Synthesis method of 4-acetyl-2-chlorobenzonitrile and aryl pyrazole compound

Abstract

The invention discloses a synthesis method of 4-acetyl-2-chlorobenzonitrile and an aryl pyrazole compound, which comprises the following steps: taking a cheap and easily available commercial reagent N-methoxy-N-methylacetamide as an acylation reagent, and carrying out substitution reaction on the N-methoxy-N-methylacetamide and commercial 4-bromo-2-chlorobenzonitrile in the presence of isopropyl magnesium chloride to obtain the 4-acetyl-2-chlorobenzonitrile and aryl pyrazole compound. 4-acetyl-2-chlorobenzonitrile can be obtained in one step, and the obtained 4-acetyl-2-chlorobenzonitrile is finally converted and synthesized into the aryl pyrazole compound. The raw materials used in the synthesis process are bulk, cheap and easily available, expensive metal catalysts or ligands are not needed, and highly toxic chemical reagents are not needed as starting materials, so that the toxicity or use safety problem caused by heavy metal residues or toxic compounds in the pharmaceutical process is avoided, the reaction system is safe and environment-friendly, and the method is suitable for industrial production. The method has the advantages of simple operation steps and post-treatment process and high yield.

Description

Technical Field

[0001] This scheme belongs to the field of synthetic technology of intermediate compounds of the anticancer drug dalolutamide, specifically involving the synthetic method of 4-acetyl-2-chlorobenzonitrile and arylpyrazole compounds. Background Technology

[0002] Prostate cancer is the second leading cause of death among men worldwide, causing hundreds of thousands of deaths annually. Darolutamide (trade name: Nubeqa, structural formula below, see WO 2011 / 051540A1, WO 2012 / 143599 A1, WO 2016 / 162604 A1), a prescription drug jointly developed by Bayer (Germany) and Orion (Finland) for the treatment of non-metastatic castration-resistant prostate cancer, is a novel androgen receptor inhibitor, providing more treatment options for prostate cancer. This drug was approved by the U.S. FDA on July 30, 2019.

[0003]

[0004] Aryl-substituted pyrazole compounds (TM-1) are an important component skeleton of dalolutamide and are of great significance in the research on the synthesis methods of this drug, and have always been a research hotspot.

[0005] Many methods for synthesizing this arylpyrazole compound (TM-1) have been developed. Among them, the method of condensing an enaminoketone compound (1ab) to obtain the arylpyrazole compound (synthetic route below) has attracted attention because it does not require the use of expensive palladium catalysts. 4-Acetyl-2-chlorobenzonitrile (1aa) is an important starting material for the synthesis of this enaminoketone compound; however, currently reported technical routes for preparing this starting material (1aa) require the use of expensive palladium as a catalyst, expensive ligands, or highly toxic chemical reagents (see [link to relevant documentation]). J. Org. Chem. 2021, 86 (12344; CN 118772058A; JP2025035859A), making these strategies unsuitable for large-scale industrial production and practical application. Therefore, developing efficient, green, and safe synthetic methods to prepare this raw material is of great significance.

[0006] Summary of the Invention

[0007] This solution aims to overcome at least one of the defects in the prior art and provide a method for synthesizing 4-acetyl-2-chlorobenzonitrile, avoiding the use of expensive palladium as a catalyst, expensive ligands, or highly toxic chemical reagents.

[0008] To solve the above-mentioned technical problems, the following technical solution is adopted: Firstly, a method for synthesizing 4-acetyl-2-chlorobenzonitrile is proposed: using the inexpensive and readily available commercial reagent N-methoxy-N-methylacetamide as the acylation reagent, and reacting it with commercially available 4-bromo-2-chlorobenzonitrile in a solution of isopropyl magnesium chloride (… i- With the participation of PrMgCl, 4-acetyl-2-chlorobenzonitrile can be obtained in one step through a substitution reaction.

[0009] The reaction route of the above synthesis method can be represented as follows:

[0010] Among them, compound (S1) is 4-bromo-2-chlorobenzonitrile, compound (S2) is N-methoxy-N-methylacetamide, and compound 1aa is 4-acetyl-2-chlorobenzonitrile.

[0011] The preferred method for synthesizing the above-mentioned 4-acetyl-2-chlorobenzonitrile includes the following steps: S101. Dissolve 4-bromo-2-chlorobenzonitrile in anhydrous tetrahydrofuran (THF); S102. Under conditions of -70 to -65°C, nitrogen atmosphere and stirring, the tetrahydrofuran solution of isopropyl magnesium chloride is slowly added dropwise to the mixture obtained in step S101 for reaction. S103. Under conditions of -70 to -65°C, nitrogen atmosphere, and stirring, N-methoxy-N-methylacetamide is slowly added dropwise to the reaction solution obtained in step S102 for reaction. S104. Quench, extract, dry and purify the product obtained in step S103.

[0012] The preferred molar amount of N-methoxy-N-methylacetamide is 1.3 ± 0.1 times that of 4-bromo-2-chlorobenzonitrile, and the preferred molar amount of isopropyl magnesium chloride is 1.3 ± 0.1 times that of 4-bromo-2-chlorobenzonitrile. The preferred concentration of the mixture obtained in step S101 is 1 ± 0.1 mol / L, and the preferred concentration of the tetrahydrofuran solution of isopropyl magnesium chloride in step S102 is 2 ± 0.2 mol / L. The preferred dropping time of the tetrahydrofuran solution of isopropyl magnesium chloride in step S102 is 30 ± 5 min, and the reaction continues for 2 ± 0.1 h after the dropping is completed. The preferred dropping time of N-methoxy-N-methylacetamide in step S103 is 30 ± 5 min, and the reaction continues until the reaction is complete after the dropping is completed. The reaction endpoint is preferably monitored by thin-layer chromatography (TLC). In step S104, the quenching operation preferably uses an ice-saturated ammonium chloride (NH4Cl) aqueous solution as a quenching agent to quench the product; the extraction operation preferably uses ethyl acetate (EtOAc) as an extractant to extract the product three times; the drying operation preferably uses anhydrous sodium sulfate (Na2SO4) as a drying agent to dry the product and concentrate it under reduced pressure; and the purification operation preferably uses petroleum ether to wash the product to purify it.

[0013] Secondly, a synthetic method for arylpyrazole compounds is proposed: starting with compounds (S1) and (S2) as raw materials, compound 1aa is synthesized by reaction, then compound 1aa is converted into compound 1ab, and finally compound 1ab is converted into the target compound TM-1. This synthetic method can be represented by the following synthetic route:

[0014] Among them, compound (S1) is 4-bromo-2-chlorobenzonitrile, compound (S2) is N-methoxy-N-methylacetamide, compound 1aa is 4-acetyl-2-chlorobenzonitrile, and compound TM-1 is an arylpyrazole compound.

[0015] The preferred method for synthesizing the above-mentioned arylpyrazole compounds includes the following steps: S1, Preparation of compound 1aa This step involves the reaction of compound (S1) and compound (S2) to synthesize compound 1aa, specifically using the synthetic method for 4-acetyl-2-chlorobenzonitrile proposed in the first aspect.

[0016] S2, Preparation of compound 1ab This step converts compound 1aa into compound 1ab, preferably by reacting compound 1aa with N,N-dimethylformamide dimethyl acetal (DMF-DMA) to synthesize compound 1ab, specifically including: S201. Under a nitrogen atmosphere, compound 1aa is mixed with N,N-dimethylformamide dimethyl acetal and reacted at 110±5℃ until the reaction is complete. S202. After the product obtained in step S201 has cooled to room temperature, purify the product.

[0017] The molar amount of N,N-dimethylformamide dimethyl acetal is preferably 10 ± 1 times the molar amount of compound 1aa. In step S201, the reaction endpoint is preferably monitored by thin-layer chromatography (TLC). In step S202, the purification operation preferably involves washing the product with cold ethanol to purify the product.

[0018] S3, Preparation of compound TM-1 This step converts compound 1ab into compound TM-1, preferably by reacting compound 1ab with a hydrazine reagent to synthesize compound TM-1, wherein the hydrazine reagent is selected from one of hydrazine monohydrochloride, hydrazine dihydrochloride, and tert-butyl hydrazine carbamate.

[0019] If the hydrazine reagent is hydrazine monohydrochloride or hydrazine dihydrochloride, the preferred steps for reacting compound 1ab with the hydrazine reagent to obtain compound TM-1 include: S311. Dissolve compound 1ab and hydrazine reagent in ethanol and react at 80±5℃ with stirring until the reaction is complete. S312. After the product obtained in step S311 is cooled to room temperature, the product is evaporated in the solvent, quenched, extracted, dried and purified.

[0020] The molar amount of hydrazine reagent is preferably 1.2 ± 0.1 times the molar amount of compound 1ab. Step S311 is preferably carried out in an oil bath, and the reaction endpoint is preferably monitored by thin-layer chromatography (TLC). In step S312, the quenching operation preferably uses sodium carbonate (Na2CO3) as the quenching agent to quench the product, the extraction operation preferably uses ethyl acetate (EtOAc) as the extractant to perform three extractions on the product, the drying operation preferably uses anhydrous sodium sulfate (Na2SO4) as the drying agent to dry the product and evaporate the solvent, and the purification operation preferably uses petroleum ether and ethyl acetate to wash the product to purify it.

[0021] If the hydrazine reagent is tert-butyl hydrazine carbamate, then the preferred steps for reacting compound 1ab with the hydrazine reagent to obtain compound TM-1 include: S321. Dissolve compound 1ab and hydrazine reagent in ethanol and react at 80±5℃ with stirring until the reaction is complete. S322. After the product obtained in step S321 has cooled to room temperature, add hydrochloric acid and react at 65±5℃ with stirring until the reaction is complete. S323. After the product obtained in step S322 is cooled to room temperature, the product is evaporated in the solvent, quenched, extracted, dried and purified.

[0022] The molar amount of hydrazine reagent is preferably 1.2 ± 0.1 times the molar amount of compound 1ab. Steps S321 and S322 are preferably carried out in an oil bath, and the reaction endpoint is preferably monitored by thin-layer chromatography (TLC). In step S323, the quenching operation preferably uses sodium carbonate (Na2CO3) as the quenching agent to quench the product, the extraction operation preferably uses ethyl acetate (EtOAc) as the extractant to perform three extractions on the product, the drying operation preferably uses anhydrous sodium sulfate (Na2SO4) as the drying agent to dry the product and evaporate the solvent, and the purification operation preferably uses petroleum ether and ethyl acetate to wash the product to purify it.

[0023] Compared with existing technologies, this solution has the following advantages: (1) There are no reaction steps that require the use of expensive palladium as a catalyst or expensive ligands, so there are no issues with heavy metal residues or toxicity caused by heavy metals in pharmaceutical products due to palladium catalysts in the pharmaceutical process. (2) No reaction steps require the use of highly toxic chemical reagents as starting or key raw materials; (3) There are no issues related to the treatment of expensive industrial heavy metal waste or toxic substances, as well as environmental protection. (4) The raw materials used are cheap and readily available, the reaction system developed is green and environmentally friendly, the operation steps and post-processing are simple, the overall yield of the route is high, and the product purity is good. (5) Subsequent translational research can be applied to the synthesis of the anticancer drug darolutamide and its intermediates. Attached Figure Description

[0024] Figure 1 It is the NMR of compound 1aa 1 H NMR spectrum.

[0025] Figure 2 It is the NMR of compound 1aa 13 C NMR spectrum.

[0026] Figure 3 It is the NMR of compound 1ab 1 H NMR spectrum.

[0027] Figure 4 It is the NMR of compound 1ab 13 C NMR spectrum.

[0028] Figure 5 It is the nuclear magnetic resonance of compound TM-11 H NMR spectrum.

[0029] Figure 6 It is the nuclear magnetic resonance of compound TM-1 13 C NMR spectrum. Detailed Implementation

[0030] This scheme proposes a method for synthesizing 4-acetyl-2-chlorobenzonitrile (1aa), and thereby proposes a new route for synthesizing arylpyrazole compounds (TM-1).

[0031]

[0032] In this process, 4-acetyl-2-chlorobenzonitrile uses the inexpensive and readily available commercial reagent N-methoxy-N-methylacetamide (S2) as the acylation agent, and reacts with commercially available 4-bromo-2-chlorobenzonitrile (S1) in isopropyl magnesium chloride (… i- With the participation of PrMgCl, 4-bromo-2-chlorobenzonitrile can be obtained in one step via a substitution reaction. It is worth noting that 4-bromo-2-chlorobenzonitrile has competing groups -Cl and -CN. If the aforementioned reaction is carried out with other reagents such as n-butyllithium (n-BuLi) and magnesium (Mg) (reaction route as shown below), in addition to the -Br group, the competing groups -Cl and -CN will also react with n-butyllithium, magnesium, etc., making the reaction product complex, difficult to purify, and hard to obtain. Only with the participation of isopropylmagnesium chloride can N-methoxy-N-methylacetamide and 4-bromo-2-chlorobenzonitrile synthesize a relatively pure product, simplifying the operation and post-processing, and achieving a high overall yield.

[0033]

[0034] 4-Acetyl-2-chlorobenzonitrile is an important raw material for the synthesis of enamine ketone compounds and can be used to prepare enamine ketone compounds (1ab). Arylpyrazole compounds (TM-1) can be prepared by condensation of this enamine ketone compound (1ab). Currently, the technical solutions for preparing arylpyrazole compounds (TM-1) by condensation of enamine ketone compounds (1ab) often use toxic and easily explosive hydrazine hydrate as the hydrazine source (see: CN 111087324 A). However, the toxicity and safety issues caused by hydrazine hydrate are particularly dangerous, leading to safety risks in large-scale industrial production and practical applications of these strategies (see: Org. Process Res.Dev. 2010, 14, 960; Org. Process Res.Dev. 2013, 17, 1580.). Therefore, in the process of preparing arylpyrazole compound (TM-1) by condensation of enamine ketone compound (1ab), this scheme uses a safe hydrazine source (hydrazine monohydrochloride, hydrazine dihydrochloride, or tert-butyl hydrazine carbamate) instead of hydrated hydrazine, making the synthesis process efficient, green, and safe, suitable for large-scale industrial production and practical application.

[0035] To enable those skilled in the art to better understand this solution, the following detailed description is provided in conjunction with specific embodiments. Unless otherwise specified, the process methods used in the embodiments are conventional methods; and unless otherwise specified, the materials used are commercially available.

[0036] Example 1 In this embodiment, 4-acetyl-2-chlorobenzonitrile (1aa) was synthesized via the following reaction route:

[0037] In an air atmosphere, 4-bromo-2-chlorobenzonitrile (S1) (CAS: 154607-01-9, 150 mmol, 32.47 g) and anhydrous THF (150 mL) were added to a 500 mL round-bottom flask equipped with a magnetic stir bar. The flask was then degassed three times with nitrogen, and the mixture was placed at -70 to -65 °C. Isopropyl magnesium chloride (CAS: 1068-55-9, 2-Min THF, 1.3 times, 195 mmol, 97.5 mL) was slowly added dropwise over approximately 30 minutes. After the addition was complete, the reaction was continued for 2 hours. N-methoxy-N-methylacetamide (S2) (CAS: 78191-00-1, 1.3 times, 195 mmol, 20.7 mL) was then slowly added dropwise to the above reaction solution over approximately 30 minutes. After the addition was complete, the reaction was stirred for 3 hours (monitored by TLC). After the reaction was complete, the mixture was quenched with 300 mL of ice-saturated NH4Cl aqueous solution and extracted with EtOAc (300 mL × 3). The organic layer was dried over anhydrous Na2SO4. The resulting solution was concentrated under reduced pressure to give a crude product, a pale yellow solid. The crude product was washed with petroleum ether (200 mL) to give the pure compound 1aa (pale yellow solid, 150 mmol scale, 19.13 g, yield 71%).

[0038] Using H respectively 1 NMR (BrukerFT) NMR and C 13 NMR (BrukerFT) The structure of the obtained compound 1aa was confirmed by NMR, and the results are as follows: Figures 1-2 As shown: 1 H NMR (400 MHz, CDCl3): δ 8.06 (d, J = 1.4 Hz, 1H), 7.93-7.90 (m, 1H), 7.81-7.79 (m, 1H), 2.64 (s, 3H); 13 C{ 1 H} NMR(100 MHz, CDCl3): 195.3, 140.9, 137.6, 134.4, 129.4, 126.5,117.0, 115.2, 26.8. Example 2 In this embodiment, the enaminoketone compound (1ab) was synthesized via the following reaction route:

[0039] Under a nitrogen atmosphere, 1aa of raw material (70 mmol, 12.57 g) was added to N,N-dimethylformamide dimethyl acetal (DMF-DMA, CAS: 4637-24-5, 10x, 93 mL). The mixture was then placed at 110 °C. o The reaction was carried out at C for 15 hours (monitored by TLC). After the reaction was complete, the mixture was cooled to room temperature, and a crude yellow solid precipitated. The crude product was washed with cold ethanol (200 mL) to give the pure compound 1ab (yellow solid, 70 mmol scale, 12.30 g, yield 75%).

[0040] Using H respectively 1 NMR (BrukerFT) NMR and C 13 NMR (BrukerFT) The structure of the obtained compound 1ab was confirmed by NMR, and the results are as follows: Figures 3-4 As shown: 1 H NMR (400 MHz, CDCl3): δ 7.97 (d, J = 1.2 Hz, 1H), 7.86-7.81 (m, 2H),7.70-7.68 (m, 1H), 5.58 (d, J = 12.0 Hz, 1H), 3.19 (s, 3H), 2.96 (s, 3H); 13 C{ 1H} NMR(100 MHz, CDCl3): 184.6, 155.4, 145.6, 136.8, 133.8, 128.7,125.8, 115.8, 114.5, 91.3. Example 3 In this embodiment, the arylpyrazole compound (TM-1) was synthesized via the following reaction route:

[0041] In a 100 mL reaction flask, add a magnetic stir bar, weigh out 1ab of enaminophen (5 mmol, 1173 mg), and the safe hydrazine reagent hydrazine monohydrochloride (CAS: 2644-70-4, 1.2 times, 411 mg), then add 20 mL of ethanol and transfer to an 80 mL container. o The reaction was carried out in an oil bath for 15 hours (monitored by thin-layer chromatography). After the reactants 1ab were completely reacted, the mixture was cooled to room temperature and the solvent was evaporated. Then, 10% sodium carbonate (50 mL) and ethyl acetate (50 mL × 3) were added for extraction. The organic layer solution was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain a pale yellow solid crude product. The crude product was washed with petroleum ether / ethyl acetate (V / V = 30 / 1, 100 mL) to obtain the target pure compound TM-1 (pale yellow solid, 5 mmol scale, 926.5 mg, yield 91%).

[0042] Example 4 In this embodiment, the arylpyrazole compound (TM-1) was synthesized via the following reaction route:

[0043] In a 100 mL reaction flask, add a magnetic stir bar, weigh out 1ab of enaminophen (5 mmol, 1173 mg), and the safe hydrazine reagent dihydrazine hydrochloride (CAS: 5341-61-7, 1.2 times, 630 mg), then add 20 mL of ethanol and transfer to an 80 mL container. o The reaction was carried out in an oil bath for 15 hours (monitored by thin-layer chromatography). After the reactants 1ab were completely reacted, the reaction tube was cooled to room temperature and the solvent was evaporated. Then, 10% sodium carbonate (50 mL) and ethyl acetate (50 mL × 3) were added for extraction. The organic layer solution was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain a pale yellow solid crude product. The crude product was washed with petroleum ether / ethyl acetate (V / V = 30 / 1, 100 mL) to obtain the target pure compound TM-1 (pale yellow solid, 5 mmol scale, 937.0 mg, yield 92%).

[0044] Example 5 In this embodiment, the arylpyrazole compound (TM-1) was synthesized via the following reaction route:

[0045] In a 50 mL reaction flask, add a magnetic stir bar, weigh out 1ab of enaminophen (2 mmol, 469.4 mg), and the safe hydrazine reagent tert-butyl hydrazine carboxylate (CAS: 870-46-2, 1.2 times, 317.2 mg), then add 8 mL of ethanol and transfer to an 80 mL container. o The reaction was carried out in an oil bath for 15 hours (monitored by thin-layer chromatography). After the reactants 1ab had reacted completely, the reaction tube was cooled to room temperature, and then 2N hydrochloric acid (2.0 times, 2 mL) was added and transferred to a 65°C container. o The reaction was continued for 8 hours in an oil bath (monitored by thin-layer chromatography). After the reaction was complete, the reaction tube was cooled to room temperature and the solvent was evaporated. Then, 10% sodium carbonate (20 mL) and ethyl acetate (20 mL × 3) were added for extraction. The organic layer solution was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain a pale yellow solid crude product. The crude product was washed with petroleum ether / ethyl acetate (V / V = 30 / 1, 50 mL) to obtain the target pure compound TM-1 (pale yellow solid, 2 mmol scale, 338.0 mg, yield 83%).

[0046] Using H respectively 1 NMR (Bruker FT) NMR and C 13 NMR (Bruker FT) The structure of compound TM-1 obtained in Examples 3-5 was confirmed by NMR, and the results are as follows: Figures 5-6 As shown: 1 H NMR (400 MHz, DMSO-d6): δ 13.27 (br, s, 1H), 8.14 (s, 1H), 7.98 (s,2H), 7.88 (s, 1H), 6.99 (d, J = 2.0 Hz, 1H); 13 C{ 1 H} NMR(100 MHz, DMSO-d6): 147.4, 140.1, 135.9, 135.0, 130.7,125.7, 124.1, 116.2, 109.8, 103.6. Obviously, the above embodiments of this solution are merely examples for clearly illustrating this solution, and are not intended to limit the implementation of this solution. Those skilled in the art can make other variations or modifications based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of this solution should be included within the scope of protection of the claims of this solution.

Claims

1. A method for synthesizing 4-acetyl-2-chlorobenzonitrile, characterized in that, 4-Acetyl-2-chlorobenzonitrile is obtained by a substitution reaction of N-methoxy-N-methylacetamide and 4-bromo-2-chlorobenzonitrile in the presence of isopropyl magnesium chloride.

2. The method for synthesizing 4-acetyl-2-chlorobenzonitrile according to claim 1, characterized in that, The reaction route is as follows: Wherein, compound (S1) is the 4-bromo-2-chlorobenzonitrile, compound (S2) is the N-methoxy-N-methylacetamide, and compound 1aa is the 4-acetyl-2-chlorobenzonitrile.

3. The method for synthesizing 4-acetyl-2-chlorobenzonitrile according to claim 1 or 2, characterized in that, The synthesis method includes the following steps: S101. Dissolve 4-bromo-2-chlorobenzonitrile in anhydrous tetrahydrofuran; S102. Under conditions of -70 to -65°C, nitrogen atmosphere and stirring, the tetrahydrofuran solution of isopropyl magnesium chloride is slowly added dropwise to the mixture obtained in step S101 for reaction. S103. Under conditions of -70 to -65°C, nitrogen atmosphere, and stirring, N-methoxy-N-methylacetamide is slowly added dropwise to the reaction solution obtained in step S102 for reaction. S104. Quench, extract, dry and purify the product obtained in step S103.

4. The method for synthesizing 4-acetyl-2-chlorobenzonitrile according to claim 3, characterized in that, The molar amount of N-methoxy-N-methylacetamide is 1.3 ± 0.1 times the molar amount of 4-bromo-2-chlorobenzonitrile, and / or the molar amount of isopropyl magnesium chloride is 1.3 ± 0.1 times the molar amount of 4-bromo-2-chlorobenzonitrile; and / or The concentration of the mixture obtained in step S101 is 1 ± 0.1 mol / L, and / or the concentration of the tetrahydrofuran solution of isopropyl magnesium chloride in step S102 is 2 ± 0.2 mol / L; and / or In step S102, the tetrahydrofuran solution of isopropyl magnesium chloride is added dropwise over a time of 30 ± 5 min, and the reaction continues for 2 ± 0.1 h after the addition is complete; and / or in step S103, the N-methoxy-N-methylacetamide is added dropwise over a time of 30 ± 5 min, and the reaction continues until the reaction is complete after the addition is complete, with the reaction endpoint monitored by thin-layer chromatography; and / or In step S104, the product is quenched with an ice-saturated ammonium chloride aqueous solution, and / or the quenched product is extracted with ethyl acetate, and / or the extracted product is dried with anhydrous sodium sulfate and concentrated under reduced pressure, and / or the dried product is washed and purified with petroleum ether.

5. A method for synthesizing an arylpyrazole compound, characterized in that, The synthetic route is as follows: The step of synthesizing compound 1aa by reacting compound (S1) with compound (S2) adopts the synthesis method of 4-acetyl-2-chlorobenzonitrile as described in any one of claims 1 to 5.

6. The method for synthesizing the arylpyrazole compound according to claim 5, characterized in that, The step of converting compound 1ab into compound TM-1 is to react compound 1ab with a hydrazine reagent to obtain compound TM-1, wherein the hydrazine reagent is selected from one of hydrazine monohydrochloride, hydrazine dihydrochloride, and tert-butyl hydrazine carbamate.

7. The method for synthesizing the arylpyrazole compound according to claim 6, characterized in that, The hydrazine reagent is hydrazine monohydrochloride or hydrazine dihydrochloride. The steps for reacting compound 1ab with the hydrazine reagent to obtain compound TM-1 include: S311. Dissolve compound 1ab and hydrazine reagent in ethanol and react at 80±5℃ with stirring until the reaction is complete. S312. After the product obtained in step S311 is cooled to room temperature, the product is evaporated in the solvent, quenched, extracted, dried and purified.

8. The method for synthesizing the arylpyrazole compound according to claim 7, characterized in that, The molar amount of the hydrazine reagent is 1.2 ± 0.1 times the molar amount of compound 1ab; and / or Step S311 is carried out in an oil bath, and the reaction endpoint is monitored by thin-layer chromatography; and / or In step S312, the product after rotary drying of solvent is quenched with sodium carbonate, the quenched product is extracted with ethyl acetate, the extracted product is dried with anhydrous sodium sulfate and the solvent is evaporated, and the dried product is washed and purified with petroleum ether and ethyl acetate.

9. The method for synthesizing the arylpyrazole compound according to claim 6, characterized in that, The hydrazine reagent is tert-butyl hydrazinoformate, and the steps for reacting compound 1ab with the hydrazine reagent to obtain compound TM-1 include: S321. Dissolve compound 1ab and hydrazine reagent in ethanol and react at 80±5℃ with stirring until the reaction is complete. S322. After the product obtained in step S321 has cooled to room temperature, add hydrochloric acid and react at 65±5℃ with stirring until the reaction is complete. S323. After the product obtained in step S322 is cooled to room temperature, the product is evaporated in the solvent, quenched, extracted, dried and purified.

10. The method for synthesizing the arylpyrazole compound according to claim 9, characterized in that, The molar amount of the hydrazine reagent is 1.2 ± 0.1 times the molar amount of compound 1ab; and / or Steps S321 and / or S322 are carried out in an oil bath, and the reaction endpoint is monitored by thin-layer chromatography; and / or In step S323, the product after rotary drying of solvent is quenched with sodium carbonate, the quenched product is extracted with ethyl acetate, the extracted product is dried with anhydrous sodium sulfate and the solvent is evaporated, and the dried product is washed and purified with petroleum ether and ethyl acetate.

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