A process for preparing N-arylpyrazole compounds

Abstract

The present invention relates to the technical field of synthesis of N-aryl pyrazole compounds, and in particular to a process for preparing N-aryl pyrazole compounds. The process of the present invention is: in ethyl acetate, N-aryl-3-pyrazolidinone compounds are used as raw materials, and iodine and tert-butyl hydroperoxide are reacted in air, room temperature or 45°C to obtain N-aryl pyrazole compounds. The present invention uses an iodine-promoted oxidation method to dehydrogenate and aromatize N-aryl-3-pyrazolidinone compounds to prepare N-aryl pyrazole compounds, and the reaction conditions are mild, the operation steps and post-processing process are simple, and the yield is high.

Description

Technical Field

[0001] The invention relates to the technical field of synthesis of N-aryl pyrazole compounds, and in particular to a process for preparing N-aryl pyrazole compounds. Background Art

[0002] Nitrogen-containing heterocyclic molecular skeletons are widely present in natural products, functional materials, drugs and related bioactive molecular compounds, and have been widely used. The development of efficient synthesis methods for nitrogen-containing heterocyclic compounds has always been one of the hot spots in organic synthesis research. N-aryl substituted pyrazoles, as an important component skeleton, have always been a hot topic in research. For example, Celebrex is used to relieve the symptoms and signs of osteoarthritis, relieve the symptoms and signs of rheumatoid arthritis in adults, and treat acute pain in adults; the pesticide fipronil, discovered by Bayer, has the characteristics of a broad insecticide spectrum and can prevent and control lepidopteran pests such as vegetables, rice and cotton.

[0003] Many methods for synthesizing N-arylpyrazole compounds have been developed. Among them, the synthesis of N-arylpyrazoles is most common through the cyclocondensation reaction of N-arylhydrazine with 1,3-dicarbonyl compounds or their substitutes. However, this method usually forms a mixture of two regioselective isomers for asymmetric 1,3-diketones. Another method is to catalyze the N-arylation reaction of 1-hydropyrazole compounds. However, in the case of asymmetric pyrazole as a raw material, since pyrazole can be used as a tautomer, the dual nucleophilic ability caused by it, therefore, the reaction also faces the problem of regioselectivity. In addition, the existing methods for synthesizing N-arylpyrazole compounds are mostly carried out at a higher temperature, with the participation of metals, and under the protection of inert gas, with a long reaction time, harsh reaction conditions, complicated operation steps and post-processing processes, and low yields. In view of this, it is necessary to develop a new process for preparing N-arylpyrazole compounds to overcome the defects of the existing process. Summary of the invention

[0004] The purpose of the present invention is to overcome at least one of the shortcomings of the above-mentioned prior art and provide a method for preparing N-aryl pyrazole compounds, wherein N-aryl-3-pyrazolidinone compounds are subjected to dehydrogenation aromatization by iodine-promoted oxidation to prepare N-aryl pyrazole compounds. The method has mild reaction conditions, simple operation steps and post-treatment processes, and high yield.

[0005] The technical solution adopted by the present invention is to provide a process for preparing N-aryl pyrazole compounds, specifically: in ethyl acetate (EtOAc), N-aryl-3-pyrazolidinone compounds as raw materials are reacted with iodine (I2) and tert-butyl hydroperoxide (TBHP) in air, room temperature or 45°C to prepare N-aryl pyrazole compounds.

[0006] Preferably, the reaction route of the process is:

[0007]

[0008] Wherein, formula (1) is the N-aryl-3-pyrazolidinone compound, and formula (2) is the N-arylpyrazole compound; in formula (1) or formula (2), R 1 is hydrogen, halogen, alkyl, haloalkyl, alkoxy or phenyl, R 2 is hydrogen, methyl or phenyl, R 3 is hydrogen or methyl.

[0009] More preferably, R 1 is hydrogen, halogen, methyl, halomethyl, methoxy or phenyl.

[0010] Preferably, the process comprises the following steps:

[0011] S1. mixing an N-aryl-3-pyrazolidinone compound, elemental iodine, tert-butyl hydroperoxide and ethyl acetate;

[0012] S2. The mixture obtained in step S1 is reacted in air, at room temperature or at 45 ° C until the reaction is complete;

[0013] S3. Extract the product obtained in step S2 with ethyl acetate, take the organic layer solution, dry it, concentrate it, separate and purify it.

[0014] More preferably, in step S1, based on the molar amount of the N-aryl-3-pyrazolidinone compound, the amount of elemental iodine added is 0.05 equivalents, and the amount of tert-butyl hydroperoxide added is 1.5 equivalents.

[0015] More preferably, in step S1, the usage ratio of the ethyl acetate to the N-aryl-3-pyrazolidinone compound is 2 mL:0.2 mmol.

[0016] More preferably, in step S2, the reaction endpoint is monitored by thin layer chromatography; and the reaction is quenched by aqueous sodium thiosulfate solution.

[0017] More preferably, in step S3, the organic layer solution is dried using anhydrous sodium sulfate, and column chromatography separation and purification is performed using petroleum ether and ethyl acetate as eluents.

[0018] Compared with the prior art, the present invention has the following beneficial effects:

[0019] (1) Using easily available N-aryl-3-pyrazolidinone compounds as starting materials helps to reduce costs and improve efficiency;

[0020] (2) The reaction temperature is easily accessible to room temperature or 45°C, and there are no special restrictions on the acid-base environment. The overall reaction conditions are mild, the reaction energy consumption is low, and the difficulty of preparing the target product is significantly reduced;

[0021] (3) The operation steps and post-processing process are simple, the product yield is high, and it is suitable for large-scale preparation;

[0022] (4) The product obtained by the method of the present invention can be used directly or as a substrate in other reactions, providing a basis for the medicinal chemistry and biological activity research of related molecules. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 NMR of compound 2a 1 H NMR spectrum.

[0024] Figure 2 NMR of compound 2a 13 C NMR spectrum.

[0025] Figure 3 NMR of compound 2b 1 H NMR spectrum.

[0026] Figure 4 NMR of compound 2b 13 C NMR spectrum.

[0027] Figure 5 NMR of compound 2c 1 H NMR spectrum.

[0028] Figure 6 NMR of compound 2c 13 C NMR spectrum.

[0029] Figure 7 NMR of compound 2c 19 F NMR spectrum.

[0030] Figure 8 NMR of compound 2d 1 H NMR spectrum.

[0031] Fig. 9 NMR of compound 2d 13 C NMR spectrum.

[0032] Fig.10 NMR of compound 2e 1 H NMR spectrum.

[0033] Fig.11 NMR of compound 2e 13 C NMR spectrum.

[0034] Fig.12 NMR of compound 2f 1 H NMR spectrum.

[0035] Fig.13 NMR of compound 2f 13 C NMR spectrum.

[0036] Fig.14 NMR of compound 2f 19 F NMR spectrum.

[0037] Fig.15 NMR of compound 2g 1 H NMR spectrum.

[0038] Fig.16 NMR of compound 2g 13 C NMR spectrum.

[0039] Fig.17 NMR of compound 2h 1 H NMR spectrum.

[0040] Fig.18 NMR of compound 2h 13 C NMR spectrum.

[0041] Fig.19 NMR of compound 2i 1 H NMR spectrum.

[0042] Fig. 20 NMR of compound 2i 13 C NMR spectrum.

[0043] Fig.21 NMR of compound 2j 1 H NMR spectrum.

[0044] Fig. 22 NMR of compound 2j 13 C NMR spectrum.

[0045] Fig.23 NMR of compound 2k 1 H NMR spectrum.

[0046] Fig.24 NMR of compound 2k 13 C NMR spectrum.

[0047] Fig.25 NMR of compound 2l 1 H NMR spectrum.

[0048] Fig.26 NMR of compound 2l 13 C NMR spectrum.

[0049] Fig. 27 NMR of compound 2m 1 H NMR spectrum.

[0050] Fig.28 NMR of compound 2m 13 C NMR spectrum.

[0051] Fig.29 NMR of compound 2n 1 H NMR spectrum.

[0052] Fig.30 NMR of compound 2n 13 C NMR spectrum.

[0053] Fig.31 NMR of compound 2o 1 H NMR spectrum.

[0054] Fig.32 NMR of compound 2o 13 C NMR spectrum.

[0055] Fig.33 NMR of compound 2p 1 H NMR spectrum.

[0056] Fig.34 NMR of compound 2p 13 C NMR spectrum.

[0057] Fig.35 The present invention provides a reaction scheme for preparing N-aryl pyrazole compounds. DETAILED DESCRIPTION

[0058] The present invention provides a process for preparing an N-aryl pyrazole compound represented by formula (2): using an N-aryl-3-pyrazolidinone compound represented by formula (1) as a raw material, ethyl acetate (EtOAc) as a reaction solvent, iodine (I2) as a catalyst, and tert-butyl hydroperoxide (TBHP) as an oxidant, reacting in an air atmosphere at room temperature or 45° C. to obtain an N-aryl pyrazole compound represented by formula (2), and the reaction route is:

[0059]

[0060] In formula (1) or formula (2), R 1is hydrogen, halogen, alkyl, haloalkyl, alkoxy or phenyl, preferably hydrogen, halogen, methyl, halomethyl, methoxy or phenyl; R 2 is hydrogen, methyl or phenyl, R 3 is hydrogen or methyl.

[0061] In a preferred embodiment of the present invention, the N-aryl pyrazole compound represented by formula (2) is selected from:

[0062]

[0063] The N-aryl-3-pyrazolidinone compound represented by formula (1) is selected from:

[0064]

[0065] The above process comprises the following steps:

[0066] S1. mixing an N-aryl-3-pyrazolidinone compound, elemental iodine, tert-butyl hydroperoxide and ethyl acetate;

[0067] S2. The mixture obtained in step S1 is reacted in air, at room temperature or at 45 ° C until the reaction is complete;

[0068] S3. Extract the product obtained in step S2 with ethyl acetate, take the organic layer solution, dry it, concentrate it, separate and purify it.

[0069] In a preferred embodiment of the present invention, in step S1, based on the molar amount of the N-aryl-3-pyrazolidinone compound, the amount of elemental iodine added is 0.05 equivalents, and the amount of tert-butyl hydroperoxide added is 1.5 equivalents.

[0070] In a preferred embodiment of the present invention, in step S1, the usage ratio of ethyl acetate to the N-aryl-3-pyrazolidinone compound is 2 mL:0.2 mmol.

[0071] In a preferred embodiment of the present invention, in step S2, the reaction time is preferably 24 hours; the reaction endpoint is monitored by thin layer chromatography; and the reaction is quenched by sodium thiosulfate (Na2S2O3) aqueous solution.

[0072] In a preferred embodiment of the present invention, in step S3, the organic layer solution is dried using anhydrous sodium sulfate, and column chromatography separation and purification is performed using petroleum ether and ethyl acetate as eluents.

[0073] In a preferred embodiment of the present invention, the reaction route of the above process is:

[0074]

[0075] Among them, formula (1), formula (2) and R 1 , R 2 As defined above.

[0076] In a preferred embodiment, the process comprises the following steps:

[0077] S1. Based on the molar amount of the N-aryl-3-pyrazolidinone compound, the N-aryl-3-pyrazolidinone compound, 0.05 equivalents of elemental iodine, 1.5 equivalents of tert-butyl hydroperoxide and ethyl acetate are mixed;

[0078] S2. The mixture obtained in step S1 was reacted in air, at room temperature or at 45° C. for 24 h, the reaction endpoint was monitored by thin layer chromatography until the reaction was complete, and the reaction was quenched with an aqueous solution of sodium thiosulfate;

[0079] S3. The product obtained in step S2 was extracted with ethyl acetate three times, the organic layer solution was dried over anhydrous sodium sulfate, concentrated, and separated and purified by column chromatography using petroleum ether and ethyl acetate as eluents.

[0080] In order to further understand the present invention, preferred embodiments of the present invention are described below in conjunction with examples. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, rather than limiting the claims of the present invention.

[0081] It should be noted that the following detailed descriptions are illustrative and are intended to provide further explanation of the present application. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present application belongs.

[0082] The present invention is now further described in conjunction with specific examples. The following examples are only for explaining the present invention, but do not constitute a limitation of the present invention. The test samples and test processes used in the following examples include the following (if the specific experimental conditions are not indicated in the examples, they are usually in accordance with conventional conditions or the conditions recommended by the reagent company; the reagents, consumables, etc. used in the following examples, if not otherwise specified, can all be obtained from commercial channels).

[0083] Among them, compound 1a, compound 1b, compound 1c, compound 1d, compound 1e, compound 1f, compound 1g, compound 1h, compound 1i, compound 1j, compound 1k, compound 1l, compound 1m, compound 1n, compound 1o, compound 1p, ethyl acetate (EtOAc), elemental iodine (I2), tert-butyl hydroperoxide (TBHP), and sodium thiosulfate (Na2S2O3) are all known substances.

[0084] Example 1

[0085] Preparation of N-arylpyrazole compound 2a

[0086] The reaction route is as follows:

[0087]

[0088] In an air atmosphere, N-aryl-3-pyrazolidinone compound 1a (32.4 mg, 1.0 equiv, 0.2 mmol), elemental iodine I2 (5.0 mol%, 2.5 mg, 0.05 equiv.), tert-butyl hydroperoxide aqueous solution (70 wt%, TBHP, 1.5 equiv, 41 uL) and 2 mL of ethyl acetate were added to a 25 mL reaction tube and reacted at room temperature for 24 hours (monitored by thin layer chromatography). After the reaction of the raw materials was complete, the reaction was quenched with sodium thiosulfate (Na2S2O3) aqueous solution. The mixture was extracted with ethyl acetate (5.0 mL) three times, the organic layer solution was dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (eluent, petroleum ether: ethyl acetate) to obtain 28.0 mg of N-aryl pyrazole compound 2a with a yield of 87%.

[0089] Using H 1 The structure of the compound 2a was confirmed by NMR (Bruker FT NMR). Figure 1 As shown: 1 H NMR (400 MHz, DMSO-d6): δ 10.25 (s, 1H), 8.22 (d, J = 2.6 Hz, 1H), 7.69-7.66 (m, 2H), 7.44-7.40 (m, 2H), 7.19-7.15 (m, 1H), 5.80 (d, J = 2.6 Hz, 1H); C 13 The structure of the compound 2a was confirmed by NMR (Bruker FT NMR). Figure 2 As shown: 13 C{ 1 H} NMR (100 MHz, DMSO-d6): 162.7, 139.8, 129.4, 128.4, 124.6, 116.7, 94.4. Figures 1-2 It can be seen that the obtained compound 2a is 3-hydroxy-N-arylpyrazole.

[0090] Example 2

[0091] Preparation of N-arylpyrazole compound 2b

[0092] The reaction route is as follows:

[0093]

[0094] In an air atmosphere, N-aryl-3-pyrazolidinone compound 1b (35.2 mg, 1.0 equiv, 0.2 mmol), elemental iodine I2 (5.0 mol%, 2.5 mg) and tert-butyl hydroperoxide aqueous solution (70 wt%, TBHP, 1.5 equiv, 41 uL) and 2 mL of ethyl acetate were added to a 25 mL reaction tube and reacted at room temperature for 24 hours (monitored by thin layer chromatography). After the reaction of the raw materials was complete, the reaction was quenched with sodium thiosulfate (Na2S2O3) aqueous solution. The mixture was extracted with ethyl acetate (5.0 mL) three times, the organic layer solution was dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (eluent, petroleum ether: ethyl acetate) to obtain 30.0 mg of N-aryl pyrazole compound 2b with a yield of 86%.

[0095] Using H 1 The structure of the compound 2b was confirmed by NMR (Bruker FT NMR). Figure 3 As shown: 1 HNMR (400 MHz, DMSO-d6): δ10.16 (s, 1H), 8.15 (d, J=2.6 Hz, 1H), 7.56-7.54 (m, 2H), 7.23-7.21 (m, 2H), 5.77 (d, J=2.6 Hz, 1H), 2.30 (s, 3H); C 13 The structure of the compound 2b was confirmed by NMR (Bruker FT NMR). Figure 4 As shown: 13 C{ 1 H} NMR (100 MHz, DMSO-d6): 162.5, 137.7, 133.7, 129.7, 128.1, 116.7, 93.9, 20.3. Figures 3-4 It can be seen that the obtained compound 2b is 3-hydroxy-N-p-methylbenzazole.

[0096] Preparation of N-arylpyrazole compound 2c

[0097] The reaction route is as follows:

[0098]

[0099] In an air atmosphere, N-aryl-3-pyrazolidinone compound 1c (36.0 mg, 1.0 equiv, 0.2 mmol), elemental iodine I2 (5.0 mol%, 2.5 mg) and tert-butyl hydroperoxide aqueous solution (70 wt%, TBHP, 1.5 equiv, 41 uL) and 2 mL of ethyl acetate were added to a 25 mL reaction tube and reacted at room temperature for 24 hours (monitored by thin layer chromatography). After the reaction of the raw materials was complete, the reaction was quenched with sodium thiosulfate (Na2S2O3) aqueous solution. The mixture was extracted with ethyl acetate (5.0 mL) three times, the organic layer solution was dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (eluent, petroleum ether: ethyl acetate) to obtain 25.0 mg, and the yield of N-aryl pyrazole compound 2c was 70%.

[0100] Using H 1 The structure of compound 2c was confirmed by NMR (Bruker FT NMR). Figure 5 As shown: 1 HNMR (400 MHz, DMSO-d6): δ 10.24 (s, 1H), 8.19 (d, J = 2.6 Hz, 1H), 7.71-7.67 (m, 2H), 7.30-7.25 (m, 2H), 5.80 (d, J = 2.6 Hz, 1H); C 13 The structure of compound 2c was confirmed by NMR (Bruker FT NMR). Figure 6 As shown: 13 C{ 1 H}NMR (100MHz, DMSO-d6): 162.7, 159.3 (d, J C-F =239.5Hz), 136.5(d, J C-F =2.6Hz), 128.6, 118.6 (d, J C-F =8.2Hz), 116.1(d, J C-F =22.7Hz), 94.3; using F 19 The structure of compound 2c was confirmed by NMR (Bruker FT NMR). Figure 7 As shown: 19 F NMR (376 MHz, DMSO-d6): -118.78 to -118.85 (m, 1F). Figures 5 to 7 It can be seen that the obtained compound 2c is 3-hydroxy-N-p-fluorophenylpyrazole.

[0101] Example 4

[0102] Preparation of N-arylpyrazole compound 2d

[0103] The reaction route is as follows:

[0104]

[0105] In an air atmosphere, N-aryl-3-pyrazolidinone compound 1d (39.6 mg, 1.0 equiv, 0.2 mmol), elemental iodine I2 (5.0 mol%, 2.5 mg) and tert-butyl hydroperoxide aqueous solution (70 wt%, TBHP, 1.5 equiv, 41 uL) and 2 mL of ethyl acetate were added to a 25 mL reaction tube and reacted at room temperature for 24 hours (monitored by thin layer chromatography). After the reaction of the raw materials was complete, the reaction was quenched with sodium thiosulfate (Na2S2O3) aqueous solution. The mixture was extracted with ethyl acetate (5.0 mL) 3 times, the organic layer solution was dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (eluent, petroleum ether: ethyl acetate) to obtain 27.1 mg of N-aryl pyrazole compound 2d with a yield of 70%.

[0106] Using H 1 The structure of the compound 2d was confirmed by NMR (Bruker FT NMR). Figure 8 As shown: 1 H NMR (400 MHz, DMSO-d6): δ 10.35 (s, 1H), 8.25 (d, J = 2.6 Hz, 1H), 7.71-7.69 (m, 2H), 7.49-7.46 (m, 2H), 5.83 (d, J = 2.6 Hz, 1H); C 13 The structure of the compound 2d was confirmed by NMR (Bruker FT NMR). Fig. 9 As shown: 13 C{ 1 H} NMR (100 MHz, DMSO-d6): 162.9, 138.7, 129.3, 128.8, 128.5, 118.3, 94.9. Figures 8-9 It can be seen that the obtained compound 2d is 3-hydroxy-N-chlorophenylpyrazole.

[0107] Example 5

[0108] Preparation of N-arylpyrazole compound 2e

[0109] The reaction route is as follows:

[0110]

[0111] In an air atmosphere, N-aryl-3-pyrazolidinone compound 1e (48.0 mg, 1.0 equiv, 0.2 mmol), elemental iodine I2 (5.0 mol%, 2.5 mg) and tert-butyl hydroperoxide aqueous solution (70 wt%, TBHP, 1.5 equiv, 41 uL) and 2 mL of ethyl acetate were added to a 25 mL reaction tube and reacted at room temperature for 24 hours (monitored by thin layer chromatography). After the reaction of the raw materials was complete, the reaction was quenched with sodium thiosulfate (Na2S2O3) aqueous solution. The mixture was extracted with ethyl acetate (5.0 mL) 3 times, the organic layer solution was dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (eluent, petroleum ether: ethyl acetate) to obtain 38.0 mg of N-aryl pyrazole compound 2e with a yield of 79%.

[0112] Using H 1 The structure of the compound 2e was confirmed by NMR (Bruker FT NMR). Fig.10 As shown: 1 H NMR (400 MHz, DMSO-d6): δ 10.36 (s, 1H), 8.25 (d, J = 2.6 Hz, 1H), 7.66-7.63 (m, 2H), 7.62-7.59 (m, 2H), 5.83 (d, J = 2.6 Hz, 1H); C 13 The structure of the compound 2e was confirmed by NMR (Bruker FT NMR). Fig.11 As shown: 13 C{ 1 H} NMR (100 MHz, DMSO-d6): 162.9, 139.1, 132.2, 128.8, 118.7, 116.6, 95.0. Figures 10-11 It can be seen that the obtained compound 2e is 3-hydroxy-N-bromophenylpyrazole.

[0113] Example 6

[0114] Preparation of N-arylpyrazole compound 2f

[0115] The reaction route is as follows:

[0116]

[0117] In an air atmosphere, N-aryl-3-pyrazolidinone compound 1f (46.0 mg, 1.0 equiv, 0.2 mmol), elemental iodine I2 (5.0 mol%, 2.5 mg) and tert-butyl hydroperoxide aqueous solution (70 wt%, TBHP, 1.5 equiv, 41 uL) and 2 mL of ethyl acetate were added to a 25 mL reaction tube and reacted at room temperature for 24 hours (monitored by thin layer chromatography). After the reaction of the raw materials was complete, the reaction was quenched with sodium thiosulfate (Na2S2O3) aqueous solution. The mixture was extracted with ethyl acetate (5.0 mL) three times, the organic layer solution was dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (eluent, petroleum ether: ethyl acetate) to obtain 35.7 mg of N-aryl pyrazole compound 2f with a yield of 78%.

[0118] Using H 1 The structure of the compound 2f was confirmed by NMR (Bruker FT NMR). Fig.12 As shown: 1 H NMR (400 MHz, DMSO-d6): δ 10.52 (s, 1H), 8.39 (d, J = 2.6 Hz, 1H), 7.89-7.87 (m, 2H), 7.79-7.77 (m, 2H), 5.91 (d, J = 2.6 Hz, 1H); C 13 The structure of the compound 2f was confirmed by NMR (Bruker FT NMR). Fig.13 As shown: 13 C{ 1 H}NMR (100MHz, DMSO-d6): 163.4, 142.6, 129.4, 126.8 (q, J C-F =3.8Hz), 124.5(q, J C-F =32.0Hz), 124.4(q, J C-F =269.8Hz), 116.8, 96.0; using F 19 The structure of the compound 2f was confirmed by NMR (Bruker FT NMR). Fig.14 As shown: 19 F NMR (376 MHz, DMSO-d6): -60.39 (s, 3F). Figures 12-14 It can be seen that the obtained compound 2f is 3-hydroxy-N-[4-(3-fluoromethyl)phenyl]pyrazole.

[0119] Example 7

[0120] Preparation of N-arylpyrazole compound 2g

[0121] The reaction route is as follows:

[0122]

[0123] In an air atmosphere, 1 g (35.2 mg, 1.0 equiv, 0.2 mmol) of N-aryl-3-pyrazolidinone compound, elemental iodine I2 (5.0 mol%, 2.5 mg) and aqueous tert-butyl hydroperoxide solution (70 wt%, TBHP, 1.5 equiv, 41 uL) and 2 mL of ethyl acetate were added to a 25 mL reaction tube and reacted at room temperature for 24 hours (monitored by thin layer chromatography). After the reaction of the raw materials was complete, the reaction was quenched with an aqueous solution of sodium thiosulfate (Na2S2O3). The mixture was extracted with ethyl acetate (5.0 mL) three times, the organic layer solution was dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (eluent, petroleum ether: ethyl acetate) to obtain 29.2 mg, and the yield of 2 g of N-aryl pyrazole compound was 84%.

[0124] Using H 1 The structure of the compound 2g was confirmed by NMR (Bruker FT NMR). Fig.15 As shown: 1 H NMR (400 MHz, DMSO-d6): δ 9.99 (s, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.34-7.32 (m, 1H), 7.29-7.25 (m, 3H), 5.73 (d, J = 2.4 Hz, 1H), 2.27 (s, 3H); C 13 The structure of the compound 2g was confirmed by NMR (Bruker FT NMR). Fig.16 As shown: 13 C{ 1 H} NMR (100 MHz, DMSO-d6): 162.1, 139.9, 132.2, 132.0, 131.3, 127.1, 126.6, 125.2, 92.4, 18.3. Figures 15-16 It can be seen that the obtained compound 2g is 3-hydroxy-N-(2-methylphenyl)pyrazole.

[0125] Example 8

[0126] Preparation of Iodinated N-Arylpyrazole Compound 2h

[0127] The reaction route is as follows:

[0128]

[0129] In an air atmosphere, N-aryl-3-pyrazolidinone compound 1h (39.2 mg, 1.0 equiv, 0.2 mmol), elemental iodine I2 (5.0 mol%, 2.5 mg) and tert-butyl hydroperoxide aqueous solution (70 wt%, TBHP, 1.5 equiv, 41 uL) and 2 mL of ethyl acetate were added to a 25 mL reaction tube and reacted at room temperature for 24 hours (monitored by thin layer chromatography). After the reaction of the raw materials was complete, the reaction was quenched with sodium thiosulfate (Na2S2O3) aqueous solution. The mixture was extracted with ethyl acetate (5.0 mL) 3 times, the organic layer solution was dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (eluent, petroleum ether: ethyl acetate) to obtain 31.5 mg of N-aryl pyrazole compound 2h, with a yield of 81%.

[0130] Using H 1 The structure of the compound 2h was confirmed by NMR (Bruker FT NMR). Fig.17 As shown: 1 H NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H), 7.86 (d, J = 2.6 Hz, 1H), 7.63-7.60 (m, 1H), 7.54-7.52 (m, 1H), 7.47-7.43 (m, 1H), 7.40-7.35 (m, 1H), 5.80 (d, J = 2.6 Hz, 1H); C 13 The structure of the compound 2h was confirmed by NMR (Bruker FT NMR). Fig.18 As shown: 13 C{ 1 H} NMR (100 MHz, DMSO-d6): 162.6, 137.8, 133.0, 130.6, 128.5, 128.2, 127.3, 126.5, 93.5. Figures 17-18 It can be seen that the obtained compound 2h is 3-hydroxy-N-(2-chlorophenyl)pyrazole.

[0131] Example 9

[0132] Preparation of N-arylpyrazole compound 2i

[0133] The reaction route is as follows:

[0134]

[0135] In an air atmosphere, N-aryl-3-pyrazolidinone compound 1i (39.2 mg, 1.0 equiv, 0.2 mmol), elemental iodine I2 (5.0 mol%, 2.5 mg) and tert-butyl hydroperoxide aqueous solution (70 wt%, TBHP, 1.5 equiv, 41 uL) and 2 mL of ethyl acetate were added to a 25 mL reaction tube and reacted at room temperature for 24 hours (monitored by thin layer chromatography). After the reaction of the raw materials was complete, the reaction was quenched with sodium thiosulfate (Na2S2O3) aqueous solution. The mixture was extracted with ethyl acetate (5.0 mL) three times, the organic layer solution was dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (eluent, petroleum ether: ethyl acetate) to obtain 32.6 mg of N-aryl pyrazole compound 2i with a yield of 84%.

[0136] Using H 1 The structure of the compound 2i was confirmed by NMR (Bruker FT NMR). Fig.19 As shown: 1 H NMR (400 MHz, DMSO-d6): δ 10.40 (s, 1H), 8.32 (d, J = 2.4 Hz, 1H), 7.77-7.76 (m, 1H), 7.67-7.64 (m, 1H), 7.46-7.42 (m, 1H), 7.23-7.20 (m, 1H), 5.85 (d, J = 2.4 Hz, 1H); C 13 The structure of the compound 2i was confirmed by NMR (Bruker FT NMR). Fig. 20 As shown: 13 C{ 1 H} NMR (100 MHz, DMSO-d6): 163.0, 141.0, 133.9, 131.1, 129.1, 124.2, 116.4, 115.2, 95.3. Figures 19-20 It can be seen that the obtained compound 2i is 3-hydroxy-N-(3-chlorophenyl)pyrazole.

[0137] Example 10

[0138] Preparation of N-arylpyrazole compound 2j

[0139] The reaction route is as follows:

[0140]

[0141] In an air atmosphere, N-aryl-3-pyrazolidinone compound 1j (48.0 mg, 1.0 equiv, 0.2 mmol), elemental iodine I2 (5.0 mol%, 2.5 mg) and tert-butyl hydroperoxide aqueous solution (70 wt%, TBHP, 1.5 equiv, 41 uL) and 2 mL of ethyl acetate were added to a 25 mL reaction tube and reacted at room temperature for 24 hours (monitored by thin layer chromatography). After the reaction of the raw materials was complete, the reaction was quenched with sodium thiosulfate (Na2S2O3) aqueous solution. The mixture was extracted with ethyl acetate (5.0 mL) three times, the organic layer solution was dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (eluent, petroleum ether: ethyl acetate) to obtain 41.6 mg of N-aryl pyrazole compound 2j with a yield of 87%.

[0142] Using H 1 The structure of the compound 2j was confirmed by NMR (Bruker FT NMR). Fig.21 As shown: 1 H NMR (400 MHz, DMSO-d6): δ 10.40 (s, 1H), 8.31 (d, J = 2.6 Hz, 1H), 7.90-7.89 (m, 1H), 7.71-7.68 (m, 1H), 7.40-7.34 (m, 2H), 5.85 (d, J = 2.6 Hz, 1H); C 13 The structure of the compound 2j was confirmed by NMR (Bruker FT NMR). Fig. 22 As shown: 13 C{ 1 H} NMR (100 MHz, DMSO-d6): 163.0, 141.1, 131.4, 129.1, 127.1, 122.3, 119.2, 115.5, 95.3. Figures 21-22 It can be seen that the obtained compound 2j is 3-hydroxy-N-(3-bromophenyl)pyrazole.

[0143] Embodiment 11

[0144] Preparation of N-arylpyrazole compound 2k

[0145] The reaction route is as follows:

[0146]

[0147] In an air atmosphere, N-aryl-3-pyrazolidinone compound 1k (46.0 mg, 1.0 equiv, 0.2 mmol), elemental iodine I2 (5.0 mol%, 2.5 mg) and tert-butyl hydroperoxide aqueous solution (70 wt%, TBHP, 1.5 equiv, 41 uL) and 2 mL of ethyl acetate were added to a 25 mL reaction tube and reacted at room temperature for 24 hours (monitored by thin layer chromatography). After the reaction of the raw materials was complete, the reaction was quenched with sodium thiosulfate (Na2S2O3) aqueous solution. The mixture was extracted with ethyl acetate (5.0 mL) three times, the organic layer solution was dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (eluent, petroleum ether: ethyl acetate) to obtain 30.4 mg of N-aryl pyrazole compound 2k with a yield of 66%.

[0148] Using H 1 The structure of the compound 2k was confirmed by NMR (Bruker FT NMR). Fig.23 As shown: 1 H NMR (400 MHz, DMSO-d6): δ 10.30 (s, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.82-7.81 (m, 1H), 7.54-7.53 (m, 2H), 5.82 (d, J = 2.4 Hz, 1H); C 13 The structure of the compound 2k was confirmed by NMR (Bruker FT NMR). Fig.24 As shown: 13 C{ 1 H} NMR (100 MHz, DMSO-d6): 162.8, 136.9, 133.2, 131.8, 130.1, 128.4, 128.3, 127.4, 94.1. Figures 23-24 It can be seen that the obtained compound 2k is 3-hydroxy-N-(2,4-dichlorophenyl)pyrazole.

[0149] Example 12

[0150] Preparation of N-arylpyrazole compound 2l

[0151] The reaction route is as follows:

[0152]

[0153] In an air atmosphere, N-aryl-3-pyrazolidinone compound 11 (42.4 mg, 1.0 equiv, 0.2 mmol), elemental iodine I2 (5.0 mol%, 2.5 mg) and tert-butyl hydroperoxide aqueous solution (70 wt%, TBHP, 1.5 equiv, 41 uL) and 2 mL of ethyl acetate were added to a 25 mL reaction tube and reacted at room temperature for 24 hours (monitored by thin layer chromatography). After the reaction of the raw materials was complete, the reaction was quenched with sodium thiosulfate (Na2S2O3) aqueous solution. The mixture was extracted with ethyl acetate (5.0 mL) three times, the organic layer solution was dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (eluent, petroleum ether: ethyl acetate) to obtain 28.2 mg of N-aryl pyrazole compound 21 with a yield of 67%.

[0154] Using H 1 The structure of the compound 21 was confirmed by NMR (Bruker FT NMR). Fig.25 As shown: 1 H NMR (400 MHz, DMSO-d6): δ 10.33 (s, 1H), 8.37 (d, J = 2.4 Hz, 1H), 8.14-8.13 (m, 1H), 8.00-7.95 (m, 2H), 7.93-7.90 (m, 2H), 7.55-7.51 (m, 1H), 7.47-7.43 (m, 1H), 5.87 (d, J = 2.4 Hz, 1H); C 13 The structure of the compound 21 was confirmed by NMR (Bruker FT NMR). Fig.26 As shown: 13 C{ 1 H} NMR (100 MHz, DMSO-d6): 162.9, 137.4, 133.4, 130.4, 129.3, 128.8, 127.7, 127.5, 127.0, 125.2, 117.0, 113.1, 94.7. Figures 25-26 It can be seen that the obtained compound 21 is 3-hydroxy-N-naphthylpyrazole.

[0155] Example 13

[0156] Preparation of N-arylpyrazole compound 2m

[0157] The reaction route is as follows:

[0158]

[0159] In an air atmosphere, N-aryl-3-pyrazolidinone compound 1m (38.4 mg, 1.0 equiv, 0.2 mmol), elemental iodine I2 (5.0 mol%, 2.5 mg) and tert-butyl hydroperoxide aqueous solution (70 wt%, TBHP, 1.5 equiv, 41 uL) and 2 mL of ethyl acetate were added to a 25 mL reaction tube and reacted at room temperature for 24 hours (monitored by thin layer chromatography). After the reaction of the raw materials was complete, the reaction was quenched with sodium thiosulfate (Na2S2O3) aqueous solution. The mixture was extracted with ethyl acetate (5.0 mL) 3 times, the organic layer solution was dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (eluent, petroleum ether: ethyl acetate) to obtain 20.3 mg of N-aryl pyrazole compound 2m with a yield of 53%.

[0160] Using H 1 The structure of the compound 2m was confirmed by NMR (Bruker FT NMR). Fig. 27 As shown: 1 H NMR (400 MHz, DMSO-d6): δ 10.29 (s, 1H), 8.24 (d, J = 2.6 Hz, 1H), 7.33-7.29 (m, 1H), 7.26-7.24 (m, 2H), 6.76-6.73 (m, 1H), 5.80 (d, J = 2.4 Hz, 1H), 3.79 (s, 3H); C 13 The structure of the compound 2m was confirmed by NMR (Bruker FT NMR). Fig.28 As shown: 13 C{ 1 H} NMR (100 MHz, DMSO-d6): 162.6, 160.1, 141.0, 130.3, 128.7, 110.3, 108.9, 102.5, 94.5, 55.3. Figures 27-28 It can be seen that the obtained compound 2m is 3-hydroxy-N-(3-methoxyphenyl)pyrazole.

[0161] Embodiment 14

[0162] Preparation of N-arylpyrazole compound 2n

[0163] The reaction route is as follows:

[0164]

[0165] In an air atmosphere, N-aryl-3-pyrazolidinone compound 1n (45.2 mg, 1.0 equiv, 0.2 mmol), elemental iodine I2 (5.0 mol%, 2.5 mg) and tert-butyl hydroperoxide aqueous solution (70 wt%, TBHP, 1.5 equiv, 41 uL) and 2 mL of ethyl acetate were added to a 25 mL reaction tube and reacted at 45°C for 3 hours (monitored by thin layer chromatography). After the reaction of the raw materials was complete, the reaction was quenched with sodium thiosulfate (Na2S2O3) aqueous solution. The mixture was extracted with ethyl acetate (5.0 mL) 3 times, the organic layer solution was dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (eluent, petroleum ether: ethyl acetate) to obtain 11.2 mg of N-aryl pyrazole compound 2n with a yield of 25%.

[0166] Using H 1 The structure of the compound 2n was confirmed by NMR (Bruker FT NMR). Fig.29 As shown: 1 H NMR (400 MHz, DMSO-d6): δ 9.99 (s, 1H), 8.01-7.95 (m, 4H), 7.68-7.66 (m, 1H), 7.58-7.50 (m, 2H), 5.64 (d, J = 0.6 Hz, 1H), 2.36 (d, J = 0.6 Hz, 3H); C 13 The structure of the compound 2n was confirmed by NMR (Bruker FT NMR). Fig.30 As shown: 13 C{ 1 H} NMR (100 MHz, DMSO-d6): 161.6, 139.9, 137.2, 133.0, 131.0, 128.7, 127.8, 127.6, 126.8, 126.0, 122.6, 120.4, 94.1, 12.9. Figures 29-30 It can be seen that the obtained compound 2n is 3-hydroxy-5-methyl-N-naphthylpyrazole.

[0167] Embodiment 15

[0168] Preparation of N-arylpyrazole compound 2o

[0169] The reaction route is as follows:

[0170]

[0171] In an air atmosphere, N-aryl-3-pyrazolidinone compound 1o (47.6 mg, 1.0 equiv, 0.2 mmol), elemental iodine I2 (5.0 mol%, 2.5 mg) and tert-butyl hydroperoxide aqueous solution (70 wt%, TBHP, 1.5 equiv, 41 uL) and 2 mL of ethyl acetate were added to a 25 mL reaction tube and reacted at 45 ° C for 24 hours (monitored by thin layer chromatography). After the reaction of the raw materials was complete, the reaction was quenched with sodium thiosulfate (Na2S2O3) aqueous solution. Ethyl acetate (5.0 mL) was extracted three times, the organic layer solution was dried over anhydrous sodium sulfate, concentrated, and then the crude product was separated by column chromatography (eluent, petroleum ether: ethyl acetate) to obtain 25.6 mg of N-aryl pyrazole compound 2o, with a yield of 54%.

[0172] Using H 1 The structure of compound 2o was confirmed by NMR (Bruker FT NMR). Fig.31 As shown: 1 H NMR (400 MHz, DMSO-d6): δ 10.16 (s, 1H), 7.33-7.32 (m, 5H), 7.27-7.25 (m, 1H), 7.24-7.20 (m, 2H), 7.17-7.15 (m, 2H), 5.93 (s, 1H); C 13 The structure of compound 2o was confirmed by NMR (Bruker FT NMR). Fig.32 As shown: 13 C{ 1 H} NMR (100 MHz, DMSO-d6): 161.7, 143.1, 139.9, 130.4, 128.8, 128.5, 128.3, 126.5, 124.5, 94.3. Figures 31-32 It can be seen that the obtained compound 2o is 3-hydroxy-N,5-diphenylpyrazole.

[0173] Example 16

[0174] Preparation of N-arylpyrazole compound 2p

[0175] The reaction route is as follows:

[0176]

[0177] In an air atmosphere, N-aryl-3-pyrazolidinone compound 1p (35.2 mg, 1.0 equiv, 0.2 mmol), elemental iodine I2 (5.0 mol%, 2.5 mg) and tert-butyl hydroperoxide aqueous solution (70 wt%, TBHP, 1.5 equiv, 41 uL) and 2 mL of ethyl acetate were added to a 25 mL reaction tube and reacted at 45°C for 24 hours (monitored by thin layer chromatography). After the reaction of the raw material 1p was complete, the reaction was quenched with sodium thiosulfate (Na2S2O3) aqueous solution. The mixture was extracted with ethyl acetate (5.0 mL) three times, the organic layer solution was dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (eluent, petroleum ether: ethyl acetate) to obtain 17.8 mg of N-aryl pyrazole compound 2p with a yield of 51%.

[0178] Using H 1 The structure of the compound 2p was confirmed by NMR (Bruker FT NMR). Fig.33 As shown: 1 H NMR (400 MHz, DMSO-d6): δ 10.17 (s, 1H), 8.04 (d, J = 1.0 Hz, 1H), 7.61-7.59 (m, 2H), 7.41-7.37 (m, 2H), 7.14-7.10 (m, 1H), 1.91 (d, J = 1.0 Hz, 3H); C 13 The structure of the compound 2p was confirmed by NMR (Bruker FT NMR). Fig.34 As shown: 13 C{ 1 H} NMR (100 MHz, DMSO-d6): 161.4, 139.9, 129.3, 126.6, 124.0, 116.1, 103.2, 7.1. Figures 33-34 It can be seen that the obtained compound 2p is 3-hydroxy-4-methyl-N-arylpyrazole.

[0179] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the embodiments here. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the claims of the present invention.

Claims

1. A process for preparing N-aryl pyrazole compounds, characterized in that: In ethyl acetate, N-aryl-3-pyrazolidinone compounds are used as raw materials, reacted with iodine and tert-butyl hydroperoxide in air, room temperature or 45°C to obtain N-aryl pyrazole compounds. The reaction route is as follows: Wherein, formula (1) is the N-aryl-3-pyrazolidinone compound, and formula (2) is the N-arylpyrazole compound; in formula (1) or (2), R1 is hydrogen, halogen, methyl, halomethyl, methoxy or phenyl, R2 is hydrogen, methyl or phenyl, and R3 is hydrogen or methyl.

2. The process for preparing N-aryl pyrazole compounds according to claim 1, characterized in that: The N-aryl pyrazole compound is selected from: 。 3. The process for preparing N-aryl pyrazole compounds according to claim 2, characterized in that: The N-aryl-3-pyrazolidinone compound is selected from: 。 4. The process for preparing N-aryl pyrazole compounds according to any one of claims 1 to 3, characterized in that: The following steps are involved: S1. mixing an N-aryl-3-pyrazolidinone compound, elemental iodine, tert-butyl hydroperoxide and ethyl acetate; S2. The mixture obtained in step S1 is reacted in air, at room temperature or at 45 ° C until the reaction is complete; S3. Extract the product obtained in step S2 with ethyl acetate, take the organic layer solution, dry it, concentrate it, separate and purify it.

5. The process for preparing N-aryl pyrazole compounds according to claim 4, characterized in that: In step S1, based on the molar amount of the N-aryl-3-pyrazolidinone compound, the amount of elemental iodine added is 0.05 equivalents, and the amount of tert-butyl hydroperoxide added is 1.5 equivalents.

6. The process for preparing N-aryl pyrazole compounds according to claim 5, characterized in that: In step S1, the usage ratio of the ethyl acetate to the N-aryl-3-pyrazolidinone compound is 2 mL:0.2 mmol.

7. The process for preparing N-aryl pyrazole compounds according to claim 4, characterized in that: In step S2, the reaction endpoint is monitored by thin layer chromatography, and the reaction is quenched with an aqueous sodium thiosulfate solution.

8. The process for preparing N-aryl pyrazole compounds according to claim 4, characterized in that: In step S3, the organic layer solution is dried using anhydrous sodium sulfate, and is separated and purified by column chromatography using petroleum ether and ethyl acetate as eluents.

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