-5-yl-2-(methylsulfonyl)-4-(trifluoromethyl)benzoate shown in formula IV through an acylation reaction and an esterification reaction;

[0009] The reaction route is as follows:

[0010]

[0011] The acylation reaction adopts a batch back-addition method to mix materials. First, the acyl chloride reagent and a catalytic amount of N,N-dimethylformamide are dissolved in an organic solvent, and then the 4-trifluoromethyl-2-methylsulfonylbenzoic acid shown in Formula I is added in batches for reaction.

[0012] Through the above technical solution, the beneficial technical effects achieved by the present invention are as follows:

[0013] The method for preparing a pyrazole sulfonyl intermediate provided by the present invention solves the problems of excessive use of thionyl chloride in the acylation reaction of the prior art and reduced selectivity of acyl chloride in the desolventizing process, can significantly reduce the use of an acyl chloride reagent (such as thionyl chloride), avoids the occurrence of side reactions, improves the reaction yield, and facilitates large-scale production of the pyrazole sulfonyl intermediate. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 This is the H NMR spectrum of 1,3-dimethyl-1H-pyrazol-5-yl-2-(methylsulfonyl)-4-(trifluoromethyl)benzoate prepared in Example 13 of the present invention. DETAILED DESCRIPTION

[0015] 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.

[0016] The present invention provides a method for preparing a pyrazole sulfonate intermediate shown in formula IV, wherein the method comprises: using 4-trifluoromethyl-2-methylsulfonylbenzoic acid shown in formula I as a starting material, and obtaining a pyrazole sulfonate intermediate 1,3-dimethyl-1H-pyrazol-5-yl-2-(methylsulfonyl)-4-(trifluoromethyl)benzoate shown in formula IV through an acylation reaction and an esterification reaction;

[0017] The reaction route is as follows:

[0018]

[0019] The acylation reaction is carried out by mixing materials in batches by back-adding. First, the acyl chloride reagent and an optional catalytic amount of N,N-dimethylformamide are dissolved in an organic solvent, and then the 4-trifluoromethyl-2-methylsulfonylbenzoic acid shown in Formula I is added in batches for reaction.

[0020] The present invention uses 4-trifluoromethyl-2-methylsulfonylbenzoic acid as a starting material, adopts a batch back-addition feeding method to prepare 4-trifluoromethyl-2-methylsulfonylbenzoyl chloride, and then prepares the intermediate 1,3-dimethyl-1H-pyrazol-5-yl-2-(methylsulfonyl)-4-(trifluoromethyl)benzoate with 1,3-dimethyl-5-hydroxypyrazole. The present invention solves the problem that the amount of thionyl chloride used in the acylation reaction in the prior art is too large, resulting in a low total yield of the two-step reaction of acylation and esterification, and has good industrial application prospects.

[0021] In some embodiments of the present invention, the batch back-addition method is a batch equal amount back-addition method or a batch gradient decreasing back-addition method, preferably a batch gradient decreasing back-addition method.

[0022] In some embodiments of the present invention, the batches of the batch-wise back-addition method are 3-6 times, preferably 4 times.

[0023] In some embodiments of the present invention, in the batch-wise back-addition method, the interval time between each batch is 0.5-2 hours, preferably 1 hour.

[0024] Preferably, in the batch gradient decreasing back addition method, the mass ratio of 4-trifluoromethyl-2-methylsulfonylbenzoic acid shown in formula I added in each batch is 1:0.5:0.25:0.25.

[0025] In some embodiments of the present invention, the acyl chloride reagent used in the acylation reaction is selected from at least one of thionyl chloride, oxalyl chloride or phosphorus pentachloride, preferably thionyl chloride.

[0026] In some embodiments of the present invention, the organic solvent used in the acylation reaction is selected from at least one of toluene, chlorobenzene or 1,2-dichloroethane, preferably 1,2-dichloroethane.

[0027] In some embodiments of the present invention, in the acylation reaction, the mass ratio of 4-trifluoromethyl-2-methylsulfonylbenzoic acid shown in Formula I to the organic solvent is 1:1-20, preferably 1:2-10, further preferably 1:3-7, and more preferably 1:4-6.

[0028] In some embodiments of the present invention, in the acylation reaction, the equivalent ratio of 4-trifluoromethyl-2-methylsulfonylbenzoic acid shown in Formula I to the acyl chloride reagent is 1:1.2-4, preferably 1:1.2-2.5, further preferably 1:1.5-2, and more preferably 1:1.5.

[0029] In some embodiments of the present invention, the temperature of the acylation reaction is 40-75°C, preferably 40-60°C, and more preferably 45-55°C.

[0030] In some embodiments of the present invention, the acylation reaction time is 5-14 hours.

[0031] In some embodiments of the present invention, the esterification reaction is carried out in the presence of an acid binding agent.

[0032] In some embodiments of the present invention, the acid binding agent is selected from an organic base or an inorganic base.

[0033] In some embodiments of the present invention, the organic base is selected from at least one of triethylamine, isopropylamine, diisopropylethylamine and pyridine.

[0034] In some embodiments of the present invention, the inorganic base is a metal carbonate, preferably at least one selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium hydroxide and calcium hydroxide, and more preferably sodium carbonate and / or potassium carbonate.

[0035] In some embodiments of the present invention, the organic solvent for the esterification reaction is selected from at least one of toluene, chlorobenzene or 1,2-dichloroethane, preferably 1,2-dichloroethane.

[0036] In some embodiments of the present invention, in the esterification reaction, the mass ratio of the compound represented by Formula II to the organic solvent is 1:4-6.

[0037] In some embodiments of the present invention, the molar ratio of the compound represented by Formula II to the compound represented by Formula III is 1:1.05-1.4, preferably 1:1.1-1.4, further preferably 1:1.15-1.3, and more preferably 1:1.2-1.25.

[0038] In some embodiments of the present invention, the molar ratio of the acid binding agent to the compound represented by formula II is 1:1-4, preferably 1:1.4-2.0.

[0039] In some embodiments of the present invention, the temperature of the esterification reaction is 0-40°C, preferably 0-30°C, and more preferably 10-25°C.

[0040] In some embodiments of the present invention, the esterification reaction time is 3-10 hours.

[0041] The present invention will be described in detail below through examples.

[0042] 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.

[0043] The product contents in the following examples were confirmed by liquid or gas chromatography, the reaction process was tracked by the area normalization method, and the selectivity of some reactions was determined by the reaction system area normalization method.

[0044] LCMS: Liquid chromatography mass spectrometry, liquid quality.

[0045] GCMS: Gas chromatography mass spectrometry, temperament.

[0046] HPLC: High Performance Liquid Chromatography

[0047] GC: Gas chromatography.

[0048] NMR: Nuclear magnetic resonance spectrometry.

[0049] The thionyl chloride and other reagents in the following examples are commercially available; if not otherwise specified, the reaction process and results were detected by high performance liquid chromatography (HPLC), and the purity and selectivity were determined by normalization.

[0050] The process of producing impurities 1 and 2 produced in the reaction process of the present invention is as follows:

[0051]

[0052] Comparative Example 1-4 Preparation of 2-methylsulfonyl-4-(trifluoromethyl)benzoyl chloride

[0053] Comparative Example 1

[0054] To a four-necked flask were added intermediate I (4-trifluoromethyl-2-methylsulfonylbenzoic acid) (2.0 g, 7.4 mmol, 98.0%), SOCl 2(6.9 g, 64.3 mmol, 8 eq) and N,N-dimethylformamide (1 drop) were stirred at room temperature, and then the temperature was raised to 75°C and the reaction was kept at this temperature for 2.5 h.

[0055] The normalized value of intermediate II (4-trifluoromethyl-2-methylsulfonylbenzoyl chloride) in the reaction solution detected by GC was 96.6%, impurity 1 was 3.2%, and impurity 2 was 0.1%. After removing the solvent, the normalized value of intermediate II detected by GC was 86.6%, impurity 1 was 11.1%, and impurity 2 was 0.2%.

[0056] Comparative Example 2

[0057] Comparative Example 1 was repeated, except that 10 g of toluene was added to the four-necked flask and SOCl 2 The dosage was reduced to 4 equivalents and the reaction was kept warm for 6 hours.

[0058] The normalized value of intermediate II in the reaction solution detected by GC was 97.0%, impurity 1 was 2.3%, and impurity 2 was 0.2%. After removing the solvent, the normalized value of intermediate II detected by GC was 89.4%, impurity 1 was 8.3%, and impurity 2 was 0.4%.

[0059] Comparative Example 3

[0060] Comparative Example 1 was repeated, except that 10 g of toluene was added to the four-necked flask, and the amount of thionyl chloride was reduced to 2.5 equivalents, and the reaction was kept warm for 9.5 hours.

[0061] The normalized value of intermediate II detected by GC was 94.4%, impurity 1 was 0.8%, and impurity 2 was 1.5%. After removing the solvent, the normalized value of intermediate II detected by GC in the reaction solution was 90.5%, impurity 1 was 1.7%, and impurity 2 was 3.2%.

[0062] Comparative Example 4

[0063] Comparative Example 1 was repeated, except that 10 g of toluene was added to the four-necked flask, and the amount of thionyl chloride was reduced to 1.5 equivalents, and the reaction was kept warm for 12 h.

[0064] The normalized value of intermediate II detected by GC was 90.3%, impurity 1 was 0.5%, and impurity 2 was 2.4%. After removing the solvent, the normalized value of intermediate II detected by GC in the reaction solution was 89.8%, impurity 1 was 0.4%, and impurity 2 was 2.5%.

[0065] For the preparation of pyrazole sulfonyl intermediate 1,3-dimethyl-1H-pyrazol-5-yl-2-(methylsulfonyl)-4-(trifluoromethyl)benzoate from 4-trifluoromethyl-2-methylsulfonylbenzoic acid through acylation reaction and esterification reaction, for the acylation reaction, all the reported feeding methods are positive addition (for example, thionyl chloride and N,N-dimethylformamide are added to the toluene solution of intermediate I in sequence), followed by heating and reflux. The amount of thionyl chloride used is greatly excessive, and although the reaction rate is fast, the total yield of the two steps is low.

[0066] Table 1

[0067]

[0068] Comparative Examples 1-4 adopt the positive addition feeding mode. When thionyl chloride greatly exceeds the stoichiometric amount (greater than 4 equivalents), the raw material can react completely faster, but impurity 1 increases during the desolvation process, resulting in a decrease in the selectivity of intermediate II. The inventor speculates that the possible reason is that the amount of thionyl chloride is too much, and the remaining thionyl chloride decomposes and converts into impurity 1 with intermediate II during the concentration process. When the amount of thionyl chloride is small (less than 2.5 equivalents), the reaction process produces more impurities 2, and the possible reason is that the main reaction rate is slow, the side reaction increases, and part of the intermediate I and the catalyst DMF are converted into impurity 2, making the reaction rate very slow at the end stage, even if the reaction time is extended, the raw material (intermediate I) still has a part of the remaining. At the same time, the inventor also found that the less the amount of thionyl chloride is used, the smaller the effect of the precipitation process on the selectivity of intermediate II.

[0069] Example 1-13 Preparation of 2-methylsulfonyl-4-(trifluoromethyl)benzoyl chloride

[0070] Example 1

[0071] Slowly add SOCl into a four-necked flask containing toluene (10.8 mL) 2 (3.5 g, 29.8 mmol, 4 eq) and N,N-dimethylformamide (1 drop), and heated with stirring at 75°C. Then, the intermediate I was divided into four equal portions (0.5 g, 0.5 g, 0.5 g, 0.5 g), and added once every 1 hour, and the reaction was kept warm for 6 hours.

[0072] The normalized value of intermediate II in the reaction solution detected by GC was 96.6%, impurity 1 was 2.6%, and impurity 2 was 0.3%. After removing the solvent, the normalized value of intermediate II in the reaction solution detected by GC was 89.2%, impurity 1 was 9.3%, and impurity 2 was 0.5%.

[0073] Example 2

[0074] Example 1 was repeated, except that the amount of thionyl chloride was reduced to 2.5 equivalents.

[0075] The normalized value of intermediate II in the reaction solution detected by GC was 96.2%, impurity 1 was 1.2%, and impurity 2 was 1.5%. After removing the solvent, the normalized value of intermediate II in the reaction solution detected by GC was 93.1%, impurity 1 was 3.4%, and impurity 2 was 3.2%.

[0076] Example 3

[0077] Example 1 was repeated, except that the amount of thionyl chloride was reduced to 1.5 equivalents.

[0078] The normalized value of intermediate II in the reaction solution detected by GC was 95.9%, impurity 1 was 0.3%, and impurity 2 was 2.0%. After removing the solvent, the normalized value of intermediate II in the reaction solution detected by GC was 95.5%, impurity 1 was 0.4%, and impurity 2 was 2.5%.

[0079] Example 4

[0080] Example 1 was repeated, except that the amount of thionyl chloride was reduced to 1.2 equivalents.

[0081] The normalized value of intermediate II in the reaction solution detected by GC was 95.7%, impurity 1 was 0.3%, and impurity 2 was 2.2%. After removing the solvent, the normalized value of intermediate II in the reaction solution detected by GC was 95.6%, impurity 1 was 0.4%, and impurity 2 was 2.3%.

[0082] Table 2

[0083]

[0084]

[0085] In order to avoid the generation of impurity 1 in the desolvation process, it is necessary to reduce the amount of thionyl chloride, and at the same time, it is necessary to avoid the generation of impurity 2 caused by too little thionyl chloride. The inventor unexpectedly found that by adjusting the feeding method from positive addition to equal back addition in batches, thionyl chloride can be greatly excessive compared to intermediate I under the condition of reducing the amount of thionyl chloride. When the equivalent of thionyl chloride is reduced to 1.5 equivalents, the raw material can be almost completely reacted, and the selectivity of intermediate I is not affected in the desolvation process, but the reaction time is long, which increases the generation of impurity 2.

[0086] In addition, using the same conditions as in Example 1, changing the batches in which intermediate I is added in equal amounts, 1 eq (2 g) of intermediate 1 is added in equal amounts in 3 or 6 batches, the content and impurity content of intermediate II obtained are basically the same as those added in 4 batches.

[0087] Example 5

[0088] Slowly add SOCl into a four-necked flask containing toluene (10.8 mL) 2 (2.2 g, 18.6 mmol, 2.5 eq) and N,N-dimethylformamide (1 drop), and heated with stirring at 75°C. Then, the intermediate I was divided into four portions with decreasing gradient (1 g, 0.5 g, 0.25 g, 0.25 g), added once every 1 h, and the reaction was kept warm for 7 h.

[0089] The normalized value of intermediate II in the reaction solution detected by GC was 95.2%, impurity 1 was 1.9%, and impurity 2 was 2.9%.

[0090] Example 6

[0091] Example 5 was repeated, except that the amount of thionyl chloride was reduced to 1.5 equivalents, and the reaction was kept warm for 8.5 hours.

[0092] The normalized value of intermediate II in the reaction solution detected by GC was 96.4%, impurity 1 was 0.4%, and impurity 2 was 3.0%.

[0093] Example 7

[0094] Example 5 was repeated, except that the amount of thionyl chloride was reduced to 1.2 equivalents, and the reaction was kept warm for 11 hours.

[0095] The normalized value of intermediate II in the reaction solution detected by GC was 96.3%, impurity 1 was 0.2%, and impurity 2 was 2.7%.

[0096] Table 3

[0097]

[0098] After changing the feeding method to batch gradient decreasing back addition, the reaction rate is improved to a certain extent compared with the batch equal amount back addition method, but the reaction time is still long, resulting in more impurity 2.

[0099] Example 8

[0100] Example 6 was repeated, except that the reaction temperature was lowered to 60° C. and the reaction was kept at this temperature for 8.5 h.

[0101] The normalized value of intermediate II in the reaction solution detected by GC was 96.9%, impurity 1 was 0.2%, and impurity 2 was 1.5%.

[0102] Example 9

[0103] Example 8 was repeated, except that the reaction temperature was lowered to 50° C. and the reaction was kept at this temperature for 9 h.

[0104] The normalized value of intermediate II in the reaction solution detected by GC was 97.6%, impurity 1 was 0.1%, and impurity 2 was 1.5%.

[0105] Example 10

[0106] Example 8 was repeated, except that the reaction temperature was lowered to 40° C. and the reaction was kept at this temperature for 11 h.

[0107] The normalized value of intermediate II in the reaction solution detected by GC was 96.7%, impurity 1 was 0.1%, and impurity 2 was 2.5%.

[0108] Table 4

[0109]

[0110] In Examples 5-7, the generation of impurity 2 is high, resulting in a selectivity of only 96.4%. The possible reason is that the higher reaction temperature and longer reaction time increase the occurrence of side reactions, and the reaction temperature is lowered for research. The inventor unexpectedly found that after lowering the reaction temperature, the selectivity of intermediate II is further improved, but when the temperature is lowered to 40°C, the reaction time is too long, the impurity 2 increases, and the selectivity of intermediate II decreases.

[0111] Embodiment 11

[0112] Slowly add SOCl into a four-necked bottle containing chlorobenzene (9 mL) 2 (1.3 g, 11.2 mmol, 1.5 eq) and N,N-dimethylformamide (1 drop), and heated with stirring at 50°C. Then, the intermediate I was divided into four portions with decreasing gradient (1 g, 0.5 g, 0.25 g, 0.25 g), added once every 1 h, and the reaction was kept warm for 9 h.

[0113] The normalized value of intermediate II in the reaction solution detected by GC was 98.3%, impurity 1 was 0.2%, and impurity 2 was 1.4%. After removing the solvent, the normalized value of intermediate II in the reaction solution detected by GC was 97.6%, impurity 1 was 0.5%, and impurity 2 was 1.6%.

[0114] Example 12

[0115] Example 11 was repeated, except that 1,2-dichloroethane was used as the solvent.

[0116] The normalized value of intermediate II in the reaction solution detected by GC was 99.4%, impurity 1 was 0.1%, and impurity 2 was 0.2%. After removing the solvent, the normalized value of intermediate II in the reaction solution detected by GC was 99.2%, impurity 1 was 0.2%, and impurity 2 was 0.4%.

[0117] Table 5

[0118]

[0119] The inventor unexpectedly discovered that by using 1,2-dichloroethane as solvent, the selectivity of intermediate II reached 99.2% and the reaction time was shortened to 5 hours.

[0120] Example 13-20 Preparation of 1,3-dimethyl-1H-pyrazol-5-yl-2-(methylsulfonyl)-4-(trifluoromethyl)benzoate

[0121] Embodiment 13

[0122] SOCl was added to a four-necked flask containing 1,2-dichloroethane (7.9 mL). 2 (1.3g, 11.2mmol, 1.5eq) and N,N-dimethylformamide (1 drop), and heated and stirred at 50°C, then the intermediate I was divided into four portions (1g, 0.5g, 0.25g, 0.25g) with a decreasing gradient, added once every 1h, and kept warm for 5h. After the intermediate I in the reaction solution was completely reacted by GC detection, the solvent was removed and it was directly used for the next step reaction.

[0123] The crude intermediate II was dissolved in 1,2-dichloroethane, and triethylamine (1.8 g, 17.8 mmol, 2.4 eq) and intermediate III (1 g, 8.6 mmol, 1.15 eq) were added in sequence. The mixture was stirred at room temperature for 3 h. After GC detection showed that the reaction of the raw materials was complete, water was added to the reaction solution, stirred for 0.5 h, filtered, and dried to obtain 2.25 g of intermediate IV with a content of 95.1%. The total yield of the two steps was 81.6%.

[0124] The analytical data of 1,3-dimethyl-1H-pyrazol-5-yl-2-(methylsulfonyl)-4-(trifluoromethyl)benzoate are as follows (see Figure 1 ):

[0125] LCMS: M+1=363

[0126] 1 H NMR(400MHz,Chloroform-d)δ8.46(s,1H),8.08-7.99(m,2H),6.07(s,1H),3.73(s,3H),3.38(s,3H),2.28(s,3H).

[0127] Embodiment 14

[0128] Example 13 was repeated, except that sodium carbonate was used as the base, the reaction was carried out at 25° C. for 10 h, and post-treatment was performed to obtain 2.54 g of intermediate IV with a content of 96.3%. The total yield of the two steps was 93.3%.

[0129] Embodiment 15

[0130] Example 14 was repeated, except that potassium carbonate was used as the base, the reaction was carried out at 25° C. for 10 h, and post-treatment was performed to obtain 2.54 g of intermediate IV with a content of 96.5%. The total yield of the two steps was 93.5%.

[0131] Table 6

[0132] serial number Alkali Reaction time (h) Intermediate IV (GC,%) content(%) Total isolated yield (%) Embodiment 13 Triethylamine 3 85.1 95.1 81.6 Embodiment 14 Sodium carbonate 10 95.7 96.3 93.3 Embodiment 15 Potassium carbonate 10 96.6 96.5 93.5

[0133] As can be seen from Table 6, the yield using inorganic bases is higher, and potassium carbonate is better than sodium carbonate.

[0134] Example 16

[0135] SOCl was added to a four-necked flask containing 1,2-dichloroethane (7.9 mL). 2 (1.3 g, 11.2 mmol, 1.5 eq) and N,N-dimethylformamide (1 drop), and heated at 50 ° C with stirring. Then, the intermediate I (2 g, 7.4 mmol) was divided into four equal and decreasing portions (1 g, 0.5 g, 0.25 g, 0.25 g), and added once every 1 h. The reaction was kept warm for 5 h. After the intermediate I in the reaction solution was detected by GC, the solvent was removed and the solution was directly used in the next step reaction.

[0136] The crude intermediate II was dissolved in 1,2-dichloroethane, and potassium carbonate (1.2 g, 8.9 mmol, 1.2 eq) and intermediate III (1.16 g, 10.4 mmol, 1.4 eq) were added in sequence. The mixture was stirred at room temperature for 3 h. After GC detection showed that the raw materials had reacted completely, water was added to the reaction solution, stirred for 0.5 h, filtered, and dried to obtain 2.53 g of intermediate IV with a content of 96.5%. The total yield of the two steps was 93.2%.

[0137] Embodiment 17

[0138] Example 16 was repeated, except that 1.3 equivalents of 1,3-dimethyl-5-hydroxypyrazole (Intermediate III) was added. After post-treatment, 2.54 g of Intermediate IV was obtained with a content of 96.4% and a total yield of 93.4% in two steps.

[0139] Embodiment 18

[0140] Example 16 was repeated, except that 1.2 equivalents of 1,3-dimethyl-5-hydroxypyrazole (Intermediate III) were added. After post-treatment, 2.54 g of Intermediate IV was obtained with a content of 96.7% and a total yield of 93.7% in two steps.

[0141] Embodiment 19

[0142] Example 16 was repeated, except that 1.1 equivalents of 1,3-dimethyl-5-hydroxypyrazole (Intermediate III) were added. After post-treatment, 2.48 g of Intermediate IV was obtained with a content of 96.7% and a total yield of 91.5% in two steps.

[0143] Embodiment 20

[0144] Example 16 was repeated, except that 1.05 equivalents of 1,3-dimethyl-5-hydroxypyrazole (Intermediate III) was added. After post-treatment, 2.45 g of Intermediate IV was obtained, with a content of 96.5% and a total yield of 90.2% in two steps.

[0145] Table 7

[0146] serial number The molar ratio of intermediates ⅠI and Ⅲ Intermediate IV (GC,%) content(%) Total isolated yield (%) Example 16 1:1.4 96.3 96.5 93.2 Embodiment 17 1:1.3 96.4 96.4 93.4 Embodiment 18 1:1.2 96.6 96.7 93.7 Embodiment 19 1:1.1 94.6 96.7 91.5 Embodiment 20 1:1.05 93.6 96.5 90.2

[0147] It can be seen from the results in Table 7 that when potassium carbonate is used as the acid binding agent, the highest total yield can be obtained by controlling the molar ratio of intermediate II to intermediate III to 1:1.2.

[0148] 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 preparing a pyrazole sulfonyl intermediate represented by formula IV, characterized in that: The method comprises: using 4-trifluoromethyl-2-methylsulfonylbenzoic acid shown in formula I as a starting material, and obtaining a sulfonylurea intermediate 1,3-dimethyl-1H-pyrazol-5-yl-2-(methylsulfonyl)-4-(trifluoromethyl)benzoate shown in formula IV through acylation reaction and esterification reaction; The reaction route is as follows: The acylation reaction is carried out by mixing materials in batches by back-adding. First, the acyl chloride reagent and an optional catalytic amount of N,N-dimethylformamide are dissolved in an organic solvent, and then the 4-trifluoromethyl-2-methylsulfonylbenzoic acid shown in Formula I is added in batches for reaction.

2. The preparation method according to claim 1, wherein The batch back-addition method is a batch equal amount back-addition method or a batch gradient decreasing back-addition method, preferably a batch gradient decreasing back-addition method; Preferably, the batches of the batch back addition method are 3-6 times, preferably 4 times; Preferably, in the batch back addition method, the interval time between each batch is 0.5-2h, preferably 1h; Preferably, in the batch gradient decreasing back addition method, the mass ratio of 4-trifluoromethyl-2-methylsulfonylbenzoic acid shown in formula I added in each batch is 1:0.5:0.25:0.

25.

3. The preparation method according to claim 1 or 2, wherein The acyl chloride reagent used in the acylation reaction is selected from at least one of thionyl chloride, oxalyl chloride or phosphorus pentachloride, preferably thionyl chloride; Preferably, the organic solvent used in the acylation reaction is selected from at least one of toluene, chlorobenzene or 1,2-dichloroethane, preferably 1,2-dichloroethane.

4. The preparation method according to any one of claims 1 to 3, wherein In the acylation reaction, the mass ratio of 4-trifluoromethyl-2-methylsulfonylbenzoic acid represented by Formula I to the organic solvent is 1:1-20, preferably 1:2-10, more preferably 1:3-7, and more preferably 1:4-6; Preferably, in the acylation reaction, the equivalent ratio of 4-trifluoromethyl-2-methylsulfonylbenzoic acid shown in Formula I to the acyl chloride reagent is 1:1.2-4, preferably 1:1.2-2.5, further preferably 1:1.5-2, and more preferably 1:1.

5.

5. The preparation method according to any one of claims 1 to 4, wherein The temperature of the acylation reaction is 40-75°C, preferably 40-60°C, and more preferably 45-55°C; Preferably, the acylation reaction time is 5-14 h.

6. The preparation method according to any one of claims 1 to 5, wherein The esterification reaction is carried out in the presence of an acid binding agent; Preferably, the acid binding agent is selected from an organic base or an inorganic base; Preferably, the organic base is selected from at least one of triethylamine, isopropylamine, diisopropylethylamine and pyridine; Preferably, the inorganic base is a metal carbonate, preferably at least one selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium hydroxide and calcium hydroxide, more preferably sodium carbonate and / or potassium carbonate.

7. The preparation method according to any one of claims 1 to 6, wherein The organic solvent for the esterification reaction is selected from at least one of toluene, chlorobenzene or 1,2-dichloroethane, preferably 1,2-dichloroethane.

8. The preparation method according to any one of claims 1 to 7, wherein In the esterification reaction, the mass ratio of the compound represented by formula II to the organic solvent is 1:4-6; Preferably, the molar ratio of the compound represented by formula II to the compound represented by formula III is 1:1.05-1.4, preferably 1:1.1-1.4, further preferably 1:1.15-1.3, and more preferably 1:1.2-1.

25.

9. The preparation method according to any one of claims 1 to 8, wherein The molar ratio of the acid binding agent to the compound represented by formula II is 1:1-4, preferably 1:1.4-2.

10. The preparation method according to any one of claims 1 to 9, wherein The temperature of the esterification reaction is 0-40°C, preferably 0-30°C, and more preferably 10-25°C; Preferably, the esterification reaction time is 3-10 hours.

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