A guaiac triarylmethane, its synthesis method, and its application in the preparation of antibacterial products.

Abstract

This invention belongs to the field of anti-inflammatory compound synthesis technology, specifically relating to a guaiazoline triarylmethane, its synthesis method, and its application in the preparation of antibacterial products. The structure of the guaiazoline triarylmethane is shown in formula (Ⅰ). This invention synthesizes guaiazoline triarylmethane by using readily available guaiazoline and p-methylenebenzoquinone as starting materials, and by a 1,6-conjugated addition reaction under Lewis acid catalysis. This method is simple to operate, has mild reaction conditions, uses economical and readily available reagents and raw materials, has a high yield of the target product, and has a wide range of substrate applicability; it has good prospects and potential for industrial application.

Description

Technical Field

[0001] This invention belongs to the field of anti-inflammatory compound synthesis technology, specifically relating to a guaiazoline triarylmethane, its synthesis method, and its application in the preparation of antibacterial products. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Guaiacenes are bicyclic sesquiterpenes composed of fused cycloheptatriene and cyclopentadiene, possessing antibacterial, antiviral, anti-inflammatory, anti-allergic, antioxidant, radiation-protective, and skin barrier-enhancing effects (Med ChemRes 2021, 30, 834). For example, sodium azulene sulfonate (also known as sodium guaiacol), obtained through simple structural modification of guaacenes, exhibits anti-inflammatory, anticancer, and anti-ulcer properties and is widely used clinically in the treatment of ophthalmitis, periodontitis, and cardiovascular diseases. In the cosmetics field, guaacenes and its derivatives are also widely used in lotions with anti-inflammatory, emollient, moisturizing, and anti-wrinkle functions. Furthermore, guaacenes can be used as dye colorants in laser printing, liquid crystal displays, fluorescence conversion films, optical recorders, and photoreceptors. Therefore, developing efficient synthetic strategies for guaacenes will provide crucial technological support for the creation and development of functional products.

[0004] Direct functional group modification based on the guaiac core is an important method for synthesizing azurite derivatives. The key lies in the rich chemical activity of guaiac: the 1,3-membered ring... The 4, 6, and 8 positions on the seven-membered ring tend to be negatively charged and readily undergo electrophilic substitution reactions, while the 4, 6, and 8 positions on the seven-membered ring... The site tends to carry a positive charge, readily undergoing nucleophilic reactions. Based on this reaction characteristic, researchers have developed a variety of efficient synthetic strategies (Org. Biomol. Chem., 2022, 20, 1510; Chin. J. Org. Chem.2022, 42, 2906; New J. Chem. 2024, 48, 17376; Chem. Biodiversity 2023, 20,e202201174; Adv. Synth. Catal. 2024, 366, 1007.) to construct structurally diverse and functionally rich guaiazoline derivatives. Furthermore, triarylmethane compounds possess strong skeletal rigidity and ease of modification, leading to their wide application in medicinal chemistry, pesticides, biomedicine, dyes, and materials science. Therefore, the synthesis of triarylmethane containing a guaiazoline structure by replacing one aryl group in a guaiazoline group is expected to have significant application value. Summary of the Invention

[0005] To address the problems existing in the prior art, the present invention provides a guaiazoline triarylmethane, its preparation method and application. The method uses readily available guaiazoline and p-methylenebenzoquinone as starting materials, and synthesizes guaiazoline triarylmethane through a 1,6-conjugated addition reaction under the action of a Lewis acid catalyst.

[0006] This invention is achieved through the following technical solution: In a first aspect, a guaiazoline triarylmethane is provided, the structure of which is shown in formula (I) below, or is a pharmaceutically acceptable salt or ester or solvate, tautomer, meso compound, racemic compound, stereoisomer, metabolite or prodrug of the compound shown in formula (I): ; Among them, R 1 It is a phenyl, a substituted phenyl, a fused-ring substituent of benzene, or a heterocyclic substituent; R 2 It is a phenyl group or an alkyl group with a low number of carbon atoms; R 3 R 4 and R 5 Alkyl groups selected independently from hydrogen atoms or low carbon atoms.

[0007] The aforementioned substituted phenyl groups include, but are not limited to, alkylphenyl, heteroalkylphenyl, heteroalkoxyphenyl, halogen phenyl, cyanophenyl, acylphenyl, ester phenyl, and nitrophenyl; furthermore, in the heteroalkylphenyl or heteroalkoxyphenyl groups, one or more carbon atoms in the alkyl group are substituted with halogens.

[0008] The fused ring substituents of the above-mentioned benzene include, but are not limited to, naphthyl, anthracene, or phenanthrene.

[0009] The aforementioned heterocyclic substituents include, but are not limited to, five-membered or six-membered rings containing sulfur and nitrogen elements, and further, thiophene or pyridinyl groups.

[0010] The aforementioned alkyl groups with a low number of carbon atoms are alkyl groups with 1 to 4 carbon atoms, including straight-chain alkyl groups and branched-chain alkyl groups; further, they are methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl.

[0011] Furthermore, R 1 It is one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 4-cyanophenyl, 4-methyl ester phenyl, 4-acetylphenyl, 4-nitrophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-chlorophenyl, 3-trifluoromethoxyphenyl, 3,4,5-methoxyphenyl, 2-methylphenyl, 2-fluorophenyl, 2-bromophenyl, 2-trifluoromethylphenyl, 2-naphthyl, 2-thienyl, and 2-pyridyl. R 2 It is one of methyl, isopropyl, tert-butyl, and phenyl; R 3 It is one of the methyl or hydrogen atoms; R 4 It is one of the methyl or hydrogen atoms; R 5 It is one of hydrogen atom and isopropyl group.

[0012] Secondly, a method for synthesizing the guaiazoline triarylmethanes described in the first aspect is provided, involving the following synthetic route: ; Formula (II) Formula (III) The synthesis method is as follows: p-methylenebenzoquinone of formula (II), guaiacium of formula (III), and Lewis acid catalyst are dissolved in an organic solvent, and the reaction product is separated to obtain the guaiac-type triarylmethane.

[0013] In the above synthesis method, the Lewis acid is a trifluoromethanesulfonic acid, further including but not limited to copper trifluoromethanesulfonate, bismuth trifluoromethanesulfonate, zinc trifluoromethanesulfonate, silver trifluoromethanesulfonate, iron trifluoromethanesulfonate, ferrous trifluoromethanesulfonate, scandium trifluoromethanesulfonate, nickel trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate, yttrium trifluoromethanesulfonate, boron trifluoride ether, p-toluenesulfonic acid, or cuprous trifluoromethanesulfonate; in some embodiments with better effects, the Lewis acid is bismuth trifluoromethanesulfonate, nickel trifluoromethanesulfonate, scandium trifluoromethanesulfonate, or boron trifluoride ether.

[0014] The organic solvent is one of dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, acetone, toluene, and tetrahydrofuran; in some embodiments where the effect is better, the organic solvent is dichloromethane.

[0015] The reaction temperature for the above synthesis method is 0~40℃, and the reaction time is 1~6h; the reaction temperature with better results is room temperature.

[0016] The molar ratio of guaiazoline, p-methylenebenzoquinone, and Lewis acid catalyst is 1.0~1.5:1:0.05~0.1, and more specifically, the molar ratio of guaiazoline, p-methylenebenzoquinone, and Lewis acid catalyst is 1.25:1:0.1.

[0017] The above-mentioned method for separating the reaction products is column chromatography, and the eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 75:1 to 50:1.

[0018] In a third aspect, a composition is provided, the composition comprising an active dose of the guaiazoline triarylmethane described in the first aspect.

[0019] In a preferred embodiment of the present invention, the above composition is used to prepare an anti-inflammatory product, wherein the active dose refers to the drug dose required to achieve the anti-inflammatory effect, and can be determined by conventional methods in the field.

[0020] In other embodiments, the above composition also includes a pharmaceutically acceptable carrier, examples of which include glucose, water, lactose, sucrose, glycerol, ethanol, propylene glycol, mannitol, corn starch, gelatin, alginate, microcrystalline cellulose, kaolin, dicalcium phosphate, sodium chloride, croscarmellose sodium, and sodium starch glycolate, etc.; it also includes hydrophilic carriers, hydrophobic carriers, or combinations thereof, wherein hydrophobic carriers include, for example, fat emulsions, lipids, polyethylene glycol phospholipids, biocompatible polymers, lipospheres, liposomes, microvesicles, polymer matrices, etc.

[0021] Fourthly, the use of the guaiazoline triarylmethane described in the first aspect and the composition described in the third aspect in the preparation of anti-inflammatory products is provided.

[0022] The anti-inflammatory product includes, but is not limited to, one of the following: personal care products, medicines, health products, or special medical foods. In one embodiment verified by this invention, the anti-inflammatory product is a medicine.

[0023] Compared with the prior art, the beneficial effects of the present invention are: This invention synthesizes guaiazolinone-based triarylmethanes by using readily available guaiazolinone and p-methylenebenzoquinone as starting materials and conducting a 1,6-conjugation addition reaction under Lewis acid catalysis. This method is simple to operate, has mild reaction conditions, uses economical and readily available reagents and raw materials, achieves high yield of the target product, and has a wide range of substrate applicability; it has good prospects and potential for industrial application. Attached Figure Description

[0024] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0025] Figure 1 For example 1, guaiazoline triarylmethane 3aa 1 HNMR MRI; Figure 2 For example 1, guaiazoline triarylmethane 3aa 13 CNMR (nuclear magnetic resonance) image; Figure 3 Example 2: Guaiacene triarylmethane 3ab 1 HNMR MRI; Figure 4 Example 2: Guaiacene triarylmethane 3ab 13 CNMR (nuclear magnetic resonance) image; Figure 5 Example 3: Guaiac-based triarylmethane 3ac 1 HNMR MRI; Figure 6 Example 3: Guaiac-based triarylmethane 3ac 13 CNMR (nuclear magnetic resonance) image; Figure 7 Example 4: Guaiacene triarylmethane 3ad 1 HNMR MRI; Figure 8 Example 4: Guaiacene triarylmethane 3ad 13 CNMR (nuclear magnetic resonance) image; Figure 9 For Example 5, guaiazoline triarylmethane 3ae 1 HNMR MRI; Figure 10 For Example 5, guaiazoline triarylmethane 3ae 13 CNMR (nuclear magnetic resonance) image; Figure 11 Example 6: Guaiacene triarylmethane 3af 1 HNMR MRI; Figure 12Example 6: Guaiacene triarylmethane 3af 13 CNMR (nuclear magnetic resonance) image; Figure 13 Example 7: 3ag of guaiazoline triarylmethane 1 HNMR MRI; Figure 14 Example 7: 3ag of guaiazoline triarylmethane 13 CNMR (nuclear magnetic resonance) image; Figure 15 Example 8: Guaiacene triarylmethane 3ah 1 HNMR MRI; Figure 16 Example 8: Guaiacene triarylmethane 3ah 13 CNMR (nuclear magnetic resonance) image; Figure 17 Example 9: Guaiacene triarylmethane 3ai 1 HNMR MRI; Figure 18 Example 9: Guaiacene triarylmethane 3ai 13 CNMR (nuclear magnetic resonance) image; Figure 19 Example 10: Guaiacene triarylmethane 3aj 1 HNMR MRI; Figure 20 Example 10: Guaiacene triarylmethane 3aj 13 CNMR (nuclear magnetic resonance) image; Figure 21 Example 11: Guaiacene triarylmethane 3ak 1 HNMR MRI; Figure 22 Example 11: Guaiacene triarylmethane 3ak 13 CNMR (nuclear magnetic resonance) image. Detailed Implementation

[0026] It should be noted that the following detailed description is illustrative and intended to provide further explanation of the invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0027] It should be noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of exemplary embodiments according to the invention. As used herein, the singular form is intended to include the plural form as well, unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0028] To enable those skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments.

[0029] Example 1 In this embodiment, a guaiazoline triarylmethane 3aa is provided, with the structure shown in the following formula: 3aa The preparation method of the above compound 3aa is as follows: Guaiacin 1a (49.5 mg, 0.25 mmol, 1.25 equiv. CAS No.: 489-84-9) and 4-fluorophenyl p-methylenebenzoquinone 2a (62.4 mg, 0.2 mmol, 1.0 equiv. CAS No.: 1634622-27-7) were added to a 10 mL reaction tube, and 1 mL of dry dichloromethane (0.4 M) was added. The mixture was stirred at room temperature until the solid was completely dissolved. Copper trifluoromethanesulfonate (7.2 mg, 0.02 mmol, 0.1 equiv.) was then added to the reaction system, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, dichloromethane was removed under reduced pressure, and then the product was separated by column chromatography (200 mesh silica gel column chromatography) (using a mixture of petroleum ether and ethyl acetate at a volume ratio of 50:1 as the eluent) to obtain guaiazoline triarylmethane 3aa, a blue oily substance, with a yield of 100.47 mg and a yield of 98.5%.

[0030] Compound 3aa 1 HNMR and 13 CNMR spectra are as follows: Figure 1 and Figure 2 As shown; 1H NMR (500 MHz, CDCl3) δ 8.07 (t, J = 2.3 Hz, 1H), 7.11 (d, J = 3.0 Hz, 1H), 6.96 (ddd, J =8.3, 5.5, 2.6 Hz, 2H), 6.90 (td, J = 8.7, 2.3 Hz, 2H), 6.84 (d, J = 3.0 Hz, 2H), 6.78 (dd, J = 10.8, 1.9 Hz, 1H), 6.38 (d, J = 2.9 Hz, 1H), 5.05 (d, J =2.2 Hz, 1H), 3.00 (pd, J = 6.9, 2.0 Hz, 1H), 2.90 (d, J = 2.5 Hz, 3H), 2.55(d, J = 2.7 Hz, 3H), 1.38 – 1.31 (m, 24H). 13 C NMR (126 MHz, CDCl3) δ161.04 (d,J = 243.5 Hz), 151.86, 145.20, 142.83 (d, J = 3.2 Hz), 140.51, 139.12,137.91, 136.50, 135.42, 134.63, 133.58, 132.47, 130.94 (d, J = 7.7 Hz), 130.45, 126.76, 126.32, 124.11, 114.83, 114.66, 51.00, 37.66, 34.38, 30.42,27.42, 24.65, 13.16. HRMS (ESI) m / z [M+Na]+calcd for C 36 H 43 FNaO: 533.3196, Found: 533.3193.

[0031] Example 2 In this embodiment, a guaiazoline triarylmethane 3ab is provided, with the following structure: 3ab The preparation method of the above compound 3ab is as follows: Guaiacin 1a (49.5 mg, 0.25 mmol, 1.25 equiv. CAS No.: 489-84-9) and 4-chlorophenyl-p-methylenebenzoquinone 2b (65.6 mg, 0.2 mmol, 1.0 equiv.) are prepared. CAS No.: 70039-17-7) was added to a 10 mL reaction tube, followed by 1 mL of dry dichloromethane (0.4 M). The mixture was stirred at room temperature until the solid was completely dissolved. Subsequently, copper trifluoromethanesulfonate (7.2 mg, 0.02 mmol, 0.1 equiv.) was added to the reaction system, and the mixture was stirred at room temperature for 1.5 hours. After the reaction was completed, the dichloromethane was removed under reduced pressure, and then the product was separated by column chromatography (200 mesh silica gel column chromatography) (using a mixture of petroleum ether and ethyl acetate at a volume ratio of 50:1 as the eluent). The product, guaiazoline triarylmethane 3ab, was obtained as a blue oil with a yield of 100.34 mg and a yield of 95.2%.

[0032] The above compound 3ab 1 HNMR and 13 CNMR spectra are as follows: Figure 3 and Figure 4 As shown; 1 H NMR (500 MHz, CDCl3) δ 8.07 (t, J = 2.6 Hz, 1H), 7.24 – 7.21 (m, 1H), 7.17 (dd, J = 8.6,2.5 Hz, 2H), 7.10 (d, J = 3.7 Hz, 1H), 6.93 (dd, J = 3.00 (pd, J = 6.9, 2.4 Hz, 1H), 2.88 (d, J =3.0 Hz, 3H), 2.54 (d, J = 3.2 Hz, 3H), 1.37 – 1.31 (m, 24H). 13C NMR (126 MHz, CDCl3) δ 151.93, 145.78, 145.17, 140.48, 139.21, 137.95, 136.10, 135.50,134.67, 133.62, 132.52, 131.28, 130.95,130.01,128.15,126.83,126.33,124.15,51.18,37.67,34.39,30.43,27.46,24.65,24.64,13.16. HRMS (ESI) m / z [M+Na]+calcd for C 36 H 43 ClNaO: 549.2900, Found: 549.2903.

[0033] Example 3 In this embodiment, a guaiazoline triarylmethane 3ac is provided, with the following structure: 3ac The preparation method of the above compound 3ac is as follows: Guaiac 1a (49.5 mg, 0.25 mmol, 1.25 equiv. CAS No.: 489-84-9) and 4-bromophenyl-p-methylenebenzoquinone 2c (74.4 mg, 0.2 mmol, 1.0 equiv.) were prepared. CAS No.: 1531596-08-3) was added to a 10 mL reaction tube, followed by 1 mL of dry dichloromethane (0.4 M). The mixture was stirred at room temperature until the solid was completely dissolved. Subsequently, copper trifluoromethanesulfonate (7.2 mg, 0.02 mmol, 0.1 equiv.) was added to the reaction system, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the dichloromethane was removed under reduced pressure, and then the product was separated by column chromatography (200 mesh silica gel column chromatography) (using a mixture of petroleum ether and ethyl acetate at a volume ratio of 50:1 as the eluent). The product, guaiazoline triarylmethane 3ac, was obtained as a blue oil with a yield of 109.9 mg and a yield of 96.2%.

[0034] Compound 3ac 1 HNMR and 13 CNMR spectra are as follows: Figure 5 and Figure 6 As shown; 1H NMR (500 MHz, Chloroform-d) δ 8.07 (d, J = 2.4 Hz, 1H), 7.33 (dd, J = 8.6, 2.4 Hz, 2H), 7.25 – 7.21 (m, 1H), 7.11 (d, J = 3.6 Hz, 1H), 6.92 – 6.82 (m, 4H), 6.78 (d,J = 10.8 Hz, 1H), 6.35 (d, J = 3.4 Hz, 1H), 5.05 (d, J = 2.3 Hz, 1H), 3.05 –2.96 (m, 1H), 2.88 (d, J = 2.9 Hz, 3H), 2.54 (d, J = 3.1 Hz, 3H), 1.34 (d, J = 3.2 Hz, 24H). 13 C NMR (126 MHz, CDCl3) δ 151.95, 146.33, 145.17, 140.47,139.23, 137.96, 135.99, 135.51, 134.68, 133.64, 132.53, 131.38, 131.10,129.90, 126.85, 126.34, 124.16, 119.45, 51.26, 37.68, 34.40, 30.44, 27.48,24.66, 13.18. HRMS (ESI) m / z [M+Na]+calcd for C 36 H 43 BrNaO: 593.2395, Found: 593.2396.

[0035] Example 4 In this embodiment, a guaiazoline triarylmethane 3ad is provided, with the following structure: 3ad The preparation method of the above compound 3ad is as follows: Guaiacin 1a (49.5 mg, 0.25 mmol, 1.25 equiv. CAS No.: 489-84-9) and 4-nitrophenyl-p-methylenebenzoquinone 2d (67.8 mg, 0.2 mmol, 1.0 equiv). CAS No.: 183666-73-1) was added to a 10 mL reaction tube, followed by 1 mL of dry dichloromethane (0.4 M). The mixture was stirred at room temperature until the solid was completely dissolved. Subsequently, copper trifluoromethanesulfonate (7.2 mg, 0.02 mmol, 0.1 equiv.) was added to the reaction system, and the mixture was stirred at room temperature for 5 hours. After the reaction was completed, the dichloromethane was removed under reduced pressure, and then the product was separated by column chromatography (200 mesh silica gel column chromatography) (using a mixture of petroleum ether and ethyl acetate at a volume ratio of 50:1 as the eluent). The product, guaiazoline triarylmethane 3ad, was obtained as a blue oil with a yield of 99.3 mg and a yield of 92.5%.

[0036] Compound 3ad 1 HNMR and 13 CNMR spectra are as follows: Figure 7 and Figure 8 As shown; 1 H NMR (500 MHz, Chloroform-d) δ 8.12 – 8.06 (m, 3H), 7.26 (dd, J = 10.6, 2.1 Hz, 1H), 7.19 –7.15 (m, 2H), 7.08 (s, 1H), 6.82 (d, J = 11.1 Hz, HRMS (ESI) m / z [M+Na]+calcd for C 36 H 43 NNaO3: 560.3141, Found: 560.3145.

[0037] Example 5 In this embodiment, a guaiazoline triarylmethane 3ae is provided, with the following structure: 3ae The preparation method of the above compound 3ae is as follows: Guaiacin 1a (49.5 mg, 0.25 mmol, 1.25 equiv. CAS No.: 489-84-9) and 4-cyanophenyl-p-methylenebenzoquinone 2e (63.8 mg, 0.2 mmol, 1.0 equiv.) are prepared. CAS No.: 183666-77-5) was added to a 10 mL reaction tube, followed by 1 mL of dry dichloromethane (0.4 M). The mixture was stirred at room temperature until the solid was completely dissolved. Subsequently, copper trifluoromethanesulfonate (7.2 mg, 0.02 mmol, 0.1 equiv.) was added to the reaction system, and the mixture was stirred at room temperature for 5 hours. After the reaction was completed, the dichloromethane was removed under reduced pressure, and then the product was separated by column chromatography (200 mesh silica gel column chromatography) (using a mixture of petroleum ether and ethyl acetate at a volume ratio of 25:1 as the eluent). The product, guaiazoline triarylmethane 3ae, was obtained as a blue oil with a yield of 102.2 mg and a yield of 98.8%.

[0038] The above compound 3ae 1 HNMR and 13 CNMR spectra are as follows: Figure 9 and Figure 10 As shown; 1 H NMR (500 MHz, CDCl3) δ 8.09 (d, J = 2.3 Hz, 1H), 7.51 (d, J = 8.1 Hz, 2H), 7.26 (dd, J =10.8, 2.2 Hz, 1H), 7.12 (d, J = 7.9 Hz, 2H), 7.07 (s, 1H), 6.82 (d, J = 6.1Hz, 3H), 6.44 (s, 1H), 5.09 (s, 1H), 3.02 (p, J = 6.8 Hz, 1H), 2.87 (s, 3H), 2.55 (s, 3H), 1.34 (d, J = 3.3 Hz, 24H). 13 C NMR (126 MHz, CDCl3) δ 152.97,152.14, 145.01, 140.23, 139.60, 138.01, 135.73, 135.16, 134.87, 133.84,132.59, 131.94, 130.29, 128.66, 127.06, 126.28, 124.32, 119.31, 109.39,51.89, 37.66, 34.37, 30.36, 27.46, 24.61, 13.12; HRMS (ESI) m / z [M+Na]+calcdfor C37 H 43 NNaO: 540.3242, Found: 540.3250.

[0039] Example 6 In this embodiment, a guaiazoline triarylmethane 3af is provided, with the structure shown in the following formula: 3af The preparation method of the above compound 3af is as follows: Guaiacin 1a (49.5 mg, 0.25 mmol, 1.25 equiv. CAS No.: 489-84-9) and 4-methyl ester phenyl p-methylenebenzoquinone 2f (70.4 mg, 0.2 mmol, 1.0 equiv.) were prepared. CAS No.: 1802888-58-9) was added to a 10 mL reaction tube, followed by 1 mL of dry dichloromethane (0.4 M). The mixture was stirred at room temperature until the solid was completely dissolved. Subsequently, copper trifluoromethanesulfonate (7.2 mg, 0.02 mmol, 0.1 equiv.) was added to the reaction system, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the dichloromethane was removed under reduced pressure, and then the product was separated by column chromatography (200 mesh silica gel column chromatography) (using a mixture of petroleum ether and ethyl acetate at a volume ratio of 50:1 as the eluent). The product, guaiazoline triarylmethane 3af, was obtained as a blue oil with a yield of 106.2 mg and a yield of 96.5%.

[0040] The above compound 3af 1 HNMR and 13 CNMR spectra are as follows: Figure 11 and Figure 12 As shown; 1 H NMR (500 MHz, CDCl3) δ 8.09 (t, J = 2.6 Hz, 1H), 7.91 (dd, J = 8.2, 3.4 Hz, 2H), 7.22 (dd,J = 10.8, 2.3 Hz, 1H), 7.15 – 7.08 (m, 3H), 6.86 (d, J = 3.8 Hz, 2H), 6.78 (dd, J = 10.8, 2.1 Hz, 1H), 6.46 (d, J = 3.8 Hz, 1H), 5.08 (d, J = 3.2 Hz, 1H), 3.85 (s, 3H), 3.00 (pd, J = 6.9, 2.1 Hz, 1H), 2.88 (d, J = 3.1 Hz, 3H), 2.55 (d, J = 3.2 Hz, 3H), 1.39 – 1.29 (m, 24H).13 C NMR (126 MHz, CDCl3) δ167.33, 152.80, 152.05, 145.17, 140.56, 139.32, 138.05, 135.87, 135.62,134.75, 133.69, 132.67, HRMS (ESI) m / z[M+Na]+calcd for C 38 H 46 NaO3: 573.3345, Found: 573.3349.

[0041] Example 7 In this embodiment, a guaiazoline triarylmethane 3ag is provided, with the structure shown in the following formula: 3ag The preparation method of the above compound 3ag is as follows: Guaiacin 1a (49.5 mg, 0.25 mmol, 1.25 equiv. CAS No.: 489-84-9) and 2 g of 3-chlorophenyl-p-methylenebenzoquinone (65.6 mg, 0.2 mmol, 1.0 equiv. CAS No.: 70039-16-6) were added to a 10 mL reaction tube, followed by 1 mL of dry dichloromethane (0.4 M). The mixture was stirred at room temperature until the solids were completely dissolved. Copper trifluoromethanesulfonate (7.2 mg, 0.02 mmol, 0.1 equiv.) was then added to the reaction system, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the dichloromethane was removed under reduced pressure, and the product was separated by column chromatography (200 mesh silica gel column chromatography) (using a mixture of petroleum ether and ethyl acetate at a volume ratio of 50:1 as the eluent) to obtain 3 g of guaiacin triarylmethane, a blue oily substance, with a yield of 99.7 mg and a yield of 94.6%.

[0042] Compound 3ag 1 HNMR and 13 CNMR spectra are as follows: Figure 13 and Figure 14 As shown; 1H NMR (500 MHz, Chloroform-d) δ 8.05 (t, J = 3.1 Hz, 1H), 7.63 (dd, J = 7.9, 2.9 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 7.26 (t, J = 7.7 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H), 7.13 (dd, J = 8.0, 4.1 Hz, 1H), 7.08 (d, J = 4.5 Hz, 1H), 6.77 (dd, J = 11.0,3.3 Hz, 2H), 6.70 (d, J = 4.1 Hz, 2H), 5.00 (d, J = 3.4 Hz, 1H), 2.99 (pd, J = 7.1, 2.8 Hz, 1H), 2.83 (d, J = 3.9 Hz, 3H), 2.52 (d, J = 3.6 Hz, 3H), 1.34– 1.27 (m, 24H). 13 C NMR (126 MHz, CDCl3) δ 151.98, 149.34, 145.13, 140.51,139.26, 138.01, 137.99, 135.87, 135.51, 134.66, 134.02, 133.64, 132.55,132.54, 129.66, 129.26, 127.88, 126.87, 126.34, 125.88, 124.22, 51.50, 37.69,34.39, 30.43, 27.54, 24.66, 13.18; HRMS (ESI) m / z [M+Na]+calcd for C 36 H 43 ClNaO:549.2900, Found: 549.2905.

[0043] Example 8 In this embodiment, a guaiazoline triarylmethane 3ah is provided, with the following structure: 3ah The preparation method of the above compound 3ah is as follows: Guaiacin 1a (49.5 mg, 0.25 mmol, 1.25 equiv. CAS No.: 489-84-9) and 2-methoxyphenyl-p-methylenebenzoquinone 2h (64.8 mg, 0.2 mmol, 1.0 equiv. CAS No.: 1634622-26-6) were added to a 10 mL reaction tube, followed by 1 mL of dry dichloromethane (0.4 M). The mixture was stirred at room temperature until the solids were completely dissolved. Copper trifluoromethanesulfonate (7.2 mg, 0.02 mmol, 0.1 equiv.) was then added to the reaction system, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the dichloromethane was removed under reduced pressure, and the product was separated by column chromatography (200 mesh silica gel column chromatography) (using a 50:1 mixture of petroleum ether and ethyl acetate as eluent) to obtain the product guaiac-derived triarylmethane 3ah, a blue oily substance, with a yield of 99.6 mg and a yield of 94.5%. The above compound 3ah 1 HNMR and 13 CNMR spectra are as follows: Figure 15 and Figure 16 As shown; 1 H NMR (500 MHz, CDCl3) δ 8.03 (d, J = 2.2 Hz, 1H), 7.19 – 7.10 (m, 3H), 6.84 – 6.78 (m, 4H), 6.77 – 6.72 (m, 2H), 6.69 (s, 1H), 4.97 (s, 1H), 3.65 (s, 3H), 2.98 (p, J =6.9 Hz, 1H), 2.89 (s, 3H), 2.53 (s, 3H), 1.32 (d, J = 5.4 Hz, 24H). 13 C NMR(126 MHz, CDCl3) δ 156.54, 151.59, 145.68, 140.74, 138.47, 137.75, 136.17,135.92, 135.05, 134.38, 133.24, 132.55, 130.95, 130.92, 126.86, 126.52,126.24, 123.67, 120.38, 110.81, 55.85, 44.81, 37.66, 34.37, 30.50, 26.88,24.69, 24.66, 13.18; HRMS (ESI) m / z [M+Na]+calcd for C 37 H 46NaO2: 545.3396, Found: 545.3398.

[0044] Example 9 In this embodiment, a guaiazoline triarylmethane 3ai is provided, with the following structure: 3ai The preparation method of the above compound 3ai is as follows: Guaiacin 1a (49.5 mg, 0.25 mmol, 1.25 equiv. CAS No.: 489-84-9) and 2-trifluoromethylphenyl-p-methylenebenzoquinone 2i (72.4 mg, 0.2 mmol, 1.0 equiv. CAS No.: 1634622-28-8) were added to a 10 mL reaction tube, followed by 1 mL of dry dichloromethane (0.4 M). The mixture was stirred at room temperature until the solids were completely dissolved. Subsequently, copper trifluoromethanesulfonate (7.2 mg, 0.02 mmol, 0.1 equiv.) was added to the reaction system, and the mixture was stirred at room temperature for 6 hours. After the reaction was completed, the dichloromethane was removed under reduced pressure, and the product was separated by column chromatography (200 mesh silica gel column chromatography) (using a mixture of petroleum ether and ethyl acetate at a volume ratio of 30:1 as the eluent) to obtain the product guaiac triarylmethane 3ai, a blue oily substance, with a yield of 99.2 mg and a yield of 88.6%.

[0045] The above compound 3ai 1 HNMR and 13 CNMR spectra are as follows: Figure 17 and Figure 18 As shown; 1H NMR (500 MHz, CDCl3) δ 8.05 (t, J = 3.1 Hz, 1H), 7.63 (dd, J = 7.9, 2.9 Hz, 1H), 7.40 (t, J= 7.7 Hz, 1H), 7.26 (t, J = 7.7 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H), 7.13 (dd,J = 8.0, 4.1 Hz, 1H), 7.08 (d, J = 4.5 Hz, 1H), 6.77 (dd, J = 11.0, 3.3 Hz,2H), 6.70 (d, J = 4.1 Hz, 2H), 5.00 (d, J = 3.4 Hz, 1H), 2.99 (pd, J = 7.1,2.8 Hz, 1H), 2.83 (d, J = 3.9 Hz, 3H), 2.52 (d, J = 3.6 Hz, 3H), 1.34 – 1.27(m, 24H). 13 C NMR (126 MHz, CDCl3) δ 151.78, 145.54, 145.39, 140.22, 138.86,137.68, 136.48, 135.37, 134.71, 133.49, 132.86, 132.65, 131.33, 128.80,128.07 (d, J = 29.5 Hz), 126.91, 126.17 (q, J = 6.0 Hz), 126.02, 125.83,124.80 (q, J = 274.8 Hz), 123.60, 47.57, 37.61, 34.27, 30.36, 26.98, 24.63,24.60, 13.14; HRMS (ESI) m / z [M+Na]+calcd for C 37 H 43 F3NaO: 583.3164, Found: 583.3166.

[0046] Example 10 In this embodiment, a guaiazoline triarylmethane 3aj is provided, with the following structure: 3aj The preparation method of the above compound 3aj is as follows: Guaifenesin 1a (49.5 mg, 0.25 mmol, 1.25 equiv). CAS No.: 489-84-9) and 2,3,4-trimethoxyphenyl-p-methylenebenzoquinone 2j (76.8 mg, 0.2 mmol, 1.0 equiv. CAS No.: 1810760-49-6) were added to a 10 mL reaction tube, followed by 1 mL of dry dichloromethane (0.4 M). The mixture was stirred at room temperature until the solid was completely dissolved. Subsequently, copper trifluoromethanesulfonate (7.2 mg, 0.02 mmol, 0.1 equiv.) was added to the reaction system, and the mixture was stirred at room temperature for 6 hours. After the reaction was completed, the dichloromethane was removed under reduced pressure, and then the product was separated by column chromatography (200 mesh silica gel column chromatography) (using a mixture of petroleum ether and ethyl acetate at a volume ratio of 30:1 as the eluent) to obtain the product guaiazoline triarylmethane 3aj, a blue oily substance with a yield of 96.1 mg and a yield of 82.6%.

[0047] The above compound 3aj 1 HNMR and 13 CNMR spectra are as follows: Figure 19 and Figure 20 As shown; 1 H NMR (500 MHz, CDCl3) δ 8.06 (d, J = 2.1 Hz, 1H), 7.22 (d, J = 9.0 Hz, 1H), 7.16 (d, J = 2.5Hz, 1H), 6.88 (d, J = 2.3 Hz, 2H), 6.79 (d, J = 10.8 Hz, 1H), 6.32 (d, J =2.4 Hz, 1H), 6.26 (d, J = 2.3 Hz, 2H), 5.04 (d, J = 1.7 Hz, 1H), 3.82 (d, J =1.9 Hz, 3H), 3.66 (d, J = 1.7 Hz, 6H), 3.04 – 2.99 (m, 1H), 2.97 (d, J = 2.1Hz, 3H), 2.55 (d, J = 2.1Hz, 3H), 1.37 – 1.31 (m, 24H). 13C NMR (126 MHz, CDCl3) δ 152.81, 151.80, 145.16, 142.89, 140.49, 138.98, 138.00, 136.14,136.01, 135.40, 134.40, 133.43, 132.53, 130.71, 126.61, 126.26, 124.08,107.16, 60.91, 56.08, 51.74, 37.65, 34.38, 30.43, 27.62, 24.64, 13.14, m / z [M+Na]+calcd for C 39 H 50 NaO4: 605.3607, Found: 605.3609.

[0048] Example 11 In this embodiment, a guaiazoline triarylmethane 3ak is provided, with the following structure: 3ak The preparation method of the above compound 3ak is as follows: Guaiacin 1a (49.5 mg, 0.25 mmol, 1.25 equiv. CAS No.: 489-84-9) and 2-naphthyl-p-methylenebenzoquinone 2k (68.8 mg, 0.2 mmol, 1.0 equiv. CAS No.: 1810760-50-9) were added to a 10 mL reaction tube, followed by 1 mL of dry dichloromethane (0.4 M). The mixture was stirred at room temperature until the solids were completely dissolved. Copper trifluoromethanesulfonate (7.2 mg, 0.02 mmol, 0.1 equiv.) was then added to the reaction system, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the dichloromethane was removed under reduced pressure, and the product was separated by column chromatography (200 mesh silica gel column chromatography) (using a mixture of petroleum ether and ethyl acetate at a volume ratio of 50:1 as the eluent) to obtain the product guaiac-type triarylmethane 3ak, a blue oily substance with a yield of 101.5 mg and a yield of 93.6%.

[0049] The above compound 3ak 1 HNMR and 13 CNMR spectra are as follows: Figure 21 and Figure 22 As shown 1H NMR (500 MHz, Chloroform-d) δ 8.08 (d, J = 2.2 Hz, 1H), 7.78 – 7.74 (m, 1H), 7.69 (d, J =8.5 Hz, 1H), 7.66 – 7.61 (m, 1H), 7.39 – 7.34 (m, 2H), 7.32 (s, 1H), 7.27(dd, J = 8.5, 1.8 Hz, 1H), 7.23 – 7.18 (m, 2H), 6.92 (s, 2H), 6.76 (d, J =10.8 Hz, 1H), 6.55 (s, 1H), 5.04 (s, 1H), 3.00 (p, J = 6.9 Hz, 1H), 2.92 (s,3H), 2.55 (s, 3H), 1.34 (s, 6H), 1.33 (s, 18H). 13 C NMR (126 MHz, CDCl3) δ151.90, 145.31, 144.92, 140.86, 139.04, 138.00, 136.33, 135.45, 134.55,133.56, 133.51, 132.66, 131.99, 130.45, 128.68, 128.03, 127.86, 127.56,127.48, 126.74, 126.58, 125.64, 125.23, 124.17, 51.98, 37.69, 34.40, 30.47,27.53, 24.68, 13.20; HRMS (ESI) m / z [M+Na]+calcd for C 40 H 46 NaO: 565.3446, Found: 565.3450.

[0050] Examples 12-23 Based on the preparation method described in Example 1, copper trifluoromethanesulfonate was replaced with other Lewis acid catalysts, and the rest of the settings were the same as in Example 1. The product was still compound 3aa, and the yields of the obtained products are shown in Table 1 below: Table 1. Lewis acid catalysts and product yields in Examples 12-23 As shown in Table 1, the target product can be obtained using different Lewis acid catalysts. Among them, bismuth trifluoromethanesulfonate, nickel trifluoromethanesulfonate, scandium trifluoromethanesulfonate, and boron trifluoride diethyl ether have better reaction effects, second only to the product yield of the optimal Lewis acid catalyst, copper trifluoromethanesulfonate.

[0051] Examples 24-31 Based on the preparation method described in Example 1, the solvent dichloromethane was replaced with the same volume of another solvent, and the rest of the settings were the same as in Example 1. The product was still compound 3aa, and the yield is shown in Table 2 below: Table 2 Solvents and product yields used in Examples 24-31 As shown in Table 2, the solvent has a certain impact on the final results. Among them, chloroform, 1,2-dichloroethane or ethyl acetate showed the best effect, with the product yield second only to the optimal solvent, dichloroform. The yields of other solvents decreased to varying degrees.

[0052] Examples 32-33 Based on the preparation method described in Example 1, the reaction temperature was adjusted, while the other settings remained the same as in Example 1. The product was still compound 3aa, and the yields are shown in Table 3 below. Table 3. Reaction temperatures and product yields used in Examples 32-32 As can be seen from the results in Table 3, the reaction products have a certain impact on the yield. Room temperature is the optimal reaction temperature. Increasing or decreasing the temperature will reduce the reaction yield.

[0053] In summary, it is clear from all the above embodiments that when the method of the present invention is used, compounds of formula (II) and formula (III) can react smoothly to obtain the target product of formula (I) with good to excellent yields and simple post-processing. These results are achieved through the combined synergistic effect of multiple factors such as Lewis acid catalysts, solvents, and temperature.

[0054] Performance testing 1. Physicochemical properties The compounds of this invention, while maintaining anti-inflammatory activity, further optimize their physicochemical properties: (1) The polyaryl structure in the molecule forms a significant transmutation barrier in space, enhancing the rigidity of the molecular skeleton, thereby effectively improving the chemical and conformational stability of the compound and helping to maintain the integrity of the active ingredient in vivo; (2) The hydroxyl functional groups present in the structure can bind to water molecules through hydrogen bonding, significantly improving the water solubility of the compound. The improvement in water solubility directly promotes the bioavailability of the drug, making the active ingredient easier for the body to absorb and utilize.

[0055] 2. In vitro anti-inflammatory activity test Sodium guaiacol sulfonate (GAS-Na) was selected as the positive control and guaiacol as the control group.

[0056] Mouse macrophages RAW 264.7 were seeded in DMEM high-glucose medium containing 10% FBS and cultured at 37 ºC in a 5% CO2 incubator, with the medium changed every 24 h. After passage to the third generation, cells were seeded at a density of 5 × 10⁴ cells / mL in 96-well plates and incubated for another 24 h. The experimental and control groups were treated with 40 μmol·L⁻¹ HCl. -1 The compound was cultured for 1 hour, then LPS (100 ng / well) was added, and the culture was continued for 48 hours. After centrifugation (1000 rpm, 1 min), the supernatant was collected. The absorbance was measured using a microplate reader, and the inhibition rate was calculated. The results are shown in Table 4 below. Table 4. In vitro anti-inflammatory activity of guaiac triarylmethanes (concentration 5 μg / mL, inhibition rate %) As shown in Table 1, the guaiac triarylmethanes exhibited a certain inhibitory effect on LPS-induced inflammation in RAW 264.7 cells, with compound 3ae showing the highest inhibitory effect, which was 4.47 times that of guaiac.

[0057] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. 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 guaiazoline-based triarylmethane, characterized in that, Its structure is shown in formula (I), or it is a pharmaceutically acceptable salt or ester or solvate of the compound shown in formula (I), a tautomer, a meso compound, a racemic compound, a stereoisomer, a metabolite, or a prodrug: ； Among them, R 1 It is a phenyl, a substituted phenyl, a fused-ring substituent of benzene, or a heterocyclic substituent; R 2 It is a phenyl group or an alkyl group with a low number of carbon atoms; R 3 R 4 and R 5 Alkyl groups selected independently from hydrogen atoms or low carbon atoms.

2. The guaiazoline triarylmethane as described in claim 1, characterized in that, The substituted phenyl groups include, but are not limited to, alkylphenyl, heteroalkylphenyl, heteroalkoxyphenyl, halogen phenyl, cyanophenyl, acylphenyl, ester phenyl, and nitrophenyl; further, in the heteroalkylphenyl or heteroalkoxyphenyl groups, one or more carbon atoms in the alkyl group are substituted with halogens; The fused-ring substituents of the benzene include, but are not limited to, naphthyl, anthraceneyl, or phenanthrene; The heterocyclic substituents include, but are not limited to, five-membered or six-membered rings containing sulfur and nitrogen elements, and further, thiophene or pyridinyl groups; The alkyl group with a low number of carbon atoms is an alkyl group with 1 to 4 carbon atoms, including straight-chain alkyl and branched-chain alkyl; further, it is methyl, ethyl, propyl, isopropyl, butyl or tert-butyl.

3. The guaiazoline triarylmethane as described in claim 1, characterized in that, The R 1 It is one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 4-cyanophenyl, 4-cyanophenyl, 4-methyl ester phenyl, 4-acetylphenyl, 4-nitrophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-chlorophenyl, 3-trifluoromethoxyphenyl, 3,4,5-methoxyphenyl, 2-methylphenyl, 2-fluorophenyl, 2-bromophenyl, 2-trifluoromethylphenyl, 2-naphthyl, 2-thienyl, and 2-pyridyl. R 2 It is one of methyl, isopropyl, tert-butyl, and phenyl; R 3 It is one of the methyl or hydrogen atoms; R 4 It is one of the methyl or hydrogen atoms; R 5 It is one of hydrogen atom and isopropyl group.

4. The method for synthesizing guaiazoline triarylmethanes according to any one of claims 1-3, characterized in that, The synthetic routes involved are as follows: ； Formula (II) Formula (III) The synthesis method is as follows: p-methylenebenzoquinone of formula (II), guaiacium of formula (III), and Lewis acid catalyst are dissolved in an organic solvent, and the reaction product is separated to obtain the guaiac-type triarylmethane.

5. The method for synthesizing guaiazoline triarylmethanes as described in claim 4, characterized in that, In the synthesis method, the Lewis acid is, but is not limited to, copper trifluoromethanesulfonate, bismuth trifluoromethanesulfonate, zinc trifluoromethanesulfonate, silver trifluoromethanesulfonate, iron trifluoromethanesulfonate, ferrous trifluoromethanesulfonate, scandium trifluoromethanesulfonate, nickel trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate, yttrium trifluoromethanesulfonate, boron trifluoride diethyl ether, p-toluenesulfonic acid, or cuprous trifluoromethanesulfonate; further, the Lewis acid is bismuth trifluoromethanesulfonate, nickel trifluoromethanesulfonate, scandium trifluoromethanesulfonate, or boron trifluoride diethyl ether. Alternatively, the organic solvent is one of dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, acetone, toluene, and tetrahydrofuran; further, the organic solvent is dichloromethane.

6. The method for synthesizing guaiazoline triarylmethanes as described in claim 4, characterized in that, The reaction temperature of the synthesis method is 0~40℃, and the reaction time is 1~6h; the reaction temperature with better effect is room temperature. Alternatively, the molar ratio of guaiazoline, p-methylenebenzoquinone, and Lewis acid catalyst is 1.0~1.5:1:0.05~0.1, and further, the molar ratio of guaiazoline, p-methylenebenzoquinone, and Lewis acid catalyst is 1.25:1:0.

1.

7. The method for synthesizing guaiazoline triarylmethanes as described in claim 4, characterized in that, The reaction products were separated by column chromatography, and the eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 75:1 to 50:

1.

8. A composition, characterized in that, The composition comprises an active dose of the guaiacol triarylmethane of claims 1-3.

9. The composition according to claim 8, characterized in that, The composition is used to prepare an anti-inflammatory product. The composition further includes a pharmaceutically acceptable carrier, including but not limited to glucose, water, lactose, sucrose, glycerol, ethanol, propylene glycol, mannitol, corn starch, gelatin, alginate, microcrystalline cellulose, kaolin, dicalcium phosphate, sodium chloride, croscarmellose sodium, and sodium starch glycolate; it also includes a hydrophilic carrier, a hydrophobic carrier, or a combination thereof, wherein the hydrophobic carrier is, for example, a fat emulsion, lipid, polyethylene glycol phospholipid, a biocompatible polymer, liposomes, liposomes, vesicles, or a polymer matrix.

10. The use of the guaiazoline triarylmethane according to any one of claims 1-3, or the composition according to claim 8 or 9, in the preparation of an anti-inflammatory product, characterized in that, The anti-inflammatory products include, but are not limited to, one of the following: personal care products, medicines, health products, or special medical foods.

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