A method for synthesizing an o-aminophenylsulfonimidate compound

Abstract

The present application relates to a synthesis method of ortho-aminophenylsulfonylimidate compounds, and belongs to the technical field of organic synthesis. The present application realizes the synthesis of ortho-aminophenylsulfonylimidate by a tandem rearrangement reaction of an aryl hydroxylamine compound and a sulfonylimidyl chloride without pre-functionalization, with the advantages of simplicity, high efficiency and high regioselectivity. The strategy has high universality in substrate range and good functional group compatibility, and has important significance for the further development and application of the strategy in the fields of agricultural chemistry, life science and medicine science.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis technology, and relates to a method for synthesizing o-aminoarylsulfonylimide esters. Background Technology

[0002] Sulfones, sulfonamides, and sulfonates are recognized S(VI) functional groups, and this fragment is present in most FDA-approved sulfur-containing drugs. However, research on their aza analogs, such as sulfonamides, sulfonamides, and sulfonamide esters, is relatively limited. Sulfonamide compounds are widely present in pharmaceuticals and agrochemicals as an important functional structure, possessing high research value. First discovered by Mellanby in 1946, this compound contains both sulfur-oxygen and sulfur-nitrogen bonds on its sulfur atom. Drugs containing this structure are used as anticancer drugs (oxytocin), insecticides (flupyridine), and in the clinical treatment of allergic asthma (RU31156), as well as nonsteroidal anti-inflammatory drugs (rofecoxib). Due to their pharmaceutical functional structure and active amine group, several synthetic methods for sulfonamide ester aromatic amines have been developed in recent years. For example, Tang Zhuo's research group reported a method for synthesizing para-aminoaryl sulfonyl imide esters, which involves mixing sulfonylimide acyl chloride with sodium p-aminophenol in tetrahydrofuran and then nucleophilically substituting the mixture to obtain para-aminoaryl sulfonyl imide esters. Han Zuilhof's research group reported a method for synthesizing para-aminoaryl sulfonyl imide esters, which involves mixing sulfonylimide acyl fluoride and p-aminophenol in acetonitrile under alkaline conditions and then nucleophilically substituting the mixture to obtain para-aminoaryl sulfonyl imide esters. However, existing methods are limited to certain specific aminophenols or sodium aminophenolates, resulting in poor reaction versatility. Furthermore, these methods typically involve a single retrosynthetic cleavage of two molecules, where the molecule with the amino group requires prefunctionalization using an oxygen unit. More importantly, existing methods introduce a sulfonylimide ester group at the para-position of the amino group, and there is no systematic method for synthesizing ortho-aminoaryl sulfonyl imide esters.

[0003] Furthermore, aryl hydroxylamines are also a class of widely used organic molecules and drug precursors, with broad applications in organic synthesis and biomedicine. Due to the mutual repulsion of the lone pairs of electrons on the nitrogen and oxygen atoms in aryl hydroxylamines, their NO bond energy is relatively low (approximately 53 kcal / mol). -1Aryl hydroxylamines are easily broken, and based on this characteristic, a series of rearrangement reactions involving the breaking of NO bonds have been developed, such as the [3,3]-σ-rearrangement and the [2,3]-σ-rearrangement. The [3,3]-σ-rearrangement involves the reaction of an aryl hydroxylamine with an alkene containing a leaving group to generate an O-alkenyl intermediate, which is then broken by NO, forming a new, stronger bond, thus completing the rearrangement reaction. Therefore, the rearrangement of hydroxylamines and their derivatives is a common method for preparing various heterocyclic compounds (such as indole compounds), biaryl compounds, and functionalized aryl amines. Numerous patent documents also utilize the tandem rearrangement reactions of aryl hydroxylamines to synthesize a series of compounds, such as CN113929605A and CN117820175A.

[0004] Therefore, based on the study of tandem rearrangement reactions of aryl hydroxylamines and the synthetic needs of sulfonyl imide compounds, it is of great significance to develop a systematic, efficient, and highly ortho-selective method for directly constructing CO bonds to synthesize ortho-amino aryl sulfonyl imide compounds in a highly modular manner. Summary of the Invention

[0005] In view of the current state of the prior art, especially the poor substrate universality for synthesizing sulfonyl imide esters of aromatic amines, the need for pre-functionalization, and the lack of methods for synthesizing o-amino aryl sulfonyl imide esters, the inventors of this invention have conducted comprehensive and in-depth research on the topic of ortho-sulfonyl imide esterification of aromatic amines. The aim is to explore a preparation strategy for o-amino sulfonyl imide ester compounds with a wide substrate applicability, high efficiency, and high regioselectivity. The inventors discovered in their research that because aryl hydroxylamines are easily deprotonated under basic conditions, they can couple with aryl sulfonyl imide acyl chlorides to generate a sulfonyl imide ester aromatic amine NO intermediate. Subsequently, due to the low bond energy of NO cleavage, a [3,3]-σ-rearrangement occurs, directly constructing a CO bond at the ortho position of the amine group. This allows for the efficient and highly regioselective modular synthesis of ortho-sulfonyl imide ester compounds of aromatic amines.

[0006] Therefore, the objective of this invention is to provide a method for synthesizing o-amino sulfonyl imide compounds, filling the gap in existing methods for ortho-functionalizing aromatic amines. This invention utilizes a tandem rearrangement reaction between an aryl hydroxylamine compound and an aryl sulfonyl imide acyl chloride, eliminating the need for pre-functionalization and directly introducing a sulfonyl imide ester group at the ortho position of the aromatic amine. This method achieves the synthesis of o-amino aryl sulfonyl imide esters with high efficiency and high regioselectivity.

[0007] The technical solution for achieving the above-mentioned objectives of this invention can be summarized as follows:

[0008] A method for synthesizing an o-aminoarylsulfonylimide ester compound having the structure shown in formula (III):

[0009]

[0010] In formula (Ⅲ), Ar is a substituted or unsubstituted aryl, heteroaryl, or biaryl group, and R is a substituted or unsubstituted aryl group. 1 It is one of benzoyl, acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, trifluoroacetyl, p-nitrobenzoyl, and 9-fluorenylmethoxycarbonyl; R 2 It is one of substituted or unsubstituted benzoyl, 2-naphthyl, or 2-thiophene; R 3 It may be a substituted or unsubstituted aryl or alkyl group;

[0011] The steps include the following:

[0012] Compound (I) and compound (II) were added to a solvent in an air atmosphere, and the mixture was reacted in the presence of a base. After the reaction was completed, the mixture was purified to obtain o-aminoarylsulfonylimide compound (III).

[0013]

[0014] According to the present invention, preferably, Ar is Where R 4 It is one or more of the following groups: fluorine, chlorine, bromine, iodine, alkyl, alkynyl, ester, aryl, heteroaryl, trifluoromethyl, and silyl.

[0015] According to the present invention, preferably, R 2 for Alkyl, cycloalkyl, wherein R 5 It is one or more of fluorine, chlorine, bromine, alkyl, trifluoromethyl, aryl, and heteroaryl.

[0016] According to the present invention, preferably, R 3 for Alkyl, cycloalkyl, wherein R 6 It is one or more of fluorine, chlorine, bromine, alkyl, trifluoromethyl, and aryl.

[0017] According to the present invention, preferably, the o-aminosulfonylimide ester compound has the following structure:

[0018]

[0019] According to the present invention, the reaction process can be tracked by TLC.

[0020] According to the present invention, a preferred purification method is as follows:

[0021] After the reaction was completed, the reaction mixture was concentrated by rotary evaporation, and the crude product was subjected to column chromatography with petroleum ether / ethyl acetate as the eluent in a ratio of 10:1 to obtain the target compound (Ⅲ).

[0022] According to the present invention, preferably, the molar ratio of compound (I) to compound (II) is 1:(1-2), more preferably 1:(1.1-1.5); most preferably, the molar ratio of compound (I) to compound (II) is 1:1.2.

[0023] According to the present invention, preferably, the alkali is sodium carbonate, potassium phosphate, sodium bicarbonate, pyridine, DABCO (triethylenediamine), DMAP (4-dimethylaminopyridine), diethylamine, DBN, or DBU; most preferably, the alkali is sodium carbonate.

[0024] According to the present invention, preferably, the molar ratio of compound (I) to base is 1:(1-3), more preferably 1:(1.7-2.2); most preferably, the molar ratio of compound (I) to base is 1:2.

[0025] According to the present invention, preferably, the solvent is DCM (dichloromethane), MeCN (acetonitrile), DCE (dichloroethane), 1,4-dioxane (1,4-dioxane), HFIP (hexafluoroisopropanol), toluene, Et2O (diethyl ether), or THF (tetrahydrofuran); most preferably, the solvent is DCM (dichloromethane).

[0026] According to the present invention, preferably, the reaction temperature is -78°C to 25°C, more preferably -30°C to 10°C, and most preferably 0°C.

[0027] The beneficial effects of this invention are:

[0028] 1. This invention provides an esterification strategy for ortho-sulfonylimides of arylamines without the involvement of transition metals and oxidants. By reacting inexpensive and readily prepared aryl hydroxylamine compounds with S-aryl sulfonylimide acyl chlorides, rapid and efficient synthesis of ortho-aminosulfonylimide esters is achieved under basic conditions. This strategy has a broad substrate scope and good functional group compatibility. In the sulfonylimide acyl chloride structure, both sulfur and nitrogen can be linked to various unsubstituted and substituted aryl and heteroaryl groups. Simultaneously, various aryl hydroxylamines, including natural product molecules, can be effectively transformed, resulting in the preparation of ortho-aminosulfonylimide ester compounds with excellent regioselectivity and diverse structures in good yields. This has significant implications for the further development and application of agrochemicals, life sciences, and pharmaceutical sciences.

[0029] 2. This invention provides a synthetic method for introducing sulfonyl imide groups at the ortho position of aromatic amines without pre-functionalization, filling the gap in existing ortho-functionalization methods for aromatic amines. It achieves the synthesis of ortho-amino aryl sulfonyl imide esters with advantages of simplicity, high efficiency, and high regioselectivity.

[0030] 3. The alkali used in this invention is a commonly used commercial reagent and is very stable. The post-processing of this invention is simple, it can be repeatedly recycled, and it has broad application prospects.

[0031] 4. The o-aminosulfonylimide ester compounds synthesized in this invention possess chiral sulfur atoms and have the potential to be resolved into single chiral compounds. The o-aminosulfonylimide ester compounds simultaneously contain nitrogen, sulfur, and oxygen atoms that readily coordinate with metals; therefore, asymmetric o-aminosulfonylimide ester compounds can be used as ligands or starting materials for asymmetric catalytic synthesis. Attached Figure Description

[0032] Figure 1 The 2-(tert-butoxycarbonyl)amino)phenyl N-benzoyl-4-methylbenzenesulfonylamino ester prepared in Example 1 1 H-NMR spectrum;

[0033] Figure 2 The 2-(tert-butoxycarbonyl)amino)phenyl N-benzoyl-4-methylbenzenesulfonylamino ester prepared in Example 1 13 C-NMR spectrum;

[0034] Figure 3 The 2-benzamido 5-chlorophenyl-N-benzoyl-4-methylbenzenesulfonylimide ester prepared in Example 2 1 H-NMR spectrum;

[0035] Figure 4 The 2-benzamido 5-chlorophenyl-N-benzoyl-4-methylbenzenesulfonylimide ester prepared in Example 2 13 C-NMR spectrum;

[0036] Figure 5 The 2-benzoamide-4,6-dimethylphenyl-N-benzoyl-4-methylbenzenesulfonyl ester prepared in Example 3 1 H-NMR spectrum;

[0037] Figure 6 The 2-benzoamide-4,6-dimethylphenyl-N-benzoyl-4-methylbenzenesulfonyl ester prepared in Example 3 13 C-NMR spectrum;

[0038] Figure 7 The 2-benzoylaminophenyl-N-benzoyl-2-chlorobenzenesulfonylimide prepared in Example 4 1 H-NMR spectrum;

[0039] Figure 8 The 2-benzoylaminophenyl-N-benzoyl-2-chlorobenzenesulfonylimide prepared in Example 4 13 C-NMR spectrum;

[0040] Figure 9 The 2-benzoylaminophenyl-4-methyl-N-(thiophene-2-carbonyl)benzenesulfonylimide ester prepared in Example 5 1 H-NMR spectrum;

[0041] Figure 10 The 2-benzoylaminophenyl-4-methyl-N-(thiophene-2-carbonyl)benzenesulfonylimide ester prepared in Example 5 13 C-NMR spectrum. Detailed Implementation

[0042] This invention provides a method for synthesizing an o-aminoarylsulfonylimide ester compound having the structure shown in formula (III):

[0043]

[0044] In formula (Ⅲ), Ar is a substituted or unsubstituted aryl, heteroaryl, or biaryl group, and R is a substituted or unsubstituted aryl group. 1 It is one of benzoyl, acetyl, tert-butoxycarbonyl, trifluoroacetyl, benzyloxycarbonyl, trifluoroacetyl, p-nitrobenzoyl, and 9-fluorenylmethoxycarbonyl; R 2 It is one of substituted or unsubstituted benzoyl, 2-naphthyl, or 2-thiophene; R 3 It can be a substituted or unsubstituted aryl or alkyl group.

[0045] The synthesis method includes the following steps:

[0046] Compound (I) and compound (II) were added to a solvent in an air atmosphere, and the mixture was reacted with the aid of a base. After the reaction was completed, the mixture was purified to obtain the o-aminoarylsulfonylimide compound (III).

[0047]

[0048] According to the present invention, the compound (I) has the following structure:

[0049]

[0050] Compound (I) can be prepared using existing technical methods, as follows:

[0051]

[0052] The synthesis steps are as follows: Under a nitrogen atmosphere, a nitro compound (1.0 equivalent) and 5% Rh / C (0.30 mol% Rh) were dissolved in THF (0.5 M). The reaction system was then cooled to 0°C, and hydrazine hydrate (1.2 equivalent) was slowly added. The reaction mixture was stirred at 0°C for 10 minutes, then slowly heated to room temperature and stirred for another 4 hours at room temperature. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated by rotary evaporation and recrystallized. The crude product, hydroxylamine, was directly used in the next reaction step.

[0053] A 0.5 M solution of crude hydroxylamine in diethyl ether was prepared by adding a saturated aqueous solution of NaHCO3. The resulting solution was then cooled to 0°C. The corresponding acyl chloride (1.1 equivalents) was slowly added dropwise to the solution, and the mixture was stirred continuously at 0°C for 10 seconds after the addition was complete. After the reaction was complete, the reaction was quenched with a saturated aqueous solution of NH4Cl. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under vacuum, and the crude product was subjected to column chromatography (eluent: dichloromethane:ethyl acetate = 50:1) to give compound (I).

[0054] According to the present invention, the compound (II)S-arylsulfonylimide chloride has the following structure:

[0055]

[0056] Compound (II) can be prepared using existing technical routes, as follows:

[0057]

[0058] The synthesis steps are as follows:

[0059] Under a nitrogen atmosphere, N-chlorosuccinimide (26 mmol, 1.3 equivalents) was dissolved in dichloromethane (50 mL) in a 100 mL reaction flask. Benzenethiol (30 mmol, 1.5 mmol) was slowly added at 0 °C, and the reaction mixture was stirred at room temperature for 12 h. The reaction solution was concentrated in a rotary evaporator, and the concentrated mixture was washed with n-hexane, filtered, and the solvent was removed from the filtrate under vacuum to obtain crude hypochlorothiobenzene, an orange liquid, which was used directly in the next reaction. Benzamide (20 mmol, 1 equivalent), NaH (60 mmol, 3 equivalents), and dried THF (80 mL) were added sequentially to a 250 mL reaction flask, and stirred at room temperature for 2 h to obtain the corresponding sodium salt. The solution was cooled to -30 °C, and the crude hypochlorothiobenzene liquid was slowly added dropwise. After the addition was complete, the reaction mixture was slowly heated to room temperature and stirred for another 12 h. After the reaction was complete, 200 mL of water was added to quench the reaction. The reaction mixture was extracted with ethyl acetate (2 × 100 mL), and the organic phase was washed successively with water and brine, dried over anhydrous magnesium sulfate, and concentrated under vacuum. The crude product was subjected to column chromatography (eluent: petroleum ether / ethyl acetate = 7:1) to give the desired sulfenamide.

[0060] In a 250 mL sample vial, the obtained sulfenamide (20 mmol), DCE (100 mL), and H₂O (20 mmol, 1 equivalent) were added, and the mixture was cooled to -25 °C. Then, TCCA (20 mmol, 1 equivalent) was rapidly added at this temperature, and the mixture was stirred for 12 h. After the reaction was completed, the solvent was removed from the reaction mixture under vacuum, and the crude product was subjected to column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1-5 / 1) to give compound (II) S-arylsulfonylimide chloride.

[0061] According to the present invention, in the o-aminoarylsulfonylimide ester compound (III), Ar, R 1 From compound (I), R 2 R 3 Ar and R derived from compound (II) are suitable for use in this invention due to the good compatibility of functional groups in compounds (I) and (II). 1 R 2 R 3 The selection range is wide, further expanding the types of functional groups in o-aminoarylsulfonylimide ester compounds.

[0062] In one or more preferred embodiments, the o-aminoarylsulfonylimide ester compound (III) is a substituted phenyl compound.

[0063]

[0064] R 4It is one or more of the following: fluorine, chlorine, bromine, iodine, methyl, ethyl, ester, methoxy, phenyl, phenylthio, benzyloxy, ethynyl, trifluoromethyl, oxytrifluoromethyl, and silyl.

[0065] In one or more preferred embodiments, the o-aminoarylsulfonylimide ester compound (III) is a substituted phenyl compound.

[0066]

[0067] R 5 It is one or more of the following: fluorine, chlorine, bromine, methyl, ethyl, ester, methoxy, phenyl, trifluoromethyl, and thiophene.

[0068] In one or more preferred embodiments, the o-aminoarylsulfonylimide ester compound (III) is a substituted phenyl compound.

[0069]

[0070] R 6 It is one or more of the following: fluorine, chlorine, bromine, methyl, ethyl, ester, methoxy, phenyl, trifluoromethyl, and thiophene.

[0071] In one or more preferred embodiments, the o-aminoarylsulfonylimide ester compound (III) has the following structure:

[0072]

[0073] According to the present invention, the reaction process can be tracked by TLC.

[0074] According to the present invention, in one or more preferred embodiments, the purification method is as follows:

[0075] After the reaction was completed, the reaction mixture was concentrated by rotary evaporation. The crude product was subjected to column chromatography with petroleum ether / ethyl acetate as the eluent, which yielded the target compound (Ⅲ).

[0076] According to the present invention, the theoretical molar ratio of compound (I) and compound (II) is 1:1. In order to fully utilize the aryl hydroxylamine and improve the reaction conversion rate, compound (II) is appropriately added in excess. After the reaction is completed, 12-16% of the remaining compound (II) can be recovered, further reducing production costs. Therefore, in one or more preferred embodiments, the molar ratio of compound (I) and compound (II) is 1:(1-2), more preferably 1:(1.1-1.5); most preferably, the molar ratio of compound (I) and compound (II) is 1:1.2.

[0077] According to the present invention, the tandem rearrangement reaction of compounds (I) and (II) needs to be carried out under basic conditions, and different basic environments have a significant impact on the yield of the target compound (III). In one or more preferred embodiments, the base is sodium carbonate, potassium phosphate, sodium bicarbonate, pyridine, DABCO (triethylenediamine), DMAP (4-dimethylaminopyridine), diethylamine, DBN, or DBU; most preferably, the base is sodium carbonate.

[0078] According to the present invention, the theoretical molar ratio of compound (I) to base is 1:1. To improve the reaction conversion rate, the base is appropriately in excess. After the reaction is completed, 85-95% of the remaining base can be recovered, further reducing production costs. Therefore, in one or more preferred embodiments, the molar ratio of compound (I) to base is 1:(1-3), more preferably 1:(1.7-2.2); most preferably, the molar ratio of compound (I) to base is 1:2.

[0079] According to the present invention, due to the solvent effect, the reaction solvent also has an important influence on the yield of the target compound (III). In one or more preferred embodiments, the solvent is DCM (dichloromethane), MeCN (acetonitrile), DCE (dichloroethane), 1,4-dioxane (1,4-dioxane), HFIP (hexafluoroisopropanol), toluene, Et2O (diethyl ether), or THF (tetrahydrofuran); most preferably, the solvent is DCM (dichloromethane).

[0080] According to the present invention, the reaction temperature also has an important influence on the yield of the target compound (III). In one or more preferred embodiments, the reaction temperature is -78°C to 25°C, more preferably -30°C to 10°C, and most preferably 0°C.

[0081] According to the present invention, the o-aminosulfonamide ester compounds are stable for several months when exposed to air, and they are compatible with almost all functional groups present on most natural products. These compounds have attracted widespread attention and shown great application prospects in organic synthetic chemistry, medicinal chemistry, chemical biology and other fields.

[0082] The technical approach of this invention is as follows:

[0083]

[0084] Taking Na2CO3 as the base as an example, the reaction mechanism of this invention is as follows:

[0085]

[0086] Arylhydroxylamine is deprotonated in the presence of Na2CO3 and coupled with arylsulfonylimide acyl chloride to generate sulfonylimide ester arylamine NO intermediate A. Then, due to the low NO bond energy, it breaks and undergoes [3,3]-σ-rearrangement to generate intermediate B. Then, aromatization is performed to complete the rearrangement reaction, and a CO bond is directly constructed at the ortho position of the amine group to finally generate the ortho-aminoarylsulfonylimide ester compound (III).

[0087] The present invention will be further described below through specific embodiments, but is not limited thereto.

[0088] Example 1: 2-(tert-butoxycarbonyl)amino)phenyl N-benzoyl-4-methylbenzenesulfonylamino ester

[0089]

[0090] In a 20 mL reaction tube, tert-butyl α-(phenyl)carbamate (0.2 mmol, 42 mg), sodium carbonate (0.4 mmol, 42 mg), and dichloromethane (2 mL) were added. The reaction system temperature was lowered to 0 °C, and N-benzoyl-4-methylbenzenesulfonylimide chloride (1.2 equiv, 71 mg) was rapidly added. The mixture was stirred at 0 °C for 2 hours, and the reaction progress was tracked by TLC. After the reaction was completed, the solvent was removed from the reaction mixture under vacuum. The crude product was subjected to column chromatography (eluent: petroleum ether / ethyl acetate = 7:1) to give 2-(tert-butoxycarbonyl)amino)phenyl N-benzoyl-4-methylbenzenesulfonylamino ester, which was a white solid with a yield of 83%.

[0091] 1 H NMR(500MHz,Chloroform-d)δ9.07(s,1H),8.28(d,J=8.3Hz,1H),8.19(dd,J=8.2,1.2Hz,2H),7.98(d,J=8.4Hz,2H),7.59–7. 53(m,1H),7.44(t,J=7.7Hz,4H),7.24–7.18(m,1H),6.80–6.74(m,1H),6.44(dd,J=8.0,1.4Hz,1H),2.52(s,3H),1.60(s,9H);

[0092] 13 C NMR(126MHz,Chloroform-d)δ172.9,153.4,146.5,138.1,135.0,134.1,133. 0,130.3,130.0,128.6,128.3,128.2,121.9,121.5,120.8,29.8,28.5,22.0.

[0093] Example 2, 2-Benzamido5-chlorophenyl-N-benzoyl-4-methylbenzenesulfonylimide

[0094]

[0095] In a 20 mL reaction tube, N-(4-chlorophenyl)-N-hydroxybenzamide (0.2 mmol, 50 mg), sodium carbonate (0.4 mmol, 42 mg), and dichloromethane (2 mL) were added. The reaction system temperature was lowered to 0 °C, and N-benzoyl-4-methylbenzenesulfonylimide chloride (1.2 equiv, 71 mg) was quickly added. The mixture was stirred at 0 °C for 2 hours, and the reaction progress was tracked by TLC. After the reaction was completed, the solvent was removed from the reaction mixture under vacuum. The crude product was subjected to column chromatography (eluent: petroleum ether / ethyl acetate = 7:1) to give 2-benzamido-5-chlorophenyl-N-benzoyl-4-methylbenzenesulfonylimide ester, which was a white solid with a yield of 81%.

[0096] 1 H NMR(400MHz, DMSO-d6)δ9.85(s,1H),8.03(dt,J=7.1,1.3Hz,2H),7.91(dd,J=8.6,1.7Hz,3H),7.83–7.77 (m,2H),7.68–7.55(m,2H),7.54–7.44(m,5H),7.37(d,J=2.4Hz,1H),7.32(d,J=8.6Hz,2H),2.27(s,3H);

[0097] 13 C NMR(101MHz,DMSO-d6)δ171.2,164.9,146.5,141.7,134.2,133.3,133.2,132.1,1 31.9,130.8,130.4,129.3,128.6,128.2,127.8,127.7,127.7,127.0,123.7,21.2.

[0098] Example 3: 2-Benzamido-4,6-dimethylphenyl-N-benzoyl-4-methylbenzenesulfonyl ester

[0099]

[0100] In a 20 mL reaction tube, N-(3,5-dimethylphenyl)-N-hydroxybenzamide (0.2 mmol, 48 mg), sodium carbonate (0.4 mmol, 42 mg), and dichloromethane (2 mL) were added. The reaction system temperature was lowered to 0 °C, and N-benzoyl-4-methylbenzenesulfonylimide chloride (1.2 equiv, 71 mg) was quickly added. The mixture was stirred at 0 °C for 2 hours, and the reaction progress was tracked by TLC. After the reaction was completed, the solvent was removed from the reaction mixture under vacuum. The crude product was subjected to column chromatography (eluent: petroleum ether / ethyl acetate = 8:1) to give 2-benzoamide-4,6-dimethylphenyl N-benzoyl-4-methylbenzenesulfonyl ester, a white solid with a yield of 90%.

[0101] 1 H NMR(500MHz,Chloroform-d)δ9.81(s,1H),8.19(d,J=2.2Hz,1H),8.07–8.01(m,4H),8.02(d,J=1.5Hz,3H),7.98–7.92(m,2H),7.54–7.4 7(m,2H),7.46–7.39(m,2H),7.37(t,J=7.8Hz,3H),7.34(d,J=8.2Hz,3H),6.71(d,J=2.2Hz,1H),2.45(s,3H),2.34(s,3H),1.81(s,3H);

[0102] 13 C NMR(126MHz,Chloroform-d)δ172.3,166.7,146.5,137.7,136.5,134.9,134.8,133.0,132.8,1 32.7,131.8,131.7,130.3,129.7,128.4,128.3,128.2,128.1,127.5,122.0,21.9,21.4,16.7.

[0103] Example 4: 2-Benzoylaminophenyl-N-benzoyl-2-chlorobenzenesulfonylimide

[0104]

[0105] In a 20 mL reaction tube, N-hydroxy-N-phenylbenzamide (0.2 mmol, 43 mg), sodium carbonate (0.4 mmol, 42 mg), and dichloromethane (2 mL) were added. The reaction system temperature was lowered to 0 °C, and N-benzoyl-2-chlorobenzenesulfonamide chloride (1.2 equiv, 75 mg) was quickly added. The mixture was stirred at 0 °C for 2 hours, and the reaction progress was tracked by TLC. After the reaction was completed, the solvent was removed from the reaction mixture under vacuum. The crude product was subjected to column chromatography (eluent: petroleum ether / ethyl acetate = 7:1) to give 2-benzoylaminophenyl-N-benzoyl-2-chlorobenzenesulfonamide, a white solid, with a yield of 77%.

[0106] 1 H NMR(400MHz, DMSO-d6)δ9.98(s,1H),8.15(dd,J=8.0,1.5Hz,1H),7.99(dd,J=8.2,1.6Hz,1H),7.94(td,J=7.9,1.4Hz,4H),7.80–7.73(m,1H),7.71(d d,J=8.1,1.4Hz,1H),7.65–7.58(m,3H),7.52–7.44(m,4H),7.42(td,J=7.7 ,1.5Hz,1H),7.24(td,J=8.1,7.5,1.6Hz,1H),7.16(dd,J=8.2,1.5Hz,1H);

[0107] 13 C NMR(101MHz,DMSO-d6)δ171.0,165.4,140.9,136.6,134.0,133.8,133.3,133.2,132.8 ,132.0,131.9,131.7,131.6,129.3,128.6,128.3,128.2,127.9,126.0,125.9,122.9.

[0108] Example 5: 2-Benzoylaminophenyl-4-methyl-N-(thiophene-2-carbonyl)benzenesulfonylimide

[0109]

[0110] In a 20 mL reaction tube, N-hydroxy-N-phenylbenzamide (0.2 mmol, 43 mg), sodium carbonate (0.4 mmol, 42 mg), and dichloromethane (2 mL) were added. The reaction system temperature was lowered to 0 °C, and 4-methyl-N-(thiophene-2-carbonyl)benzenesulfonamide chloride (1.2 equiv, 72 mg) was quickly added. The mixture was stirred at 0 °C for 2 hours, and the reaction progress was tracked by TLC. After the reaction was completed, the solvent was removed from the reaction mixture under vacuum. The crude product was subjected to column chromatography (eluent: petroleum ether / ethyl acetate = 7:1) to give 2-benzoylaminophenyl-4-methyl-N-(thiophene-2-carbonyl)benzenesulfonamide ester, which was a white solid with a yield of 81%.

[0111] 1 H NMR(400MHz, DMSO-d6)δ9.83(s,1H),7.92(dd,J=8.2,1.4Hz,1H),7.90(dd,J=5.0,1.3Hz,1H),7.88–7.82(m,4H),7.76(dd,J=3.7,1.3Hz,1H),7 .64–7.57(m,1H),7.50(t,J=7.6Hz,2H),7.41–7.36(m,1H),7.34(d,J=8 .0Hz,2H),7.26–7.20(m,2H),7.18(dd,J=5.0,3.7Hz,1H),2.30(s,3H);

[0112] 13 C NMR (101MHz, DMSO-d6) δ165.9,165.1,146.4,141.2,139.7,134.2,133.7,133.3,132. 1,131.8,131.6,130.4,128.5,128.2,127.8,127.8,127.8,125.8,125.6,123.2,21.2.

[0113] Experimental Example 1

[0114] Using N-hydroxy-N-phenylbenzamide and N-benzoyl-4-methylbenzenesulfonylimide chloride as raw materials, 4-dimethylaminopyridine as a base, the amount of base used was 2.0 equivalents, the reaction temperature was 25℃, and the reaction was carried out in air for 2 hours. The effect of the type of solvent on the reaction was investigated, as shown in Table 1.

[0115] Table 1 Effect of solvent on reaction

[0116]

[0117] As can be seen from the experimental results in Table 1, DCM is the optimal solvent for this reaction.

[0118] Experimental Example 2

[0119] Using N-hydroxy-N-phenylbenzamide and N-benzoyl-4-methylbenzenesulfonylimide chloride as raw materials and dichloromethane as solvent, the reaction was carried out at 25℃ in air for 2 hours. The effect of the type of base on the reaction was investigated, as shown in Table 2.

[0120] Table 2 Effect of base on reaction

[0121]

[0122] As can be seen from the experimental results in Table 2, Na2CO3 is the optimal base for this reaction.

[0123] Experimental Example 3

[0124] Using N-hydroxy-N-phenylbenzamide and N-benzoyl-4-methylbenzenesulfonylimide chloride as raw materials, dichloromethane as solvent, and Na2CO3 as base (2.0 equivalents), the reaction was carried out in air for 2 hours. The effect of temperature on the reaction was investigated, as shown in Table 3.

[0125] Table 3 Effect of temperature on the reaction

[0126]

[0127] As can be seen from the experimental results in Table 3, 0℃ is the optimal temperature for this reaction.

Claims

1. A method for synthesizing an o-aminoarylsulfonylimide ester compound having the structure shown in formula (III): ； In equation (Ⅲ), Ar is , where R 4 It is one of the following: fluorine, chlorine, bromine, iodine, methyl, ethyl, methoxy, phenyl, phenylthio, benzyloxy, ethynyl, trifluoromethyl, oxotrifluoromethyl, and silyl. R 1 It is one of benzoyl, acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, trifluoroacetyl, p-nitrobenzoyl, and 9-fluorenylmethoxycarbonyl. R 2 for , where R 5 It is one of fluorine, chlorine, bromine, methyl, ethyl, methoxy, phenyl, trifluoromethyl, and thiophene. R 3 for , where R 6 It is one of fluorine, chlorine, bromine, methyl, ethyl, methoxy, phenyl, trifluoromethyl, and thiophene. The steps include the following: Compound (I) and compound (II) were added to a solvent in an air atmosphere, and the mixture was reacted in the presence of a base. After the reaction was completed, the mixture was purified to obtain o-aminoarylsulfonylimide compound (III). 。 2. The method for synthesizing the o-aminoarylsulfonylimide ester compound according to claim 1, characterized in that, The o-aminoarylsulfonylimide ester compound has the following structure: 。 3. The method for synthesizing the o-aminoarylsulfonylimide ester compound according to claim 1, characterized in that, The purification method is as follows: After the reaction was completed, the solvent was removed from the reaction mixture under vacuum. The crude product was subjected to column chromatography with petroleum ether / ethyl acetate as the eluent (10:1).

4. The method for synthesizing the o-aminoarylsulfonylimide ester compound according to claim 1, characterized in that, The molar ratio of compound (I) to compound (II) is 1:(1-2), and the molar ratio of compound (I) to base is 1:(1-3).

5. The method for synthesizing the o-aminoarylsulfonylimide ester compound according to claim 1, characterized in that, The alkali is sodium carbonate, potassium phosphate, sodium bicarbonate, pyridine, DABCO, DMAP, diethylamine, DBN, or DBU.

6. The method for synthesizing the o-aminoarylsulfonylimide ester compound according to claim 1, characterized in that, The solvent is dichloromethane, acetonitrile, dichloroethane, 1,4-dioxane, hexafluoroisopropanol, toluene, diethyl ether, or tetrahydrofuran.

7. The method for synthesizing the o-aminoarylsulfonylimide ester compound according to claim 1, characterized in that, The reaction temperature is -78 ℃ ~ 25 ℃.

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