2, 2-dimethylchroman compound with higher water solubility as well as preparation method and application of 2, 2-dimethylchroman compound

Abstract

The invention discloses a 2, 2-dimethylchroman compound as well as a preparation method and application thereof. According to the synthesis method provided by the invention, hydroxyl can be efficiently and conveniently synthesized and increased on a 2, 2-dimethylchroman mother nucleus under the conditions of room temperature and normal pressure, no catalyst and no strong reaction reagent, the planar conformation of the 2, 2-dimethylchroman mother nucleus is changed, and the original 2, 2-dimethylchroman mother nucleus with very low water solubility is obviously increased. The water solubility of the 2, 2-dimethyl chroman compound is improved. Therefore, compared with the 2, 2-dimethylchromene raw material compound, the 2, 2-dimethylchroman compound synthesized by the synthesis method provided by the invention is easier to use in research, formula, preparation and production of medicines and cosmetics. The 2, 2-dimethyl chroman compound provided by the invention has remarkable melanin activity inhibition activity or antioxidant activity, and can be used for antioxidant application in the fields of skin whitening and medical health care.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis. More specifically, it relates to 2,2-dimethylchroman compounds with higher water solubility, and their preparation methods and applications. Background Art

[0002] Synthetic chromene compounds have important values in the application of the pharmaceutical field, covering multiple aspects such as anti-tumor, anti-microbial, anti-inflammatory, anti-oxidant, and treatment of Alzheimer's disease. For example, the 2H-chromene thiazole derivatives synthesized by Azizmohammadi et al. (Eur J MedChem. 2013; 59: 15-22.) showed good inhibitory activities against various cancer cells. Gopinath et al. (Eur J Med Chem. 2016; 124: 750-762.) synthesized 2H-chromene imidazole compounds that can be applied in cataract treatment drugs. In addition, certain 2H-chromene compounds can be used as photosensitive materials in materials science, including laser dyes, organic light-emitting devices, optical brighteners, triplet sensitizers, etc. Therefore, such compounds have wide application values, and thus the modification of the structures of such compounds has always been a research hotspot.

[0003] Chroman is the dihydride of chromene, that is, one double bond in the chromene molecule is reduced to a single bond. Compounds with a chroman structural unit have good antihypertensive effects, and at the same time have a direct protective effect on the myocardium, can reduce the occurrence of coronary artery diseases, and have activities such as anti-mycobacterium, anti-tumor, and anti-hypertensive.

[0004] However, the current modification of 2H-chromene is mainly on the benzene ring and the methyl group at the 2-position. The modification involving the double bond is only the substitution of hydrogen and ring formation, and the double bond addition as a modification scheme is relatively rare. For example, the reaction of adding an oxygen atom or a hydroxyl group to the double bond of 2H-chromene in the existing scheme can be achieved by an oxidant. However, it is difficult for a reducing compound such as benzenethiol to be added to this double bond at the same time, and it must use a catalyst or be under harsh conditions such as high temperature and high pressure to complete the reaction. In addition, the existing chroman compounds have poor inhibitory effects on melanin activity and poor hydrophilicity, which limit their applications in subsequent development. Summary of the Invention

[0005] Aiming at the above existing technical problems, the primary object of the present invention is to provide a 2,2-dimethylchroman compound, which has a significant inhibitory effect on melanin activity and can play a whitening role; in addition, it also has the advantages of good hydrophilicity and better water solubility, broadening the application market.

[0006] The second object of the present invention is to provide a method for preparing 2,2-dimethylchroman compounds. The method can carry out reactions under mild conditions (room temperature, without a catalyst), and can achieve the simultaneous addition of arylthiophenol groups, as well as hydroxyl or alkoxy groups, to the double bond of 2H-chromene.

[0007] The third object of the present invention is to provide the use of 2,2-dimethylchroman compounds in the preparation of products with antioxidant and / or melanogenesis inhibitory properties.

[0008] The above objects of the present invention are achieved by the following technical solutions:

[0009] The present invention claims protection for a 2,2-dimethylchroman compound having the structure shown in formula (III) or (IV):

[0010]

[0011] Wherein, R 1 and R 2 each independently selected from hydrogen, C 1-8 alkyl, amino, halogen, hydroxyl, C 1-5 alkoxy, phenyl; or

[0012] R 1 and R 2 together with the benzene ring to which they are attached form an aryl, heteroaryl, C 3-8 cycloalkyl, C 3-8 heterocyclic group;

[0013] R 3 is selected from hydroxyl, R 4 is selected from hydroxyl, amino, halogen, C 1-8 alkyl, C 1-8 alkyl ester group; or

[0014] R 3 and R 4 together with the benzene ring to which they are attached form an aryl, heteroaryl, C 3-8 cycloalkyl, C 3-8 heterocyclic group; wherein, the aryl, heteroaryl, C 3-8 cycloalkyl, C 3-8 heterocyclic group is substituted by one or more groups selected from hydroxyl, aryl, heteroaryl; wherein, the aryl, heteroaryl is substituted by one or more hydroxyl groups, and at least one of the hydroxyl groups is para-substituted;

[0015] R 5 is selected from C 1-8 alkyl, aryl;

[0016] Ar is an aryl group, and the aryl group is unsubstituted or substituted by one or more hydroxyl, C 1-8 alkyl, C1-8 Alkoxy substitution.

[0017] The 2,2-dimethylchroman compounds provided by the present invention, like glabridin, have a significant effect of inhibiting melanin activity and can play a role in whitening. Further, the 2,2-dimethylchroman compounds provided by the present invention have better hydrophilicity than glabridin and better water solubility, thus broadening the application market.

[0018] In some embodiments, R 1 and R 2 are each independently selected from hydrogen, C 1-6 alkyl, amino, halogen, hydroxy, C 1-4 alkoxy, phenyl; or

[0019] R 1 and R 2 together with the benzene ring to which they are attached form a 5- or 6-membered aromatic ring, 5- or 6-membered aromatic heterocycle, C 3-6 cycloalkyl, C 3-6 heterocyclic group;

[0020] R 3 is selected from hydroxy, R 4 is selected from hydroxy, amino, halogen, C 1-6 alkyl, C 1-4 alkyl ester group; or

[0021] R 3 and R 4 together with the benzene ring to which they are attached form a 5- or 6-membered aromatic ring, 5- or 6-membered aromatic heterocycle, C 3-6 cycloalkyl, C 3-6 heterocyclic group; wherein, the 5- or 6-membered aromatic ring, 5- or 6-membered aromatic heterocycle, C 3-6 cycloalkyl, C 3-6 heterocyclic group is substituted by one or more substituents selected from hydroxy, 5- or 6-membered aromatic ring, 5- or 6-membered aromatic heterocycle; wherein, the 5- or 6-membered aromatic ring, 5- or 6-membered aromatic heterocycle is substituted by one or more hydroxy groups, and at least one of the hydroxy groups is para-substituted;

[0022] R 5 is selected from C 1-6 alkyl, phenyl;

[0023] Ar is phenyl, naphthyl, and the phenyl, naphthyl is unsubstituted or substituted by one or more hydroxy, C 1-6 alkyl, C 1-6 alkoxy.

[0024] In some embodiments, R 1 and R 2Each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, amino, methoxy, phenyl; or

[0025] R 1 and R 2 and the benzene ring to which it is attached together form a phenyl group;

[0026] R 3 is selected from hydroxyl, R 4 is selected from hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, C 1-4 alkyl ester group; or

[0027] R 3 and R 4 and the benzene ring to which it is attached together form a phenyl group, pyranyl group; wherein, the phenyl group, pyranyl group is substituted by one or more selected from hydroxyl, phenyl; wherein, the phenyl group is substituted by one or more hydroxyl groups, and at least one of the hydroxyl groups is para-substituted;

[0028] R 5 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, phenyl;

[0029] Ar is phenyl, naphthyl, and the phenyl group, naphthyl group is unsubstituted or substituted by one or more hydroxyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, propoxy.

[0030] In some embodiments, the 2,2-dimethylchroman compounds are selected from any of the following structures:

[0031]

[0032] Furthermore, the present invention claims a method for preparing a 2,2-dimethylchroman compound, by mixing a 2,2-dimethyl-2H-chromene compound shown in formula (I), an arylthiophenol compound shown in formula (II) and an organic solvent, and obtaining a 2,2-dimethylchroman compound shown in formula (III) through an addition reaction; or

[0033] mixing a 2,2-dimethyl-2H-chromene compound shown in formula (I), an oxidant and an organic solvent, and then adding an arylthiophenol compound shown in formula (II) and an alkyl alcohol solvent for mixing reaction to obtain a 2,2-dimethylchroman compound shown in formula (IV);

[0034] The reaction formula is as follows:

[0035]

[0036] Wherein, R 1 and R 2 each independently selected from hydrogen, C1-8 alkyl, amino, halogen, hydroxy, C 1-5 alkoxy, phenyl; or

[0037] R 1 and R 2 and the benzene ring to which it is attached together form an aryl group, a heteroaryl group, C 3-8 cycloalkyl, C 3-8 heterocyclic group;

[0038] R 3 is selected from hydroxy, R 4 is selected from hydroxy, amino, halogen, C 1-8 alkyl, C 1-8 alkyl ester group; or

[0039] R 3 and R 4 and the benzene ring to which it is attached together form an aryl group, a heteroaryl group, C 3-8 cycloalkyl, C 3-8 heterocyclic group; wherein, the aryl group, heteroaryl group, C 3-8 cycloalkyl, C 3-8 heterocyclic group is substituted by one or more groups selected from hydroxy, aryl, heteroaryl; wherein, the aryl group, heteroaryl group is substituted by one or more hydroxy groups, and at least one of the hydroxy groups is para-substituted;

[0040] R 5 is selected from C 1-8 alkyl, aryl;

[0041] Ar is an aryl group, and the aryl group is unsubstituted or substituted by one or more hydroxy groups, C 1-8 alkyl, C 1-8 alkoxy.

[0042] The key to the reaction provided by the present invention lies in the formation of a stable system with long conjugation in the molecule, and R 3 is selected from hydroxy or R 3 and R 4 The para-substituted hydroxy group after cyclization is the key to the formation of the long conjugation chain. Under mild conditions, when 2,2-dimethyl-2H-chromene reacts with benzenethiol compounds, a radical intermediate is first formed. This intermediate combines with a hydroxyl radical or an alkoxy radical, and then the benzenethiol radical attacks the double bond of 2H-chromene to form an addition product. Finally, the addition product undergoes the migration of a hydroxy group or an alkoxy group to obtain the end product 2,2-dimethylchroman compounds. When preparing alkoxy-added 2,2-dimethylchroman compounds, by selecting different types of alkyl alcohol solvents, the corresponding alkoxy-added products can be prepared.

[0043] The method provided by the present invention can carry out the reaction under mild conditions (room temperature, without catalyst), and can achieve the simultaneous addition of arylthiophenol groups, as well as hydroxyl or alkoxy groups, to the double bond of 2H-chromene. There is no need to add strong acids or strong bases, the reaction is rapid, environmentally friendly, has a high yield, mild conditions, and simple operation. The method provided by the present invention provides a new direction for the structural optimization and synthesis of 2,2-dimethyl-2H-chromene compounds.

[0044] In some embodiments, the alkyl alcohol solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, or 2-ethylhexanol.

[0045] In some embodiments, the organic solvent is selected from one or more of methanol, ethanol, n-butanol, dichloromethane, acetonitrile, chloroform, tetrahydrofuran, isopropanol, benzyl alcohol, toluene, benzene, dimethyl sulfoxide, acetone, cyclohexane, N,N-dimethylformamide.

[0046] In some embodiments, the oxidant is selected from one or more of ammonium cerium nitrate, potassium permanganate, hydrogen peroxide, potassium dichromate, potassium chlorate, nitric acid, or sodium bromide.

[0047] In some embodiments, the temperature of the addition reaction is 20 - 30 °C. More specifically, the time of the addition reaction is 1 - 6 h.

[0048] In some embodiments, the temperature for mixing the 2,2-dimethyl-2H-chromene compound, the oxidant, and the organic solvent is -2 - 2 °C; the temperature for the mixing reaction is 20 - 30 °C. Further, stir at 20 - 30 °C for 10 - 20 min.

[0049] In some embodiments, the molar ratio of the 2,2-dimethyl-2H-chromene compound shown in formula (I) to the arylthiophenol compound shown in formula (II) is 1:(1 - 3).

[0050] In some embodiments, the molar ratio of the 2,2-dimethyl-2H-chromene compound shown in formula (I) to the oxidant is 1:(1.5 - 2.5).

[0051] In some embodiments, the 2,2-dimethyl-2H-chromene compound shown in formula (I) is selected from

[0052]

[0053] Furthermore, the present invention claims the application of 2,2-dimethylchroman compounds in the preparation of products for antioxidation and / or inhibiting melanogenesis.

[0054] Compared with the prior art, the present invention has the following beneficial effects:

[0055] (1) The 2,2-dimethylchroman compounds provided by the present invention, like glabridin, have a significant effect of inhibiting melanin activity and can play a role in whitening. In addition, the hydrophilicity of the 2,2-dimethylchroman compounds is better than that of glabridin, and the water solubility is better, which broadens the application market.

[0056] (2) The present invention provides a preparation method of 2,2-dimethylchroman compounds. The preparation method can carry out the reaction under mild conditions (room temperature, without catalyst), and can achieve the simultaneous addition of arylthiophenol groups, as well as hydroxyl or alkoxy groups, to the double bond of 2H-chromene. There is no need to add strong acids or strong bases, the reaction is rapid, environmentally friendly, with high yield, mild conditions and simple operation. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] Figure 1 1H NMR spectrum of the target product obtained in Example 1.

[0058] Figure 2 Mass spectrum of the target product obtained in Example 1.

[0059] Figure 3 1H NMR spectrum of the target product obtained in Example 2.

[0060] Figure 4 Mass spectrum of the target product obtained in Example 2.

[0061] Figure 5 1H NMR spectrum of the target product obtained in Example 3.

[0062] Figure 6 Mass spectrum of the target product obtained in Example 3.

[0063] Figure 7 LC-MS chromatogram of the target product obtained in Example 4.

[0064] Figure 8 LC-MS mass spectrum of the target product obtained in Example 4.

[0065] Figure 9 LC-MS chromatogram of the target product obtained in Example 5.

[0066] Figure 10 LC-MS mass spectrum of the target product obtained in Example 5.

[0067] Figure 11 1H NMR spectrum of the target product obtained in Example 6.

[0068] Figure 12 Mass spectrum of the target product obtained in Example 6.

[0069] Figure 131H NMR spectrum of the target product obtained in Example 7.

[0070] Figure 14 Mass spectrum of the target product obtained in Example 7.

[0071] Figure 15 LC-MS chromatogram of the target product obtained in Example 8.

[0072] Figure 16 LC-MS spectrum of the target product obtained in Example 8.

[0073] Figure 17 LC-MS chromatogram of the target product obtained in Example 9.

[0074] Figure 18 LC-MS spectrum of the target product obtained in Example 9.

[0075] Figure 19 1H NMR spectrum of the target product obtained in Example 10.

[0076] Figure 20 Mass spectrum of the target product obtained in Example 10.

[0077] Figure 21 LC-MS chromatogram of the target product obtained in Example 11.

[0078] Figure 22 LC-MS spectrum of the target product obtained in Example 11.

[0079] Figure 23 LC-MS chromatogram of the target product obtained in Example 12.

[0080] Figure 24 LC-MS spectrum of the target product obtained in Example 12.

[0081] Figure 25 Schematic diagram of the antioxidant activities of rubimaillin and 2,2-dimethylchroman compounds.

[0082] Figure 26 Experiment on the inhibition of melanin by glabridin and 2,2-dimethylchroman compounds.

[0083] Figure 27 Water solubility test of glabridin and 2,2-dimethylchroman compounds.

[0084] Figure 28 3D conformation diagrams of glabridin and compounds 6-9. Detailed implementation manners

[0085] The present invention will be further described below in conjunction with the accompanying drawings of the specification and specific embodiments, but the embodiments do not limit the present invention in any form. Unless otherwise specified, the reagents, methods, and equipment used in the present invention are conventional reagents, methods, and equipment in the technical field.

[0086] Unless otherwise specified, the reagents and materials used in the following examples are commercially available.

[0087] The term "cycloalkyl" refers to a saturated or partially unsaturated cycloalkyl group, which includes monocyclic or polycyclic groups. Unless otherwise specified, the cycloalkyl group has 3 - 8 carbon atoms. For example, the cycloalkyl group can be a monocyclic group having 3 - 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, 1 - cyclopent - 3 - enyl, cyclohexene, 1 - cyclohex - 1 - enyl, cyclohexadiene, cycloheptene, cyclooctene, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, or similar groups.

[0088] The term "heterocyclic group" refers to a ring selected from the following: saturated or partially unsaturated monocyclic, bicyclic, and tricyclic rings having 3 - 8 members, which contain at least one carbon atom in addition to 1, 2, 3, or 4 heteroatoms selected from O, S, and N. The heterocyclic ring can be saturated or contain at least one double bond. The heterocyclic ring can be oxo - substituted, i.e., substituted by the group =O. The heterocyclic group can be connected to the rest of the molecule through a carbon atom or a heteroatom. Examples of the heterocyclic group include, but are not limited to, tetrahydrofuranyl, azetidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, aminopiperidinyl, etc.

[0089] The term "aryl" refers to a 5 - 6 - membered aromatic ring, a 7 - 12 - membered bicyclic system, or a 10 - 15 - membered tricyclic system, wherein at least one ring in the bicyclic system or tricyclic system is an aromatic ring. For example, (a) the 5 - 6 - membered aromatic ring includes, but is not limited to, phenyl; (b) the aryl of the 7 - 12 - membered bicyclic system, wherein at least one ring is an aromatic ring, such as naphthyl; (c) the aryl of the 10 - 15 - membered tricyclic system, wherein at least one ring is an aromatic ring, such as fluorenyl, anthracenyl, or phenanthryl, etc.

[0090] The term "heteroaryl" refers to a 5 - 6 - membered aromatic ring, a 7 - 12 - membered bicyclic system, or a 10 - 15 - membered tricyclic system, wherein at least one ring in the bicyclic system or tricyclic system is an aromatic ring, and the aromatic ring contains at least one heteroatom selected from O, S, and N. For example, (a) the 5 - 6 - membered heteroaryl includes, but is not limited to, pyranyl, pyridyl, or furyl; (b) the heteroaryl of the 7 - 12 - membered bicyclic system includes, but is not limited to, quinolinyl.

[0091] The term "alkyl ester group" refers to the group - COOR, where R is an alkyl group. Unless otherwise specified, the alkyl group in the alkyl ester group has 1 - 8 carbon atoms.

[0092] Example 1: A Preparation Method of 2,2-Dimethylchroman Compounds

[0093] Put the 2,2-dimethyl-2H-chromene compound rubimaillin (100 mg, 0.35 mmol, 1.0 eq) and the arylthiophenol compound 3,5-dimethylbenzenethiol (55 μl, 0.42 mmol, 1.2 eq) into a 50 mL flask, add 20 mL of dichloromethane to dissolve, stir the reaction solution at 25 °C for 2 hours. After the reaction, remove the solvent with a rotary evaporator, and further purify the residue with a silica gel chromatographic column (the purification solution is cyclohexane and ethyl acetate, with a volume ratio of 100:7) to obtain an orange solid product, which is the 2,2-dimethylchroman compound, with a yield of 54% and a purity of 95%. The structure was confirmed by nuclear magnetic resonance hydrogen spectrum (as Figure 1 shown) and mass spectrum (as Figure 2 shown). The reaction formula of the above method is as follows:

[0094]

[0095] Example 2: A Preparation Method of 2,2-Dimethylchroman Compounds

[0096] The difference between this example and Example 1 is that: the arylthiophenol compound is selected as 2-naphthalenethiol (55 μl, 0.42 mmol, 1.2 eq), with a yield of 61% and a purity of 95%. The nuclear magnetic resonance hydrogen spectrum and mass spectrum of the target product obtained in Example 2 are respectively as Figure 3 and Figure 4 shown. The reaction formula is as follows:

[0097]

[0098] Example 3: A Preparation Method of 2,2-Dimethylchroman Compounds

[0099] The difference between this example and Example 1 is that: the arylthiophenol compound is selected as o-methoxybenzenethiol (51 μl, 0.42 mmol, 1.2 eq), with a yield of 48% and a purity of 96%. The nuclear magnetic resonance hydrogen spectrum and mass spectrum of the target product obtained in Example 3 are respectively as Figure 5 and Figure 6 shown. The reaction formula is as follows:

[0100]

[0101] Example 4: A Preparation Method of 2,2-Dimethylchroman Compounds

[0102] The difference between this example and Example 1 is that: the arylthiophenol compound used is 2,6-dimethylbenzenethiol (56 μl, 0.42 mmol, 1.2 eq), the yield is 51%, and the purity is 94%. The liquid chromatography-mass spectrometry (LC-MS) chromatogram and LC-MS mass spectrum of the target product obtained in Example 4 are respectively as shown in Figure 7 and Figure 8 shown below. The reaction formula is as follows:

[0103]

[0104] Example 5 A method for preparing 2,2-dimethylchroman compounds

[0105] The difference between this example and Example 1 is that: the arylthiophenol compound used is 2,4-dimethylbenzenethiol (56 μl, 0.42 mmol, 1.2 eq), the yield is 21%, and the purity is 96%. The LC-MS chromatogram and LC-MS mass spectrum of the target product obtained in Example 5 are respectively as shown in Figure 9 and Figure 10 shown below. The reaction formula is as follows:

[0106]

[0107] Example 6 A method for preparing 2,2-dimethylchroman compounds

[0108] Put glabridin (100 mg, 0.31 mmol, 1.0 eq), a 2,2-dimethyl-2H-chromene compound, and 3-hydroxythiophenol (47 μl, 0.37 mmol, 1.2 eq), an arylthiophenol compound, into a 50 mL flask, and add 5 mL of methanol to dissolve. Stir the reaction solution at 25 °C for 2 hours. Then remove the solvent with a rotary evaporator, and further purify the residue with a silica gel chromatography column (the purification solution is cyclohexane and acetone, with a volume ratio of 100:15) to obtain a white solid product with a yield of 58% and a purity of 95%. The nuclear magnetic resonance hydrogen spectrum and mass spectrum of the target product obtained in Example 6 are respectively as shown in Figure 11 and Figure 12 shown below. The reaction formula is as follows:

[0109]

[0110] Example 7 A method for preparing 2,2-dimethylchroman compounds

[0111] The difference between this example and Example 6 is that: the arylthiophenol compound used is 3,5-dimethylbenzenethiol (50 μl,, 0.37 mmol, 1.2 eq), the yield is 48%, and the purity is 97%. The nuclear magnetic resonance hydrogen spectrum and mass spectrum of the target product obtained in Example 7 are respectively as shown in Figure 13 and Figure 14 shown below. The reaction formula is as follows:

[0112]

[0113] Example 8 A method for preparing 2,2-dimethylchroman compounds

[0114] The difference between this example and Example 6 is that: the arylthiophenol compound used is 4-hydroxythiophenol (37 μl, 0.37 mmol, 1.2 eq), the yield is 43%, and the purity is 97%. The LC-MS chromatogram and LC-MS mass spectrum of the target product obtained in Example 8 are respectively as shown in Figure 15 and Figure 16 shown. The reaction formula is as follows:

[0115]

[0116] Example 9 A method for preparing 2,2-dimethylchroman compounds

[0117] The difference between this example and Example 6 is that: the arylthiophenol compound used is 4-aminothiophenol (41 μl, 0.37 mmol, 1.2 eq), the yield is 46%, and the purity is 95%. The LC-MS chromatogram and LC-MS mass spectrum of the target product obtained in Example 9 are respectively as shown in Figure 17 and Figure 18 shown. The reaction formula is as follows:

[0118]

[0119] Example 10 A method for preparing 2,2-dimethylchroman compounds

[0120] Dissolve rubimaillin (100 mg, 0.35 mmol, 1.0 eq), a 2,2-dimethyl-2H-chromene compound, in 15 mL of acetonitrile, and cool the resulting homogeneous solution to 0 °C. Dissolve ammonium cerium(IV) nitrate (400 mg, 0.74 mmol, 2.0 eq) in 15 mL of methanol. Add the methanol solution to the above acetonitrile solution at 0 °C, and stir the reaction for 15 min. After the stirring is completed, adjust the pH value of the reaction solution to 7-8 with saturated sodium bicarbonate solution, and extract the reaction solution 3 times with dichloromethane and water. Combine the organic phases, concentrate under reduced pressure, and then mix with 3,5-dimethylthiophenol (55 μl, 0.42 mmol, 1.2 eq), an arylthiophenol compound. The reaction solvent is methanol, and the reaction is carried out at 25 °C for 3 h. After the reaction is completed, remove the solvent with a rotary evaporator, and purify the residue with a silica gel chromatography column (the purification solution is cyclohexane and ethyl acetate, with a volume ratio of 100:4) to obtain a 2,2-dimethylchroman compound. LC-MS detection shows that the molecular weights are all consistent with the expected products, the yield is 61%, and the purity is 96%. The 1H NMR spectrum and mass spectrum of the target product obtained in Example 10 are respectively as shown in Figure 19 and Figure 20As shown below. The reaction formula is as follows:

[0121]

[0122] Example 11 A method for preparing 2,2-dimethylchroman compounds

[0123] The difference between this example and Example 10 is that: ethanol is selected as the organic solvent used in the reaction, the yield is 58%, and the purity is 97%. The liquid chromatography-mass spectrometry (LC-MS) chromatogram and LC-MS mass spectrum of the target product obtained in Example 11 are respectively as shown in Figure 21 and Figure 22 As shown below. The reaction formula is as follows:

[0124]

[0125] Example 12 A method for preparing 2,2-dimethylchroman compounds

[0126] The difference between this example and Example 10 is that: n-butanol is selected as the organic solvent used in the reaction, the yield is 52%, and the purity is 97%. The LC-MS chromatogram and LC-MS mass spectrum of the target product obtained in Example 12 are respectively as shown in Figure 23 and Figure 24 As shown below. The reaction formula is as follows:

[0127]

[0128] Test Example 1 Antioxidant activities of rubimaillin and 2,2-dimethylchroman compounds

[0129] (1) Experimental materials: Each compound to be tested (the target products synthesized in Examples 1, 2, 3, and 10), rubimaillin, Trolox standard solution, ABTS, 80% ethanol, 96-well plates.

[0130] (2) Experimental method:

[0131] a. Prepare the ABTS working mother liquor one day in advance and store it in the dark at room temperature for 12 - 16 hours before use.

[0132] b. On the day of use, dilute the ABTS working mother liquor 40 times with 80% ethanol to prepare the ABTS working solution, and dilute the standard curve and compounds to 1.5 mM, 1.2 mM, 0.9 mM, 0.6 mM, 0.3 mM, and 0.15 mM with 80% ethanol.

[0133] c. Add 200 μL of the ABTS working solution to each detection well of the 96-well plate.

[0134] d. Add 10 μL of distilled water to the blank control well; add 10 μL of Trolox standard solutions at various concentrations to the standard curve detection wells; add 10 μL of each test compound and rubiadin to the sample detection wells. Mix gently.

[0135] e. Measure the OD after incubation at room temperature for 30 minutes 405 。

[0136] (3) Experimental results:

[0137] Figure 25 It is a schematic diagram of the antioxidant activities of rubiadin and 2,2-dimethylchroman compounds. As Figure 25 shown, relative to 1 mM Trolox% activity of the compounds, the antioxidant activities of the compounds synthesized in Examples 1, 2, 3, and 10 are all superior to that of the parent nucleus rubiadin, indicating that the compounds prepared by the preparation method of the present invention have excellent antioxidant activities.

[0138] Test Example 2 Inhibitory experiment on melanin production of glabridin and 2,2-dimethylchroman compounds

[0139] I. Detection of relative melanin content

[0140] 1. Cell seeding: Seed cells at an inoculation density of 1×10 5 cells / well into a 6-well plate, 2 ml / well. Incubate overnight in an incubator.

[0141] 2. Drug administration: When the cell confluence reaches 40-60%, carry out drug administration:

[0142] (1) Model group: 20 nM α-melanocyte stimulating hormone (α-MSH).

[0143] (2) Solvent group: 20 nM α-MSH + solvent (DMSO).

[0144] (3) Positive control group: 20 nM α-MSH + glabridin.

[0145] (4) Sample group: 20 nM α-MSH + test sample (compounds synthesized in Examples 6-9).

[0146] (5) After drug administration, place the 6-well plate in an incubator and culture for 48 h.

[0147] 3. Sample collection: After the culture is completed, aspirate the remaining culture medium in the wells, add 700 μl of 0.25% trypsin to each well, and digest the melanocytes at 37 °C for 1-2 min. Add medium to terminate digestion, collect the cells into a 1.5 ml EP tube, and centrifuge at 500 g for 5 min for cell counting.

[0148] 4. Dissolution: Centrifuge at 10000 r / min for 10 min, discard the supernatant, and add 1 ml of 1 mol / L NaOH aqueous solution containing 10% (volume fraction) DMSO. Heat in a water bath at 80 °C for 1 h, and shake well every 15 min.

[0149] 5. Reading: Take 150 μl of the suspension from each tube of the sample into a 96-well plate and read the OD value at 405 nm.

[0150] 6. Calculation: Based on the concentration and absorbance value of the standard product, draw a standard curve of melanin content - absorbance, and substitute the OD value of the sample into the standard curve to calculate the melanin content.

[0151] As Figure 26 shown, glabridin has significant melanin inhibitory activity, and Compounds 6 - 9 have whitening activities similar to that of glabridin.

[0152] Test Example 3 Water Solubility Test of Glabridin and Compounds Synthesized in Examples 6 - 9

[0153] The water solubility of glabridin is very poor. According to literature reports, its solubility at room temperature is 0.1 mg / L. Therefore, in this test, the solubility of the corresponding compounds in 50% methanol aqueous solution was measured to compare their water solubilities. The specific method is as follows:

[0154] Accurately weigh 3 mg of glabridin and the compounds synthesized in Examples 6 - 9 and add them to a 25 ml EP tube. Add 500 μl of 50% methanol aqueous solution, shake and ultrasonicate, and observe the dissolution state. If it is not completely dissolved, add another 50 μl, shake and ultrasonicate, and observe the dissolution state. If it is still not completely dissolved, repeat the above operation until the EP tube shows a homogeneous and clear state. Record the volume of the solvent added and calculate the solubility (the maximum mass of the compound that can be dissolved in 100 g of the solvent). The above tests were performed on glabridin and the compounds synthesized in Examples 7 - 9 (corresponding Compounds 7 - 9).

[0155] As Figure 27 shown, the solubility of Compounds 6 - 9 in 50% methanol aqueous solution increased by 14 - 22 times compared to glabridin, and their hydrophilicity is better than that of glabridin. On the premise of basically retaining the whitening activity, the water solubility of Compounds 6 - 9 has been greatly improved, broadening the application market.

[0156] Test Example 4 Conformational Calculation of Glabridin and Compounds Synthesized in Examples 6 - 9

[0157] The lowest energy conformations of glabridin and the compounds synthesized in Examples 6-9 were calculated by the MMFF94 method of Chem3D 20.0 (Perkinelmer), with the parameters: Maximum No. of Iterations 30000, Minium RMS 0.1. Comparing the conformations of glabridin and the compounds synthesized in Examples 6-9, it was found that the C1 to C6 ring structure of glabridin was planar and substantially coplanar with the rest of the glabridin structure; while after modifying glabridin by the present synthesis method, the above structure of Compounds 6-9 was not planar due to the disruption of conjugation and was not planar with other parts of the molecule (as Figure 28 shown). The above structural changes are not conducive to the close packing between planar molecules, resulting in low water solubility, but are conducive to the binding of water molecules between the molecules and the formation of hydrogen bonds with the newly added oxygen atoms, thereby enhancing their water solubility.

[0158] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement methods and are all included in the protection scope of the present invention.

Claims

1. A 2,2-dimethylchroman compound, characterized in that, It has the structure shown in formula (III) or (IV): wherein, R 1 and R 2 are each independently selected from hydrogen, C 1-8 alkyl, amino, halogen, hydroxy, C 1-5 alkoxy, phenyl; or R 1 and R 2 together with the benzene ring connected thereto form an aryl group, heteroaryl group, C 3-8 cycloalkyl group, C 3-8 heterocyclic group; R 3 selected from hydroxyl, R 4 selected from hydroxyl, amino, halogen, C 1-8 alkyl, C 1-8 alkyl ester group; or R 3 and R 4 together with the benzene ring connected thereto form an aryl group, a heteroaryl group, a C 3-8 cycloalkyl group, a C 3-8 heterocyclic group; wherein, the aryl group, heteroaryl group, C 3-8 cycloalkyl group, C 3-8 heterocyclic group are substituted by one or more substituents selected from a hydroxyl group, an aryl group, and a heteroaryl group; wherein, the aryl group and heteroaryl group are substituted by one or more hydroxyl groups, and at least one of the hydroxyl groups is para-substituted; R 5 selected from C 1-8 alkyl, aryl; Ar is an aryl group, and the aryl group is unsubstituted or substituted by one or more hydroxyl groups, C 1-8 alkyl groups, C 1-8 alkoxy groups.

2. The 2,2-dimethylchroman compound according to claim 1, wherein R 1 and R 2 each independently selected from hydrogen, C 1-6 alkyl, amino, halogen, hydroxy, C 1-4 alkoxy, phenyl; or R 1 and R 2 together with the benzene ring connected thereto form a 5-6 membered aromatic ring, a 5-6 membered aromatic heterocyclic ring, a C 3-6 cycloalkyl, a C 3-6 heterocyclic group; R 3 selected from hydroxyl, R 4 selected from hydroxyl, amino, halogen, C 1-6 alkyl, C 1-4 alkyl ester group; or R 3 and R 4 together with the benzene ring connected thereto form a 5- to 6-membered aromatic ring, a 5- to 6-membered aromatic heterocyclic ring, a C 3-6 cycloalkyl group, or a C 3-6 heterocyclic group; wherein, the 5- to 6-membered aromatic ring, the 5- to 6-membered aromatic heterocyclic ring, the C 3-6 cycloalkyl group, or the C 3-6 heterocyclic group is substituted by one or more substituents selected from a hydroxyl group, a 5- to 6-membered aromatic ring, and a 5- to 6-membered aromatic heterocyclic ring; wherein, the 5- to 6-membered aromatic ring and the 5- to 6-membered aromatic heterocyclic ring are substituted by one or more hydroxyl groups, and at least one of the hydroxyl groups is para-substituted; R 5 selected from C 1-6 alkyl, phenyl; Ar is phenyl or naphthyl, and the phenyl and naphthyl are unsubstituted or substituted by one or more hydroxyl groups, C 1-6 alkyl, C 1-6 alkoxy groups.

3. The 2,2-dimethylchroman compound according to claim 1, wherein R 1 and R 2 are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, amino, methoxy, phenyl; or R 1 and R 2 together with the benzene ring to which it is attached form a phenyl group; R 3 selected from hydroxyl, R 4 selected from hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, C 1-4 alkyl ester group; or R 3 and R 4 together with the benzene ring connected thereto form a phenyl group or a pyranyl group; wherein, the phenyl group or the pyranyl group is substituted by one or more substituents selected from hydroxyl groups and phenyl groups; wherein, the phenyl group is substituted by one or more hydroxyl groups, and at least one of the hydroxyl groups is para-substituted; R 5 selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, phenyl; Ar is phenyl or naphthyl, and the phenyl and naphthyl are unsubstituted or substituted by one or more hydroxyl groups, methyl groups, ethyl groups, n-propyl groups, isopropyl groups, methoxy groups, ethoxy groups, or propoxy groups.

4. The 2,2-dimethylchroman compound according to claim 1, wherein The 2,2-dimethylchroman compound is selected from any of the following structures:

5. A method for preparing a 2,2-dimethylchroman compound according to any one of claims 1-4, characterized in that, Mix the 2,2-dimethyl-2H-chromene compound shown in formula (I), the arylthiophenol compound shown in formula (II), and an organic solvent, and obtain the 2,2-dimethylchroman compound shown in formula (III) through an addition reaction; or Mix the 2,2-dimethyl-2H-chromene compound shown in formula (I), an oxidant, and an organic solvent, then add the arylthiophenol compound shown in formula (II) and an alkyl alcohol solvent for a mixed reaction to obtain the 2,2-dimethylchroman compound shown in formula (IV); The reaction formula is as follows: wherein, R 1 and R 2 each independently selected from hydrogen, C 1-8 alkyl, amino, halogen, hydroxy, C 1-5 alkoxy, phenyl; or R 1 and R 2 together with the benzene ring linked thereto form an aryl group, heteroaryl group, C 3-8 cycloalkyl group, C 3-8 heterocyclic group; R 3 selected from hydroxyl, R 4 selected from hydroxyl, amino, halogen, C 1-8 alkyl, C 1-8 alkyl ester group; or R 3 and R 4 together with the benzene ring connected thereto form an aryl group, heteroaryl group, C 3-8 cycloalkyl group, C 3-8 heterocyclic group; wherein, the aryl group, heteroaryl group, C 3-8 cycloalkyl group, C 3-8 heterocyclic group are substituted by one or more substituents selected from a hydroxyl group, aryl group, heteroaryl group; wherein, the aryl group, heteroaryl group are substituted by one or more hydroxyl groups, and at least one of the hydroxyl groups is para-substituted; R 5 Selected from C 1-8 alkyl, aryl; Ar is an aryl group, which is unsubstituted or substituted by one or more hydroxyl groups, C 1-8 alkyl groups, C 1-8 alkoxy groups.

6. The preparation method according to claim 5, characterized in that, The alkyl alcohol solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, or 2-ethylhexanol.

7. The preparation method according to claim 5, characterized in that, The organic solvent is selected from one or more of methanol, ethanol, n-butanol, dichloromethane, acetonitrile, chloroform, tetrahydrofuran, isopropanol, benzyl alcohol, toluene, benzene, dimethyl sulfoxide, acetone, cyclohexane, N,N-dimethylformamide.

8. The preparation method according to claim 5, characterized in that, The oxidant is selected from one or more of ammonium cerium nitrate, potassium permanganate, hydrogen peroxide, potassium dichromate, potassium chlorate, nitric acid, sodium bromide.

9. The preparation method according to claim 5, wherein The temperature for mixing the 2,2-dimethyl-2H-chromene compound, the oxidant, and the organic solvent is -2 to 2 °C; the temperature for the mixed reaction is 20 to 30 °C.

10. Use of the 2,2-dimethylchroman compound according to any one of claims 1-4 in the preparation of a product for antioxidation and / or inhibition of melanin production.

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