Benzazepine nona-ring lactone compounds, methods for preparing the same, and uses thereof

Abstract

The application discloses a benzazepine nine-membered ring lactone compound and a preparation method and application thereof, and adopts a palladium and azepine carbene catalyst synergistic catalysis reaction, so that reaction steps are simplified, reaction conditions are more moderate, an ideal yield can be obtained, a feasible reaction path is provided for preparation of the benzazepine nine-membered ring lactone compound and industrial production thereof, meanwhile, the prepared benzazepine nine-membered ring lactone compound can effectively inhibit MRSE and MSSE, has good antibacterial activity, and is expected to be applied to preparation or screening of drugs for inhibiting MRSE or MSSE.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to benzoza-9-membered ring lactone compounds, their preparation methods, and applications. Background Technology

[0002] Nine-membered rings, as a special class of compounds, are widely found in natural products and synthetic drugs. Their unique conformation allows for unconventional stereoselective transformations during reactions. Related studies have shown that compounds containing a benzoza nine-membered ring skeleton possess a variety of important biological and pharmaceutical activities. Therefore, in recent years, substituent modification, derivatization of structural analogs, and further re-evaluation of biological activities have become research hotspots for these compounds.

[0003] However, there is currently limited research on compounds containing benzoza nine-membered ring skeletons, mainly due to a lack of suitable preparation methods. Furthermore, existing palladium-catalyzed synthesis of nine-membered rings is not applicable to the synthesis of benzoza nine-membered ring skeletons.

[0004] Therefore, it is necessary to design a suitable method for preparing compounds containing a benzoza-9-membered ring skeleton to improve their yield and to provide a class of compounds with a benzoza-9-membered ring skeleton. Summary of the Invention

[0005] One objective of this invention is to provide a benzoza-9-membered ring lactone compound that, according to bioantibacterial activity tests, can effectively inhibit methicillin-resistant Staphylococcus epidermidis (MRSE) and methicillin-sensitive Staphylococcus epidermidis (MSSE), exhibiting good antibacterial activity and is expected to be used in the preparation or screening of drugs that inhibit MRSE or MSSE.

[0006] The above-mentioned objective of the present invention is achieved through the following technical solution:

[0007] Benzaza-9-membered ring lactone compounds have the structural formula shown in Formula I:

[0008]

[0009] In formula I, R 1 The group is selected from p-methylbenzenesulfonyl or nitrobenzenesulfonyl; R 2 The group is selected from substituted or unsubstituted phenyl or naphthyl groups, wherein the substituent of the substituted phenyl or naphthyl group is alkyl, alkoxy, phenyl, or halogen.

[0010] In this technical solution, a [5+4]benzoza-9-membered ring lactone compound was prepared by synergistic catalysis of palladium and nitrogen heterocyclic carbene catalyst (NHC). The R of this compound... 1The group can be either p-methylbenzenesulfonyl (TS) or nitrobenzenesulfonyl (NS). 2 The group can be either an unsubstituted phenyl or naphthyl group, or a substituted phenyl or naphthyl group.

[0011] In some embodiments, the substitution on the phenyl or naphthyl group can be monosubstituted, disubstituted, or trisubstituted.

[0012] In some embodiments, the substituent on the phenyl or naphthyl group may be an alkyl, alkoxy, phenyl, or halogen. In one or more preferred embodiments, the alkyl group is a C1-C4 straight-chain alkyl or branched alkyl group, and more preferably, the alkyl group is methyl or ethyl. In one or more preferred embodiments, the alkoxy group is methoxy or ethoxy. In one or more preferred embodiments, the halogen is chlorine or bromine.

[0013] Furthermore, the benzoza-9-membered ring lactone compound is selected from the following compounds:

[0014]

[0015] Another objective of this invention is to provide a method for preparing any of the aforementioned benzoza-9-membered ring lactone compounds. This method employs a synergistic catalytic reaction of palladium and nitrogen heterocyclic carbene catalysts (NHC), which not only makes the reaction conditions mild but also achieves a high yield, providing a feasible reaction route for the preparation of benzoza-9-membered ring lactone compounds and their industrial production.

[0016] The above-mentioned objective of the present invention is achieved through the following technical solution:

[0017] A method for preparing benzoza-9-membered ring lactone compounds includes the following steps:

[0018] The benzo[a]aza nine-membered ring lactone compound of formula I was prepared by reacting the compound shown in formula II, the compound shown in formula III, triphenylphosphine palladium, a nitrogen heterocyclic carbene catalyst, an oxidant, a basic reagent, and a solvent under an inert atmosphere.

[0019]

[0020] In this technical solution, the compound represented by Formula II and the carbonate represented by Formula III are used as reactants, and a palladium and nitrogen heterocyclic carbene catalyst are used for a synergistic catalytic reaction. The reaction pathway is as follows:

[0021]

[0022] The reaction mechanism of the above reaction pathway is as follows: the carbonate shown in Formula III is activated by triphenylphosphine palladium to remove one molecule of CO2 to obtain a benign ion Π-allylpalladium species. The aldehyde group of the compound shown in Formula II reacts with the nitrogen heterocyclic carbene catalyst to generate the Breslow intermediate. The carbonyl group of the Breslow intermediate after being oxidized by the oxidant is attacked by the exposed oxygen anion of the Π-allylpalladium species. Then, the N atom in the molecule attacks the Π-allylpalladium species to obtain the target product, the benzo[a]aza nine-membered ring lactone compound.

[0023] In this technical solution, triphenylphosphine palladium, a nitrogen heterocyclic carbene catalyst, the compound shown in Formula II, an oxidant, and a basic reagent are first mixed. After evacuation and replacement of the inert gas, such as argon, a solvent is added. Then, the carbonate shown in Formula III is added to the reaction system. After the addition is complete, the reaction is carried out under an inert atmosphere. The reaction progress is monitored by thin-layer chromatography. After the reaction is completed, the product is purified to obtain a benzo[a]aza nine-membered ring lactone compound.

[0024] In some preferred embodiments, while adding the carbonate shown in Formula III, a desiccant, such as a dry 4A molecular sieve, may also be added to the reaction system to reduce the moisture in the reaction system.

[0025] In this technical solution, the solvent is preferably dry trifluorotoluene. In some embodiments, other solvents capable of dissolving the product may also be used.

[0026] In this technical solution, a catalytic amount of triphenylphosphine palladium and a nitrogen-containing heterocyclic carbene catalyst are used to catalyze the reaction. In some preferred embodiments, the compound represented by Formula II is used as 1 equivalent, the amount of triphenylphosphine palladium is 5 mol% eq, and the amount of nitrogen-containing heterocyclic carbene catalyst is 10 mol% eq.

[0027] In this technical solution, the reaction temperature for preparing the benzoza-9-membered ring lactone compound is 40–70°C. Preferably, the reaction temperature is 40–60°C, and more preferably, the reaction temperature is 50–60°C.

[0028] In this technical solution, the oxidant can be any existing oxidant capable of oxidizing Breslow intermediates. In some preferred embodiments, the oxidant is dodecyl mercaptan or 2,3-dichloro-5,6-dicyanobenzoquinone. In one or more embodiments, the oxidant is dodecyl mercaptan.

[0029] In this technical solution, the alkaline reagent can be any existing alkaline reagent, such as sodium hydroxide, sodium carbonate, etc. In some preferred embodiments, the alkaline reagent is potassium carbonate, cesium carbonate, or potassium phosphate; in one or more embodiments, the alkaline reagent is cesium carbonate.

[0030] The preparation method provided in this technical solution uses palladium and nitrogen heterocyclic carbene catalysts for synergistic catalysis, which not only simplifies the reaction steps and makes the reaction conditions milder, but also achieves ideal yields, providing a feasible reaction route for the preparation of benzoza-9-membered ring lactone compounds and their industrial production.

[0031] Furthermore, the method for preparing the compound represented by Formula II includes the following steps:

[0032] After dissolving 2-aminobenzyl alcohol in chloroform, p-toluenesulfonyl chloride or p-nitrobenzenesulfonyl chloride and pyridine are added and reacted to obtain an intermediate;

[0033] The intermediate was dissolved in dichloromethane and then reacted with pyridine chlorochromate to give the compound shown in Formula II.

[0034] In this technical solution, 2-aminophenyl alcohol is used as a raw material, which is dissolved in chloroform, and then... (The sentence is incomplete and requires more context to translate accurately.) 1 The group is p-methylbenzenesulfonyl or nitrobenzenesulfonyl, and toluenesulfonyl chloride or p-nitrobenzenesulfonyl chloride is added, followed by the addition of pyridine. In some preferred embodiments, the reaction temperature is room temperature. After the reaction is complete, the solvent is removed to obtain the intermediate, as detected by TLC. R 1 Taking p-methylbenzenesulfonyl as an example, the reaction pathway for this step is as follows:

[0035]

[0036] In this technical solution, the intermediate can be purified before proceeding to the next reaction, or it can be added directly to dichloromethane without purification, followed by the addition of a certain amount of pyridine chlorochromate. In some preferred embodiments, the reaction temperature is room temperature. In one or more embodiments, the reaction time is 3–6 hours, preferably 4–5 hours. After the reaction is complete, the compound represented by Formula II is isolated by TLC detection. (The last sentence appears to be incomplete and possibly refers to R.) 1 Taking p-methylbenzenesulfonyl as an example, the reaction pathway for this step is as follows:

[0037]

[0038] In this technical solution, any existing nitrogen-heterocyclic carbene catalyst can be selected. In some embodiments, preferably, the nitrogen-heterocyclic carbene catalyst has the structure shown in Formula IV, so that the Breslow intermediate generated by its reaction with the aldehyde group can be better attacked by the oxygen anion of the Π-allylpalladium species, which is beneficial to the synthesis of benzo[a]aza-nine-membered ring lactone compounds.

[0039]

[0040] Another object of the present invention is to provide the application of any of the aforementioned benzoza-9-membered ring lactone compounds. Specifically, through antibacterial activity tests on multiple clinically isolated pathogenic bacteria, it has been found that benzoza-9-membered ring lactone compounds can effectively inhibit methicillin-resistant Staphylococcus epidermidis (MRSE) and methicillin-sensitive Staphylococcus epidermidis (MSSE), exhibiting good antibacterial activity. Therefore, benzoza-9-membered ring lactone compounds are expected to be used for the preparation or screening of drugs that inhibit MRSE and MSSE.

[0041] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0042] 1. The preparation method of the present invention uses palladium and nitrogen heterocyclic carbene catalysts for synergistic catalysis, which not only simplifies the reaction steps and makes the reaction conditions milder, but also achieves ideal yields, providing a feasible reaction route for the preparation of benzoza nine-membered ring lactone compounds and their industrial production.

[0043] 2. The benzoza-9-membered ring lactone compound prepared by this invention can effectively inhibit MRSE and MSSE, and has good antibacterial activity. It is expected to be used in the preparation or screening of drugs that inhibit MRSE or MSSE. Attached Figure Description

[0044] The accompanying drawings, which are included to provide a further understanding of embodiments of the invention and form part of this application, do not constitute a limitation thereof. In the drawings:

[0045] Figure 1 This is the single-crystal structure of compound 1 in a specific embodiment of the present invention. Detailed Implementation

[0046] To make the objectives, technical solutions, and advantages of the present invention clearer, the present invention will be further described in detail below with reference to the embodiments and accompanying drawings. The illustrative embodiments and descriptions of the present invention are only used to explain the present invention and are not intended to limit the present invention.

[0047] The sources of all raw materials used in this invention are not particularly limited; they can be purchased commercially or prepared using conventional methods well-known to those skilled in the art. The purity of all raw materials used in this invention is not particularly limited; however, analytical grade or pharmaceutical chemistry purity requirements are preferred. The expression of the substituents in this invention is not particularly limited; all expressions are well-known to those skilled in the art, and their meaning can be correctly understood based on common sense.

[0048] All raw materials of this invention are conventional in the field, and each brand name and abbreviation is clear and distinct in its relevant application. Those skilled in the art can purchase them from the market or prepare them by conventional methods based on the brand name, abbreviation and corresponding application.

[0049] The term “link” as used herein, unless otherwise specified, can mean a direct link or an indirect link via other groups.

[0050] I. Preparation of the o-aminobenzaldehyde compound represented by Formula II

[0051] Example 1:

[0052]

[0053] R 1 The preparation method of o-aminobenzaldehyde compounds with a p-methylbenzenesulfonyl group includes the following steps:

[0054] (1) Prepare a dry, nitrogen-purged 250ml Schlenk sealing tube, set up a magnetic stir bar, weigh 2-aminobenzene alcohol (2.46g, 20mmol), add chloroform (100mL) as solvent, add TsCl (4.18g, 22mmol) and pyridine (0.1mL), stir the reaction mixture at room temperature for 12h, and after the reaction is completed by TLC, remove the solvent by vacuum evaporation;

[0055] (2) The previous reaction was carried out without purification. Dichloromethane (50 mL) was added directly to the mixture, along with pyridine chlorochromate (5.17 g, 30 mmol). The reaction mixture was stirred at room temperature for 4 h, filtered through a Celite 545 filter, and washed with dichloromethane. The solvent was then removed by vacuum evaporation (petroleum ether / ethyl acetate: 6 / 1) to give N-Ts aminobenzaldehyde (3.6 g, 87%).

[0056] Example 2:

[0057] Based on Example 1, the TsCl added in the first step was replaced with NsCl, while the reaction conditions remained unchanged, and the reaction yielded R. 1 o-aminobenzaldehyde compounds with nitrobenzenesulfonyl groups.

[0058] II. Preparation of Benzoaza nine-membered ring lactone compounds

[0059] Example 3: (Z)-1-((4-nitrophenyl)sulfonyl)-4-phenyl-2,5-dihydrobenzo[c][1,5]oxazol-7(1H)-carbonyl, compound 1

[0060]

[0061] Add 5 mol% eq Pd(PPh3)4, 10 mol% eq NHC, N-nitrobenzenesulfonyl o-aminobenzaldehyde compound, DQ, and Cs2CO3 to a dry 10 mL sealed tube. Cover the tube, evacuate, and add 0.3 mL of dry trifluorotoluene under an argon atmosphere. Then add carbonate substrate and dry 4A molecular sieve. Cover the tube tightly and stir the resulting suspension at 60 °C for 12 h. The reaction is monitored by thin-layer chromatography. The reaction mixture is then directly purified by column chromatography to obtain the target product with a yield of 58%.

[0062] 1 H-NMR(600MHz,CHLOROFORM-D)δ8.07(d,J=9.0Hz,2H),7.75(d,J=8.4Hz,1H),7.62-7.57(m,3H),7.54(d,J=7.8,1.4Hz, 1H),7.47(t,J=7.2Hz,1H),7.41-7.39(m,3H),7.23(d,J=7.8Hz,2H),6.14(t,J=9Hz,1H),5.02(brs,2H),4.60(brs,2H)

[0063] 13 C-NMR(151MHz,CHLOROFORM-D)δ166.7,149.7,146.2,141.7,138.6,138.1,132 .5,132.4,131.9,128.9,128.8,128.7,128.0,126.2,123.7,123.3,65.6,50.6

[0064] In this embodiment, the single-crystal structure of compound 1 obtained is as follows: Figure 1 As shown, the single-crystal data for compound 1 are presented in Table 1:

[0065] Table 1

[0066]

[0067]

[0068] Example 4: (Z)-4-phenyl-1-toluenesulfonyl-2,5-dihydrobenzo[c][1,5]oxazol-7(1H)-carbonyl, compound 2

[0069]

[0070] Add 5 mol% eq Pd(PPh3)4, 10 mol% eq NHC, N-methylbenzenesulfonyl o-aminobenzaldehyde compound, DQ, and Cs2CO3 to a dry 10 mL sealed tube. Cover the tube, evacuate, and add 0.3 mL of dry trifluorotoluene under an argon atmosphere. Then add carbonate substrate and dry 4A molecular sieve. Cover the tube tightly and stir the resulting suspension at 40 °C for 12 h. The reaction is monitored by thin-layer chromatography. The reaction mixture is then directly purified by column chromatography to obtain the target product with a yield of 69%.

[0071] 1 H-NMR(600MHz,CHLOROFORM-D)δ7.73(d,J=7.8Hz,1H),7.56-7.53(m,2H),7.42-7.34(m,5H),7.24 (d,J=6Hz,2H),7.08(d,J=7.8Hz,2H),6.10(t,J=7.8Hz,1H),5.02(s,2H),4.54(s,2H),2.34(s,3H)

[0072] 13 C-NMR(151MHz,CHLOROFORM-D)δ167.0,143.2,140.3,139.9,138.7,137.8,132.4,13 2.1,131.8,129.1,128.5,128.3,128.1,128.1,127.5,126.3,124.2,65.9,50.3,21.5

[0073] Example 5: (Z)-4-(2-naphthyl)-1-toluenesulfonyl-2,5-dihydrobenzo[c][1,5]oxazol-7(1H)-carbonyl, compound 3

[0074]

[0075] Add 5 mol% eq Pd(PPh3)4, 10 mol% eq NHC, N-methylbenzenesulfonyl o-aminobenzaldehyde compound, DQ and Cs2CO3 to a dry 10 mL sealed tube. Cover the tube, evacuate, and add 0.3 mL of dry trifluorotoluene under an argon atmosphere. Then add 2-naphthalene carbonate substrate and dry 4A molecular sieve. Cover the tube tightly and stir the resulting suspension at 50 °C for 12 h. The reaction is monitored by thin-layer chromatography. The reaction mixture is then directly purified by column chromatography to obtain the target product with a yield of 62%.

[0076] 1H-NMR(600MHz,CHLOROFORM-D)δ7.86(t,J=9Hz,3H),7.75(d,J=7.2Hz,1H),7.64(s,1H),7.60-7.51(m,4H),7.44(d,J= 7.8Hz,1H),7.41(d,J=8.4Hz,3H),7.05(d,J=8.4Hz,2H),6.26(t,J=7.2Hz,1H),5.12(s,2H),4.59(s,2H),2.31(s,3H)

[0077] 13 C-NMR(151MHz,CHLOROFORM-D)δ167.1,143.2,140.1,140.0,137.9,135.9,133.1,133.0,132.4,132.2 ,131.9,129.2,128.2,128.2,128.1,127.6,127.5,126.6,126.4,125.1,124.,124.3,65.8,50.4,21.5

[0078] Example 6: (Z)-4-([1,1'-biphenyl]-4-phenyl)-1-toluenesulfonyl-2,5-dihydrobenzo[c][1,5]oxazol-7(1H)-carbonyl, compound 4

[0079]

[0080] Add 5 mol% eq Pd(PPh3)4, 10 mol% eq NHC, N-methylbenzenesulfonyl o-aminobenzaldehyde compound, DQ and Cs2CO3 to a dry 10 mL sealed tube. Cover the tube, evacuate, and add 0.3 mL of dry trifluorotoluene under an argon atmosphere. Then add 4-phenyl carbonate substrate and dry 4A molecular sieve. Cover the tube tightly and stir the resulting suspension at 50 °C for 12 h. The reaction is monitored by thin-layer chromatography. The reaction mixture is then directly purified by column chromatography to obtain the target product with a yield of 53%.

[0081] 1H-NMR (600MHz, CHLOROFORM-D) δ7.74(d,J=7.8Hz,1H),7.63(d,J=7.2Hz,2H),7.61(d,J=8.4Hz,2H),7.56(t,J=7.8Hz,2H),7.48(t,J=7. 8Hz,2H),7.434-7.376(m,4H),7.33(d,J=8.4Hz,2H),7.09(d,J=7.8Hz,2H),6.18(t,J=7.2Hz,1H),5.06(s,2H),4.56(s,2H),2.35(s,3H)

[0082] 13 C-NMR(151MHz,CHLOROFORM-D)δ167.0,143.2,141.1,140.3,139.9,139.8,137.9,137.5,132.4,13 2.1,131.9,129.2,128.9,128.2,128.1,127.6,127.5,127.2,127.0,126.6,124.2,65.7,50.3,21.5

[0083] Example 7: (Z)-4-(4-methoxyphenyl)-1-toluenesulfonyl-2,5-dihydrobenzo[c][1,5]oxazol-7(1H)-carbonyl, compound 5

[0084]

[0085] Add 5 mol% eq Pd(PPh3)4, 10 mol% eq NHC, N-methylbenzenesulfonyl o-aminobenzaldehyde compound, DQ, and Cs2CO3 to a dry 10 mL sealed tube. Cover the tube, evacuate, and add 0.3 mL of dry trifluorotoluene under an argon atmosphere. Then add 4-methoxycarbonate substrate and dry 4A molecular sieve. Seal the tube tightly and stir the resulting suspension at 50 °C for 12 h. The reaction is monitored by thin-layer chromatography. The reaction mixture is then directly purified by column chromatography to obtain the target product with a yield of 63%.

[0086] 1H-NMR (600MHz, CHLOROFORM-D) δ7.72(d,J=7.8Hz,1H),7.56-7.54(m,2H),7.41(t,J=7.2Hz,1H),7.38(d,J=9.0Hz,2H),7.18(d,J= 9.0Hz,2H),7.07(d,J=7.8Hz,2H),6.89(d,J=9.0Hz,2H),6.04(t,J=7.2Hz,1H),4.97(s,2H),4.52(s,2H),3.84(s,3H),2.34(s,3H)

[0087] 13 C-NMR(151MHz,CHLOROFORM-D)δ167.0,159.6,143.1,139.9,139.7,137.9,132.3,132.2 ,131.8,131.0,129.1,128.2,128.1,127.5,127.4,122.6,113.8,65.8,55.3,50.4,21.5

[0088] Example 8: (Z)-4-(4-methylphenyl)-1-toluenesulfonyl-2,5-dihydrobenzo[c][1,5]oxazol-7(1H)-carbonyl, compound 6

[0089]

[0090] Add 5 mol% eq Pd(PPh3)4, 10 mol% eq NHC, N-methylbenzenesulfonyl o-aminobenzaldehyde compound, DQ and Cs2CO3 to a dry 10 mL sealed tube. Cover the tube, evacuate, and add 0.3 mL of dry trifluorotoluene under an argon atmosphere. Then add 4-methyl carbonate substrate and dry 4A molecular sieve. Cover the tube tightly and stir the resulting suspension at 50 °C for 12 h. The reaction is monitored by thin-layer chromatography. The reaction mixture is then directly purified by column chromatography to obtain the target product with a yield of 60%.

[0091] 1H-NMR (600MHz, CHLOROFORM-D) δ7.73(d,J=7.8Hz,1H),7.57-7.54(m,2H),7.42(d,J=7.8Hz,1H),7.38(d,J=6Hz,2H),7.18(d,J=7 .8Hz,2H),7.14(d,J=8.4Hz,2H),7.07(d,J=8.4Hz,2H),6.08(t,J=7.2Hz,1H),4.98(s,2H),4.52(s,2H),2.38(s,3H),2.34(s,3H)

[0092] 13 C-NMR(151MHz,CHLOROFORM-D)δ167.0,143.1,140.1,139.9,138.2,137.9,135.7,132.4 ,132.2,131.8,129.2,129.1,128.2,128.1,127.5,126.1,123.3,65.8,50.3,21.5,21.1

[0093] Example 9: (Z)-4-(3-methoxyphenyl)-1-toluenesulfonyl-2,5-dihydrobenzo[c][1,5]oxazol-7(1H)-carbonyl, compound 7

[0094]

[0095] Add 5 mol% eq Pd(PPh3)4, 10 mol% eq NHC, N-methylbenzenesulfonyl o-aminobenzaldehyde compound, DQ and Cs2CO3 to a dry 10 mL sealed tube. Cover the tube, evacuate, and add 0.3 mL of dry trifluorotoluene under an argon atmosphere. Then add 3-methoxycarbonate substrate and dry 4A molecular sieve. Seal the tube tightly and stir the resulting suspension at 50 °C for 12 h. The reaction is monitored by thin-layer chromatography. The reaction mixture is then directly purified by column chromatography to obtain the target product with a yield of 51%.

[0096] 1H-NMR (600MHz, CHLOROFORM-D) δ7.73(d,J=9Hz,1H),7.56-7.54(m,2H),7.42-7.38(m,3H),7.28(t,J=7.8Hz,1H),7.09(d,J=8.4Hz,2H ),6.89(d,J=7.8Hz,1H),6.82(d,J=7.8Hz,1H),6.76(s,1H),6.10(t,J=6.9Hz,1H),4.98(s,2H),4.52(s,2H),3.85(s,3H),2.35(s,3H)

[0097] 13 C-NMR(151MHz,CHLOROFORM-D)δ167.0,159.6,143.2,140.2,140.1,139.9,137.8,132.3,132.1 ,131.8,129.5,129.2,128.2,128.1,127.5,124.2,118.7,113.3,112.4,65.7,55.3,50.2,21.5

[0098] Example 10: (Z)-4-(3-methylphenyl)-1-toluenesulfonyl-2,5-dihydrobenzo[c][1,5]oxazol-7(1H)-carbonyl, compound 8

[0099]

[0100] Add 5 mol% eq Pd(PPh3)4, 10 mol% eq NHC, N-methylbenzenesulfonyl o-aminobenzaldehyde compound, DQ, and Cs2CO3 to a dry 10 mL sealed tube. Cover the tube, evacuate, and add 0.3 mL of dry trifluorotoluene under an argon atmosphere. Then add 3-methyl carbonate substrate and dry 4A molecular sieve. Seal the tube tightly and stir the resulting suspension at 60 °C for 12 h. The reaction is monitored by thin-layer chromatography. The reaction mixture is then directly purified by column chromatography to obtain the target product with a yield of 38%.

[0101] 1H-NMR(600MHz,CHLOROFORM-D)δ7.73(d,J=8.4Hz,1H),7.57-7.54(m,2H),7.42(d,J=7.8Hz,1H),7.39(d,J=7.8Hz,2H),7.26(t,J=7.8Hz,1H), 7.16(d,J=7.8Hz,1H),7.08(d,J=7.8Hz,2H),7.03(d,J=6.6Hz,2H),6.08(t,J=7.2Hz,1H),4.99(s,2H),4.53(s,2H),2.39(s,3H),2.35(s,3H)

[0102] 13 C-NMR(151MHz,CHLOROFORM-D)δ167.1,143.1,140.5,139.7,138.7,138.2,137.9,132.4,132.2 ,131.8,129.1,129.0,128.4,128.2,128.1,127.5,127.0,123.8,123.4,65.8,50.3,21.5,21.5

[0103] Example 11: (Z)-4-(3-bromophenyl)-1-toluenesulfonyl-2,5-dihydrobenzo[c][1,5]oxazol-7(1H)-carbonyl, compound 9

[0104] Add 5 mol% eq Pd(PPh3)4, 10 mol% eq NHC, N-methylbenzenesulfonyl o-aminobenzaldehyde compound, DQ and Cs2CO3 to a dry 10 mL sealed tube. Cover the tube, evacuate, and add 0.3 mL of dry trifluorotoluene under an argon atmosphere. Then add 3-methyl carbonate substrate and dry 4A molecular sieve. Cover the tube tightly and stir the resulting suspension at 60 °C for 12 h. The reaction is monitored by thin-layer chromatography. The reaction mixture is then directly purified by column chromatography to obtain the target product with a yield of 53%.

[0105] 1H-NMR (600MHz, CHLOROFORM-D) δ7.70(d,J=7.8Hz,1H),7.56(t,J=6.9Hz,2H),7.47(d,J=9.0Hz,1H),7.42(t,J=7.8Hz,1H),7.39(d,J=7.8Hz,2 H),7.29(s,1H),7.26-7.23(m,1H),7.16(d,J=7.8Hz,1H),7.12(d,J=7.2Hz,2H),6.06(t,J=7.2Hz,1H),4.95(s,2H),4.53(s,2H),2.37(s,3H)

[0106] 13 C-NMR(151MHz,CHLOROFORM-D)δ167.0,143.4,140.8,139.8,139.2,137.9,132.3,132.1,13 1.9,131.3,130.1,129.4,129.2,128.2,128.1,127.5,125.4,125.0,122.6,65.5,50.0,21.6

[0107] Example 12: (Z)-4-(3,4-dimethylphenyl)-1-toluenesulfonyl-2,5-dihydrobenzo[c][1,5]oxazol-7(1H)-carbonyl, compound 10

[0108]

[0109] Add 5 mol% eq Pd(PPh3)4, 10 mol% eq NHC, N-methylbenzenesulfonyl o-aminobenzaldehyde compound, DQ and Cs2CO3 to a dry 10 mL sealed tube. Cover the tube, evacuate, and add 0.3 mL of dry trifluorotoluene under an argon atmosphere. Then add 3-methyl carbonate substrate and dry 4A molecular sieve. Cover the tube tightly and stir the resulting suspension at 60 °C for 12 h. The reaction is monitored by thin-layer chromatography. The reaction mixture is then directly purified by column chromatography to obtain the target product with a yield of 62%.

[0110] 1H-NMR (600MHz, CHLOROFORM-D) δ7.73(d,J=6Hz,1H),7.55(s,2H),7.39(t,J=7.8Hz,3H),7.13(d,J=7.2Hz,1H),7.08( d,J=6.6Hz,2H),7.00(s,1H),6.97(d,J=7.8Hz,1H),6.06(s,1H),4.97(s,2H),4.52(s,2H),2.35(s,3H),2.29(s,6H)

[0111] 13 C-NMR(151MHz,CHLOROFORM-D)δ167.0,143.0,140.3,139.9,137.9,136.8,136.7,136.2,132.4,1 32.2,131.8,129.7,129.1,128.2,128.1,127.5,127.5,123.6,123.0,65.9,50.4,21.5,19.9,19.5

[0112] III. Antibacterial Activity Test

[0113] 1. Experimental Objective

[0114] The MIC values ​​of compound 1 were determined using the agar plate two-fold dilution method for approximately 24 clinically isolated pathogenic bacteria collected from hospitals in Chengdu over the past 2-3 years, including approximately 1-3 strains each of methicillin-resistant Staphylococcus aureus (MRSA), methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and methicillin-sensitive Staphylococcus epidermidis (MSSE) Gram-positive bacteria, as well as approximately 1-3 strains each of Klebsiella pneumoniae (ESBLs+), Klebsiella pneumoniae (ESBLs-), Escherichia coli (ESBLs+), Escherichia coli (ESBLs-), standard strain of Escherichia coli (ATCC25922), and standard strain of Staphylococcus aureus (ATCC29213).

[0115] 2. Experimental Basis

[0116] The minimum inhibitory concentration (MIC) was determined using the agar double dilution method recommended by the Clinical and Laboratory Standards Institute (CLSI).

[0117] 3. Experimental Methods

[0118] Add 1 mL of the test drug solution to a sterile Petri dish, followed by 14 mL of melted 50℃ MHA medium. Mix well to achieve final drug concentrations of 128, 64, 32, 16, and 8 μg / mL in each dish, respectively. After cooling, inoculate bacteria using a multi-point inoculation device at an inoculation density of approximately 10⁴ CFU / mL. Cover the dishes and incubate at 36±1℃ for 20–24 hours. After incubation, visually inspect the Petri dishes. The lowest sample concentration at which no bacterial growth is observed is the minimum inhibitory concentration (MIC). A blank control without any sample is also included.

[0119] 4. Experimental Results

[0120] Compound 1 exhibited activity against methicillin-resistant Staphylococcus epidermidis (MRSE) 20-1 and 20-2 (MIC values ​​of 16 μg / ml) and against methicillin-sensitive Staphylococcus epidermidis (MSSE) 20-1 (MIC value of 8 μg / ml). Therefore, the benzoza-9-membered ring lactone compound prepared in this invention can effectively inhibit both MRSE and MSSE, demonstrating good antibacterial activity. It holds promise for applications in the preparation or screening of drugs that inhibit MRSE or MSSE.

[0121] The specific embodiments described above further illustrate the purpose, technical solution, and beneficial effects of the present invention. It should be understood that the above description is only a specific embodiment of the present invention and is not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A benzoza-9-membered ring lactone compound, characterized in that, The benzo[a]aza-9-membered ring lactone compound is selected from the following compounds:

2. A method for preparing benzoza-9-membered ring lactone compounds, characterized in that, The method for preparing the benzoza-a nine-membered ring lactone compound of claim 1 comprises the following steps: The benzo[a]aza nine-membered ring lactone compound of formula I was prepared by reacting the compound shown in formula II, the compound shown in formula III, triphenylphosphine palladium, a nitrogen-containing heterocyclic carbene catalyst, an oxidant, a basic reagent, and a solvent under an inert atmosphere. Among them, group R 1 R 2 It matches the benzoza-9-membered ring lactone compound of claim 1.

3. The method for preparing the benzo[a]aza nine-membered ring lactone compound according to claim 2, characterized in that, The preparation method of the compound represented by Formula II includes the following steps: After dissolving 2-aminobenzyl alcohol in chloroform, p-toluenesulfonyl chloride or p-nitrobenzenesulfonyl chloride and pyridine are added and reacted to obtain an intermediate; The intermediate was dissolved in dichloromethane and then reacted with pyridine chlorochromate to give the compound shown in Formula II.

4. The method for preparing the benzo[a]aza nine-membered ring lactone compound according to claim 2, characterized in that, The nitrogen heterocyclic carbene catalyst has the structural formula shown in Formula IV:

5. The method for preparing the benzoza-9-membered ring lactone compound according to claim 2, characterized in that, The compound shown in Formula II was used as 1 equivalent, the amount of triphenylphosphine palladium was 5 mol% eq, and the amount of nitrogen heterocyclic carbene catalyst was 10 mol% eq.

6. The method for preparing the benzoza-9-membered ring lactone compound according to any one of claims 2 to 5, characterized in that, The reaction temperature for preparing benzoza-9-membered ring lactone compounds is 40–70 °C.

7. The method for preparing the benzo[a]aza nine-membered ring lactone compound according to claim 6, characterized in that, The oxidant is dodecyl mercaptan or 2,3-dichloro-5,6-dicyanobenzoquinone.

8. The method for preparing the benzo[a]aza nine-membered ring lactone compound according to claim 6, characterized in that, The alkaline reagent is potassium carbonate, cesium carbonate, or potassium phosphate.

9. The application of benzoza-9-membered ring lactone compounds, characterized in that, The benzoza-9-membered ring lactone compound is the benzoza-9-membered ring lactone compound according to claim 1, and the benzoza-9-membered ring lactone compound is used to prepare or screen drugs that inhibit methicillin-resistant Staphylococcus epidermidis and methicillin-sensitive Staphylococcus epidermidis.

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