Synthesis method of o-amido aryl sulfimide ester compound

Abstract

The invention relates to a synthesis method of an o-amido aryl sulfimide ester compound, and belongs to the technical field of organic synthesis. According to the invention, the aryl hydroxylamine compound and the sulfimide acyl chloride are subjected to a tandem rearrangement reaction, pre-functionalization is not needed, and synthesis of the o-amido aryl sulfimide ester is realized with the advantages of simplicity, high efficiency and high regioselectivity. The strategy is high in substrate range universality and good in functional group compatibility, and has important significance in further development and application of the strategy in the fields of agricultural chemistry, life, medical science and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemical synthesis and relates to a method for synthesizing ortho-aminoaryl sulfonyl imide ester compounds. Background Art

[0002] Sulfone, sulfonamide and sulfonate are well-known S(VI) functional groups, which are present in most FDA-approved sulfur-containing drugs, while their aza analogs, such as sulfonimide, sulfonamide and sulfonimide ester, are less studied. Sulfonimide compounds, as an important functional structure, are widely present in drugs and agricultural chemicals and have high research value. In 1946, Mellanby first discovered this compound, which contains both sulfur-oxygen bonds and sulfur-nitrogen bonds on its sulfur atom. Drugs containing this structure are used as anticancer drugs (otoxiclib), insecticides (sulfoxaflor), and for the clinical treatment of allergic asthma (RU31156) and non-steroidal anti-inflammatory drugs (rofecoxib). Sulfonimide ester aromatic amines have several synthetic methods developed in recent years due to their drug functional structure and amine active groups. For example: Tang Zhuo's research group reported a method for synthesizing para-aminoaryl sulfonyl imide esters, where sulfonyl imide chloride and sodium p-aminophenol were mixed in tetrahydrofuran and nucleophilically substituted to obtain p-aminoaryl sulfonyl imide esters. Han Zuilhof's research group reported a method for synthesizing para-aminoaryl sulfonyl imide esters, where sulfonyl imide fluoride and p-aminophenol were mixed in acetonitrile under alkaline conditions and nucleophilically substituted to obtain p-aminoaryl sulfonyl imide esters. However, the existing methods are limited to certain specific aminophenols or sodium salts of aminophenols, the universality of the reaction is poor, and the above methods usually involve a single retrosynthetic cleavage with two molecules, in which the molecule with the amino moiety needs to be pre-functionalized with an oxygen unit. More importantly, the existing methods introduce the sulfonyl imide ester group at the para position of the amine group, and there is no method for systematically synthesizing ortho-aminoaryl sulfonyl imide esters.

[0003] In addition, arylhydroxylamines are also a class of widely used organic molecules and drug precursors, which are widely used in organic synthesis and biomedicine. In arylhydroxylamines, the lone pair electrons on the nitrogen atom and the oxygen atom repel each other, resulting in a low bond energy of the NO bond (about 53 kcal mol -1), which is easy to break. Based on this feature, a series of rearrangement reactions related to the breaking of the NO bond have been developed, such as [3,3]-σ-rearrangement, [2,3]-σ-rearrangement, etc. Among them, the [3,3]-σ-rearrangement is to generate an O-alkenyl intermediate by reacting an aromatic hydroxylamine with an olefin-like alkene containing an easy-to-leave group, and then through the breaking of NO, a new bond with a stronger bond energy is formed, thereby completing the rearrangement reaction. Therefore, the rearrangement of hydroxylamine and its derivatives is a common method for preparing different heterocyclic compounds (such as indole compounds), biaryl compounds and functionalized aromatic amines. There are also many patent documents that use the tandem rearrangement reaction of aromatic hydroxylamines to synthesize a series of compounds, such as: CN113929605A, CN117820175A, etc.

[0004] Therefore, based on the research on the tandem rearrangement reaction of aromatic hydroxylamines and the synthesis needs of sulfonyl imide compounds, it is of great significance to develop a system that is efficient, highly ortho-selective, and can directly construct CO bonds in a highly modular manner to synthesize ortho-amino aromatic sulfonyl imide ester compounds. Summary of the invention

[0005] In view of the current status of the above-mentioned prior art, especially the poor universality of the substrates for synthesizing sulfonyl imide ester aromatic amines, the need for pre-functionalization, and the lack of methods for ortho-amino aromatic sulfonyl imide esters, the inventors of the present 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 ortho-amino aromatic sulfonyl imide ester compounds with a wide range of substrate applications, high efficiency, and high regioselectivity. The inventors of the present invention found in the study that since aromatic hydroxylamines are easily deprotonated under alkaline conditions, they can be coupled with aromatic sulfonyl imide chlorides to generate sulfonyl imide ester aromatic amine NO intermediates, and then due to the breakage of NO with lower bond energy, [3,3]-σ-rearrangement occurs, and a CO bond is directly constructed at the ortho position of the amine group, which can achieve efficient and highly regioselective modular synthesis of ortho-amino aromatic sulfonyl imide ester compounds.

[0006] Therefore, the purpose of the present invention is to provide a method for synthesizing an ortho-amino sulfonyl imide ester compound to fill the gap in the existing ortho-position functionalization of aromatic amines. The present invention directly introduces a sulfonyl imide ester group at the ortho position of aromatic amine by a tandem rearrangement reaction of an aromatic hydroxylamine compound and an aromatic sulfonyl imide chloride without pre-functionalization, thereby achieving the synthesis of ortho-amino aryl sulfonyl imide esters with the advantages of high efficiency and high regioselectivity.

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

[0008] A method for synthesizing an ortho-aminoaryl sulfonyl imide ester compound, wherein the compound has a structure shown in formula (III):

[0009]

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

[0011] The steps include:

[0012] In an air atmosphere, compound (I) and compound (II) are added to a solvent, and the mixed solution is reacted in the presence of a base. After the reaction is completed, the mixture is purified to obtain an ortho-aminoarylsulfonyl imide ester compound (III);

[0013]

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

[0015] According to the present invention, preferably, R 2 for Alkyl, cycloalkyl, where 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, where R 6 It is one or more of fluorine, chlorine, bromine, alkyl, trifluoromethyl and aryl.

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

[0018]

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

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

[0021] After the reaction was completed, the reaction mixture was concentrated by a rotary evaporator, and the crude product was subjected to column chromatography with the eluent being petroleum ether / ethyl acetate = 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), further 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 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.

[0024] According to the present invention, preferably, the molar ratio of compound (I) to the base is 1:(1-3), more preferably 1:(1.7-2.2); most preferably, the molar ratio of compound (I) to the 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 (toluene), Et2O (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] Beneficial effects of the present invention:

[0028] 1. The present invention provides a transition metal-free and oxidant-free ortho-sulfonyl imide esterification strategy for aromatic amines. By reacting cheap and easy-to-prepare aromatic hydroxylamine compounds with S-arylsulfonyl imide chlorides, rapid and efficient synthesis of ortho-aminosulfonyl imide esters can be achieved under alkaline conditions. The strategy has a wide range of substrates and good functional group compatibility. In the structure of sulfonyl imide chloride, both sulfur and nitrogen can be connected to a variety of unsubstituted and substituted aromatic and heteroaryl groups. At the same time, various aromatic hydroxylamines, including natural product molecules, can be effectively converted, and ortho-aminosulfonyl imide ester compounds with excellent regioselectivity and diverse structures are prepared in good yields. It is of great significance for the further development and application in the fields of agricultural chemistry, life and pharmaceutical sciences.

[0029] 2. The present invention provides a method for synthesizing a sulfonyl imide ester group at the ortho position of an aromatic amine without pre-functionalization, so as to fill the gap in the existing ortho-position functionalization of aromatic amines. The synthesis of ortho-amino aromatic sulfonyl imide esters is achieved with the advantages of simplicity, high efficiency and high regioselectivity.

[0030] 3. The alkali used in the present invention is also a commonly used commercial reagent and is very stable. The present invention is simple to post-process, can be recycled repeatedly, and has a wide range of application prospects.

[0031] 4. The o-aminosulfonyl imide ester compound synthesized by the present invention has a chiral sulfur atom and has the potential to be split into a single chiral compound. The o-aminosulfonyl imide ester compound also contains nitrogen atoms, sulfur atoms and oxygen atoms that are easy to coordinate with metals. Therefore, the asymmetric o-aminosulfonyl imide ester compound can be used as a ligand or raw material for asymmetric catalytic synthesis. BRIEF DESCRIPTION OF THE DRAWINGS

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

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

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

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

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

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

[0038] Figure 7 2-Benzoylaminophenyl-N-benzoyl-2-chlorobenzenesulfonimide prepared in Example 4 1 H-NMR spectrum;

[0039] Figure 8 2-Benzoylaminophenyl-N-benzoyl-2-chlorobenzenesulfonimide prepared in Example 4 13 C-NMR spectrum;

[0040] Fig. 9 2-Benzoylaminophenyl-4-methyl-N-(thiophene-2-carbonyl)benzenesulfonyl imide ester prepared in Example 5 1 H-NMR spectrum;

[0041] Fig.10 2-Benzoylaminophenyl-4-methyl-N-(thiophene-2-carbonyl)benzenesulfonyl imide ester prepared in Example 5 13 C-NMR spectrum. DETAILED DESCRIPTION

[0042] The present invention provides a method for synthesizing an ortho-aminoaryl sulfonyl imide ester compound, wherein the compound has a structure shown in formula (III):

[0043]

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

[0045] The synthesis method comprises the following steps:

[0046] In an air atmosphere, compound (I) and compound (II) are added to a solvent, and the mixture is reacted in the presence of a base. After the reaction is completed, the mixture is purified to obtain an o-aminoarylsulfonyl imide ester compound (III).

[0047]

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

[0049]

[0050] Compound (I) can be prepared according to the existing technical route, and the preparation route is 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) are dissolved in THF (0.5 M), and then the reaction system is cooled to 0°C, and hydrazine hydrate (1.2 equivalent) is slowly added. The reaction mixture is stirred at 0°C for 10 minutes, then slowly warmed to room temperature, and continued to stir at room temperature for 4 hours. After the reaction is completed, the reaction mixture is filtered through diatomaceous earth, and the filtrate is concentrated by rotary evaporation and recrystallized, and the crude product hydroxylamine is directly used in the next reaction.

[0053] Prepare a solution of crude hydroxylamine in ether (0.5M), and add a saturated aqueous solution of NaHCO3 thereto. Subsequently, the resulting solution is cooled to 0°C. The corresponding acyl chloride (1.1 equivalents) is slowly added dropwise to the solution, and after the addition is completed, stirring is continued at 0°C for 10 seconds. After the reaction is completed, the reaction is quenched with a saturated aqueous solution of NH4Cl, the reaction mixture is extracted with ethyl acetate, and the organic layer is washed with saturated brine and dried over anhydrous sodium sulfate. The solvent is removed under vacuum, and the crude product is subjected to column chromatography (eluent is dichloromethane: ethyl acetate = 50:1) to obtain compound (I).

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

[0055]

[0056] Compound (II) can be prepared according to the existing technical route, and the preparation route is as follows:

[0057]

[0058] The synthesis steps are as follows:

[0059] Under nitrogen atmosphere, N-chlorosuccinimide (26mmol, 1.3 equivalents) was placed in a 100mL reaction bottle and dissolved in dichloromethane (50mL). Benzenethiol (30mmol, 1.5mmol) was slowly added at 0°C, and the reaction mixture was stirred at room temperature for 12h. The reaction solution was concentrated in a rotary evaporator, the concentrated mixture was washed with n-hexane and filtered, and the obtained filtrate was freed from the solvent under vacuum conditions to obtain crude hypochlorothiobenzene, which was an orange liquid and was directly used for the next step. Benzamide (20mmol, 1 equivalent), NaH (60mmol, 3 equivalents) and dry THF (80mL) were added to a 250mL reaction bottle in sequence and stirred at room temperature for 2h 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 warmed to room temperature and continued to stir for 12 hours. After the reaction was completed, 200mL 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 with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The crude product was subjected to column chromatography (eluent: petroleum ether / ethyl acetate = 7:1) to obtain the desired sulfenamide.

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

[0061] According to the present invention, in the o-aminoarylsulfonyl imide ester compound (III), Ar, R 1 From compound (I), R 2 , R 3 Composed of compound (II), since the functional groups in compound (I) and compound (II) are compatible, Ar, R 1 , R 2 , R 3 The selection range is wide, further broadening the group types of ortho-aminoarylsulfonyl imide ester compounds.

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

[0063]

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

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

[0066]

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

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

[0069]

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

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

[0072]

[0073] According to the present invention, during the reaction, the progress of the reaction 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 a rotary evaporator, and the crude product was subjected to column chromatography. The eluent for the column chromatography was petroleum ether / ethyl acetate = 10:1, to obtain the target compound (III).

[0076] According to the present invention, the reaction molar ratio of compound (I) to compound (II) is theoretically 1:1. In order to make full use of the arylhydroxylamine and improve the reaction conversion rate, compound (II) is appropriately excessive. After the reaction is completed, the remaining compound (II) can be recovered by 12-16%, further reducing the production cost. Therefore, in one or more preferred embodiments, the molar ratio of compound (I) to compound (II) is 1: (1-2), and more preferably 1: (1.1-1.5); most preferably, the molar ratio of compound (I) to compound (II) is 1: 1.2.

[0077] According to the present invention, the tandem rearrangement reaction of compound (I) and compound (II) needs to be carried out under alkaline conditions, and different alkaline environments have an important influence 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 reaction molar ratio of compound (I) and base is theoretically 1:1. In order to improve the reaction conversion rate, the base is appropriately excessive, and the remaining base after the reaction is completed can be recovered by 85-95%, further reducing the production cost. Therefore, in one or more preferred embodiments, the molar ratio of compound (I) and base is 1: (1-3), further preferably 1: (1.7-2.2); most preferably, the molar ratio of compound (I) and 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 (toluene), Et2O (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, further preferably -30°C to 10°C, and most preferably 0°C.

[0081] According to the present invention, the o-aminosulfonyl imide ester compounds are stable for several months when exposed to air, and are compatible with functional groups present on almost all natural products. The compounds have received extensive attention in organic synthetic chemistry, medicinal chemistry, chemical biology, etc. and have shown good application prospects.

[0082] The technical route of the present invention is as follows:

[0083]

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

[0085]

[0086] Aryl hydroxylamine is deprotonated in the presence of Na2CO3 and coupled with arylsulfonyl imide chloride to generate sulfonyl imide ester aromatic amine NO intermediate A, which then breaks due to the low NO bond energy and undergoes [3,3]-σ-rearrangement to generate intermediate B, which is then aromatized to complete the rearrangement reaction and directly construct a CO bond at the ortho position of the amine group to ultimately generate ortho-amino aromatic sulfonyl imide ester compound (III).

[0087] The present invention is further described below by means of specific examples, but is not limited thereto.

[0088] Example 1, 2-(tert-Butyloxycarbonyl)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 temperature of the reaction system was lowered to 0°C, N-benzoyl-4-methylbenzenesulfonyl imide chloride (1.2 equiv, 71 mg) was quickly added, and the mixture was stirred at 0°C for 2 hours. The reaction progress was tracked by TLC. After the reaction was completed, the solvent was removed from the reaction mixture under vacuum conditions. The crude product was subjected to column chromatography (eluent: petroleum ether / ethyl acetate = 7:1) to obtain 2-(tert-butoxycarbonyl)amino)phenyl N-benzoyl-4-methylbenzenesulfonylamino ester as 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-Benzamido 5-chlorophenyl-N-benzoyl-4-methylbenzenesulfonyl imide ester

[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 temperature of the reaction system was lowered to 0°C, N-benzoyl-4-methylbenzenesulfonyl imide chloride (1.2 equiv, 71 mg) was quickly added, and the mixture was stirred at 0°C for 2 hours. The reaction progress was tracked by TLC. After the reaction was completed, the solvent was removed from the reaction mixture under vacuum conditions. The crude product was subjected to column chromatography (eluent: petroleum ether / ethyl acetate = 7:1) to obtain 2-benzamido 5-chlorophenyl-N-benzoyl-4-methylbenzenesulfonyl imide ester as 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 temperature of the reaction system was lowered to 0°C, N-benzoyl-4-methylbenzenesulfonyl imide chloride (1.2 equiv, 71 mg) was quickly added, and the mixture was stirred at 0°C for 2 hours. The reaction progress was tracked by TLC. After the reaction was completed, the solvent was removed from the reaction mixture under vacuum conditions. The crude product was subjected to column chromatography (eluent: petroleum ether / ethyl acetate = 8:1) to obtain 2-benzamide-4,6-dimethylphenyl N-benzoyl-4-methylbenzenesulfonyl ester as 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-chlorobenzenesulfonimide

[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 temperature of the reaction system was lowered to 0°C, N-benzoyl-2-chlorobenzenesulfonamide chloride (1.2 equiv, 75 mg) was quickly added, and the mixture was stirred at 0°C for 2 hours. The reaction progress was tracked by TLC. After the reaction was completed, the solvent was removed from the reaction mixture under vacuum conditions. The crude product was subjected to column chromatography (eluent: petroleum ether / ethyl acetate = 7:1) to obtain 2-benzamidophenyl-N-benzoyl-2-chlorobenzenesulfonimide as 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)benzenesulfonyl imide ester

[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 temperature of the reaction system was lowered to 0°C, 4-methyl-N-(thiophene-2-carbonyl)benzenesulfonamide chloride (1.2 equiv, 72 mg) was quickly added, and the mixture was stirred at 0°C for 2 hours. The reaction progress was tracked by TLC. After the reaction was completed, the solvent was removed from the reaction mixture under vacuum conditions, and the crude product was subjected to column chromatography (eluent: petroleum ether / ethyl acetate = 7:1) to obtain 2-benzamidophenyl-4-methyl-N-(thiophene-2-carbonyl)benzenesulfonyl imide ester as 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] Test Example 1

[0114] Using N-hydroxy-N-phenylbenzamide and N-benzoyl-4-methylbenzenesulfonyl imide chloride as raw materials, 4-dimethylaminopyridine as base, the amount of base used was 2.0 equivalents, the reaction temperature was 25°C, and the reaction was carried out in an air atmosphere 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] From the experimental results in Table 1, it can be seen that DCM is the best solvent for this reaction.

[0118] Test Example 2

[0119] Using N-hydroxy-N-phenylbenzamide and N-benzoyl-4-methylbenzenesulfonyl imide chloride as raw materials, dichloromethane as solvent, the reaction temperature was 25°C, and the reaction was carried out in an air atmosphere 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 alkali on the reaction

[0121]

[0122] From the experimental results in Table 2, it can be seen that Na2CO3 is the best base for this reaction.

[0123] Test Example 3

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

[0125] Table 3 Effect of temperature on reaction

[0126]

[0127] From the experimental results in Table 3, it can be seen that 0°C is the optimal temperature for the reaction.

Claims

1. A method for synthesizing an ortho-aminoaryl sulfonyl imide ester compound, wherein the compound has a structure shown in formula (III): In formula (III), Ar is a substituted or unsubstituted aryl, heteroaryl or biaryl group, R 1 is one of benzoyl, acetyl, tert-butyloxycarbonyl, benzyloxycarbonyl, trifluoroacetyl, p-nitrobenzoyl and 9-fluorenylmethoxycarbonyl; R 2 is a substituted or unsubstituted benzoyl, 2-naphthyl, or 2-thienyl group; R 3 is a substituted or unsubstituted aryl or alkyl group; The steps include: In an air atmosphere, compound (I) and compound (II) are added to a solvent, and the mixed solution is reacted in the presence of a base. After the reaction is completed, the mixture is purified to obtain an ortho-aminoarylsulfonyl imide ester compound (III); 2. The method for synthesizing an ortho-aminoarylsulfonyl imide ester compound according to claim 1, characterized in that: Ar Where R 4 It is one or more of fluorine, chlorine, bromine, iodine, alkyl, alkynyl, ester, aryl, heteroaryl, trifluoromethyl, and silicon.

3. The method for synthesizing an ortho-aminoarylsulfonyl imide ester compound according to claim 1, characterized in that: R 2 for Alkyl, cycloalkyl, where R 5 It is one or more of fluorine, chlorine, bromine, alkyl, trifluoromethyl, aryl and heteroaryl.

4. The method for synthesizing an ortho-aminoarylsulfonyl imide ester compound according to claim 1, characterized in that: R 3 for Alkyl, cycloalkyl, where R 6 It is one or more of fluorine, chlorine, bromine, alkyl, trifluoromethyl and aryl.

5. The method for synthesizing an o-aminoarylsulfonyl imide ester compound according to claim 1, characterized in that: The o-aminoaryl sulfonyl imide ester compound has the following structure:

6. The method for synthesizing an ortho-aminoarylsulfonyl imide ester compound according to claim 1, characterized in that: The purification method is as follows: After the reaction was completed, the reaction mixture was freed from the solvent under vacuum conditions, and the crude product was subjected to column chromatography with the eluent being petroleum ether / ethyl acetate = 10:

1.

7. The method for synthesizing an o-aminoarylsulfonyl imide ester compound according to claim 1, characterized in that: The molar ratio of compound (I) to compound (II) is 1:(1-2); Preferably, the molar ratio of compound (I) to the base is 1:(1-3).

8. The method for synthesizing an o-aminoarylsulfonyl imide ester compound according to claim 1, characterized in that: The base is sodium carbonate, potassium phosphate, sodium bicarbonate, pyridine, DABCO, DMAP, diethylamine, DBN or DBU.

9. The method for synthesizing an o-aminoarylsulfonyl imide ester compound according to claim 1, characterized in that: The solvent is dichloromethane, acetonitrile, dichloroethane, 1,4-dioxane, hexafluoroisopropanol, toluene, ether or tetrahydrofuran.

10. The method for synthesizing an o-aminoarylsulfonyl imide ester compound according to claim 1, characterized in that: The reaction temperature is -78°C to 25°C.

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