Substituted phenol and maleimide derivative as well as preparation method and application thereof

Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a substituted phenol and maleimide derivative as well as a preparation method and application thereof. The substituted phenol and maleimide derivative has the following structural general formula: # imgabs0 #, wherein Ar1 and Ar2 are independently selected from a benzene ring or a substituted benzene ring respectively, and the structures of Ar1 and Ar2 are different; r is selected from halogen, C1-C8 alkyl, aryl, C3-C8 cycloalkyl and substituted phenyl; the substituent group of the substituted benzene ring is selected from halogen, phenyl, C1-C8 alkoxy, C1-C8 alkyl, C1-C8 alkyl ester group and substituted C1-C8 alkoxy; a substituent group on a substituted C1-C8 alkoxy group is halogen; the substituted phenol and maleimide derivative disclosed by the invention can be applied to a plurality of fields of fluorescent probes, medicines, luminescent materials, antifouling materials and the like.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and particularly relates to a substituted phenol maleimide derivative and a preparation method and application thereof. Background Art

[0002] Substituted phenol maleimide derivatives are commonly found in natural products, bioactive molecules and pesticide molecules as dominant skeletons, and also have the activities of regulating immunity, analgesia, antibacterial (including fungi), antitumor, anticonvulsant, antihistamine, hypolipidemic, herbicidal, etc. For example, some commercial drugs containing polysubstituted phenol maleimide derivative skeletons can be used to treat multiple myeloma (Pomalyst) and psoriasis (Otezla). In addition, due to their good luminescence properties, they are also widely used as optoelectronic materials, such as fluorescent probes (BHID Bpin) of ESIPT.

[0003] At present, there are reports of substituted phenol maleimide skeletons using acetophenone-like substances as reaction substrates (such as the prior art CN116332823A), but this method is often limited to the synthesis of symmetrical substituted phenol maleimide derivatives, and the synthesis of asymmetrical substituted phenol maleimide derivatives is limited and cannot be achieved. Summary of the invention

[0004] The purpose of the present invention is to provide a new substituted phenol maleimide derivative and a preparation method and application thereof.

[0005] In order to achieve the above object, the technical solution of the present invention is as follows:

[0006] A substituted phenol maleimide derivative, the general structural formula of which is shown in Formula I:

[0007]

[0008] Where:

[0009] Ar 1 ,Ar 2 are independently selected from a benzene ring or a substituted benzene ring, wherein Ar 1 ,Ar 2 different;

[0010] The substituent of the substituted benzene ring is selected from the group consisting of: halogen, phenyl, C1-C8 alkoxy, C1-C8 alkyl, C1-C8 alkyl ester, substituted C1-C8 alkoxy;

[0011] The substituent on the C1-C8 alkoxy group is halogen;

[0012] R is selected from halogen, C1-C8 alkyl, aryl, C3-C8 cycloalkyl, substituted phenyl;

[0013] In one preferred embodiment, the substituent of the substituted benzene ring is selected from: halogen, phenyl, C1-C4 alkoxy, C1-C4 alkyl, C1-C4 alkyl ester, substituted C1-C4 alkoxy; the substituent on the substituted C1-C4 alkoxy is halogen.

[0014] In one preferred embodiment, the substituent of the substituted benzene ring is selected from: halogen, phenyl, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkyl ester, substituted C1-C3 alkoxy; the substituent on the substituted C1-C3 alkoxy is halogen.

[0015] In a preferred embodiment, the substituted C1-C4 alkoxy group is selected from trifluoromethoxy, trifluoroethoxy, trifluoropropoxy, trichloromethoxy, trichloroethoxy, trichloropropoxy, tribromomethoxy, tribromoethoxy, and tribromopropoxy.

[0016] In a preferred embodiment, the aromatic group includes one or more of azulene, naphthalene, anthracene, acenaphthene, phenanthrene, tetracene, pyrene, benzopyrene, and pentacene.

[0017] In one preferred embodiment, Ar 1 ,Ar 2 Each of the following is independently selected from a benzene ring, p-methoxyphenyl, p-ethoxyphenyl, p-propoxyphenyl, bromophenyl, dibromophenyl, chlorophenyl, dichlorophenyl, fluorophenyl, difluorophenyl, tolyl, ethylphenyl, propylphenyl, biphenyl, p-benzoyl, p-ethylphenyl, p-propylphenyl, trifluoromethoxyphenyl, trifluoroethoxyphenyl, trifluoropropoxyphenyl, trichloromethoxyphenyl and tribromomethoxyphenyl.

[0018] In one preferred embodiment, the structure of the substituted phenol maleimide derivative is as follows:

[0019]

[0020] Based on the same inventive concept, the present invention also claims a method for preparing the substituted phenol maleimide derivative, comprising: heating an unsaturated ketone compound, a maleimide compound and water in an iodine reagent, a protonic acid and an organic solvent to obtain a reaction;

[0021] The general formula of the unsaturated ketene compound is Formula II:

[0022]

[0024] The general formula of the maleimide compound is Formula III:

[0025]

[0026] Ar 1 ,Ar 2 are independently selected from a benzene ring or a substituted benzene ring, wherein Ar 1 ,Ar 2 different;

[0027] The substituent of the substituted benzene ring is selected from the group consisting of: halogen, phenyl, C1-C8 alkoxy, C1-C8 alkyl, C1-C8 alkyl ester, substituted C1-C8 alkoxy;

[0028] The substituent on the C1-C8 alkoxy group is halogen;

[0029] R is selected from halogen, C1-C8 alkyl, aryl, C3-C8 cycloalkyl, substituted phenyl;

[0030] In one preferred embodiment, the iodine reagent is iodine element or a common commercially available iodine-containing compound, and the iodine reagent is NH 4 I, KI, NaI, IBr, PhI(OAc) 2 、NIS、I 2 O 5 ,I 2 , PIFA or several thereof.

[0031] According to the catalytic effect of the iodine reagent on the reaction substrate in the reaction, elemental iodine (I 2 ) or I 2 O 5 As initiator and oxidant.

[0032] In a preferred embodiment, the protonic acid is a commercially available proton-releasing + ), wherein the protonic acid reagent includes AcOH, TFA, TsOH, TfOH, benzoic acid and BF 3 ·Et 2 O, according to the effect of the protonic acid on the formation of the target product, preferably p-toluenesulfonic acid (TsOH) is used as the protonic acid.

[0033] In one preferred embodiment, the molar ratio of the unsaturated ketene compound to the maleimide compound is 1.0:(0.5-2.0). If the molar ratio of the unsaturated ketene compound to the maleimide compound is too small, the yield is reduced, and if it is too large, the yield is not significantly increased and is not conducive to the formation of the product.

[0034] In one preferred embodiment, the molar ratio of the unsaturated ketene compound to water is 1.0:(1.0-3.0). If the molar ratio of the unsaturated ketene compound to water is too small or too large, the yield is reduced, which is not conducive to the formation of the product.

[0035] In one preferred embodiment, the molar ratio of the unsaturated ketene compound to the iodine reagent is 1.0:(0.5-2.0). If the molar ratio of the unsaturated ketene compound to the iodine reagent is too small, the yield will decrease, and if it is too large, the reaction byproducts will increase and the system will become more chaotic.

[0036] In one preferred embodiment, the molar ratio of the unsaturated ketene compound to the protic acid reagent is 1.0:(0.5-1.5). If the molar ratio of the unsaturated ketene compound to the protic acid reagent is too small, the yield is reduced, and if it is too large, the yield is not significantly increased and is not conducive to the formation of the product.

[0037] In one preferred embodiment, the organic solvent is a polar or non-polar solvent, and the polar or non-polar solvent includes one or more of acetonitrile, 1,4-dioxane, toluene, chlorobenzene, N-methylpyrrolidone, dimethyl sulfoxide, and p-xylene. The organic solvent is preferably toluene, chlorobenzene, p-xylene, and o-xylene, and chlorobenzene (PhCl) is further preferred.

[0038] In a preferred embodiment, the amount of the organic solvent is 0.5-2.0 mL / mmol of the unsaturated ketone compound.

[0039] In one preferred embodiment, the reaction temperature is 25-120°C. According to the product yield and heating energy consumption, the suitable reaction temperature is preferably 80-120°C.

[0040] In one preferred embodiment, the reaction time is 2-12 h. Depending on the yield of the target product and the formation of by-products, the appropriate time is preferably 4-8 h.

[0041] The synthetic route of the substituted phenol maleimide derivative is:

[0042]

[0043] A method for preparing a substituted phenol maleimide derivative comprises: heating an unsaturated ketone compound, a maleimide compound and water in an iodine reagent, a protonic acid and an organic solvent to obtain a reaction;

[0044] The general formula of the unsaturated ketene compound is Formula II:

[0045]

[0046] The general formula of the maleimide compound is Formula III:

[0047]

[0048] Ar1 ,Ar 2 are independently selected from a benzene ring or a substituted benzene ring, wherein Ar 1 ,Ar 2 same;

[0049] The substituent of the substituted benzene ring is selected from the group consisting of: halogen, phenyl, C1-C8 alkoxy, C1-C8 alkyl, C1-C8 alkyl ester, substituted C1-C8 alkoxy;

[0050] The substituent on the C1-C8 alkoxy group is halogen;

[0051] R is selected from halogen, C1-C8 alkyl, aryl, C3-C8 cycloalkyl, substituted phenyl;

[0052] In one preferred embodiment, the structure of the substituted phenol maleimide derivative is as follows:

[0053]

[0054] The present invention proposes a method for constructing such a skeleton using unsaturated ketene as a raw material, and selectively synthesizing symmetrical / asymmetrical substituted phenol maleimide derivatives by regulating different types of substituent groups on the aromatic ring of the unsaturated ketene. For such asymmetrical substituted phenol maleimide derivatives, good control of luminescence properties can be exhibited through different substituents connected to the aromatic ring of the unsaturated ketene, which greatly promotes the development of such a skeleton in the field of optoelectronic materials.

[0055] Based on the same inventive concept, the present invention also claims to protect the use of the substituted phenol maleimide derivatives in antibacterial applications.

[0056] In a preferred embodiment, the bacteria include one or more of Staphylococcus aureus, Escherichia coli or Pseudomonas aeruginosa.

[0057] Compared with the prior art, the present invention has the following beneficial effects:

[0058] 1. The present invention adopts a "one-pot method" to react unsaturated ketone compounds, maleimide compounds and water with the synergistic promotion of iodine reagent and protonic acid to achieve a three-component reaction in a chlorobenzene solution, and obtains a technical solution for preparing substituted phenol maleimide derivatives through a [4+2] addition cyclization process, and the reaction yield is medium to high. At the same time, the use of expensive metals is avoided, and there is no need to introduce additional directing groups. The synthesis process is simple, the raw materials are cheap and easy to obtain, and the atom economy is high.

[0059] Second, the present invention can selectively control the synthesis of two types of symmetrically substituted and asymmetrically substituted phenol maleimide derivatives by simply replacing different unsaturated enone compounds, effectively solving the technical shortcoming of only being able to synthesize symmetrically substituted phenol maleimide derivatives. In addition, some asymmetrically substituted phenol maleimide derivatives synthesized by this technology show good antibacterial activity and have certain antifouling application prospects, further confirming the practical value of the phenol maleimide molecular skeleton, and also providing a theoretical basis for the commercial application of such derivatives in multiple fields such as antifouling materials and medicine. BRIEF DESCRIPTION OF THE DRAWINGS

[0060] Figure 1 is the chemical reaction formula of the reaction of the present invention;

[0061] Figure 2 is the hydrogen spectrum of the product of Example 2;

[0062] Figure 3 is the carbon spectrum of the product of Example 2;

[0063] Figure 4 is the hydrogen spectrum of the product of Example 4;

[0064] Figure 5 is the carbon spectrum of the product of Example 4;

[0065] Figure 6 is the hydrogen spectrum of the product of Example 10;

[0066] Figure 7 is the carbon spectrum of the product of Example 10;

[0067] Figure 8 is the hydrogen spectrum of the product of Example 13;

[0068] Fig. 9 is the carbon spectrum of the product of Example 13;

[0069] Fig.10 The product of Example 15 is isotopically 18 O-labeled mass spectrum. DETAILED DESCRIPTION

[0070] The present invention will now be described in further detail with reference to the following figures. These figures are simplified schematic diagrams, which only illustrate the basic structure of the present invention in a schematic manner, and therefore only show the components related to the present invention.

[0071] The substituted phenol maleimide derivative of the present invention can be used as a pharmaceutically acceptable salt. The salt can be an acid salt of at least one of the following acids, including inorganic acids and organic acid salts, wherein the inorganic acids include hydrochloric acid, sulfuric acid, phosphoric acid and methanesulfonic acid, and the organic acids include formic acid, acetic acid, trichloroacetic acid, propionic acid, butyric acid, maleic acid, p-toluenesulfonic acid, malic acid, malonic acid, cinnamic acid, citric acid, fumaric acid, camphoric acid, digluconic acid, aspartic acid and tartaric acid.

[0072] In the above statements, the term "alkyl" can be used alone or in a combination, such as "alkylthio" or "haloalkyl", and C1-C8 alkyl includes straight chain or branched chain alkyl, such as methyl, ethyl, n-propyl, isopropyl, or different butyl groups including n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl or hexyl and isomers thereof, heptane and isomers thereof, octane and isomers thereof.

[0073] The term "halogen", which may be used alone or in combination, such as "haloalkyl", includes fluorine, chlorine, bromine or iodine, and, when used in a combination such as "haloalkyl", the alkyl group may be partially or completely substituted with halogen atoms, which may be the same or different. Examples of haloalkyl groups include ClCHCH 3 、F 3 C,ClCH 2 , C.F. 3 CH 2 and CF 3 CCl 2 , and others include 1,2-dichloro-n-propyl, 1-fluoro-n-butyl, perfluoro-n-pentyl, and the like.

[0074] The synthetic route of the present invention is as follows:

[0075]

[0076] Examples 1-19

[0077] The following steps are involved:

[0078] (1) adding an unsaturated ketene compound (0.2 mmol), a maleimide compound, water, an iodine reagent, a protonic acid and an organic solvent into a reaction vessel;

[0079] (2) After the reactants are stirred evenly, they are placed in an oil bath at 25-120°C and reacted under a suitable gas atmosphere for 2-12 hours;

[0080] (3) According to the method shown in step (1), the general formula of the unsaturated ketone compound is Formula II:

[0081]

[0082] Where:

[0083] Ar 1 ≠Ar 2 or Ar 1 =Ar 2 , each independently selected from a benzene ring or a substituted benzene ring;

[0084] R is selected from halogen, C1-C8 alkyl, aryl, C3-C8 cycloalkyl, substituted phenyl;

[0085] The substituent of the substituted benzene ring is selected from the group consisting of: halogen, phenyl, C1-C8 alkoxy, C1-C8 alkyl, C1-C8 alkyl ester, substituted C1-C8 alkoxy;

[0086] The substituent on the substituted C1-C8 alkoxy group is halogen.

[0087] (4) According to the method shown in step (1), the general formula of the maleimide compound is Formula III:

[0088]

[0089] Where:

[0090] R is selected from halogen, C1-C8 alkyl, aryl, C3-C8 cycloalkyl, substituted phenyl.

[0091] The molar mass of the maleimide compound is 0.3 mmol.

[0092] (5) According to the method shown in step (1), the molar mass of the water is preferably 0.4 mmol.

[0093] (6) According to the method shown in step (1), the iodine reagent is: NH 4 I, KI, NaI, IBr, PhI(OAc) 2 、NIS、I 2 O 5 ,I 2 , PIFA, preferably elemental iodine (I 2 ) as an initiator and an oxidant, the I 2 The molar mass is more preferably 0.2 mmol.

[0094] (7) According to the method shown in step (1), the protonic acid is: AcOH, TFA, TsOH, TfOH, benzoic acid and BF 3 ·Et 2 O, preferably p-toluenesulfonic acid (TsOH) as the protonic acid, and the molar mass of the TsOH is more preferably 0.2 mmol.

[0095] (8) According to the method shown in step (1), the organic solvent is selected from one or two of tetrahydrofuran, toluene, acetonitrile, chlorobenzene, dimethyl sulfoxide, p-xylene, and o-xylene, and the preferred non-polar solvent chlorobenzene (PhCl) is the organic solvent for the reaction. The further preferred amount of the solvent is: 1.5 mL.

[0096] (9) According to the method shown in step (1), the reaction temperature is 25-120°C, and the optimal reaction temperature is preferably 80°C.

[0097] (10) According to the method shown in step (1), the reaction time is 2-12 hours, and the optimal reaction temperature is preferably 4 hours.

[0098] (11) According to the method shown in step (1), the suitable gas atmosphere for the reaction is nitrogen atmosphere, oxygen atmosphere and air atmosphere, and the preferred suitable gas atmosphere is: air atmosphere.

[0099] Unsaturated ketene compounds, maleimide compounds, water, reaction conditions, reaction products and yields are shown in Table 1:

[0100] Table 1 Reactants and reaction conditions in Examples 1-19

[0101]

[0102]

[0103]

[0104]

[0105] The raw materials of unsaturated ketene compounds in Example 10 were purchased from Shijiazhuang Yaobo Pharmaceutical Technology Co., Ltd., and the raw materials of unsaturated ketene compounds in Examples 15-19 were purchased from Rudong Physical Chemical Factory; the raw materials of unsaturated ketene compounds in other examples were purchased according to the products synthesized in the prior art CN115850048A. The raw materials of maleimide compounds in Examples 1-19 were all purchased from Shanghai Haohong Biopharmaceutical Technology Co., Ltd., and other reagents were commercially available.

[0106] The product NMR data of the embodiment are:

[0107] The NMR data of the product of Example 1 are as follows:

[0108] 1 H NMR (400 MHz, CDCl 3)δ8.52(s,1H),7.70-7.50(m,5H),7.50-7.37(m,3H),7.01(d,J=8.4Hz,2H),3.87(s,3H),3.14(s,3H). 13 C NMR (100 MHz, CDCl 3 )δ171.1,167.3,159.9,151.8,138.3,136.0,133.9,130.5,129.2,128.5,128.2,127.5,124.9,115.6,114.0,55.4,23.7.

[0109] The NMR data of the product of Example 2 are as follows:

[0110] 1 H NMR (400 MHz, CDCl 3 )δ8.52(s,1H),7.77(d,J=1.4Hz,1H),7.65-7.48(m,5H),7.00(d,J=8.4Hz,2H),3.87(s,3H),3.15(s,3H). 13 C NMR (100 MHz, CDCl 3 )δ170.9,167.3,160.0,151.3,138.4,134.7,134.1,131.7,130.8,130.5,128.0,125.5,122.9,115.8,113.7,55.4,23.8.

[0111] The NMR data of the product of Example 3 are as follows:

[0112] 1 H NMR (400 MHz, CDCl 3 )δ7.66-7.48(m,7H),6.99(d,J=8.7Hz,2H),3.86(s,3H),3.14(s,3H). 13 C NMR (100 MHz, CDCl 3 )δ170.9,167.4,160.3,152.3,136.3,134.3,134.4,131.5,130.5,130.6,128.1,125.5,122.9,115.8,113.7,55.3,23.7.

[0113] The NMR data of the product of Example 4 are as follows:

[0114] 1 H NMR (400 MHz, CDCl 3)δ8.52(s,1H),7.77(d,J=1.4Hz,1H),7.57-7.49(m,5H),7.00(d,J=8.4Hz,2H),3.87(s,3H),3.15(s,3H). 13 C NMR (100 MHz, CDCl 3 )δ170.9,167.3,160.0,151.3,138.4,134.7,134.1,133.8,131.7,131.5,130.8,130.5,128.0,125.5,122.9,115.8,113.7,55.4,23.8.

[0115] The NMR data of the product of Example 5 are as follows:

[0116] 1 H NMR (400 MHz, CDCl 3 )δ8.50(s,1H),7.69-.59(m,2H),7.59-7.49(m,3H),7.16(t,J=7.9Hz,2H),6.99(d,J=8.7Hz,2H),3.87(s,3H),3.15(s,3H). 13 C NMR (100 MHz, CDCl 3 )δ171.1,167.2,163.0(d,J=248.4Hz),151.7,138.5,135.1,134.1,132.8,131.8, 131.7, 131.0 (d, J = 8.4Hz), 130.8, 125.6, 115.6 (d, J = 21.4Hz), 113.6, 55.4, 23.7.

[0117] The NMR data of the product of Example 6 are as follows:

[0118] 1 H NMR (400 MHz, CDCl 3 )δ8.51(s,1H),7.62(d,J=8.4Hz,2H),7.57(s,1H),7.53(d,J=8.7Hz,2H),7.28(t,J=6.4Hz,4H),3.86(s,3H),3.14(s,3H),2.42(s,3H). 13 C NMR (100 MHz, CDCl 3)δ171.1,167.5,159.9,159.8,153.5,138.2,135.7,133.7,130.5,130.4,128.6,127.2,124.3,115.2,114.2,112.6,55.4,23.7,21.4.

[0119] The NMR data of the product of Example 7 are as follows:

[0120] 1 H NMR (400 MHz, CDCl 3 )δ8.42(s,1H),8.14(dd,J=8.2,3.4Hz,4H),7.62(d,J=8.4Hz,2H),7.57(s,1H),7.53(d,J=8.7Hz,2H),3.95(s,3H),3.86(s,3H),3.15(s,3H). 13 CNMR (100MHz, CDCl 3 )δ170.7,166.9,166.6,152.2,140.2,139.4,138.6,135.0,132.6,130 .2,130.1,129.8,129.5,129.3,129.2,126.6,116.0,55.4,52.3,23.9.

[0121] The NMR data of the product of Example 8 are as follows:

[0122] 1 H NMR (400 MHz, CDCl 3 )δ8.50(s,1H),7.75-7.63(m,5H),7.63(d,J=8.4Hz,2H),7.57(s,1H),7.53(d,J=8.7Hz,2H),7.03-6.96(m,4H),3.86(s,3H),3.14(s,3H). 13 C NMR (100 MHz, CDCl 3 )171.0,167.4,151.9,141.4,140.6,139.4,138.7,135.7,134.8,133.5,129.7,128.9,127.7,127.3,127.1,127.0,125.5,115.8,55.4,23.8.

[0123] The NMR data of the product of Example 9 are as follows:

[0124] 1 H NMR (400 MHz, CDCl 3)δ8.50(s,1H),7.70-7.55(m,2H),7.53-7.50(m,3H),7.15(t,J=7.4Hz,2H),6.99(d,J=8.7Hz,2H),3.87(s,3H),3.15(s,3H). 13 C NMR (100 MHz, CDCl 3 )δ170.7,167.0,151.5,149.3,138.1,134.9,134.2,133.5,132.3,130. 8,130.7,129.6,126.0,122.1(q,J=254.3Hz),121.0,115.9,55.4,23.9.

[0125] The NMR data of the product of Example 10 are as follows:

[0126] 1 H NMR (400 MHz, CDCl 3 )δ8.48(s,1H),7.61(s,1H),7.57(d,J=8.1Hz,2H),7.48(d,J=8.1Hz,2H),7.28(t,J=6.4Hz,4H),3.14(s,3H),2.42(s,6H). 13 C NMR (100 MHz, CDCl 3 )δ171.1,167.4,151.7,138.64,138.61,138.5,136.1,134.0,133.1,132.3,129.3,129.1,129.0,128.9,125.1,115.6,23.8,21.36,21.35.

[0127] The NMR data of the product of Example 11 are as follows:

[0128] 1 H NMR (400 MHz, CDCl 3 )δ8.52(s,1H),7.60(d,J=8.5Hz,2H),7.55(s,1H),7.51(d,J=8.5Hz,2H),7.47-7.41(m,4H),3.15(s,3H). 13 C NMR (100 MHz, CDCl 3 )δ170.8,167.1,151.9,138.3,134.9,134.8,134.7,134.1,133.3,132.6,130.6,130.5,128.8,128.5,125.9,115.9,23.9.

[0129] The NMR data of the product of Example 12 are as follows:

[0130] 1 H NMR (400 MHz, CDCl 3 )δ8.55(s,1H),7.70(d,J=8.4Hz,2H),7.62(s,1H),7.59(d,J=6.4Hz,2H),7.32(t,J=7.6Hz,4H),3.16(s,3H). 13 C NMR (100 MHz, CDCl 3 )δ170.7,167.1,151.9,149.5,138.5,134.7,134.2,133.5,132.3,130.8,130.7,12 9.6,126.0,122.1(q,J=254.3Hz),121.8(q,J=257.9Hz),121.0,120.6,115.9,23.9. 19 F NMR (376 MHz, CDCl 3 )δ-57.69,-57.73.

[0131] The NMR data of the product of Example 13 are as follows:

[0132] 1 H NMR (400 MHz, CDCl 3 )δ8.50(s,1H),7.63(d,J=8.4Hz,2H),7.57(s,1H),7.53(d,J=8.7Hz,2H),7.03-6.96(m,4H),3.86(s,6H),3.14(s,3H). 13 C NMR (100 MHz, CDCl 3 )δ171.1,167.5,159.9,159.8,151.5,138.2,135.7,133.7,130.5,130.4,128.3,127.5,124.5,115.6,114.0,113.7,55.4,55.3,23.7.

[0133] The NMR data of the product of Example 14 are as follows:

[0134] 1 H NMR (400 MHz, CDCl 3 )δ8.10(s,1H),7.34-7.19(m,9H),3.12(s,3H),2.27(s,3H),2.21(s,3H). 13 C NMR (100 MHz, CDCl3 )δ170.9,167.2,151.5,139.9,136.6,136.5,135.9,135.0,132.5,130.2,130 .1,129.8,129.6,128.7,128.4,127.2,125.8,125.6,114.8,23.7,20.1,20.0.

[0135] The NMR data of the product of Example 15 are as follows:

[0136] 1 H NMR (400 MHz, CDCl 3 )δ8.51(s,1H),7.67(d,J=6.8Hz,2H),7.64(s,1H),7.59(dd,J=7.9,1.7Hz,2H),7.52-7.40(m,6H),3.15(s,3H). 13 C NMR (100 MHz, CDCl 3 )δ171.0,167.3,151.8,138.9,136.0,135.9,135.1,133.9,129.3,129.2,128.63,128.56,128.5,128.2,125.6,115.7,23.8.

[0138] The NMR data of the product of Example 16 are as follows:

[0139] 1 H NMR (400 MHz, CDCl 3 )δ8.67(s,1H),7.67(d,J=7.4Hz,2H),7.62(s,1H),7.59(d,J=7.5Hz,2H),7.53-7.38 (m,6H),4.69-4.54(m,1H),2.21-2.06(m,2H),2.00-1.88(m,4H),1.69-1.60(m,2H). 13 C NMR (100 MHz, CDCl 3 )δ171.3,167.3,151.9,138.8,136.0,135.9,135.3,133.6,129.3,129.2,128.5,128.4,128.2,127.4,125.5,115.6,51.0,29.6,25.1.

[0140] The NMR data of the product of Example 17 are as follows:

[0141] 1 H NMR (400 MHz, CDCl3 )δ8.53(s,1H),7.66(d,J=7.2Hz,2H),7.64(s,1H),7.59(d,J=7.2Hz,2H),7.51-7.42(m,8H),7.36-7.29(m,3H),4.82(s,2H). 13 C NMR (100 MHz, CDCl 3 )δ170.7,166.8,151.9,139.1,136.2,136.1,135.9,135.1,134.0,129.3,1 29.3,129.2,128.8,128.7,128.6,128.3,127.9,127.4,125.4,115.6,41.6.

[0142] The NMR data of the product of Example 18 are as follows:

[0143] 1 H NMR (400 MHz, CDCl 3 )δ8.65(s,1H),7.73(s,1H),7.70(d,J=7.4Hz,2H),7.65-7.58(m,4H),7.54-7.42(m,6H),7.36(d,J=8.9Hz,2H). 13 C NMR (100 MHz, CDCl 3 )δ169.7,165.7,152.5,139.6,136.7,135.7,134.9,134.6,132.3,130.3 ,129.3,129.2,128.8,128.7,128.6,128.3,127.8,124.7,121.9,115.0.

[0144] The NMR data of the product of Example 19 are as follows:

[0145] 1 H NMR (400 MHz, CDCl 3 )δ8.71(s,1H),8.04-7.92(m,2H),7.80(s,1H),7.77-7.67(m,5H),7.60(t,J=7.4Hz,1H),7.56-7.42(m,9H). 13 C NMR (100 MHz, CDCl 3)δ170.5,166.6,152.5,139.6,136.7,135.7,135.1,134.6,134.5,130.3,130.1,129.6,129.4,129.3 ,129.2,128.8,128.7,128.6,128.3,127.7,127.5,127.3,127.1,126.6,125.4,125.2,122.5,115.5.

[0146] Embodiment 20

[0147] Taking derivative 1 as an example, optimize the iodine reagent

[0148] The structural formula of derivative 1 is:

[0149] The parallel synthesis steps are as follows:

[0150] (1) Add unsaturated ketene compounds into the reaction vessel (0.2mmol), maleimide compounds (0.3 mmol), water 0.4 mmol, protic acid TsOH (0.2 mmol) and organic solvent PhCl (1.5 mL);

[0151] (2) Add 0.2 mmol of iodine reagent NH 4 I, KI, NaI, IBr, PhI(OAc) 2 、NIS、I 2 O 5 ,I 2 , PIFA;

[0152] (3) After the reactants are stirred evenly, they are placed in an oil bath at 80°C and reacted for 4 hours under air atmosphere to obtain the products.

[0153] Different iodine reagents NH 4 I, KI, NaI, IBr, PhI(OAc) 2 、NIS、I 2 O 5 ,I 2 , PIFA promoted, the yields of derivative 1 were: <10%, <10%, <10%, 13%, 40%, 31%, 55%, 65%, 37%, so I is preferred. 2 and I 2 O 5 It is a preferred iodine reagent.

[0154] Embodiment 21

[0155] Taking derivative 1 as an example, optimize the proton acid

[0156] The structural formula of derivative 1 is:

[0157] The parallel synthesis steps are as follows:

[0158] (1) Add unsaturated ketene compounds into the reaction vessel (0.2mmol), maleimide compounds (0.3mmol), water 0.4mmol, iodine reagent I 2 (0.2 mmol) and organic solvent PhCl (1.5 mL);

[0159] (2) Add 0.2 mmol of proton acid AcOH, TFA, TsOH, TfOH, benzoic acid and BF into the above parallel reaction vessels respectively. 3 ·Et 2 O;

[0160] (3) After the reactants are stirred evenly, they are placed in an oil bath at 80°C and reacted for 4 hours under air atmosphere to obtain the products.

[0161] Different protonic acids AcOH, TFA, TsOH, TfOH, benzoic acid and BF 3 ·Et 2 Under O promotion, the yields of derivative 1 were 17%, 21%, 65%, 30%, 43% and 28%, respectively, so TsOH was preferred as the best proton acid.

[0162] Embodiment 22

[0163] Taking derivative 1 as an example, optimize the reaction solvent

[0164] The structural formula of derivative 1 is:

[0165] The parallel synthesis steps are as follows:

[0166] (1) Add unsaturated ketene compounds into the reaction vessel (0.2mmol), maleimide compounds (0.3mmol), water 0.4mmol, iodine reagent I 2 (0.2 mmol), protic acid TsOH (0.2 mmol) and organic solvent PhCl (1.5 mL);

[0167] (2) Add 1.5 mL of solvent water, tetrahydrofuran, toluene, acetonitrile, chlorobenzene, dimethyl sulfoxide, p-xylene, and o-xylene to the above parallel reaction vessels respectively;

[0168] (3) After the reactants are stirred evenly, they are placed in an oil bath at 80°C and reacted for 4 hours under air atmosphere to obtain the products.

[0169] The yields of derivative 1 in different solvents water, tetrahydrofuran, toluene, acetonitrile, chlorobenzene, dimethyl sulfoxide, p-xylene and o-xylene were: <10%, 18%, 53%, 25%, 65%, 12%, 59% and 54%, respectively. It can be seen that toluene, chlorobenzene, p-xylene and o-xylene are all suitable solvents, but PhCl is the best solvent.

[0170] Embodiment 23

[0171] Taking derivative 1 as an example, optimize the reaction temperature

[0172] The structural formula of derivative 1 is:

[0173] The parallel synthesis steps are as follows:

[0174] (1) Add unsaturated ketene compounds into the reaction vessel (0.2mmol), maleimide compounds (0.3mmol), water 0.4mmol, iodine reagent I 2 (0.2 mmol), protic acid TsOH (0.2 mmol) and organic solvent PhCl (1.5 mL);

[0175] (2) After the reactants are stirred evenly, they are placed in an oil bath at 25, 50, 80, 100, or 120° C. and reacted for 4 h in an air atmosphere to obtain the product.

[0176] The yields of derivative 1 at 25, 50, 80, 100 and 120°C were: <10%, 25%, 65%, 52% and 47%, respectively. It can be seen that with the increase of reaction temperature, the yield first increased and then decreased, and 80°C was the best.

[0177] Embodiment 24

[0178] Taking derivative 1 as an example, optimize the reaction time

[0179] The structural formula of derivative 1 is:

[0180] The parallel synthesis steps are as follows:

[0181] (1) Add unsaturated ketene compounds into the reaction vessel (0.2mmol), maleimide compounds (0.3mmol), water 0.4mmol, iodine reagent I 2(0.2 mmol), protic acid TsOH (0.2 mmol) and organic solvent PhCl (1.5 mL);

[0182] (2) After the reactants were stirred evenly, they were placed in an oil bath at 80°C and reacted in an air atmosphere for 2, 4, 6, 8, 10, and 12 h to obtain the products.

[0183] After 2, 4, 6, 8, 10, and 12 hours of reaction, the yields of derivative 1 were 34%, 65%, 53%, 44%, 32%, and 19%, respectively. It can be seen that the yield is better when the reaction time is 4-8 hours, and 4 hours is the optimal reaction time.

[0184] Comparative Example 1

[0185] On the basis of Example 1, experiments were conducted according to the reaction conditions in the prior art CN116332823A to verify the synthesis of asymmetric structure derivative 1

[0186] The structural formula of derivative 1 is:

[0187] (1) Add unsaturated ketene compounds into the reaction vessel (0.2mmol), maleimide compounds (0.3mmol), I 2 (0.2mmol), BF 3 ·Et 2 O (0.2 mmol), p-xylene (0.5 mL), and chlorobenzene (0.5 mL);

[0188] (2) After the reactants are stirred evenly, they are placed in an oil bath at 140°C and reacted in an oxygen atmosphere for 24 hours.

[0189] The experimental results show that under the above reaction conditions, the yield of derivative 1 is only 14%. On the one hand, it may be because the protonic acid BF 3 ·Et 2 O has a poor coordination-promoting effect on the formation of asymmetric derivative 1; on the other hand, it may be because the long-term high-temperature reaction system increases the by-products, which in turn affects the formation of derivative 1.

[0190] Embodiment 25

[0191] Based on Example 15, the source of phenolic hydroxyl groups was determined using isotope tracing

[0192] The structural formula of the product of Example 15 is:

[0193] The structural formula of the target product is:

[0194] The synthesis steps are as follows:

[0195] (1) Add unsaturated ketene compounds into the reaction vessel (0.2mmol), maleimide compounds (0.3mmol), H 2 18 O (0.4 mmol), iodine reagent I 2 (0.2 mmol), protic acid TsOH (0.2 mmol) and organic solvent PhCl (1.5 mL);

[0196] (2) After the reactants are stirred evenly, they are placed in an oil bath at 80°C and reacted for 4 hours under air atmosphere to obtain the product.

[0197] In being 18 The corresponding characteristic peak position in the high-resolution mass spectrum of the target product labeled with O is 331.1, indicating that the oxygen of the phenolic hydroxyl group in this series of derivatives comes from water. It also verifies that water is one of the reaction substrates of this reaction and provides a reliable basis for inferring the reaction mechanism of this reaction.

[0198] Embodiment 26

[0199] Minimum inhibitory concentration (MIC) test

[0200] In order to evaluate the antibacterial activity of the polysubstituted phenol maleimide derivatives of the present invention, the microbroth dilution method was used to test the antibacterial activity of the compounds of Examples 1-19 against Staphylococcus aureus (S. aureus) ATCC 29213, Escherichia coli (E. coli) ATCC 25922 and Pseudomonas aeruginosa (P. aeruginosa) 19-7. The experimental well plate was placed in a 37°C constant temperature incubator for 18 hours, and the lowest compound concentration that completely inhibited bacterial growth in the well was taken as MIC. The test results are shown in Table 2 below. Most of the derivatives had an antibacterial activity against the selected Gram-positive (G + ) bacteria and Gram-negative (G - ) bacteria showed moderate to good antibacterial activity (MIC was 2-64 μg / mL), and Examples 1-4 showed better antibacterial activity against the selected three bacteria as a whole than the derivatives of other Examples.

[0201] Table 2 In vitro antibacterial activity of derivatives of Examples 1-19

[0202]

[0203] The above is only a preferred embodiment of the present application and does not constitute any form of limitation to the present application. Although the present application is disclosed as a preferred embodiment as above, it is not intended to limit the present application. Any technician familiar with the profession, without departing from the scope of the technical solution of the present application, using the technical content disclosed above to make slight changes or modifications are equivalent to equivalent implementation cases and fall within the scope of the technical solution.

Claims

1. A substituted phenol maleimide derivative, characterized in that: Its general structural formula is shown in Formula I: Where: Ar 1 ,Ar 2 are independently selected from a benzene ring or a substituted benzene ring, Ar 1 ,Ar 2 Different structures; The substituent of the substituted benzene ring is selected from: halogen, phenyl, C1-C8 alkoxy, C1-C8 alkyl, C1-C8 alkyl ester or substituted C1-C8 alkoxy; The substituent on the C1-C8 alkoxy group is halogen; R is selected from halogen, C1-C8 alkyl, aryl, C3-C8 cycloalkyl or substituted phenyl.

2. The substituted phenol maleimide derivative according to claim 1, characterized in that: The substituents of the substituted benzene ring are selected from: halogen, phenyl, C1-C4 alkoxy, C1-C4 alkyl, C1-C4 alkyl ester, substituted C1-C4 alkoxy; the substituents on the substituted C1-C4 alkoxy are halogen.

3. The substituted phenol maleimide derivative according to claim 1, characterized in that: The substituents of the substituted benzene ring are selected from: halogen, phenyl, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkyl ester, substituted C1-C3 alkoxy; the substituents on the substituted C1-C3 alkoxy are halogen.

4. The substituted phenol maleimide derivative according to claim 1, characterized in that: Ar 1 ,Ar 2 Each of the following is independently selected from a benzene ring, p-methoxyphenyl, p-ethoxyphenyl, p-propoxyphenyl, bromophenyl, dibromophenyl, chlorophenyl, dichlorophenyl, fluorophenyl, difluorophenyl, tolyl, ethylphenyl, propylphenyl, biphenyl, p-benzoyl, p-ethylphenyl, p-propylphenyl, trifluoromethoxyphenyl, trifluoroethoxyphenyl, trifluoropropoxyphenyl, trichloromethoxyphenyl and tribromomethoxyphenyl.

5. The substituted phenol maleimide derivative according to any one of claims 1 to 4, characterized in that: The structure of the substituted phenol maleimide derivative is shown below:

6. The method for preparing a substituted phenol maleimide derivative according to any one of claims 1 to 5, characterized in that: include: The unsaturated enone compound, the maleimide compound and water are heated in an iodine reagent, a protonic acid and an organic solvent to react to obtain; The general formula of the unsaturated ketene compound is Formula II: The general formula of the maleimide compound is Formula III: Ar 1 ,Ar 2 are independently selected from a benzene ring or a substituted benzene ring; R is selected from halogen, C1-C8 alkyl, aryl, C3-C8 cycloalkyl, substituted phenyl; The substituent of the substituted benzene ring is selected from the group consisting of: halogen, phenyl, C1-C8 alkoxy, C1-C8 alkyl, C1-C8 alkyl ester, substituted C1-C8 alkoxy; The substituent on the C1-C8 alkoxy group is halogen; The Ar 1 ,Ar 2 Different or the same.

7. The preparation method according to claim 6, characterized in that: The iodine reagent is one or more of NH4I, KI, NaI, IBr, PhI(OAc)2, NIS, I2O5, I2, and bis(trifluoroacetoxy)iodobenzene (PIFA); the protonic acid reagent is one or more of AcOH, trifluoroacetic acid (TFA), TsOH, TfOH, benzoic acid, and BF3·Et2O; the organic solvent is a polar or non-polar solvent, and the polar or non-polar solvent includes one or more of acetonitrile, 1,4-dioxane, toluene, chlorobenzene, N-methylpyrrolidone, dimethyl sulfoxide, and p-xylene.

8. The preparation method according to claim 6, characterized in that: The molar ratio of the unsaturated ketene compound to the maleimide compound is 1.0:(0.5-2.0); the molar ratio of the unsaturated ketene compound to water is 1.0:(1.0-3.0); the molar ratio of the unsaturated ketene compound to the iodine reagent is 1.0:(0.5-2.0); the molar ratio of the unsaturated ketene compound to the protonic acid reagent is 1.0:(0.5-1.5); The amount of the organic solvent used is 0.5-2.0 mL / mmol of the unsaturated ketene compound.

9. The preparation method according to claim 6, characterized in that: The reaction temperature is 25-120°C; the reaction time is 2-12h.

10. Use of the substituted phenol maleimide derivative according to any one of claims 1 to 5 in antibacterial applications.

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