Process for the synthesis of 1h-arylpyrazoles

Abstract

The scheme belongs to the technical field of pyrazole compound synthesis, and discloses a synthesis method of 1H-aryl pyrazole compounds. Green and safe p-toluenesulfonyl hydrazide is used as a safe hydrazine source reagent, and is reacted with N,N-dimethyl enamine ketone compounds in a mixed solvent of ethanol and water, sodium acetate is used as a base, 1H-phenyl pyrazole compounds are obtained through condensation reaction and one-pot method. In the synthesis process, no expensive metal catalyst or ligand is needed, and no toxic or easily explosive hydrazine hydrate is needed as a hydrazine source reagent, so there is no problem of toxicity or use safety caused by heavy metal residues or hydrazine hydrate in the pharmaceutical process. In addition, the raw materials used in the synthesis process are abundant, cheap and easy to obtain, the reaction system is green and environmentally friendly, the operation steps and post-processing process are simple, and the yield is high. The obtained 1H-phenyl pyrazole compounds can be applied to the synthesis of pharmaceutical intermediates.

Description

Technical Field

[0001] This scheme belongs to the field of pyrazole compound synthesis technology, specifically involving a method for synthesizing 1H-arylpyrazole compounds. Background Technology

[0002] Nitrogen-containing heterocyclic skeletons are widely found in natural products, pharmaceuticals, and related bioactive molecules, and have been extensively applied. Developing efficient synthetic methods for nitrogen-containing heterocyclic compounds has always been a hot topic in organic synthesis research. 1H-aryl-substituted pyrazoles, as important structural components, have consistently been a focus of research. For example, the successfully marketed pyrazole anticancer drug darolutamide (trade name: Nubeqa, structural formula below) and the candidate drug molecule with anticancer activity (BMS-986299, structural formula below) both contain the 1H-arylpyrazole structure. 1H-arylpyrazole, as a crucial structural component, is of paramount importance in the research of synthetic methods for this pharmaceutical skeleton.

[0003]

[0004] Many methods for synthesizing 1H-arylpyrazole compounds have been developed. Among them, the condensation of 1H-arylpyrazole compounds with N,N-dimethylenamine ketones via hydrazine hydrate is the most common, but the toxicity or safety issues caused by hydrazine hydrate are particularly dangerous (see Org. Process Res. Dev. 2010, 14, 960-976; Org. Process Res. Dev. 2013, 17, 1580-1590). Another method is to use palladium-catalyzed coupling reactions as the key step to synthesize the relevant 1H-arylpyrazole intermediates, but this method still has limitations, such as: (1) the palladium catalysts used are usually very expensive and sensitive to air or moisture, and the operation must be strictly controlled; (2) palladium catalysts are toxic with heavy metals, and the metal residues in the target product are a very challenging issue in the pharmaceutical industry. Summary of the Invention

[0005] This solution aims to overcome at least one defect in the prior art and provide a method for synthesizing 1H-arylpyrazole compounds, avoiding the use of hydrazine hydrate and transition metal palladium catalysts, and obtaining 1H-arylpyrazole compounds in a "one-pot" process.

[0006] To solve the above-mentioned technical problems, the following technical solution is adopted:

[0007] Using green and safe p-toluenesulfonyl hydrazine (TsNHNH2) as a safe hydrazine source reagent, 1H-phenylpyrazole compounds were obtained by condensation reaction with N,N-dimethylenamine ketones in a mixed solvent of ethanol (EtOH) and water (H2O) using sodium acetate (NaOAc) as a base, in a "one-pot" process.

[0008] The above synthetic method can synthesize any one of the following 1H-phenylpyrazole compounds:

[0009]

[0010] Accordingly, N,N-dimethylenamine ketone compounds can be selected from any of the following compounds:

[0011]

[0012] In the above synthesis method, the molar amount of p-toluenesulfonyl hydrazine is preferably 2.0 ± 0.2 times the molar amount of N,N-dimethylenamino ketone compounds; the molar amount of sodium acetate is preferably 1.5 ± 0.2 times the molar amount of N,N-dimethylenamino ketone compounds; and the volume ratio of ethanol to water in the mixed solvent is preferably 2:3.

[0013] The above synthesis method preferably includes the following steps:

[0014] S1. Dissolve N,N-dimethylenamine ketone compounds, p-toluenesulfonyl hydrazine, and sodium acetate in ethanol and water;

[0015] S2. Place the mixture obtained in step S1 at 85±5℃ and react until the reaction is complete;

[0016] S3. Extract, dry, and purify the product obtained in step S2.

[0017] In step S2, the reaction endpoint is preferably monitored by thin-layer chromatography. In step S3, extraction is preferably performed with ethyl acetate, more preferably three times, with a 10% NaOH aqueous solution added before extraction; drying is preferably performed first with anhydrous sodium sulfate, followed by evaporation of the solvent; purification is performed by column chromatography.

[0018] Compared with existing technologies, this solution has the following advantages:

[0019] (1) No expensive metal catalysts or ligands are required, so there is no toxicity problem caused by heavy metal residues in the pharmaceutical process;

[0020] (2) It does not require the use of toxic or easily explosive hydrazine hydrate as a hydrazine source reagent, so there are no toxicity or safety issues caused by hydrazine hydrate in the pharmaceutical process.

[0021] (3) The raw materials used in the synthesis process are abundant, inexpensive and readily available. The reaction system is green and environmentally friendly, and has the advantages of simple operation steps and post-processing as well as high yield.

[0022] (4) The obtained 1H-phenylpyrazole compounds can be used in pharmaceutical intermediates, such as the synthesis of intermediate structures for the anticancer drug darolutamide and the synthesis of intermediate structures for candidate drugs with anticancer activity (BMS-986299). Detailed Implementation

[0023] This scheme proposes a novel method for synthesizing 1H-arylpyrazole compounds: using green and safe p-toluenesulfonyl hydrazine (TsNHNH2) as a safe hydrazine source reagent, and N,N-dimethylenamino ketone compounds in a mixed solvent of ethanol (EtOH) and water (H2O), with sodium acetate (NaOAc) as a base, the 1H-phenylpyrazole compounds are obtained through a condensation reaction in a "one-pot" process.

[0024] The reaction route of the above synthesis method is as follows:

[0025]

[0026] Among them, formula (1) is an N,N-dimethylenamine ketone compound, and formula (3) is a 1H-phenylpyrazole compound.

[0027] 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. Example 1

[0028] In this embodiment, 1H-arylpyrazole compound 3a was synthesized via the following reaction route:

[0029]

[0030] In a 35 mL reaction tube, a magnetic stir bar was added, and N,N-dimethylenamine ketone 1a (0.50 mmol, 87.6 mg), p-toluenesulfonyl hydrazine (2.0 times, 186.2 mg), and sodium acetate (1.5 times, 61.5 mg) were weighed out. Then, an ethanol-water mixture (5 mL, volume ratio 2:3) was added to dissolve the mixture. The reaction tube was capped and transferred to an 85 °C oil bath. The reaction was carried out for 18 hours (monitored by thin-layer chromatography). After the reactant 1a had reacted completely, the reaction tube was cooled to room temperature. Then, 10% NaOH (10 mL) and ethyl acetate (10 mL × 3) were added for extraction. The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether and ethyl acetate) to obtain 1H-arylpyrazole compound 3a (pale yellow liquid, 61.5 mg, yield 85%).

[0031] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained compound 3a was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows:

[0032] 1 H NMR (400MHz, CDCl3): δ10.30(br,s,1H),7.81-7.78(m,2H),7.63(d,J=2.2Hz,1H),7.45-7.41(m,2H),7.38-7.34(m,1H),6.64(d,J=2.2Hz,1H);

[0033] 13 C{1H}NMR(100MHz,CDCl3):149.1,133.4,132.1,128.8,128.1,125.9,102.7. Example 2

[0034] In this embodiment, 1H-arylpyrazole compound 3b was synthesized via the following reaction route:

[0035]

[0036] In a 35 mL reaction tube, a magnetic stir bar was added, and N,N-dimethylenamine ketone 1b (0.50 mmol, 94.6 mg), p-toluenesulfonyl hydrazine (2.0 times, 186.2 mg), and sodium acetate (1.5 times, 61.5 mg) were weighed out. Then, an ethanol-water mixture (5 mL, 2:3 v / v) was added to dissolve the mixture. The reaction tube was capped and transferred to an 85 °C oil bath. The reaction was carried out for 18 hours (monitored by thin-layer chromatography). After the reactant 1b had completely reacted, the reaction tube was cooled to room temperature. Then, 10% NaOH (10 mL) and ethyl acetate (10 mL × 3) were added for extraction. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether and ethyl acetate) to obtain 1H-arylpyrazole compound 3b (pale yellow liquid, 71.0 mg, yield 90%).

[0037] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained compound 3b was confirmed by Bruker FT-NMR, and the results are as follows:

[0038] 1 H NMR (400MHz, CDCl3): δ9.37(br,s,1H),7.65-7.63(m,2H),7.60(d,J=2.2Hz,1H),7.22-7.20(m,2H),6.57(d,J=2.2Hz,1H),2.38(s,3H);

[0039] 13 C{ 1 ¹H NMR (100MHz, CDCl₃): 148.6, 137.9, 133.7, 129.4, 129.0, 125.7, 102.3, 21.2. Example 3

[0040] In this embodiment, the 1H-arylpyrazole compound 3c was synthesized via the following reaction route:

[0041]

[0042] In a 35 mL reaction tube, a magnetic stir bar was added, and N,N-dimethylenamine ketone 1c (0.50 mmol, 96.6 mg), p-toluenesulfonyl hydrazine (2.0 times, 186.2 mg), and sodium acetate (1.5 times, 61.5 mg) were weighed out. Then, an ethanol-water mixture (5 mL, 2:3 v / v) was added to dissolve the mixture. The reaction tube was capped and transferred to an 85 °C oil bath. The reaction was carried out for 18 hours (monitored by thin-layer chromatography). After the reaction of starting material 1c was complete, the reaction tube was cooled to room temperature, and then extracted with 10% NaOH (10 mL) and ethyl acetate (10 mL × 3). The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether and ethyl acetate) to give 1H-arylpyrazole compound 3c (pale yellow solid, 60.0 mg, yield 74%).

[0043] Using H respectively 1 -NMR (Bruker FT-NMR), C 13 -NMR (Bruker FT-NMR) and F 19 The structure of compound 3c obtained above was confirmed by Bruker FT-NMR, and the results are as follows:

[0044] 1 H NMR (400MHz, CDCl3): δ9.45(br,s,1H),7.75-7.70(m,2H),7.59(d,J=2.2Hz,1H),7.11-7.05(m,2H),6.57(d,J=2.2Hz,1H);

[0045] 13 C{ 1 H} NMR (100MHz, CDCl3): 162.7 (d, J = 245.5Hz), 149.0, 132.5, 128.7, 127.6 (d, J = 8.1Hz), 115.7 (d, J = 21.6Hz), 102.6;

[0046] 19 F NMR(376MHz, CDCl3):-113.97(s,1F). Example 4

[0047] In this embodiment, the 1H-arylpyrazole compound 3d was synthesized via the following reaction route:

[0048]

[0049] In a 35 mL reaction tube, a magnetic stir bar was added, and N,N-dimethylenamine ketone 1d (0.50 mmol, 104.8 mg), p-toluenesulfonyl hydrazine (2.0 times, 186.2 mg), and sodium acetate (1.5 times, 61.5 mg) were weighed out. Then, an ethanol-water mixture (5 mL, 2:3 v / v) was added to dissolve the mixture. The reaction tube was capped and transferred to an 85 °C oil bath. The reaction was carried out for 18 hours (monitored by thin-layer chromatography). After the reactant 1d had completely reacted, the reaction tube was cooled to room temperature. Then, 10% NaOH (10 mL) and ethyl acetate (10 mL × 3) were added for extraction. The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether and ethyl acetate) to give 1H-arylpyrazole compound 3d (pale yellow solid, 71.5 mg, yield 80%).

[0050] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of compound 3d obtained above was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows:

[0051] 1 H NMR (400MHz, CDCl3): δ7.68-7.66(m,2H),7.58(d,J=2.2Hz,1H),7.36-7.33(m,2H),6.58(d,J=2.2Hz,1H);

[0052] 13 C{ 1 H}NMR(100MHz, CDCl3):148.8,133.8,132.6,130.9,129.0,127.1,102.8. Example 5

[0053] In this embodiment, the 1H-arylpyrazole compound 3e was synthesized via the following reaction route:

[0054]

[0055] In a 35 mL reaction tube, a magnetic stir bar was added, and N,N-dimethylenamine ketone 1e (0.50 mmol, 127.1 mg), p-toluenesulfonyl hydrazine (2.0 times, 186.2 mg), and sodium acetate (1.5 times, 61.5 mg) were weighed out. Then, an ethanol-water mixture (5 mL, 2:3 v / v) was added to dissolve the mixture. The reaction tube was capped and transferred to an 85 °C oil bath. The reaction was carried out for 18 hours (monitored by thin-layer chromatography). After the reactant 1e had completely reacted, the reaction tube was cooled to room temperature. Then, 10% NaOH (10 mL) and ethyl acetate (10 mL × 3) were added for extraction. The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether and ethyl acetate) to give 1H-arylpyrazole compound 3e (pale yellow solid, 94.8 mg, yield 85%).

[0056] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained compound 3e was confirmed by Bruker FT-NMR, and the results are as follows:

[0057] 1 H NMR (400MHz, CDCl3): δ7.62-7.59(m,2H),7.58(d,J=2.2Hz,1H),7.52-7.48(m,2H),6.58(d,J=2.2Hz,1H);

[0058] 13 C{ 1 H}NMR(100MHz, CDCl3):148.9,132.4,131.8,131.3,127.3,121.9,102.7. Example 6

[0059] In this embodiment, the 1H-arylpyrazole compound 3f was synthesized via the following reaction route:

[0060]

[0061] In a 35 mL reaction tube, a magnetic stir bar was added, and N,N-dimethylenamine ketone 1f (0.50 mmol, 150.6 mg), p-toluenesulfonyl hydrazine (2.0 times, 186.2 mg), and sodium acetate (1.5 times, 61.5 mg) were weighed out. Then, an ethanol-water mixture (5 mL, 2:3 v / v) was added to dissolve the mixture. The reaction tube was capped and transferred to an 85 °C oil bath. The reaction was carried out for 18 hours (monitored by thin-layer chromatography). After the reaction of starting material 1f was complete, the reaction tube was cooled to room temperature, and then extracted with 10% NaOH (10 mL) and ethyl acetate (10 mL × 3). The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether and ethyl acetate) to obtain 1H-arylpyrazole compound 3f (yellow solid, 100.0 mg, yield 74%).

[0062] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained compound 3f was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows:

[0063] 1 H NMR (400MHz, DMSO-d6): δ12.95(br,s,1H),7.78-7.74(m,3H),7.63-7.62(m,2H),6.73(d,J=2.2Hz,1H);

[0064] 13 C{ 1 ¹H NMR (100MHz, DMSO-d6): 149.1, 137.3, 133.4, 130.0, 127.2, 101.9, 92.9. Example 7

[0065] In this embodiment, 3g of a 1H-arylpyrazole compound was synthesized, and the reaction route is as follows:

[0066]

[0067] In a 35 mL reaction tube, a magnetic stir bar was added, and 1 g (0.50 mmol, 125.7 mg) of N,N-dimethylenamine ketone, 2.0 times (186.2 mg) of p-toluenesulfonyl hydrazine, and 1.5 times (61.5 mg) of sodium acetate were weighed out. The mixture was then dissolved in 5 mL of an ethanol-water mixture (2:3 v / v). The reaction tube was capped and transferred to an 85 °C oil bath. The reaction was carried out for 18 hours (monitored by thin-layer chromatography). After the 1 g of starting material had completely reacted, the reaction tube was cooled to room temperature. Extraction was then performed using 10% NaOH (10 mL) and ethyl acetate (10 mL × 3). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether and ethyl acetate) to give 3 g of 1H-arylpyrazole compound (yellow solid, 74.2 mg, yield 67%).

[0068] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained compound 3g was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows:

[0069] 1 H NMR (400MHz, CDCl3): δ7.85-7.83(m,2H),7.66-7.61(m,5H),7.47-7.43(m,2H),7.38-7.34(m,1H),6.66(d,J=2.2Hz,1H);

[0070] 13 C{ 1 H}NMR(100MHz, CDCl3):148.9,140.7,140.5,133.3,131.0,128.8,127.4,127.3,126.9,126.2,102.7. Example 8

[0071] In this embodiment, the 1H-arylpyrazole compound was synthesized over 3 hours, and the reaction route is as follows:

[0072]

[0073] In a 35 mL reaction tube, a magnetic stir bar was added, and N,N-dimethylenamine ketone 1h (0.50 mmol, 116.6 mg), p-toluenesulfonyl hydrazine (2.0 times, 186.2 mg), and sodium acetate (1.5 times, 61.5 mg) were weighed out. Then, an ethanol-water mixture (5 mL, 2:3 v / v) was added to dissolve the mixture. The reaction tube was capped and transferred to an 85 °C oil bath. The reaction was carried out for 18 hours (monitored by thin-layer chromatography). After the reactants had reacted completely in 1h, the reaction tube was cooled to room temperature. Then, 10% NaOH (10 mL) and ethyl acetate (10 mL × 3) were added for extraction. The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether and ethyl acetate) to obtain 1H-arylpyrazole compound 3h (yellow solid, 74.0 mg, yield 73%).

[0074] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained compound 3h was confirmed by Bruker FT-NMR, and the results are as follows:

[0075] 1 H NMR (400MHz, CDCl3): δ8.08-8.05(m,2H),7.85-7.83(m,2H),6.64(d,J=2.2Hz,1H),7.00(d,J=2.2Hz,1H),3.93(s,3H);

[0076] 13 C{ 1 H}NMR(100MHz, CDCl3):166.9,149.1,136.8,132.0,130.1,129.3,125.5,103.4,52.2. Example 9

[0077] In this embodiment, the 1H-arylpyrazole compound 3i was synthesized via the following reaction route:

[0078]

[0079] In a 35 mL reaction tube, a magnetic stir bar was added, and N,N-dimethylenamine ketone 1i (0.50 mmol, 121.6 mg), p-toluenesulfonyl hydrazine (2.0 times, 186.2 mg), and sodium acetate (1.5 times, 61.5 mg) were weighed out. Then, an ethanol-water mixture (5 mL, 2:3 v / v) was added to dissolve the mixture. The reaction tube was capped and transferred to an 85 °C oil bath. The reaction was carried out for 18 hours (monitored by thin-layer chromatography). After the reactant 1i had completely reacted, the reaction tube was cooled to room temperature. Then, 10% NaOH (10 mL) and ethyl acetate (10 mL × 3) were added for extraction. The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether and ethyl acetate) to obtain 1H-arylpyrazole compound 3i (yellow solid, 94.0 mg, yield 89%).

[0080] Using H respectively 1 -NMR (Bruker FT-NMR), C 13 -NMR (Bruker FT-NMR) and F 19 The structure of the obtained compound 3i was confirmed by Bruker FT-NMR, and the results are as follows:

[0081] 1 H NMR (400MHz, CDCl3): δ12.72(br,s,1H),7.86-7.84(m,2H),7.62-7.60(m,3H),6.66(d,J=2.2Hz,1H);

[0082] 13 C{ 1 H}NMR (100MHz, CDCl3): 148.7, 135.8, 132.3, 129.8 (q, J = 32.2Hz), 125.9, 125.7 (q, J = 3.8Hz), 124.1 (q, J = 270.2Hz), 103.3;

[0083] 19 F NMR(376MHz, CDCl3):-62.58(s,3F). Example 10

[0084] In this embodiment, 1H-arylpyrazole compound 3j was synthesized via the following reaction route:

[0085]

[0086] In a 35 mL reaction tube, a magnetic stir bar was added, and N,N-dimethylenamine ketone 1j (0.50 mmol, 100.1 mg), p-toluenesulfonyl hydrazine (2.0 times, 186.2 mg), and sodium acetate (1.5 times, 61.5 mg) were weighed out. Then, an ethanol-water mixture (5 mL, volume ratio 2:3) was added to dissolve the mixture. The reaction tube was capped and transferred to an 85 °C oil bath. The reaction was carried out for 18 hours (monitored by thin-layer chromatography). After the reactant 1j had completely reacted, the reaction tube was cooled to room temperature. Then, 10% NaOH (10 mL) and ethyl acetate (10 mL × 3) were added for extraction. The organic layer solution was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether and ethyl acetate) to obtain 1H-arylpyrazole compound 3j (yellow solid, 71.0 mg, yield 84%).

[0087] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained compound 3j was confirmed by Bruker FT-NMR, and the results are as follows:

[0088] 1 H NMR (400MHz, CDCl3): δ7.89-7.86(m,2H),7.68-7.65(m,2H),7.63(d,J=2.2Hz,1H),6.68(d,J=2.2Hz,1H);

[0089] 13 C{ 1 ¹H NMR (100MHz, CDCl₃): 149.0, 137.2, 132.6, 131.6, 126.2, 118.9, 111.2, 103.5. Example 11

[0090] In this embodiment, the 1H-arylpyrazole compound 3k was synthesized via the following reaction route:

[0091]

[0092] In a 35 mL reaction tube, a magnetic stir bar was added, and N,N-dimethylenamine 1k (0.50 mmol, 94.6 mg), p-toluenesulfonyl hydrazine (2.0 times, 186.2 mg), and sodium acetate (1.5 times, 61.5 mg) were weighed out. Then, an ethanol-water mixture (5 mL, 2:3 v / v) was added to dissolve the mixture. The reaction tube was capped and transferred to an 85 °C oil bath. The reaction was carried out for 18 hours (monitored by thin-layer chromatography). After the reactant 1k had completely reacted, the reaction tube was cooled to room temperature. Then, 10% NaOH (10 mL) and ethyl acetate (10 mL × 3) were added for extraction. The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether and ethyl acetate) to obtain 1H-arylpyrazole compound 3k (pale yellow liquid, 71.3 mg, 90% yield).

[0093] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained compound 3k was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows:

[0094] 1 H NMR (400MHz, CDCl3): δ7.60(d,J=2.2Hz,1H),7.59-7.55(m,2H),7.31-7.28(m,1H),7.16-7.14(m,1H),6.60(d,J=2.2Hz,1H),2.38(s,3H);

[0095] 13 C{ 1 H}NMR(100MHz, CDCl3):148.9,138.5,133.6,131.9,128.8,128.7,126.5,122.9,102.6,21.4. Example 12

[0096] In this embodiment, 1H-arylpyrazole compound 3l was synthesized via the following reaction route:

[0097]

[0098] In a 35 mL reaction tube, a magnetic stir bar was added, and 1 L of N,N-dimethylenamine ketone (0.50 mmol, 94.6 mg), p-toluenesulfonyl hydrazine (2.0 times, 186.2 mg), and sodium acetate (1.5 times, 61.5 mg) were weighed out. Then, an ethanol-water mixture (5 mL, 2:3 v / v) was added to dissolve the mixture. The reaction tube was capped and transferred to an 85 °C oil bath. The reaction was carried out for 18 hours (monitored by thin-layer chromatography). After the reactant 1 L had completely reacted, the reaction tube was cooled to room temperature. Then, 10% NaOH (10 mL) and ethyl acetate (10 mL × 3) were added for extraction. The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether and ethyl acetate) to give 3 L of 1H-arylpyrazole compound (pale yellow liquid, 70.0 mg, yield 88%).

[0099] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained compound 3l was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows:

[0100] 1 H NMR (400MHz, CDCl3): δ7.54(d,J=2.2Hz,1H),7.49-7.47(m,1H),7.30-7.27(m,2H),7.25-7.21(m,1H),6.43(d,J=2.2Hz,1H),2.42(s,3H);

[0101] 13 C{ 1 H}NMR(100MHz, CDCl3):147.0,136.0,134.2,131.5,130.8,129.2,128.1,125.9,105.4,20.8. Example 13

[0102] In this embodiment, the 1H-arylpyrazole compound 3m was synthesized via the following reaction route:

[0103]

[0104] In a 35 mL reaction tube, a magnetic stir bar was added, and 1 m of N,N-dimethylenamine ketone (0.50 mmol, 112.6 mg), p-toluenesulfonyl hydrazine (2.0 times, 186.2 mg), and sodium acetate (1.5 times, 61.5 mg) were weighed out. Then, 5 mL of an ethanol-water mixture (2:3 v / v) was added to dissolve the mixture. The reaction tube was capped and transferred to an 85 °C oil bath. The reaction was carried out for 18 hours (monitored by thin-layer chromatography). After the reactant 1 m was completely reacted, the reaction tube was cooled to room temperature. Extraction was then performed with 10% NaOH (10 mL) and ethyl acetate (10 mL × 3). The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether and ethyl acetate) to obtain 3 m of 1H-arylpyrazole compound (pale yellow liquid, 60.0 mg, yield 62%).

[0105] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained compound 3m was confirmed by Bruker FT-NMR, and the results are as follows:

[0106] 1 H NMR (400MHz, CDCl3): δ8.33-8.31(m,1H),7.91-7.85(m,2H),7.62-7.60(m,1H),7.54-7.42(m,3H),7.37(d,J=2.2Hz,1H),6.55(d,J=2.2Hz,1H);

[0107] 13 C{ 1 H}NMR(100MHz, CDCl3):147.4,133.8,132.8,131.4,130.3,128.5,128.3,127.1,126.4,125.9,125.7,125.2,106.1. Example 14

[0108] In this embodiment, the 1H-arylpyrazole compound 3n was synthesized via the following reaction route:

[0109]

[0110] In a 35 mL reaction tube, a magnetic stir bar was added, and N,N-dimethylenamine ketone 1n (0.50 mmol, 112.6 mg), p-toluenesulfonyl hydrazine (2.0 times, 186.2 mg), and sodium acetate (1.5 times, 61.5 mg) were weighed out. Then, an ethanol-water mixture (5 mL, 2:3 v / v) was added to dissolve the mixture. The reaction tube was capped and transferred to an 85 °C oil bath. The reaction was carried out for 18 hours (monitored by thin-layer chromatography). After the reactant 1n had completely reacted, the reaction tube was cooled to room temperature. Extraction was then performed with 10% NaOH (10 mL) and ethyl acetate (10 mL × 3). The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether and ethyl acetate) to obtain 1H-arylpyrazole compound 3n (pale yellow solid, 81.0 mg, yield 83%).

[0111] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained compound 3n was confirmed by Bruker FT-NMR, and the results are as follows:

[0112] 1 H NMR (400MHz, CDCl3): δ8.22(s,1H),7.93-7.91(m,1H),7.87-7.81(m,3H),7.67(d,J=2.2Hz,1H),7.50-7.45(m,2H),6.75(d,J=2.2Hz,1H);

[0113] 13 C{ 1 H}NMR(100MHz, CDCl3):149.3,133.5,133.0,129.5,128.5,128.1,127.7,126.3,126.0,124.4,124.0,103.0. Example 15

[0114] In this embodiment, 1H-arylpyrazole compound 3o was synthesized via the following reaction route:

[0115]

[0116] In a 35 mL reaction tube, a magnetic stir bar was added, and N,N-dimethylenamine ketone 1o (0.50 mmol, 102.6 mg), p-toluenesulfonyl hydrazine (2.0 times, 186.2 mg), and sodium acetate (1.5 times, 61.5 mg) were weighed out. Then, an ethanol-water mixture (5 mL, 2:3 v / v) was added to dissolve the mixture. The reaction tube was capped and transferred to an 85 °C oil bath. The reaction was carried out for 18 hours (monitored by thin-layer chromatography). After the reactant 1o had completely reacted, the reaction tube was cooled to room temperature. Then, 10% NaOH (10 mL) and ethyl acetate (10 mL × 3) were added for extraction. The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether and ethyl acetate) to give 1H-arylpyrazole compound 3o (pale yellow solid, 66.0 mg, yield 76%).

[0117] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained compound 3o was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows:

[0118] 1 H NMR (400MHz, CDCl3): δ10.42(br,s,1H),7.68-7.65(m,2H),7.58(d,J=2.0Hz,1H),6.92-6.89(m,2H),6.52(d,J=2.0Hz,1H),3.82(s,3H);

[0119] 13 C{ 1 ¹H NMR (100MHz, CDCl₃): 159.5, 148.5, 133.7, 127.2, 124.8, 114.2, 102.1, 55.3. Example 16

[0120] In this embodiment, the 1H-arylpyrazole compound 3p was synthesized via the following reaction route:

[0121]

[0122] In a 35 mL reaction tube, add a magnetic stir bar, weigh out 1 p of N,N-dimethylenamine ketone (0.50 mmol, 110.0 mg), p-toluenesulfonyl hydrazine (2.0 times, 186.2 mg), and sodium acetate (1.5 times, 61.5 mg), then dissolve in 5 mL of an ethanol-water mixture (2:3 volume ratio). Cap the reaction tube and transfer it to an 85°C container. ℃The reaction was carried out in an oil bath for 18 hours (monitored by thin-layer chromatography). After the reactant 1p had reacted completely, the reaction tube was cooled to room temperature, and then 10% NaOH (10 mL) and ethyl acetate (10 mL × 3) were added for extraction. The organic layer solution was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether and ethyl acetate) to give 1H-arylpyrazole compound 3p (pale yellow solid, 67.1 mg, yield 71%).

[0123] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained compound 3p was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows:

[0124] 1 H NMR (400MHz, DMSO-d6): δ13.24(br,s,1H),8.27-8.25(m,2H),8.10-8.08(m,2H),7.88(s,1H),6.93(d,J=2.2Hz,1H);

[0125] 13 C{ 1 ¹H NMR (100MHz, DMSO-d6): 148.2, 146.3, 140.3, 130.6, 125.8, 124.1, 103.3. Example 17

[0126] In this embodiment, the 1H-arylpyrazole compound 3q was synthesized via the following reaction route:

[0127]

[0128] In a 35 mL reaction tube, a magnetic stir bar was added, and N,N-dimethylenamine ketone 1q (0.50 mmol, 127.3 mg), p-toluenesulfonyl hydrazine (2.0 times, 186.2 mg), and sodium acetate (1.5 times, 61.5 mg) were weighed out. Then, an ethanol-water mixture (5 mL, 2:3 v / v) was added to dissolve the mixture. The reaction tube was capped and transferred to an 85 °C oil bath. The reaction was carried out for 18 hours (monitored by thin-layer chromatography). After the reactant 1q had completely reacted, the reaction tube was cooled to room temperature. Then, 10% NaOH (10 mL) and ethyl acetate (10 mL × 3) were added for extraction. The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether and ethyl acetate) to obtain 1H-arylpyrazole compound 3q (pale yellow solid, 78.3 mg, yield 70%).

[0129] Using H respectively 1-NMR (Bruker FT-NMR) and C 13 The structure of the obtained compound 3q was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows:

[0130] 1 H NMR (400MHz, DMSO-d6): δ13.19(br,s,1H),8.44(d,J=2.0Hz,1H),8.14(dd,J=8 .4Hz,2.0Hz,1H),7.87-7.86(m,1H),7.80(d,J=8.4Hz,1H),6.92-6.91(m,1H);

[0131] 13 C{ 1 H}NMR(100MHz,DMSO-d6):148.1,147.2,134.4,131.9,130.7,129.9,123.0,121.5,102.8. Example 18

[0132] In this embodiment, the 1H-arylpyrazole compound 3r was synthesized via the following reaction route:

[0133]

[0134] In a 35 mL reaction tube, a magnetic stir bar was added, and N,N-dimethylenamine ketone 1r (0.50 mmol, 149.6 mg), p-toluenesulfonyl hydrazine (2.0 times, 186.2 mg), and sodium acetate (1.5 times, 61.5 mg) were weighed out. Then, an ethanol-water mixture (5 mL, 2:3 v / v) was added to dissolve the mixture. The reaction tube was capped and transferred to an 85 °C oil bath. The reaction was carried out for 18 hours (monitored by thin-layer chromatography). After the reactant 1r had completely reacted, the reaction tube was cooled to room temperature. Then, 10% NaOH (10 mL) and ethyl acetate (10 mL × 3) were added for extraction. The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether and ethyl acetate) to give 1H-arylpyrazole compound 3r (pale yellow solid, 70.0 mg, yield 52%).

[0135] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained compound 3r was confirmed by Bruker FT-NMR, and the results are as follows:

[0136] 1H NMR (400MHz, DMSO-d6): δ13.20(br,s,1H),8.40(d,J=2.0Hz,1H),8.05-8.03(m,1H),7.93-7.91(m,1H),7.87(s,1H),6.92(d,J=2.0Hz,1H);

[0137] 13 C{ 1 H}NMR(100MHz,DMSO-d6):150.2,147.3,135.0,134.9,130.7,129.8,121.4,110.9,102.9. Example 19

[0138] In this embodiment, the 1H-arylpyrazole compound 3S was synthesized via the following reaction route:

[0139]

[0140] In a 35 mL reaction tube, a magnetic stir bar was added, and N,N-dimethylenamine 1s (0.50 mmol, 82.6 mg), p-toluenesulfonyl hydrazine (2.0 times, 186.2 mg), and sodium acetate (1.5 times, 61.5 mg) were weighed out. Then, an ethanol-water mixture (5 mL, 2:3 v / v) was added to dissolve the mixture. The reaction tube was capped and transferred to an 85 °C oil bath. The reaction was carried out for 18 hours (monitored by thin-layer chromatography). After the reactant 1s had completely reacted, the reaction tube was cooled to room temperature. Then, 10% NaOH (10 mL) and ethyl acetate (10 mL × 3) were added for extraction. The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether and ethyl acetate) to give 1H-arylpyrazole compound 3s (white solid, 50.4 mg, yield 75%).

[0141] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained compound 3S was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows:

[0142] 1 H NMR (400MHz, CDCl3): δ7.66(d,J=2.2Hz,1H),7.48-7.47(m,1H),6.67-6.66(m,1H),6.56(d,J=2.2Hz,1H),7.50-7.48(m,1H);

[0143] 13 C{ 1H}NMR(100MHz, CDCl3):148.3,142.0,141.7,131.5,111.4,106.0,102.0. Example 20

[0144] In this embodiment, the 1H-arylpyrazole compound 3t was synthesized via the following reaction route:

[0145]

[0146] In a 35 mL reaction tube, a magnetic stir bar was added, and 1 t of N,N-dimethylenamine ketone (0.50 mmol, 115.7 mg), p-toluenesulfonyl hydrazine (2.0 times, 186.2 mg), and sodium acetate (1.5 times, 61.5 mg) were weighed out. Then, an ethanol-water mixture (5 mL, volume ratio 2:3) was added to dissolve the mixture. The reaction tube was capped and transferred to an 85 °C oil bath. The reaction was carried out for 18 hours (monitored by thin-layer chromatography). After the 1 t of raw material had completely reacted, the reaction tube was cooled to room temperature. Then, 10% NaOH (10 mL) and ethyl acetate (10 mL × 3) were added for extraction. The organic layer solution was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether and ethyl acetate) to obtain 3 t of 1H-arylpyrazole compound (pale yellow solid, 73.0 mg, yield 73%).

[0147] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained compound 3t was confirmed by Bruker FT-NMR, and the results are as follows:

[0148] 1 H NMR (400MHz, CDCl3): δ7.85-7.83(m,1H),7.77-7.75(m,1H),7.70(d,J=2.4Hz,1H),7.58(s,1H),7.38-7.31(m,1H),6.68(d,J=2.4Hz,1H);

[0149] 13 C{ 1 H}NMR(100MHz, CDCl3):146.0,140.2,139.2,135.9,131.1,124.5,123.5,122.3,120.4,103.2. Example 21

[0150] In this embodiment, the 1H-arylpyrazole compound 3u was synthesized via the following reaction route:

[0151]

[0152] In a 35 mL reaction tube, a magnetic stir bar was added, and 1 unit (0.50 mmol, 88.1 mg) of N,N-dimethylenamine ketone, 2.0 times (186.2 mg), and 1.5 times (61.5 mg) of sodium acetate were weighed out. The mixture was then dissolved in 5 mL of an ethanol-water mixture (2:3 v / v). The reaction tube was capped and transferred to an 85 °C oil bath. The reaction was carried out for 18 hours (monitored by thin-layer chromatography). After the 1 unit of reactant was completely reacted, the reaction tube was cooled to room temperature. Extraction was then performed using 10% NaOH (10 mL) and ethyl acetate (10 mL × 3). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: dichloromethane:methanol) to obtain 3 units (pale yellow solid, 36.9 mg, yield 51%) of 1H-arylpyrazole compound.

[0153] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained compound 3u was confirmed by Bruker FT-NMR, and the results are as follows:

[0154] 1 H NMR (400MHz, CDCl3): δ8.68-8.67(m,1H),7.77-7.69(m,2H),7.66(d,J=2.0Hz,1H),7.23-7.19(m,1H),6.80(d,J=2.0Hz,1H);

[0155] 13 C{ 1 ¹H NMR (100MHz, CDCl₃): 149.6, 149.3, 145.3, 137.0, 136.7, 122.7, 120.2, 103.4. Example 22

[0156] In this embodiment, the 1H-arylpyrazole compound 3v was synthesized via the following reaction route:

[0157]

[0158] In a 35 mL reaction tube, a magnetic stir bar was added, and 1 v of N,N-dimethylenamine ketone (0.50 mmol, 111.9 mg), p-toluenesulfonyl hydrazine (2.0 times, 186.2 mg), and sodium acetate (1.5 times, 61.5 mg) were weighed out. Then, 5 mL of an ethanol-water mixture (2:3 v / v) was added to dissolve the mixture. The reaction tube was capped and transferred to an 85 °C oil bath. The reaction was carried out for 18 hours (monitored by thin-layer chromatography). After the reactant 1 v had reacted completely, the reaction tube was cooled to room temperature. Extraction was then performed with 10% NaOH (10 mL) and ethyl acetate (10 mL × 3). The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether and ethyl acetate) to give 3 v of 1H-arylpyrazole compound (pale yellow solid, 68.0 mg, yield 71%).

[0159] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained compound 3v was confirmed by Bruker FT-NMR, and the results are as follows:

[0160] 1 H NMR (400MHz, CDCl3): δ7.53-7.50(m,2H),7.38(s,1H),7.37-7.34(m,2H),2.22(s,3H);

[0161] 13 C{ 1 ¹H NMR (100MHz, CDCl₃): 145.1, 133.7, 133.6, 131.0, 128.8, 128.6, 113.2, 9.7. Example 23

[0162] In this embodiment, the 1H-arylpyrazole compound 3w was synthesized via the following reaction route:

[0163]

[0164] In a 35 mL reaction tube, a magnetic stir bar was added, and 1 w of N,N-dimethylenamine ketone (0.50 mmol, 100.6 mg), p-toluenesulfonyl hydrazine (2.0 times, 186.2 mg), and sodium acetate (1.5 times, 61.5 mg) were weighed out. Then, an ethanol-water mixture (5 mL, 2:3 v / v) was added to dissolve the mixture. The reaction tube was capped and transferred to an 85 °C oil bath. The reaction was carried out for 18 hours (monitored by thin-layer chromatography). After the initial 1 w of reactants had completely reacted, the reaction tube was cooled to room temperature. Extraction was then performed using 10% NaOH (10 mL) and ethyl acetate (10 mL × 3). The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether and ethyl acetate) to obtain 3 w of 1H-arylpyrazole compound (pale yellow solid, 48.0 mg, yield 56%).

[0165] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained compound 3w was confirmed by Bruker FT-NMR, and the results are as follows:

[0166] 1 H NMR (400MHz, CDCl3): δ9.92(br,s,1H),7.83-7.81(m,1H),7.43(s,1H),7.30-7.22(m,2H),3.00-2.97(m,2H),2.85-2.81(m,2H);

[0167] 13 C{ 1 H}NMR(100MHz, CDCl3):146.0,136.8,129.0,128.4,128.0,127.5,126.8,121.9,116.0,29.8,19.2. Example 24

[0168] In this embodiment, the 1H-arylpyrazole compound 3x was synthesized via the following reaction route:

[0169]

[0170] In a 35 mL reaction tube, a magnetic stir bar was added, and 1x N,N-dimethylenamine ketone (0.50 mmol, 125.7 mg), p-toluenesulfonyl hydrazine (2.0 times, 186.2 mg), and sodium acetate (1.5 times, 61.5 mg) were weighed out. Then, an ethanol-water mixture (5 mL, 2:3 v / v) was added to dissolve the mixture. The reaction tube was capped and transferred to an 85 °C oil bath. The reaction was carried out for 18 hours (monitored by thin-layer chromatography). After the reactant 1x had completely reacted, the reaction tube was cooled to room temperature. Extraction was then performed with 10% NaOH (10 mL) and ethyl acetate (10 mL × 3). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether and ethyl acetate) to obtain 3x 1H-arylpyrazole compound (pale yellow solid, 70.2 mg, yield 64%).

[0171] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained compound 3x was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows:

[0172] 1 H NMR (400MHz, CDCl3): δ7.65(s,1H),7.55-7.53(m,2H),7.39-7.34(m,7H),7.33-7.27(m,1H);

[0173] 13 C{ 1 H}NMR(100MHz, CDCl3):143.7,134.8,133.1,131.3,128.5,128.4,128.3,128.2,128.1,126.5,119.7. Example 25

[0174] In this embodiment, the 1H-arylpyrazole compound 3y was synthesized via the following reaction route:

[0175]

[0176] In a 500 mL reaction flask, a magnetic stir bar was added, and N,N-dimethylenamine ketone 1y (50 mmol, 11.73 g), p-toluenesulfonyl hydrazine (2.0 times, 18.62 g), and sodium acetate (1.5 times, 6.15 g) were weighed out. Then, an ethanol-water mixture (200 mL, volume ratio 2:3) was added to dissolve the mixture. The reaction tube was capped and transferred to an 85 °C oil bath. The reaction was carried out for 18 hours (monitored by thin-layer chromatography). After the reactant 1y had completely reacted, the reaction tube was cooled to room temperature. Then, 10% NaOH (300 mL) and ethyl acetate (300 mL × 3) were added for extraction. The organic layer solution was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then washed with petroleum ether / ethyl acetate (V / V = 5 / 1, 400 mL) to give 1H-arylpyrazole compound 3y (pale yellow solid, 50 mmol, 7.53 g, yield 74%). In particular, compound 3y is a key intermediate in the anticancer drug dalolutamide (see WO2016 / 162604A1; US10189789B2; WO2011 / 051540A1; WO 2012 / 143599 A1; CN111116476A, CN 111087324A).

[0177] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained compound 3y was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows:

[0178] 1 H NMR (400MHz, DMSO-d6): δ13.27(br,s,1H),8.14(s,1H),7.98(s,2H),7.88(s,1H),6.99(d,J=2.0Hz,1H);

[0179] 13 C{ 1 H}NMR(100MHz,DMSO-d6):147.4,140.1,135.9,135.0,130.7,125.7,124.1,116.2,109.8,103.6. Example 26

[0180] In this embodiment, a 1H-arylpyrazole compound 3q was synthesized, and it was used to synthesize a candidate drug (BMS-986299) with anticancer activity. The reaction route is as follows:

[0181]

[0182] Step 1: In a 500 mL reaction flask, add a magnetic stir bar, weigh out 1q of N,N-dimethylamino ketone (45 mmol, 11.46 g), p-toluenesulfonyl hydrazine (2.0 times, 90 mmol, 16.76 g), and sodium acetate (1.5 times, 67.5 mmol, 5.54 g), then add 200 mL of ethanol-water mixed solvent (volume ratio 2:3) to dissolve it. Cover the reaction tube and transfer it to an 85 °C oil bath. React for 24 hours (monitored by thin-layer chromatography). After the reaction of the raw material 1q was complete, the reaction tube was cooled to room temperature, and then 10% NaOH (300 mL) and ethyl acetate (300 mL × 3) were added for extraction. The organic layer solution was collected, the solvent was evaporated, and then the crude product was separated by column chromatography (eluent: petroleum ether and ethyl acetate, V / V = 10 / 1, 400 mL) to obtain 1H-arylpyrazole compound 3q (pale yellow solid, 45 mmol, 6.94 g, yield 69%).

[0183] Step 2: Under a nitrogen atmosphere, a THF solution (150 mL) of 3,4-dihydro-2H-pyran (3.0 equivalent, 90 mmol, 8.20 mL) was added to a 500 mL reaction flask containing 3q (30 mmol, 6.71 g) and p-toluenesulfonic acid monohydrate (10 mol%, 0.57 g). The mixture was then stirred in an oil bath at 80 °C for 24 h (monitored by TLC). After the reaction was complete, it was cooled to room temperature. The resulting solution was concentrated under reduced pressure to obtain a crude yellow solid product. The crude product was washed with petroleum ether to give the desired product 4a (yellow solid, 30 mmol, 7.85 g, yield 85%). The product was then analyzed using H₂O. 1 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained product 4a was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows:

[0184] 1 H NMR (400MHz, CDCl3): δ8.32(d,J=2.0Hz,1H),7.96(dd,J=8.4Hz,2.0Hz,1H),7.68(d,J=2.0Hz,1H),7.54(d,J=8.4Hz,1H),6.6 4(d,J=2.2Hz,1H),5.43(dd,J=9.8Hz,2.2Hz,1H),4.11-4.08(m,1H),3.76-3.70(m,1H),2.22-2.04(m,3H),1.75-1.62(m,3H);

[0185] 13 C{ 1H}NMR(100MHz, CDCl3):148.3,148.2,133.7,131.9,130.0,129.7,125.4,122.5,103.6,87.9,67.9,30.5,24.9,22.3.

[0186] Step 3: Weigh 4a (20 mmol, 6.15 g) and 4,4'-bipyridine (0.5 mol%, 15.6 mg) into a 500 mL reaction flask in an ice-water bath at 0 °C, and dissolve them in DMF (100 mL). Then slowly add B2(OH)4 (3.0 equivalents, 60 mmol, 5.40 g) over approximately 5 minutes. After the addition is complete, keep the mixture stirred in an ice bath at 0 °C for 0.5 hours (monitored by TLC). After the reaction is complete, quench the reaction with ice water (300 mL), extract with ethyl acetate (300 mL × 3), collect the organic layer solution, evaporate the solvent to dryness, and obtain the target compound 4b (pale yellow viscous solid, 20 mmol, 5.11 g, yield 92%). Specifically, compound 4b is an intermediate structure of a candidate drug (BMS-986299) with anticancer activity (see WO2017 / 184746 and WO2018 / 152396). Using H... 1 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained product 4b was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows:

[0187] 1 H NMR (400MHz, CDCl3): δ7.61(d,J=2.4Hz,1H),7.29(d,J=2.0Hz,1H),7.24(d,J=8.2Hz,1H),7.11(dd,J=8.2Hz,2.0Hz,1H),6.53(d,J=2 .4Hz,1H),5.40(dd,J=9.8Hz,2.4Hz,1H),4.11-4.10(m,1H),4.07(br,s,2H),3.75-3.68(m,1H),2.16-2.04(m,3H),1.76-1.59(m,3H);

[0188] 13 C{ 1 H}NMR(100MHz, CDCl3):150.8,142.8,132.9,129.4,128.8,118.6,116.7,112.9,103.4,87.8,67.9,30.6,24.9,22.5.

[0189] 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 1H-arylpyrazole compounds, characterized in that, 1H-arylpyrazole compounds were obtained by condensation of N,N-dimethylenamino ketones with p-toluenesulfonyl hydrazine under alkaline and mixed solvent conditions. The 1H-arylpyrazole compound is selected from any one of the following compounds: ； The N,N-dimethylenamine ketone compound is selected from any one of the following compounds: ； The molar amount of p-toluenesulfonyl hydrazine is 2.0 ± 0.2 times the molar amount of the N,N-dimethylenamino ketone compound; The base is sodium acetate, and the molar amount of sodium acetate is 1.5 ± 0.2 times the molar amount of the N,N-dimethylenamine ketone compound; The mixed solvent includes ethanol and water, and the volume ratio of ethanol to water in the mixed solvent is 2:3; The condensation was carried out at 85±5℃ until the reaction was complete.

2. The method for synthesizing 1H-arylpyrazole compounds according to claim 1, characterized in that, The synthesis method includes the following steps: S1. Dissolve N,N-dimethylenamine ketone compounds, p-toluenesulfonyl hydrazine, and sodium acetate in ethanol and water; S2. Place the mixture obtained in step S1 at 85±5℃ and react until the reaction is complete; S3. Extract, dry, and purify the product obtained in step S2.

3. The method for synthesizing 1H-arylpyrazole compounds according to claim 2, characterized in that, Step S3 involves extraction with ethyl acetate, followed by post-treatment with a 10% (w / w) NaOH aqueous solution before extraction.

4. The method for synthesizing 1H-arylpyrazole compounds according to claim 2, characterized in that, In step S3, the solvent is first dried with anhydrous sodium sulfate and then evaporated.

5. The method for synthesizing 1H-arylpyrazole compounds according to claim 2, characterized in that, Step S3 involves purification via column chromatography.

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