A N-oxazole-4-methylbenzenesulfonamide compound and its preparation method and application

Abstract

The present invention provides an N-oxazole-4-methylbenzenesulfonamide compound and a preparation method and application thereof. Sulfonylaminophenol, an azole compound and a hypervalent iodine reagent are added to a solvent, and then stirred and reacted at 50°C to 70°C for 12 to 15 hours. After the reaction is completed, the N-oxazole-4-methylbenzenesulfonamide compound is obtained through separation and purification. The N-oxazole-4-methylbenzenesulfonamide compound can be used as a pharmaceutical intermediate. The present invention overcomes the shortcomings of the prior art, has mild reaction conditions, uses cheap and readily available raw materials, is simple to operate, can significantly reduce production costs, and improves production safety.

Description

Technical Field

[0001] The present invention relates to the technical field of preparation of benzenesulfonamide compounds, and in particular to an N-oxazole-4-methylbenzenesulfonamide compound and a preparation method and application thereof. Background Art

[0002] N-oxazole-4-methylbenzenesulfonamide compounds are an important class of compounds that exhibit some excellent properties in terms of biological activity and can be used as drug lead compounds, such as sulfabenzazole, celecoxib, lecithinamide, niraparib, etc.

[0003] The most common approaches to obtain N-oxazole-4-methylbenzenesulfonamide compounds are through nucleophilic substitution reactions between azole compounds and halogenated aromatic hydrocarbons, or through electrochemical synthesis of N-oxazole-4-methylbenzenesulfonamide compounds. However, the preparation of simple N-oxazole-4-methylbenzenesulfonamide compounds through electrocatalysis is relatively cumbersome, requires nitrogen protection, and is inconvenient for post-processing. N-oxazole-4-methylbenzenesulfonamide compounds are important pharmaceutical synthesis intermediates, which limits their further development and application. Summary of the Invention

[0004] The purpose of the present invention is to provide an N-oxazole-4-methylbenzenesulfonamide compound and a preparation method and application thereof, which overcome the shortcomings of the prior art.

[0005] In order to solve the above problems, the technical solutions adopted by the present invention are as follows:

[0006] The method for preparing an N-oxazole-4-methylbenzenesulfonamide compound comprises adding a sulfonylaminophenol, an azole compound and a high-valent iodine reagent into a solvent, and then stirring the mixture at 50° C.-70° C. for 12 h-15 h. After the reaction is completed, the mixture is separated and purified to obtain the N-oxazole-4-methylbenzenesulfonamide compound.

[0007] The azole compound is at least one of pyrazole, 1,2,4-triazole, 1,2,3-triazole, 1H-indazole, 2H-indazole, benzotriazole, 4-fluoropyrazole, 4-chloropyrazole, 4-bromopyrazole, 4-iodopyrazole, 4-acetylpyrazole, 3-methylpyrazole, 3-isopropylpyrazole, 4-tert-butylpyrazole, 3-phenylpyrazole, 3-thienylpyrazole, and 3,5-dimethylpyrazole.

[0008] Wherein, the sulfonylaminophenol is 4-tolylsulfonylphenol, and the structural formula is:

[0009]

[0010] R1 is p-tolyl.

[0011] Wherein, the high-valent iodine reagent is a trivalent iodine compound or a pentavalent iodine compound.

[0012] Wherein, the hypervalent iodine reagent is at least one of iodobenzene acetate, [bis(trifluoroacetoxy)iodo]benzene, dichloroiodobenzene, 2-iodoacylbenzoic acid, and Dess-Martin reagent.

[0013] The molar ratio of the sulfonylaminophenol, the azole compound and the hypervalent iodine reagent is 1.25:1:1.25.

[0014] The separation and purification steps include extraction, reduced pressure distillation and column chromatography separation.

[0015] The extraction used water and dichloromethane, and the column chromatography separation used a mixture of petroleum ether and ethyl acetate as an eluent.

[0016] Wherein, the solvent is dichloromethane.

[0017] The structure of the prepared N-oxazole-4-methylbenzenesulfonamide compound is as follows:

[0018]

[0019] Wherein, R1 is p-tolyl; R2 is hydrogen, fluorine, chlorine, bromine, iodine, acetyl, methoxy, methyl, isopropyl, tert-butyl, thienyl or phenyl.

[0020] Compared with the prior art, the present invention has the following advantages: The present invention provides a method for synthesizing an N-oxazole-4-methylbenzenesulfonamide compound. This method, without the involvement of transition metals, utilizes sulfonylaminophenol, an azole compound, and a hypervalent iodine reagent for direct oxidative coupling to obtain the N-oxazole-4-methylbenzenesulfonamide compound. The use of a safe hypervalent iodine reagent as an inducing agent, along with mild reaction conditions, readily available and inexpensive raw materials, and simple operation, can significantly reduce production costs and improve production safety. The N-oxazole-4-methylbenzenesulfonamide compound obtained by the present invention is an important pharmaceutical intermediate. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 Schematic diagram of the reaction mechanism of Example 1. DETAILED DESCRIPTION

[0022] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0023] Example 1

[0024] First, sulfonylaminophenol, azole compound, hypervalent iodine reagent, and solvent were added to a dry reaction tube in sequence. After mixing and stirring at room temperature for a while, the reaction solution was placed in a 60°C oil bath and stirred for 12 hours. In this example, the R1 group in the sulfonylaminophenol is p-tolyl, and the amount of sulfonylaminophenol added in the synthesis reaction is 0.5 mmol. The azole compound is pyrazole, and the amount of azole compound added in the synthesis reaction is 0.4 mmol. The reaction equation is as follows:

[0025]

[0026] The hypervalent iodine reagent is a trivalent iodine compound, iodobenzene acetate. The hypervalent iodine reagent can also be replaced by a trivalent iodine compound, [bis(trifluoroacetoxy)iodo]benzene or dichloroiodobenzene, or a pentavalent iodine compound, 2-iodoacylbenzoic acid, or a Dess-Martin reagent. The amount of the hypervalent iodine reagent added is 0.5 mmol, and the solvent is CH2Cl2 (dichloromethane), and the amount of CH2Cl2 added is 4 mL. After completion of the reaction, 10 mL of water is added to the reaction solution, and the reaction solution is extracted with dichloromethane. The organic phase is dried over anhydrous Na2SO4, filtered, and the solvent is removed by distillation under reduced pressure. The product is then separated by column chromatography using silica gel as a filler (the eluent is a mixture of petroleum ether and ethyl acetate) to obtain N-(4-hydroxy-3-(1H-pyrazol-1-yl)phenyl)-4-methylbenzenesulfonamide in a yield of 79%.

[0027] Example 2

[0028] The synthetic reaction operation steps of this embodiment are the same as those of Example 1, except that the raw materials are different. The R1 group in the sulfonylaminophenol is p-tolyl, and the amount of sulfonylaminophenol added in the synthetic reaction is 0.5 mmol. The azole compound is 1,2,4-triazole, and the amount of azole compound added in the synthetic reaction is 0.4 mmol.

[0029] The hypervalent iodine reagent is a trivalent iodine compound iodobenzene acetate. The hypervalent iodine reagent can also be replaced by a trivalent iodine compound [bis(trifluoroacetyloxy)iodine]benzene or dichloroiodobenzene, or a pentavalent iodine compound 2-iodoacylbenzoic acid or Dess-Martin reagent. The amount of the hypervalent iodine reagent added is 0.5 mmol, and the solvent is CH2Cl2 (dichloromethane), and the amount of CH2Cl2 added is 4 mL. After the reaction is completed, the operation steps are the same as in Example 1, and the product is N-(4-hydroxy-3-(1H-1,2,4-triazol-1-yl)phenyl)-4-methylbenzenesulfonamide, with a yield of 50%.

[0030] Example 3

[0031] The synthetic reaction operation steps of this embodiment are the same as those of Example 1, except that the raw materials are different. The R1 group in the sulfonylaminophenol is p-tolyl, and the amount of sulfonylaminophenol added in the synthetic reaction is 0.5 mmol; the azole compound is 1,2,3-triazole, and the amount of azole compound added in the synthetic reaction is 0.4 mmol.

[0032] The hypervalent iodine reagent is a trivalent iodine compound iodobenzene acetate. The hypervalent iodine reagent can also be replaced by a trivalent iodine compound [bis(trifluoroacetyloxy)iodine]benzene or dichloroiodobenzene, or a pentavalent iodine compound 2-iodoacylbenzoic acid or Dess-Martin reagent. The amount of the hypervalent iodine reagent added is 0.5 mmol, and the solvent is CH2Cl2 (dichloromethane), and the amount of CH2Cl2 added is 4 mL. After the reaction is completed, the operating steps are the same as in Example 1, and the product obtained is N-(4-hydroxy-3-(1H-1,2,3-triazol-1-yl)phenyl)-4-methylbenzenesulfonamide, with a yield of 77%.

[0033] Example 4

[0034] The synthetic reaction operation steps of this embodiment are the same as those of Example 1, except that the raw materials are different. The R1 group in the sulfonylaminophenol is p-tolyl, and the amount of sulfonylaminophenol added in the synthetic reaction is 0.5 mmol. The azole compound is 1H-indazole, and the amount of azole compound added in the synthetic reaction is 0.4 mmol.

[0035] The hypervalent iodine reagent is a trivalent iodine compound, iodobenzene acetate. The hypervalent iodine reagent can also be replaced by a trivalent iodine compound, [bis(trifluoroacetyloxy)iodine]benzene or dichloroiodobenzene, or a pentavalent iodine compound, 2-iodoxybenzoic acid, or a Dess-Martin reagent. The amount of the hypervalent iodine reagent added is 0.5 mmol, and the solvent is CH2Cl2 (dichloromethane), and the amount of CH2Cl2 added is 4 mL. After completion of the reaction, the operation steps are the same as in Example 1, and the product obtained is N-(4-hydroxy-3-(1H-indazol-1-yl)phenyl)-4-methylbenzenesulfonamide, with a yield of 63%.

[0036] Example 5

[0037] The synthetic reaction operation steps of this embodiment are the same as those of Example 1, except that the raw materials are different. The R1 group in the sulfonylaminophenol is p-tolyl, and the amount of sulfonylaminophenol added in the synthetic reaction is 0.5 mmol; the azole compound is 2H-indazole, and the amount of azole compound added in the synthetic reaction is 0.4 mmol.

[0038] The hypervalent iodine reagent is a trivalent iodine compound, iodobenzene acetate. The hypervalent iodine reagent can also be replaced by a trivalent iodine compound, [bis(trifluoroacetyloxy)iodine]benzene or dichloroiodobenzene, or a pentavalent iodine compound, 2-iodoacylbenzoic acid, or a Dess-Martin reagent. The amount of the hypervalent iodine reagent added is 0.5 mmol, and the solvent is CH2Cl2 (dichloromethane), and the amount of CH2Cl2 added is 4 mL. After completion of the reaction, the operation steps are the same as in Example 1, and the product obtained is N-(4-hydroxy-3-(2H-indazol-2-yl)phenyl)-4-methylbenzenesulfonamide, with a yield of 68%.

[0039] Example 6

[0040] The synthetic reaction operation steps of this embodiment are the same as those of Example 1, except that the raw materials are different. The R1 group in the sulfonylaminophenol is p-tolyl, and the amount of sulfonylaminophenol added in the synthetic reaction is 0.5 mmol; the azole compound is benzotriazole, and the amount of azole compound added in the synthetic reaction is 0.4 mmol.

[0041] The hypervalent iodine reagent is a trivalent iodine compound, iodobenzene acetate. The hypervalent iodine reagent can also be replaced by a trivalent iodine compound, [bis(trifluoroacetyloxy)iodo]benzene or dichloroiodobenzene, or a pentavalent iodine compound, 2-iodoacylbenzoic acid, or a Dess-Martin reagent. The amount of the hypervalent iodine reagent added is 0.5 mmol, and the solvent is CH2Cl2 (dichloromethane), and the amount of CH2Cl2 added is 4 mL. After completion of the reaction, the operation steps are the same as in Example 1, and the product is N-(3-(1H-benzo[d][1,2,3]triazol-1-yl)-4-hydroxyphenyl)-4-methylbenzenesulfonamide, with a yield of 51%.

[0042] Example 7

[0043] The synthetic reaction operation steps of this embodiment are the same as those of Example 1, except that the raw materials are different. The R1 group in the sulfonylaminophenol is p-tolyl, and the amount of sulfonylaminophenol added in the synthetic reaction is 0.5 mmol. The azole compound is 4-fluoropyrazole, and the amount of azole compound added in the synthetic reaction is 0.4 mmol.

[0044] The hypervalent iodine reagent is a trivalent iodine compound, iodobenzene acetate. The hypervalent iodine reagent can also be replaced by a trivalent iodine compound, [bis(trifluoroacetyloxy)iodine]benzene or dichloroiodobenzene, or a pentavalent iodine compound, 2-iodoacylbenzoic acid, or a Dess-Martin reagent. The amount of the hypervalent iodine reagent added is 0.5 mmol, and the solvent is CH2Cl2 (dichloromethane), and the amount of CH2Cl2 added is 4 mL. After completion of the reaction, the operation steps are the same as in Example 1, and the product obtained is N-(3-(4-fluoro-1H-pyrazol-1-yl)-4-hydroxyphenyl)-4-methylbenzenesulfonamide, with a yield of 68%.

[0045] Example 8

[0046] The synthetic reaction operation steps of this embodiment are the same as those of Example 1, except that the raw materials are different. The R1 group in the sulfonylaminophenol is p-tolyl, and the amount of sulfonylaminophenol added in the synthetic reaction is 0.5 mmol; the azole compound is 4-chloropyrazole, and the amount of azole compound added in the synthetic reaction is 0.4 mmol.

[0047] The hypervalent iodine reagent is a trivalent iodine compound, iodobenzene acetate. The hypervalent iodine reagent can also be replaced by a trivalent iodine compound, [bis(trifluoroacetyloxy)iodine]benzene or dichloroiodobenzene, or a pentavalent iodine compound, 2-iodoacylbenzoic acid, or a Dess-Martin reagent. The amount of the hypervalent iodine reagent added is 0.5 mmol, and the solvent is CH2Cl2 (dichloromethane), and the amount of CH2Cl2 added is 4 mL. After completion of the reaction, the operation steps are the same as in Example 1, and the product obtained is N-(3-(4-chloro-1H-pyrazol-1-yl)-4-hydroxyphenyl)-4-methylbenzenesulfonamide, with a yield of 65%.

[0048] Example 9

[0049] The synthetic reaction operation steps of this embodiment are the same as those of Example 1, except that the raw materials are different. The R1 group in the sulfonylaminophenol is p-tolyl, and the amount of sulfonylaminophenol added in the synthetic reaction is 0.5 mmol. The azole compound is 4-bromopyrazole, and the amount of azole compound added in the synthetic reaction is 0.4 mmol.

[0050] The hypervalent iodine reagent is a trivalent iodine compound, iodobenzene acetate. The hypervalent iodine reagent can also be replaced by a trivalent iodine compound, [bis(trifluoroacetyloxy)iodine]benzene or dichloroiodobenzene, or a pentavalent iodine compound, 2-iodoacylbenzoic acid, or a Dess-Martin reagent. The amount of the hypervalent iodine reagent added is 0.5 mmol, and the solvent is CH2Cl2 (dichloromethane), and the amount of CH2Cl2 added is 4 mL. After completion of the reaction, the operation steps are the same as in Example 1, and the product obtained is N-(3-(4-bromo-1H-pyrazol-1-yl)-4-hydroxyphenyl)-4-methylbenzenesulfonamide, with a yield of 60%.

[0051] Example 10

[0052] The synthetic reaction operation steps of this embodiment are the same as those of Example 1, except that the raw materials are different. The R1 group in the sulfonylaminophenol is p-tolyl, and the amount of sulfonylaminophenol added in the synthetic reaction is 0.5 mmol. The azole compound is 4-iodopyrazole, and the amount of azole compound added in the synthetic reaction is 0.4 mmol.

[0053] The hypervalent iodine reagent is a trivalent iodine compound, iodobenzene acetate. The hypervalent iodine reagent can also be replaced by a trivalent iodine compound, [bis(trifluoroacetyloxy)iodine]benzene or dichloroiodobenzene, or a pentavalent iodine compound, 2-iodoacylbenzoic acid, or a Dess-Martin reagent. The amount of the hypervalent iodine reagent added is 0.5 mmol, and the solvent is CH2Cl2 (dichloromethane), and the amount of CH2Cl2 added is 4 mL. After completion of the reaction, the operation steps are the same as in Example 1, and the product obtained is N-(4-hydroxy-3-(4-iodo-1H-pyrazol-1-yl)phenyl)-4-methylbenzenesulfonamide, with a yield of 50%.

[0054] Example 11

[0055] The synthetic reaction operation steps of this embodiment are the same as those of Example 1, except that the raw materials are different. The R1 group in the sulfonylaminophenol is p-tolyl, and the amount of sulfonylaminophenol added in the synthetic reaction is 0.5 mmol. The azole compound is 4-acetylpyrazole, and the amount of azole compound added in the synthetic reaction is 0.4 mmol.

[0056] The hypervalent iodine reagent is a trivalent iodine compound, iodobenzene acetate. The hypervalent iodine reagent can also be replaced by a trivalent iodine compound, [bis(trifluoroacetyloxy)iodine]benzene or dichloroiodobenzene, or a pentavalent iodine compound, 2-iodoacylbenzoic acid, or a Dess-Martin reagent. The amount of the hypervalent iodine reagent added is 0.5 mmol, and the solvent is CH2Cl2 (dichloromethane), and the amount of CH2Cl2 added is 4 mL. After completion of the reaction, the operation steps are the same as in Example 1, and the product obtained is N-(3-(4-acetyl-1H-pyrazol-1-yl)-4-hydroxyphenyl)-4-methylbenzenesulfonamide, with a yield of 36%.

[0057] Example 12

[0058] The synthetic reaction operation steps of this embodiment are the same as those of Example 1, except that the raw materials are different. The R1 group in the sulfonylaminophenol is p-tolyl, and the amount of sulfonylaminophenol added in the synthetic reaction is 0.5 mmol; the azole compound is 3-methylpyrazole, and the amount of azole compound added in the synthetic reaction is 0.4 mmol.

[0059] The hypervalent iodine reagent is a trivalent iodine compound, iodobenzene acetate. The hypervalent iodine reagent can also be replaced by a trivalent iodine compound, [bis(trifluoroacetyloxy)iodine]benzene or dichloroiodobenzene, or a pentavalent iodine compound, 2-iodoacylbenzoic acid, or a Dess-Martin reagent. The amount of the hypervalent iodine reagent added is 0.5 mmol, and the solvent is CH2Cl2 (dichloromethane), and the amount of CH2Cl2 added is 4 mL. After completion of the reaction, the operation steps are the same as in Example 1, and the product obtained is N-(4-hydroxy-3-(3-methyl-1H-pyrazol-1-yl)phenyl)-4-methylbenzenesulfonamide, with a yield of 75%.

[0060] Example 13

[0061] The synthetic reaction operation steps of this embodiment are the same as those of Example 1, except that the raw materials are different. The R1 group in the sulfonylaminophenol is p-tolyl, and the amount of sulfonylaminophenol added in the synthetic reaction is 0.5 mmol. The azole compound is 3-isopropylpyrazole, and the amount of azole compound added in the synthetic reaction is 0.4 mmol.

[0062] The hypervalent iodine reagent is a trivalent iodine compound, iodobenzene acetate. The hypervalent iodine reagent can also be replaced by a trivalent iodine compound, [bis(trifluoroacetyloxy)iodine]benzene or dichloroiodobenzene, or a pentavalent iodine compound, 2-iodoacylbenzoic acid, or a Dess-Martin reagent. The amount of the hypervalent iodine reagent added is 0.5 mmol, and the solvent is CH2Cl2 (dichloromethane), and the amount of CH2Cl2 added is 4 mL. After completion of the reaction, the operation steps are the same as in Example 1, and the product obtained is N-(4-hydroxy-3-(3-isopropyl-1H-pyrazol-1-yl)phenyl)-4-methylbenzenesulfonamide, with a yield of 83%.

[0063] Example 14

[0064] The synthetic reaction operation steps of this embodiment are the same as those of Example 1, except that the raw materials are different. The R1 group in the sulfonylaminophenol is p-tolyl, and the amount of sulfonylaminophenol added in the synthetic reaction is 0.5 mmol. The azole compound is 4-tert-butylpyrazole, and the amount of azole compound added in the synthetic reaction is 0.4 mmol.

[0065] The hypervalent iodine reagent is a trivalent iodine compound, iodobenzene acetate. The hypervalent iodine reagent can also be replaced by a trivalent iodine compound, [bis(trifluoroacetyloxy)iodine]benzene or dichloroiodobenzene, or a pentavalent iodine compound, 2-iodoacylbenzoic acid, or a Dess-Martin reagent. The amount of the hypervalent iodine reagent added is 0.5 mmol, and the solvent is CH2Cl2 (dichloromethane), and the amount of CH2Cl2 added is 4 mL. After completion of the reaction, the operation steps are the same as in Example 1, and the product obtained is N-(3-(4-(tert-butyl)-1H-pyrazol-1-yl)-4-hydroxyphenyl)-4-methylbenzenesulfonamide, with a yield of 79%.

[0066] Example 15

[0067] The synthetic reaction operation steps of this embodiment are the same as those of Example 1, except that the raw materials are different. The R1 group in the sulfonylaminophenol is p-tolyl, and the amount of sulfonylaminophenol added in the synthetic reaction is 0.5 mmol. The azole compound is 3-phenylpyrazole, and the amount of azole compound added in the synthetic reaction is 0.4 mmol.

[0068] The hypervalent iodine reagent is a trivalent iodine compound, iodobenzene acetate. The hypervalent iodine reagent can also be replaced by a trivalent iodine compound, [bis(trifluoroacetyloxy)iodine]benzene or dichloroiodobenzene, or a pentavalent iodine compound, 2-iodoacylbenzoic acid, or a Dess-Martin reagent. The amount of the hypervalent iodine reagent added is 0.5 mmol, and the solvent is CH2Cl2 (dichloromethane), and the amount of CH2Cl2 added is 4 mL. After completion of the reaction, the operation steps are the same as in Example 1, and the product obtained is N-(4-hydroxy-3-(3-phenyl-1H-pyrazol-1-yl)phenyl)-4-methylbenzenesulfonamide, with a yield of 65%.

[0069] Example 16

[0070] The synthetic reaction operation steps of this embodiment are the same as those of Example 1, except that the raw materials are different. The R1 group in the sulfonylaminophenol is p-tolyl, and the amount of sulfonylaminophenol added in the synthetic reaction is 0.5 mmol. The azole compound is 3-thienylpyrazole, and the amount of azole compound added in the synthetic reaction is 0.4 mmol.

[0071] The hypervalent iodine reagent is a trivalent iodine compound, iodobenzene acetate. The hypervalent iodine reagent can also be replaced by a trivalent iodine compound, [bis(trifluoroacetyloxy)iodine]benzene or dichloroiodobenzene, or a pentavalent iodine compound, 2-iodoxybenzoic acid, or a Dess-Martin reagent. The amount of the hypervalent iodine reagent added is 0.5 mmol, and the solvent is CH2Cl2 (dichloromethane), and the amount of CH2Cl2 added is 4 mL. After completion of the reaction, the operation steps are the same as in Example 1, and the product obtained is N-(4-hydroxy-3-(3-(thiophen-2-yl)-1H-pyrazol-1-yl)phenyl)-4-methylbenzenesulfonamide, with a yield of 48%.

[0072] Example 17

[0073] The synthetic reaction operation steps of this embodiment are the same as those of Example 1, except that the raw materials are different. The R1 group in the sulfonylaminophenol is p-tolyl, and the amount of sulfonylaminophenol added in the synthetic reaction is 0.5 mmol. The azole compound is 3,5-dimethylpyrazole, and the amount of azole compound added in the synthetic reaction is 0.4 mmol.

[0074] The hypervalent iodine reagent is a trivalent iodine compound iodobenzene acetate. The hypervalent iodine reagent can also be replaced by a trivalent iodine compound [bis(trifluoroacetyloxy)iodine]benzene or dichloroiodobenzene, or a pentavalent iodine compound 2-iodoacylbenzoic acid or Dess-Martin reagent. The amount of the hypervalent iodine reagent added is 0.5 mmol, and the solvent is CH2Cl2 (dichloromethane), and the amount of CH2Cl2 added is 4 mL. After the reaction is completed, the operating steps are the same as in Example 1, and the product obtained is N-(3-(3,5-dimethyl-1H-pyrazol-1-yl)-4-hydroxyphenyl)-4-methylbenzenesulfonamide, with a yield of 73%.

[0075] The raw material ratios used in the synthesis reactions of Examples 1-17 are shown in the following table:

[0076]

[0077] The structural characterization data of the N-oxazole-4-methylbenzenesulfonamide compound prepared by Example 1-17 are as follows:

[0078] The structural characterization data of N-(4-hydroxy-3-(1H-pyrazol-1-yl)phenyl)-4-methylbenzenesulfonamide prepared in Example 1 are as follows:

[0079]

[0080] 1 H NMR (600MHz, (CD3)2SO) δ (ppm) 10.34 (s, 1H), 9.95 (s, 1H), 8.27 (d, J = 2.4Hz, 1H), 7.68 (d, J = 1.8Hz, 1H), 7. 58(d,J=7.8Hz,2H),7.45(d,J=2.4Hz,1H),7.32(d,J=7.8Hz,2H),6.90-6.85(m,2H),6.45(t,J=2.4Hz,1H). 13 C NMR (150MHz, (CD3)2SO) δ (ppm) 145.8, 143.5, 140.0, 137.0, 131.4, 130.0, 129.9, 127.6, 127.1, 121.3, 118.0, 117.2, 107.0, 21.4.

[0081] The structural characterization data of N-(3-(1H-benzo[d][1,2,3]triazol-1-yl)-4-hydroxyphenyl)-4-methylbenzenesulfonamide prepared in Example 2 are as follows:

[0082]

[0083] 1 H NMR(600MHz,(CD3)2SO)δ(ppm),10.10(s,2H),8.46(d,J=0.6Hz,1H),7.87(d,J=1.2Hz,1H),7.60(d,J=8.4Hz ,2H),7.35(d,J=2.4Hz,1H),7.34(s,1H),7.32(s,1H),7.06-7.04(m,1H),6.97(d,J=9.0Hz,1H),2.32(s,3H). 13CNMR(150MHz,(CD3)2SO)δ(ppm)146.9,143.6,136.9,133.7,130.1,129.8,127.2,126.8,124.7,123.7,118.5,118.0,21.4.

[0084] The structural characterization data of N-(4-hydroxy-3-(1H-1,2,4-triazol-1-yl)phenyl)-4-methylbenzenesulfonamide prepared in Example 3 are as follows:

[0085]

[0086] 1 H NMR(600MHz,(CD3)2SO)δ(ppm)10.59(s,1H),10.02(s,1H),8.97(s,1H),8.16(s,1H),7.59(d, J=7.8Hz,2H),7.41(d,J=2.4Hz,1H),7.32(d,J=8.4Hz,2H),6.95(t,J=2.4Hz,2H),2.31(s,3H). 13 C NMR (150MHz, (CD3)2SO) δ (ppm) 151.5, 146.3, 145.1, 143.6, 136.9, 130.1, 130.0, 127.1, 124.9, 122.5, 117.9, 117.4, 21.4.

[0087] The structural characterization data of N-(4-hydroxy-3-(1H-indazol-1-yl)phenyl)-4-methylbenzenesulfonamide prepared in Example 4 are as follows:

[0088]

[0089] 1 H NMR (600MHz, (CD3)2SO) δ (ppm) 10.75 (s, 1H), 10.09 (s, 1H), 8.91 (s, 1H), 7.76 (d, J = 8.4Hz, 1H) ,7.72-7.68(m,2H),7.65(d,J=8.4Hz,2H),7.31-7.29(m,3H),7.08-7.04(m,3H),2.27(s,3H). 13C NMR(150MHz,(CD3)2SO)δ(ppm)148.1,146.9,143.6,137.0,130.1,129.7,127.7,12 7.26,127.24,126.1,125.7,122.8,122.2,122.1,121.4,118.6,118.4,117.4,21.3.

[0090] The structural characterization data of N-(4-hydroxy-3-(2H-indazol-2-yl)phenyl)-4-methylbenzenesulfonamide prepared in Example 5 are as follows:

[0091]

[0092] 1 H NMR (600MHz, (CD3)2SO) δ (ppm) 10.67 (s, 1H), 10.02 (s, 1H), 8.88 (s, 1H), 7.78-7.76 (m, 1H), 7.68-7.67 (m, 1H), 7.63 (d, J = 1. 8Hz,1H),7.62-7.60(m,2H),7.33(d,J=7.8Hz,2H),7.31-7.29(m,1H),7.09-7.06(m,1H),7.00(t,J=2.4Hz,2H),2.31(s,3H). 13 CNMR(150MHz,(CD3)2SO)δ(ppm)148.1,146.8,143.6,136.9,130.1,130.0,12 7.7,127.22,127.20,125.7,122.8,122.1,121.5,118.6,118.3,117.4,21.4.

[0093] The structural characterization data of N-(3-(1H-benzo[d][1,2,3]triazol-1-yl)-4-hydroxyphenyl)-4-methylbenzenesulfonamide prepared in Example 6 are as follows:

[0094]

[0095] 1H NMR (600MHz, (CD3)2SO) δ (ppm) 10.38 (s, 1H), 10.10 (s, 1H), 8.11 (d, J = 8.4Hz, 1H), 7.63 (d, J = 8.4Hz, 2H), 7.54 (t, J = 7.8Hz, 1H), 7.43 (t ,J=7.8Hz,1H),7.34(d,J=7.8Hz,2H),7.32(d,J=7.8Hz,1H),7.23-7.21(m,1H),7.12(d,J=3.0Hz,1H),7.08(d,J=8.4,1H),2.31(s,3H). 13 CNMR(150MHz,(CD3)2SO)δ(ppm)149.5,145.3,143.7,136.8,133.8,130.1,1 29.9,128.3,127.2,125.3,124.6,123.5,121.6,119.7,118.1,111.7,21.3.

[0096] The structural characterization data of N-(3-(4-fluoro-1H-pyrazol-1-yl)-4-hydroxyphenyl)-4-methylbenzenesulfonamide prepared in Example 7 are as follows:

[0097]

[0098] 1 H NMR (600MHz, (CD3)2SO) δ (ppm) 10.38 (s, 1H), 10.00 (s, 1H), 8.35 (d, J = 4.2Hz, 1H), 7.75 (d, J = 3.6Hz, 1H) ,7.61-7.60(m,2H),7.44(d,J=2.4Hz,1H),7.30(s,1H),7.29(s,1H),6.93(t,J=2.4Hz,2H),2.28(s,3H). 13 CNMR(150MHz,(CD3)2SO)δ(ppm)150.7,149.0,145.8,143.5,137.0,130.06,13 0.00,127.8,127.69,127.60,127.2,121.7,118.3,118.1,117.9,117.2,21.3.

[0099] The structural characterization data of N-(3-(4-chloro-1H-pyrazol-1-yl)-4-hydroxyphenyl)-4-methylbenzenesulfonamide prepared in Example 8 are as follows:

[0100]

[0101] 1 H NMR(600MHz,(CD3)2SO)δ(ppm)10.36(s,1H),10.00(s,1H),8.40(s,1H),7.79(s,1H),7 .59(d,J=8.4Hz,2H),7.40(s,1H),7.31(s,1H),7.30(s,1H),6.92(s,2H),2.30(s,3H). 13 C NMR (150MHz, (CD3)2SO) δ (ppm) 146.1, 143.6, 138.5, 136.9, 130.0, 129.9, 127.4, 127.1, 122.0, 117.9, 117.4, 109.8, 21.3.

[0102] The structural characterization data of N-(3-(4-bromo-1H-pyrazol-1-yl)-4-hydroxyphenyl)-4-methylbenzenesulfonamide prepared in Example 9 are as follows:

[0103]

[0104] 1 H NMR(600MHz,(CD3)2SO)δ(ppm)10.01(s,2H),8.40(s,1H),7.79(s,1H),7.59-7.5 7(m,2H),7.39(t,J=1.8Hz,1H),7.31(d,J=7.8Hz,2H),6.91(s,2H),2.30(s,3H). 13 CNMR(150MHz,(CD3)2SO)δ(ppm)146.1,143.6,140.5,136.9,131.9,130.0,129.9,127.4,127.1,122.0,117.9,117.4,93.7,21.3.

[0105] The structural characterization data of N-(4-hydroxy-3-(4-iodo-1H-pyrazol-1-yl)phenyl)-4-methylbenzenesulfonamide prepared in Example 10 are as follows:

[0106]

[0107] 1H NMR(600MHz,(CD3)2SO)δ(ppm)10.39(s,1H),9.99(s,1H),8.35(s,1H),7.77(s,1H),7.59(d,J= 7.8Hz,2H),7.40(t,J=1.8Hz,1H),7.31(s,1H),7.30(s,1H),6.92(d,J=1.8Hz,2H),2.29(s,3H). 13 C NMR (150MHz, (CD3)2SO) δ (ppm) 146.1, 144.9, 143.5, 136.9, 135.8, 130.0, 129.9, 127.3, 127.1, 121.9, 117.9, 117.3, 59.3, 21.4.

[0108] The structural characterization data of N-(3-(4-acetyl-1H-pyrazol-1-yl)-4-hydroxyphenyl)-4-methylbenzenesulfonyl prepared in Example 11 are as follows:

[0109]

[0110] 1 H NMR(600MHz,(CD3)2SO)δ(ppm)10.50(s,1H),10.02(s,1H),8.79(s,1H),8.13(s,1H),7.59(d,J=8.4H z,2H),7.45(d,J=2.4Hz,1H),7.32(d,J=8.4Hz,2H),6.95(d,J=2.4Hz,2H),2.41(s,3H),2.30(s,3H). 13 CNMR(150MHz,(CD3)2SO)δ(ppm)192.2,146.3,143.6,140.7,136.9,134.7,130.1,129.9,127.1,127.0,124.8,122.4,118.0,117.9,28.4,21.3.

[0111] The structural characterization data of N-(4-hydroxy-3-(3-methyl-1H-pyrazol-1-yl)phenyl)-4-methylbenzenesulfonamide prepared in Example 12 are as follows:

[0112]

[0113] 1HNMR (600MHz, (CD3)2SO) δ (ppm) 10.44 (s, 1H), 9.92 (s, 1H), 8.19 (d, J = 2.4Hz, 1H), 7.61-7.60 (m, 2H), 7.45 ( d,J=3.0Hz,1H),7.29(d,J=7.8Hz,2H),6.90-6.85(m,2H),6.24(d,J=2.4Hz,1H),2.27(s,3H),2.23(s,3H). 13 CNMR(150MHz,(CD3)2SO)δ(ppm)148.7,145.6,143.5,137.0,131.8,130.0,129.9,127.4,127.2,120.9,118.0,116.5,107.0,21.3,13.7.

[0114] The structural characterization data of N-(4-hydroxy-3-(3-isopropyl-1H-pyrazol-1-yl)phenyl)-4-methylbenzenesulfonamide prepared in Example 13 are as follows:

[0115]

[0116] 1 H NMR (600MHz, (CD3)2SO) δ (ppm) 10.52 (s, 1H), 9.92 (s, 1H), 8.19 (d, J = 2.4Hz, 1H), 7.62-7.61 (m, 2H), 7.45 (d, J = 3.0Hz, 1H), 7.29 (d, J =7.8Hz,2H),6.89(d,J=8.4Hz,1H),6.86-6.84(m,1H),6.30(d,J=2.4Hz,1H),2.98-2.91(m,1H),2.27(s,3H),1.21(d,J=7.2Hz,6H). 13 CNMR(150MHz,(CD3)2SO)δ(ppm)158.9,145.7,143.5,137.1,131.4,130.0,129.8,127.3,127.2,121.0,118.0,116.4,104.2,27.6,22.8,21.3.

[0117] The structural characterization data of N-(3-(4-(tert-butyl)-1H-pyrazol-1-yl)-4-hydroxyphenyl)-4-methylbenzenesulfonamide prepared in Example 14 are as follows:

[0118]

[0119] 1H NMR (600MHz, (CD3)2SO) δ (ppm) 10.40 (s, 1H), 9.93 (s, 1H), 8.08 (s, 1H), 7.62 (s, 1H), 7.59 (d, J = 8.4Hz, 2H), 7. 45(d,J=2.4Hz,1H),7.30(d,J=7.8Hz,2H),6.89(d,J=9.0Hz,1H),6.85-6.83(m,1H),2.29(s,3H),1.23(s,9H). 13 CNMR(150MHz,(CD3)2SO)δ(ppm)145.6,143.5,137.7,137.0,133.8,130.0,129.8,127.5,127.2,126.8,121.0,118.0,116.7,31.8,29.5,21.3.

[0120] The structural characterization data of N-(4-hydroxy-3-(3-phenyl-1H-pyrazol-1-yl)phenyl)-4-methylbenzenesulfonamide prepared in Example 15 are as follows:

[0121]

[0122] 1 H NMR (600MHz, (CD3)2SO) δ (ppm) 10.43 (s, 1H), 9.99 (s, 1H), 8.35 (s, 1H), 7.87 (d, J = 7.8Hz, 2H), 7.64 (d ,J=7.8Hz,2H),7.54(s,1H),7.45(t,J=7.2Hz,2H),7.36-7.33(m,3H),6.96-6.92(m,3H),2.31(s,3H). 13 CNMR(150MHz,(CD3)2SO)δ(ppm)151.0,146.0,143.5,137.1,133.3,133.1,130. 0,129.9,129.2,128.5,127.6,127.3,125.8,121.6,118.0,117.4,104.5,21.4.

[0123] The structural characterization data of N-(4-hydroxy-3-(3-(thiophen-2-yl)-1H-pyrazol-1-yl)phenyl)-4-methylbenzenesulfonamide prepared in Example 16 are as follows:

[0124]

[0125] 1H NMR (600MHz, (CD3)2SO) δ (ppm) 10.37 (s, 1H), 9.98 (s, 1H), 8.30 (d, J = 2.4Hz, 1H), 7.63-7.62 (m, 2H), 7.52-7.51 (m, 1H), 7.50-7.49 (m,1H),7.44(d,J=2.4Hz,1H),7.33(d,J=7.8Hz,2H),7.13-7.11(m,1H),6.91(t,J=2.4Hz,2H),6.83(d,J=2.4Hz,1H),2.32(s,3H). 13 C NMR(150MHz,(CD3)2SO)δ(ppm)153.5,153.1,143.2,136.9,132.6,129.9,129.8,129.3,1 29.0,128.9,128.2,127.3,127.1,126.9,123.9,123.3,119.9,118.3,116.4,115.5,21.4.

[0126] The structural characterization data of N-(3-(3,5-dimethyl-1H-pyrazol-1-yl)-4-hydroxyphenyl)-4-methylbenzenesulfonamide prepared in Example 17 are as follows:

[0127]

[0128] 1 H NMR (600MHz, (CD3)2SO) δ (ppm) 9.90 (s, 2H), 7.58-7.57 (m, 2H), 7.30 (d, J = 8.4Hz, 2H), 7.04-7.02 (m, 1 H),6.89(d,J=8.4Hz,1H),6.84(d,J=2.4Hz,1H),5.92(s,1H),2.30(s,3H),2.12(s,3H),1.94(s,3H). 13 C NMR (150MHz, (CD3)2SO) δ (ppm) 150.0, 147.8, 143.5, 141.0, 136.8, 130.0, 129.3, 127.2, 123.8, 122.7, 117.4, 105.6, 21.3, 13.7, 11.3.

[0129] In summary, the present invention provides a method for synthesizing N-oxazole-4-methylbenzenesulfonamide compounds. This method, which does not require the involvement of transition metals, allows direct oxidative coupling of sulfonylaminophenol, an azole compound, and a hypervalent iodine reagent to obtain the N-oxazole-4-methylbenzenesulfonamide compound. The reaction conditions are mild, the raw materials are readily available and inexpensive, and the operation is simple, significantly reducing production costs and improving production safety. The N-oxazole-4-methylbenzenesulfonamide compound obtained by the present invention is an important pharmaceutical intermediate.

[0130] The synthesis of the N-oxazole-4-methylbenzenesulfonamide compound of the present invention involves two reaction routes: taking Example 1 as an example, Figure 1 As shown, 1a is first oxidized to form 4-methyl-N-(4-oxocyclohexa-2,5-diene-1-ethyl)benzenesulfonamide 6. Subsequently, 4-methyl-N-(4-oxocyclohexa-2,5-diene-1-ethyl)benzenesulfonamide 6 is attacked by 1H-pyrazole 2a via a Michael reaction, proposing pathway (I). Another competing reaction pathway involves the conversion of N-(4-hydroxyphenyl)-4-methylbenzenesulfonamide 1a to the radical intermediate 9 in the presence of the oxidizing agent iodobenzene acetate [PhI(OAc)2]. Simultaneously, 1H-pyrazole 2a is oxidized to form the corresponding nitrogen-centered radical 8. Intermediate 9 is then attacked by nitrogen-centered radical 8, and the radicals couple to form intermediate 3a′, which is rapidly converted to the final product 3a. This reaction pathway is pathway (II).

[0131] While embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions, and variations may be made to these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing N-oxazole-4-methylbenzenesulfonamide compounds, characterized in that: Adding sulfonylaminophenol, azole compound and high-valent iodine reagent into a solvent, and then stirring and reacting at 50°C-70°C for 12-15 hours. After the reaction is completed, the N-oxazole-4-methylbenzenesulfonamide compound is obtained by separation and purification; The azole compound is at least one of pyrazole, 1,2,4-triazole, 1,2,3-triazole, 1H-indazole, 2H-indazole, benzotriazole, 4-fluoropyrazole, 4-chloropyrazole, 4-bromopyrazole, 4-iodopyrazole, 4-acetylpyrazole, 3-methylpyrazole, 3-isopropylpyrazole, 4-tert-butylpyrazole, 3-phenylpyrazole, 3-thienylpyrazole, and 3,5-dimethylpyrazole; The sulfonylaminophenol is 4-tolylsulfonylphenol, and its structural formula is: R1 is p-tolyl; The structural formula of the N-oxazole-4-methylbenzenesulfonamide compound is: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； The hypervalent iodine reagent is a trivalent iodine compound or a pentavalent iodine compound.

2. The method for preparing N-oxazole-4-methylbenzenesulfonamide compound according to claim 1, characterized in that: The hypervalent iodine reagent is at least one of iodobenzene acetate, [bis(trifluoroacetoxy)iodo]benzene, dichloroiodobenzene, 2-iodoacylbenzoic acid, and Dess-Martin reagent.

3. The method for preparing N-oxazole-4-methylbenzenesulfonamide compound according to claim 1, characterized in that: The molar ratio of the sulfonylaminophenol, the azole compound and the hypervalent iodine reagent is 1.25:1:1.

25.

4. The method for preparing the N-oxazole-4-methylbenzenesulfonamide compound according to claim 1, characterized in that: The solvent is dichloromethane.

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