Preparation method and antibacterial application of diaryl and seven-membered oxygen heterocyclic skeleton containing indole

Abstract

The invention discloses an indole-containing diaryl and seven-membered oxygen heterocyclic skeleton as well as a synthesis method and application of the indole-containing diaryl and seven-membered oxygen heterocyclic skeleton. The invention provides a diaryl and seven-membered oxygen heterocyclic ring skeleton structure containing indole. The invention provides a synthesis method of the indole-containing diaryl seven-membered oxygen heterocyclic compound, which comprises the following steps: uniformly mixing substituted indole and o-benzyloxy substituted benzaldehyde in a solvent, and reacting at 100-120 DEG C under an acidic condition to prepare the indole-containing diaryl seven-membered oxygen heterocyclic compound. The invention also provides an application of the diaryl and seven-membered oxygen heterocyclic skeleton containing indole in preparation of a bacteriostatic agent. The invention provides a method for green synthesis of a diaryl and seven-membered oxygen heterocyclic compound containing indole.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical intermediates and chemical synthesis, and in particular to an indole-containing diaryl seven-membered oxygen heterocyclic structure, a synthesis method and application thereof. Background Art

[0002] The diaryl and seven-membered oxygen heterocyclic structure is widely present in many natural products and drug molecules, and has important application value in medicine and pesticides. For example, doxepin is an antidepressant, and the natural product eurotinone has a diaryl and seven-membered oxygen heterocyclic structure, which shows very good anti-tumor activity. However, the types of this skeleton are not rich enough at present, and there is a lack of effective methods to construct diaryl and seven-membered oxygen heterocyclic structures, which seriously hinders the subsequent biological activity research of diaryl and seven-membered oxygen heterocyclic molecules with diverse structures. Therefore, the efficient construction of diaryl and seven-membered oxygen heterocyclics is of great significance for drug development.

[0003]

[0004] For example, in 2020, Huang Xueliang's research group at the Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, realized the transition metal palladium-catalyzed cyclization reaction of o-bromobenzaldehyde and o-hydroxyphenylhydrazone, and efficiently synthesized a diaryl seven-membered oxygen heterocyclic ketone structure in one step (Nature Communications, 2020, 11, 461).

[0005]

[0006] Indole is the core structure of many natural products and drug molecules. The diaryl and seven-membered oxygen heterocyclic structure has significant biological activity, but the efficient synthesis method of diaryl and seven-membered oxygen heterocyclic structure containing indole has not been reported. Therefore, the development of an efficient and direct method for synthesizing diaryl and seven-membered oxygen heterocyclic structure compounds containing indole is of great significance for the development of new antibacterial agents and drugs, especially drugs for the treatment of tumors, pain, depression and other diseases. Summary of the invention

[0007] The purpose of the present invention is to provide a biologically active indole-containing diaryl and seven-membered oxygen heterocyclic structure and its synthesis method and application in view of the deficiencies in the prior art. The indole-containing diaryl and seven-membered oxygen heterocyclic structure provided by the present invention will provide a new model molecule for drug development. The synthesis method of the indole-containing diaryl and seven-membered oxygen heterocyclic skeleton provided by the present invention is the first to react N-arylmethyl indole with o-alkoxy substituted benzaldehyde through nucleophilic addition / cyclization reaction to efficiently synthesize the skeleton in one step, which is simple to operate, efficient and practical, and the constructed skeleton contains a variety of functional groups, which is conducive to the later synthesis and application of the skeleton. The technical solution of the present invention is achieved in this way: The indole-containing diaryl seven-membered oxygen heterocyclic skeleton has a structural formula as shown in Formula 1:

[0008] In formula 1, R 1 is any one of a hydrogen atom, a benzyl group, and a methyl group; R 2 is any one of a hydrogen atom and a methyl group; R 3 is any one of hydrogen, fluorine, chlorine, bromine and methyl; R 4 is any one of a hydrogen atom and a tert-butyl group; R 5 is any one of a hydrogen atom and a methoxy group; wherein R 1 , R 2 , R 3 , R 4 , R 5 They are the same as or different from each other and each independently represents a substituent.

[0009] The compounds involved in the present invention may exist in the form of one or more stereoisomers. Various isomers include tautomers, geometric isomers, enantiomers, diastereomers, etc. These isomers and mixtures of these isomers are all within the protection scope of the present invention.

[0010] Based on the same inventive concept, the present invention also provides a method for synthesizing a diaryl and seven-membered oxygen heterocyclic skeleton containing indole. The synthetic process route of the present invention is as follows: Figure 1 As shown, the following steps are included: The N-arylmethyl indole and the o-alkoxy substituted benzaldehyde are uniformly mixed in a solvent, and reacted at 100-120° C. under acidic conditions to obtain a diaryl seven-membered oxygen heterocyclic compound containing indole; Wherein, the structural formula of the substituted indole is shown in Formula 2:

[0011] In formula 2, R 1 is any one of a hydrogen atom, a benzyl group, and a methyl group; R 2 is any one of a hydrogen atom and a methyl group; R 3 Any one of hydrogen, fluorine, chlorine, bromine and methyl; Wherein, the structural formula of the above-mentioned o-benzyloxy-substituted benzaldehyde is shown in Formula 3:

[0012] In formula 3, R 4 is any one of a hydrogen atom and a tert-butyl group; R 5 It is any one of a hydrogen atom and a methoxy group.

[0013] The reaction conditions can be detected by thin layer chromatography, and purification is performed after the reaction is completed to obtain a purified product of an indole-containing diaryl seven-membered oxygen heterocyclic compound. The above reaction process is specifically as follows: Two molecules of substituted indole react with o-benzyloxy substituted benzaldehyde under acidic conditions to generate triarylmethane intermediate 7a, which then undergoes reverse Friedel-Crafts alkylation to generate intermediate I, followed by intramolecular nucleophilic addition cyclization to generate indole-containing diaryl seven-membered oxygen heterocyclic compound. The synthesis principle route is as follows:

[0014] Preferably, the synthesis method as described above is carried out at 120°C.

[0015] In the above-mentioned synthesis method, the molar ratio of the substituted indole to the o-benzyloxy substituted benzaldehyde is 1:(1-3). Preferably, the molar ratio of the substituted indole to the o-benzyloxy substituted benzaldehyde is 1:1.2.

[0016] In the above-mentioned synthesis method, the solvent is ethanol or methanol.

[0017] In the above-mentioned synthesis method, the amount of the solvent is: 10 to 25 L of solvent is added per mole of substituted indole and o-benzyloxy substituted benzaldehyde. Preferably, the amount of the solvent is: 10 L of solvent is added per mole of substituted indole and o-benzyloxy substituted benzaldehyde.

[0018] In the above-mentioned synthesis method, the acidic catalyst is added before the reaction, and the catalyst is a Lewis acid. Preferably, the catalyst is any one of boron trifluoride etherate, p-toluenesulfonic acid, camphorsulfonic acid, and scandium trifluoromethanesulfonate.

[0019] In the above-mentioned synthesis method, the amount of the acidic catalyst is 20-100 mol%. Preferably, the amount of the catalyst is 30 mol%.

[0020] Based on the same inventive concept, the present invention also provides a pharmaceutical composition, which comprises the indole-containing diaryl and seven-membered oxygen heterocyclic skeleton as described above and its pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, geometric isomer, enantiomer, diastereomer or mixture or prodrug thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof. The present invention does not specifically limit the carrier, diluent and excipient, and can be a carrier, diluent and excipient suitable for pharmaceutical compositions that are well known to those skilled in the art.

[0021] Based on the same inventive concept, the present invention also provides the use of an indole-containing diaryl seven-membered oxygen heterocyclic skeleton in antibacterial applications. The beneficial effects of the present invention are: 1. The present invention efficiently synthesizes an indole-containing diaryl and seven-membered oxygen heterocyclic skeleton through multi-step continuous reactions under mild conditions. The technical solution of the present invention provides a convenient and concise synthesis method for the indole-containing diaryl and seven-membered oxygen heterocyclic skeleton.

[0022] 2. The present invention develops a method for efficiently synthesizing indole-containing diaryl and seven-membered oxygen heterocyclic compounds containing multiple functional groups, provides a compound library of indole-containing diaryl and seven-membered oxygen heterocyclic skeletons, and provides new model molecules for drug development.

[0023] 3. The present invention provides an experimental basis for the efficient construction of an indole-containing diaryl seven-membered oxygen heterocyclic skeleton with good biological activity, and has great practical significance and application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 The synthetic process route diagram of the present invention is shown in FIG. DETAILED DESCRIPTION

[0025] The following will combine the contents in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0026] Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used in this specification includes any and all combinations of one or more of the related listed items.

[0027] The experimental methods used in the following examples are conventional methods unless otherwise specified; the reagents, materials, instruments, etc. used in the following examples are all commercially available unless otherwise specified; the reaction vessel used in the following examples is a 25 mL thick-walled pressure-resistant tube.

[0028] Example 1 1. This embodiment provides a method for synthesizing an indole-containing diaryl seven-membered oxygen heterocyclic skeleton, which comprises the following steps: Take 0.13 mmol of substituted indole in a reaction bottle, add 0.10 mmol of o-benzyloxy substituted benzaldehyde, 0.03 mmol of catalyst, and finally add 1 mL of solvent. Control the reaction temperature of the system, keep stirring, and track the reaction by spotting on a thin layer chromatography plate until the raw material reacts completely. After the reaction is completed, use a silica gel column for separation and purification, and evaporate the purified product to obtain the target product.

[0029] The reaction formula is as follows:

[0030] 2. According to the above method, 7 parallel test groups were set up, using different acidic catalysts and solvents. The catalysts were boron trifluoride etherate (BF3·OEt2), scandium trifluoromethanesulfonate Sc(OTf)3, camphorsulfonic acid (CSA), p-toluenesulfonic acid ( p -TsOH . H2O); the solvents were ethanol (EtOH) and methanol (MeOH). The specific acidic catalysts, solvents and corresponding yields used in the experimental group are shown in Table 1: Table 1 Corresponding yields under different acidic catalysts and solvents

[0031] Note: substituted indole (0.13mmol), solvent (1 mL), o-benzyloxy substituted benzaldehyde (0.1 mmol), acid catalyst dosage (0.03 mmol); the above yield is the isolated yield. According to the analysis of the above parallel test results, it can be seen that the yield of the product is the highest when boron trifluoride etherate (BF3·OEt2) is used as an acid catalyst.

[0032] 3. According to the above method, set up the following three parallel test groups, using different reaction conditions, such as different reaction temperatures. The specific settings of different test groups are shown in Table 2: Table 2 Reaction yields under different temperature conditions

[0033] Note: Catalyst BF3·OEt2 (0.03 mmol), solvent (1 mL); the above yields are isolated yields.

[0034] According to the analysis of the above parallel test results, the yield of the product is the highest when the synthesis reaction of the present invention is carried out at 120 ° C with ethanol (1 mL) as solvent, substituted indole (0.13 mmol), o-benzyloxy substituted benzaldehyde (0.1 mmol), and catalyst boron trifluoride etherate (BF3·OEt2) (0.03 mmol).

[0035] In the following examples 2-11, the reaction was carried out according to the operating steps of example 1; 0.13 mmol of substituted indole was taken in a reaction bottle, 0.1 mmol of o-benzyloxy substituted benzaldehyde, 0.03 mmol of catalyst boron trifluoride etherate (BF3·OEt2) were added in sequence, and finally 1 mL of ethanol was added. The reaction temperature of the system was controlled to be 120 °C, stirring was continued, and the reaction was tracked by spotting on a thin layer chromatography plate until the raw material reaction was complete. After the reaction was completed, a silica gel column was used for separation and purification, and the purified product was rotary evaporated to obtain the target product.

[0036] Example 2 raw material:

[0037] Product 2a: Chemical formula: C 25 H 23 NO3 Structural formula:

[0038] Yield: 69% 1 H NMR (500 MHz, DMSO -d6 ) δ 7.37 – 7.29 (m, 2H), 7.24 – 7.15 (m, 2H), 7.06 – 7.11 (m, 1H), 6.98 – 6.86 (m, 3H), 6.73 (d, J = 2.4 Hz, 1H), 6.62 (d,J = 1.4 Hz, 1H), 6.54 (d, J = 2.4 Hz, 1H), 5.96 (d, J = 1.5 Hz, 1H), 5.70 (d,J = 12.6 Hz, 1H), 4.64 (d, J = 12.8 Hz, 1H), 3.96 (s, 3H), 3.78 (s, 3H), 3.64(s, 3H). 13 C NMR(125 MHz, DMSO-d6) δ 159.6, 157.6, 157.3, 138.1, 137.5, 133.3,128.9, 128.0, 126.2, 122.9, 121.7, 121.5, 120.5, 119.7, 119.6, 119.0, 110.0,106.5, 98.9, 69.5, 56.5, 55.7, 38.0, 32.6.HRMS (ESI)m / z:[M+H] + Calculate for C 25 H 24 NO3 +386.1751; found: 386.1753. Example 3 raw material:

[0039] Product 3a: Chemical formula: C 37 H 39 NO5 Structural formula:

[0040] Yield: 84% 1 H NMR (500 MHz, DMSO -d6 ) δ 7.36 – 7.23 (m, 3H), 7.17 (d, J = 7.8 Hz,1H), 7.00 (t, J = 7.6 Hz, 1H), 6.93 (t, J = 7.6 Hz, 1H), 6.90 – 6.81 (m, 2H),6.58 (d, J = 2.5 Hz, 1H), 6.44 (d, J = 2.5 Hz, 1H), 6.32 (d, J = 2.7 Hz, 1H), 6.20 (d, J = 2.2 Hz, 2H), 5.88 (s, 1H), 5.54 (d, J = 14.4 Hz, 1H), 5.21 (s,2H), 4.80 (d, J = 14.4 Hz, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 3.63 (s, 6H), 1.31 (s, 9H). 13 C NMR (100 MHz, DMSO -d6 ) δ 161.0, 159.2, 157.7, 157.6, 141.2,141.1, 138.9, 136.4, 134.0, 130.2, 128.0, 127.0, 126.1, 122.6, 121.3, HRMS (ESI) m / z:[M+H] + Calculate for C 37 H 40 NO5 + 578.2901;found: 578.2903. Example 4 raw material:

[0041] Product 4a: Chemical formula: C 38 H 41 NO5 Structural formula:

[0042] Yield: 72% 1 H NMR (400 MHz, DMSO -d6 ) δ 7.32 (dd, J = 7.7, 1.6 Hz, 1H), 7.27 (d, J= 8.1 Hz, 1H), 7.19 (d, J = 8.2 Hz, 1H), 7.14 (dd, J = 7.9, 1.6 Hz, 1H), 6.94– 6.85 (m, 2H), 6.79 –6.73(m, 1H), 6.53 (d, J = 2.5 Hz, 1H), 6.45 (d, J = 2.4Hz, 1H), 6.32 (t, J = 2.3 Hz, 1H), 5.96 (d, J = 2.3 Hz, 2H), 5.90 (s, 1H),5.51 (d, J = 14.4 Hz, 1H), 5.25 (s, 2H), 4.83 (d, J = 14.4 Hz, 1H), 3.75 (d,J = 4.0 Hz, 6H), 3.60 (s, 6H), 2.12 (s, 3H), 1.31 (s, 9H). 13 C NMR (100 MHz, DMSO -d6 ) δ 161.1, 159.1, 158.1, 158.0, 141.5, 140.9, 138.7, 136.2, 134.7,133.1, 130.2, 127.4, 125.8, 122.8, 121.0, 120.3, 119.7, 118.8, 115.5, 109.4,104.4, 103.8, 98.4, 98.2, 72.7, 56.3, 55.6, 55.4, 45.7, 35.0, 30.7, 10.7.HRMS(ESI) m / z:[M+H] + Calculate for C 38 H 42 NO5 + 592.3058; found: 592.3059. Example 5 raw material:

[0043] Product 5a: Chemical formula: C 37 H 38 FNO5 Structural formula:

[0044] Yield: 85% 1 H NMR (400 MHz, DMSO -d6 ) δ 7.35 – 7.29 (m, 1H), 7.18 – 7.09 (m, 3H), 7.00 – 6.90 (m, 2H), 6.71 (dd, J = 11.6, 7.7 Hz, 1H), 6.45 (d, J = 2.4 Hz,1H), 6.37 (d, J = 2.4 Hz, 1H), 6.31 (t, J = 2.2 Hz, 1H), 6.19 (d, J = 2.3 Hz,2H), 6.06 (s, 1H), 5.53 (d, J = 15.9 Hz, 1H), 5.20 (s, 2H), 4.87 (d, J = 15.7Hz, 1H), 3.74 (s, 3H), 3.69 (s, 3H), 3.61 (s, 6H), 1.30 (s, 9H). 13 C NMR (100MHz, DMSO -d6 ) δ 161.0, 159.0, 158.6, 157.8, 156.9 (d, J = 244.0 Hz), 141.7,140.8, 138.9, 138.5 (d, J = 12.0 Hz), 138.4, 129.1, 128.8, 126.1, 123.7,121.6 (d, J = 7.0 Hz), 120.2, 118.5 (d, J = 5.0 Hz), 115.7 (d, J = 19.0 Hz),107.1, 105.5, 104.4 (d, J = 20.0 Hz), 102.3, 98.7, 97.8, 73.8, 56.4, 55.5,55.4, 49.6, 38.7, 38.7, 35.0, 31.0.HRMS (ESI) m / z:[M+H] + Calculate for C 37 H39 FNO5 + 596.2807; found: 596.2808. Example 6 raw material:

[0045] Product 6a: Chemical formula: C 31 H 27 NO3 Structural formula:

[0046] Yield: 93% 1 H NMR (500 MHz, DMSO -d6 ) δ 7.24 – 7.18 (m, 2H), 7.16 – 7.11 (m, 2H), 7.10 – 7.04 (m, 3H), 6.97 – 6.87 (m, 3H), 6.83 – 6.74 (m, 3H), 6.69 (d, J =1.4 Hz, 1H), 6.62 (d, J = 2.5 Hz, 1H), 6.44 (d, J = 2.5 Hz, 1H), 5.86 (d, J =1.4 Hz, 1H), 5.60 (d, J = 12.7 Hz, 1H), 5.19 (s, 2H), 4.54 (d, J = 12.7 Hz,1H), 3.84 (s, 3H), 3.65 (s, 3H). 13 C NMR (125 MHz, DMSO -d6 ) δ 159.6, 157.5,157.3, 138.9, 138.0, 137.1, 133.3, 128.9, 128.6, 127.7, 127.6, 127.1, 126.5,126.5, 123.0, 123.0, 121.8, 121.6, 120.4, 120.4, 120.3, 119.9, 119.3, 110.7,106.7, 99.0, 69.2, 56.5, 55.7, 49.3, 38.1.HRMS (ESI) m / z:[M+H] + Calculate for C 31 H 28 NO3 + 462.2064; found: 462.2066. Example 7 raw material:

[0047] Product 7a: Chemical formula: C 37 H 38 ClNO5 Structural formula:

[0048] Yield: 75% 1 H NMR (400 MHz, DMSO -d6 ) δ 7.41 – 7.30 (m, 2H), 7.23 – 7.15 (m, 2H), 7.03 – 6.92 (m, 3H), 6.58 (d, J = 2.4 Hz, 1H), 6.44 (d, J = 2.5 Hz, 1H), 6.33(t, J = 2.3 Hz, 1H), 6.19 (d, J = 2.2 Hz, 2H), 5.83 (d, J = 1.0 Hz, 1H), 5.49(d, J = 14.8 Hz, 1H), 5.22 (s, 2H), 4.81 (d, J = 14.7 Hz, 1H), 3.82 (s, 3H),3.75 (s, 3H), 3.63 (s, 6H), 1.30 (s, 9H). 13 C NMR (100 MHz, DMSO -d6 ) δ 161.0,159.3, 157.9, 157.6, 141.3, 140.9, 138.9, 134.8, 134.3, 130.1, 129.7, 128.0,126.2, 123.8, 122.9, 121.2, 120.6, 119.8, 118.8, 112.1, 105.3, 103.9, 99.0,98.2, 72.0, 56.4, 55.6, 55.5, 49.4, 38.4, 35.1, 30.8.HRMS (ESI) m / z:[M+H] + Calculate for C 37 H 39 ClNO5 + 612.2511; found: 612.2512. Example 8 raw material:

[0049] Product 8a: Chemical formula: C 37 H 38BrNO5 Structural formula:

[0050] Yield: 76% 1 H NMR (400 MHz, DMSO -d6 ) δ 7.40 – 7.31 (m, 2H), 7.28 (d, J = 8.8 Hz, 1H), 7.19 (dd, J = 7.9, 1.7 Hz, 1H), 7.11 (dd, J = 8.7, 2.0 Hz, 1H), 6.98 –6.91 (m, 2H), 6.58 (d, J = 2.4 Hz, 1H), 6.44 (d, J = 2.4 Hz, 1H), 6.33 (t, J= 2.3 Hz, 1H), 6.18 (d, J = 2.3 Hz, 2H), 5.82 (d, J = 1.0 Hz, 1H), 5.49 (d, J= 14.8 Hz, 1H), 5.22 (s, 2H), 4.81 (d, J = 14.7 Hz, 1H), 3.83 (s, 3H), 3.75 (s, 3H), 3.62 (s, 6H), 1.30 (s, 9H). 13 C NMR (100 MHz, DMSO -d6 ) δ 161.0, 159.3,157.9, 157.6, 141.3, 140.9, 138.9, 135.1, 134.2, 130.1, 129.5, 128.7, 126.2,123.7, 122.9, 121.9, 120.6, 119.7, 112.6, 111.8, 105.3, 104.0, 99.0, 98.2,72.0, 56.4, 55.6, 55.5, 49.4, 38.4, 35.1, 30.8.HRMS (ESI) m / z:[M+H] + Calculate for C 37 H 39 BrNO5 + 656.2006; found: 656.2008. Example 9 raw material:

[0051] Product 9a: Chemical formula: C 37 H 38 FNO5 Structural formula:

[0052] Yield: 78% 1 H NMR (500 MHz, DMSO -d6 ) δ 7.32 (dd, J = 7.7, 1.6 Hz, 1H), 7.22 –7.14 (m, 3H), 6.92 (t, J = 7.7 Hz, 1H), 6.82 (d, J = 1.1 Hz, 1H), 6.73 (td, J= 9.3, 2.4 Hz, 1H), 6.57 (d, J = 2.4 Hz, 1H), 6.43 (d, J = 2.4 Hz, 1H), 6.33(t, J = 2.3 Hz, 1H), 6.21 (d, J = 2.3 Hz, 2H), 5.84 (s, 1H), 5.49 (d, J =14.6 Hz, 1H), 5.17 (s, 2H), 4.79 (d, J = 14.5 Hz, 1H), 3.81 (s, 3H), 3.75 (s, 3H), 3.63 (s, 6H), 1.29 (s, 9H). 13 C NMR (100 MHz, DMSO- d6 ) δ 161.0, 159.3,159.1 (d, J = 233.0 Hz), 157.7 (d, J = 11.0 Hz), 141.2, 140.9, 138.9, 136.5(d, J = 13.0 Hz), 134.1, 130.1, 128.5 (d, J = 3.0 Hz), 126.2, 123.8, 122.7,120.8, 120.5 (d, J = 10.0 Hz), 120.4, 107.4 (d, J = 24.0 Hz), 105.4, 104.0,99.0, 98.1, 96.9, 96.6, 71.8, 56.4, 55.6, 55.5, 49.3, 38.5, 35.1, 30.7.HRMS(ESI) m / z:[M+H] + Calculate for C 37 H 39 FNO5 + 596.2807; found: 596.2808. Example 10 raw material:

[0053] Product 10a: Chemical formula: C 38 H 41 NO5 Structural formula:

[0054] Yield: 61% 1 H NMR (400 MHz, DMSO -d6 ) δ 7.35 (dd, J = 7.6, 1.6 Hz, 1H), 7.24 –7.13 (m, 2H), 6.92 (t, J = 7.6 Hz, 1H), 6.80 – 6.66 (m, 3H), 6.56 (d, J = 2.5Hz, 1H), 6.42 (d, J = 2.4 Hz, 1H), 6.31 (t, J = 2.3 Hz, 1H), 5.89 (d, J = 2.2Hz, 2H), 5.85 (s, 1H), 5.54 (d, J = 14.7 Hz, 1H), 5.48 – 5.32 (m, 2H), 4.81(d, J = 14.7 Hz, 1H), 3.80 (s, 3H), 3.75 (s, 3H), 3.59 (s, 6H), 2.38 (s, 3H), 1.30 (s, 9H). 13 C NMR (125 MHz, DMSO -d6 ) δ 161.1, 159.2, 157.8, 157.7, 143.6,141.2, 138.9, 135.1, 134.7, 130.2, 130.0, 128.2, 126.1, 124.1, 122.7, HRMS (ESI) m / z:[M+H] + Calculate for C 38 H 42 NO5 + 592.3058;found: 592.3055. Embodiment 11 raw material:

[0055] Product 11a: Chemical formula: C 28 H 29 NO2 Structural formula:

[0056] Yield: 70% 1 H NMR(500 MHz, CDCl3) δ 7.40 (d, J = 8.4 Hz, 1H), 7.26 – 7.17 (m,4H), 7.14 – 7.09 (m,1H), 6.98 – 6.89 (m, 2H), 6.80 (dd, J = 8.4, 2.7 Hz, 1H), 6.63 (d, J = 2.8 Hz, 1H), 6.56 (d, J = 1.2 Hz, 1H), 5.49 (d, J = 14.2 Hz, 1H), 5.34 (d, J = 1.1 Hz, 1H), 4.83 (d, J = 14.2 Hz, 1H), 3.77 (s, 3H), 3.62 (s, 3H), 1.36 (s, 9H). 13 C NMR(100 MHz, CDCl3) δ 158.5, 157.2, 141.6, 137.7,137.1, 133.7, 132.9, 131.4, 129.5, 128.2, 126.6, 126.0, 122.2, 121.2, 119.8,119.7, 118.7, 112.8, 112.5, 109.1, 71.8, 55.3, 48.8, 35.2, 32.7, 30.6.HRMS(ESI) m / z:[M+H] + Calculate for C 28 H 30 NO2 + 412.2271; found: 412.2273. Antibacterial test results: The inhibition rates of the compounds of the present invention on Botrytis cinerea

[0057] Most of the compounds in the present invention have an inhibition rate of more than 62% on gray mold at a concentration of 50 mg / L; the compounds in the present invention have a good effect of inhibiting the growth of gray mold, and therefore have a good application prospect in antibacterial aspects.

[0058] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. An indole-containing diaryl seven-membered oxygen heterocyclic skeleton, characterized in that: Its structural formula is shown in Formula 1: In formula 1, R 1 is any one of a hydrogen atom, a benzyl group, and a methyl group; R 2 is any one of a hydrogen atom and a methyl group; R 3 is any one of hydrogen, fluorine, chlorine, bromine and methyl; R 4 is any one of a hydrogen atom and a tert-butyl group; R 5 is any one of a hydrogen atom and a methoxy group; wherein R 1 , R 2 , R 3 , R 4 , R 5 They are the same as or different from each other and each independently represents a substituent.

2. The method for synthesizing the indole-containing diaryl seven-membered oxygen heterocyclic skeleton according to claim 1, characterized in that: The following steps are involved: The substituted indole and o-benzyloxy substituted benzaldehyde are uniformly mixed in a solvent, and reacted at 100-120° C. under the catalysis of Lewis acid to obtain a diaryl seven-membered oxygen heterocyclic compound containing indole; Wherein, the structural formula of the substituted indole is shown in Formula 2: In formula 2, R 1 is any one of a hydrogen atom, a benzyl group, and a methyl group; R 2 is any one of a hydrogen atom and a methyl group; R 3 Any one of hydrogen, fluorine, chlorine, bromine and methyl; Wherein, the structural formula of the above-mentioned o-benzyloxy-substituted benzaldehyde is shown in Formula 3: In formula 3, R 4 is any one of a hydrogen atom and a tert-butyl group; R 5 It is any one of a hydrogen atom and a methoxy group.

3. The synthesis method according to claim 2, characterized in that The molar ratio of the substituted indole to the o-benzyloxy substituted benzaldehyde is (1-2):

1.

4. The synthesis method according to claim 2, characterized in that The solvent is ethanol or methanol.

5. The synthesis method according to claim 2, characterized in that The amount of the solvent is as follows: 10 to 25 L of solvent is added per mole of substituted indole and o-benzyloxy substituted benzaldehyde.

6. The synthesis method according to claim 2, characterized in that The catalyst is any one of boron trifluoride etherate, p-toluenesulfonic acid, camphorsulfonic acid, and scandium trifluoromethanesulfonate.

7. The synthesis method according to claim 2, characterized in that The amount of the catalyst used is 20 to 100 mol%.

8. Use of the indole-containing diaryl seven-membered oxygen heterocyclic biologically active skeleton according to claim 1 in the preparation of an antibacterial agent.

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