Aminohydroxybenzoic acid ester derivative and use thereof

Abstract

To provide a new compound useful as an antioxidant.SOLUTION: An aminohydroxybenzoic acid ester derivative represented by the following general formula (I) or a salt thereof: SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to aminohydroxybenzoic acid ester derivatives and uses thereof. [Background technology]

[0002] Antioxidants are used to prevent and inhibit autoxidation of fats and oils, foods, lubricating oils, plastics, rubber, etc. In the case of rubber, they are also called antioxidants. Phenols and aromatic amines are used for antioxidant purposes in lubricating oils and rubber. These inhibit autoxidation by quenching the active radicals generated during autoxidation, thereby interrupting the radical chain growth reaction.

[0003] Patent Document 1 discloses that the reaction product of diphenylamine with bisphenol and its modified derivatives are excellent antioxidants for polyamide and rubber materials, and Patent Document 2 discloses that the reaction product of diphenylamine with bisphenol and its modified derivatives are excellent antioxidants for polyamide and rubber materials, and

[0004] [ka]

[0005] (In the formula, X represents O or NH, and R represents a hydrocarbon group having 10 to 22 carbon atoms.) It is disclosed that an aromatic amine compound derivative represented by the following formula is useful as an antioxidant for rubber compositions. However, Patent Documents 1 and 2 do not disclose diphenylamines containing a carboxylic acid ester in the molecule. On the other hand, diphenylamine containing an ethyl ester in the molecule has been reported to be investigated as a synthetic fluorescent dye (Non-Patent Document 1), but there is no description of its antioxidant capacity. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Japanese Patent Application Publication No. 198652 / 1983 [Patent Document 2] Japanese Patent Application Laid-Open No. 2008-189555 [Non-patent literature]

[0007] [Non-Patent Document 1] Dyes and Pigments, Volume.210, February 2023, p.111041 Summary of the Invention [Problem to be solved by the invention]

[0008] The present invention is directed to providing novel compounds useful as antioxidants. [Means for solving the problem]

[0009] The present inventors have conducted extensive research to solve the above problems and have found that a compound represented by the following general formula (I) exhibits excellent antioxidant activity. The compound represented by the general formula (I) is a novel compound not described in the above-mentioned prior art documents.

[0010] That is, the present invention relates to the following 1) and 2). 1) A compound represented by the following general formula (I):

[0011] [ka]

[0012] (In the formula, R1 represents an alkyl group, an aralkyl group, or an aryl group, and R2 represents an aryl group substituted with an alkyl group or a hydroxyalkyl group having 6 to 20 carbon atoms.) An aminohydroxybenzoic acid ester derivative represented by the formula (I) or a salt thereof. 2) An antioxidant containing an aminohydroxybenzoic acid ester derivative represented by the above general formula (I) or a salt thereof. [Effects of the Invention]

[0013] The aminohydroxybenzoic acid ester derivatives of the present invention have excellent antioxidant activity and can be used to prevent deterioration of the quality of various substances due to oxidation. [Brief explanation of the drawings]

[0014] [Figure 1] Antioxidant activity of aminohydroxybenzoic acid ester derivatives. [Figure 2] Antioxidant activity of aminohydroxybenzoic acid ester derivatives. [Figure 3] The stability of aminohydroxybenzoic acid ester derivatives is shown. DETAILED DESCRIPTION OF THE INVENTION

[0015] In the aminohydroxybenzoic acid ester derivatives represented by the general formula (I) of the present invention, R1 represents an alkyl group, an aralkyl group, or an aryl group. Examples of the alkyl group represented by R1 include linear, branched, and cyclic alkyl groups. Preferably, it is a linear, branched, or cyclic alkyl group having 1 to 10 carbon atoms. Examples include a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-nonyl group, n-decyl group, pentan-3-yl group, 3-methylbutyl group, 3,3-dimethylbutyl group, 3-methylpentan-2-yl group, 4-methylpentan-2-yl group, hexane-3-yl group, 5-methylhexyl group, octan-2-yl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, and cycloheptyl group.

[0016] Examples of the aralkyl group represented by R1 include an aralkyl group having 7 to 20 carbon atoms. The aralkyl group is preferably an aralkyl group having 7 to 9 carbon atoms. Examples of the aralkyl group include a phenylmethyl group, a 1-phenylethyl group, a 2-phenylethyl group, a 1-phenylpropyl group, a naphthylmethyl group, and a 1-naphthylethyl group.

[0017] The aryl group represented by R1 includes an aryl group having a carbon number of 6 to 14. The aryl group is preferably an aryl group having a carbon number of 6 to 10. Examples thereof include a phenyl group and a naphthyl group.

[0018] In the aminohydroxybenzoic acid ester derivatives of the present invention represented by general formula (I), R2 represents an aryl group substituted with an alkyl group or a hydroxyalkyl group having 6 to 20 carbon atoms. Examples of the alkyl group having 6 to 20 carbon atoms represented by R2 include linear, branched, and cyclic alkyl groups having 6 to 20 carbon atoms, such as n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, n-icosyl, isohexyl, neohexyl, isooctyl, isononyl, isodecyl, neodecanyl, and isostearyl groups. The alkyl group is preferably an alkyl group having 8 to 18 carbon atoms, more preferably an alkyl group having 12 to 16 carbon atoms, and even more preferably an n-hexadecyl group.

[0019] In the aryl group substituted with a hydroxyalkyl group represented by R2, the hydroxyalkyl group may be a group in which at least one hydrogen atom of a linear or branched alkyl group having 1 to 6 carbon atoms has been substituted with a hydroxy group. The hydroxyalkyl group is preferably a group in which one hydrogen atom of an alkyl group having 1 to 3 carbon atoms has been substituted with a hydroxy group. Examples of the hydroxyalkyl group include a hydroxymethyl group, a hydroxyethyl group, and a hydroxypropyl group. The aryl group includes an aryl group having a carbon number of 6 to 14. The aryl group is preferably an aryl group having a carbon number of 6 to 10. Examples thereof include a phenyl group and a naphthyl group. The aryl group substituted with a hydroxyalkyl group is preferably a hydroxy C 1-6An aryl group having 6 to 14 carbon atoms substituted with an alkyl group, more preferably a hydroxy C 1-3 It is an aryl group having 6 to 10 carbon atoms substituted with an alkyl group, and more preferably a hydroxymethylphenyl group.

[0020] In the aminohydroxybenzoic acid ester derivatives of the present invention represented by general formula (I), the substitution position of the ester group of formula -C(O)OR2 may be any position on the benzene ring. For example, in the structure having an amino group, the ester group is preferably at the 3- or 4-position, and particularly preferably at the 4-position.

[0021] In the aminohydroxybenzoic acid ester derivatives of the present invention represented by general formula (I), the substitution position of the hydroxy group may be any position on the benzene ring. For example, in the structure having an amino group, those having a hydroxy group at the 2- or 3-position are preferred, and those having a hydroxy group at the 2-position are particularly preferred.

[0022] From the viewpoint of the efficiency of the antioxidant effect, in the aminohydroxybenzoic acid ester derivatives represented by the general formula (I) of the present invention, a suitable compound is one in which R1 is an alkyl group having 1 to 10 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, or an aryl group having 6 to 14 carbon atoms, and R2 is an alkyl group having 6 to 20 carbon atoms or a hydroxy group having 6 to 20 carbon atoms. 1-6 It is a compound that is an aryl group having 6 to 14 carbon atoms substituted with an alkyl group.

[0023] Furthermore, from the viewpoint of substance stability, a more preferred aminohydroxybenzoic acid ester derivative represented by general formula (I) of the present invention is a compound in which R1 is an alkyl group having 1 to 10 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, or an aryl group having 6 to 14 carbon atoms, and R2 is an alkyl group having 8 to 18 carbon atoms.

[0024] From the viewpoint of substance stability, a more preferred aminohydroxybenzoic acid ester derivative represented by general formula (I) of the present invention is a compound in which R1 is a branched or cyclic alkyl group having 3 to 10 carbon atoms, an aralkyl group having 7 to 9 carbon atoms, or an aryl group having 6 to 10 carbon atoms, and R2 is an alkyl group having 8 to 18 carbon atoms.

[0025] Furthermore, from the viewpoint of substance stability, even more preferred aminohydroxybenzoic acid ester derivatives of the present invention represented by general formula (I) are those in which R1 is a branched or cyclic alkyl group having 3 to 10 carbon atoms and R2 is an alkyl group having 8 to 18 carbon atoms.

[0026] Among the aminohydroxybenzoic acid ester derivatives represented by the general formula (I) of the present invention, the following compounds are particularly preferred. hexadecyl 3-hydroxy-4-((4-methylpentan-2-yl)amino)benzoate, hexadecyl 3-hydroxy-4-(phenylamino)benzoate, hexadecyl 3-hydroxy-4-isopropylaminobenzoate, hexadecyl 3-hydroxy-4-sec-butylaminobenzoate, hexadecyl 3-hydroxy-4-pentan-3ylaminobenzoate, hexadecyl 3-hydroxy-4-((3-methylbutan-2-yl)amino)benzoate, hexadecyl 3-hydroxy-4-(octan-2-ylamino)benzoate, hexadecyl 3-hydroxy-4-((5-methylhexan-2-yl)amino)benzoate, hexadecyl 3-hydroxy-4-cyclohexylaminobenzoate, hexadecyl 3-hydroxy-4-((1-phenylethyl)amino)benzoate, Hexadecyl 3-hydroxy-4-(3,3-dimethylbutan-2-ylamino)benzoate Octyl 3-hydroxy-4-((4-methylpentan-2-yl)amino)benzoate, hexadecyl 4-hydroxy-3-((4-methylpentan-2-yl)amino)benzoate.

[0027] In this specification, the structural formula of a compound may conveniently represent a certain isomer, but the present invention includes all geometric isomers arising from the structure of the compound, isomers such as optical isomers based on asymmetric carbons, stereoisomers, tautomers, and mixtures of isomers, and is not limited to the description of the formula for convenience, and may be any one isomer or a mixture. Therefore, when the aminohydroxybenzoic acid ester derivative of the present invention represented by general formula (I) has an asymmetric carbon atom in the molecule and exists as an optically active substance or a racemic substance, the present invention is not limited and includes both.

[0028] The present invention includes salts of the aminohydroxybenzoic acid ester derivatives of the present invention. The salts are not particularly limited as long as they are pharmaceutically acceptable, and examples thereof include inorganic salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate; acid addition salts with organic acids such as formate, acetate, trichloroacetate, trifluoroacetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, tartrate, citrate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, aspartate, and glutamate; salts with inorganic bases such as sodium salt, potassium salt, magnesium salt, calcium salt, and aluminum salt; salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, and ornithine; and ammonium salts.

[0029] The present invention also includes prodrugs of the aminohydroxybenzoic acid ester derivatives of the present invention or their salts. Prodrugs are compounds that are converted into the compounds of the present invention or their salts by reactions (oxidation, reduction, hydrolysis, etc.) mediated by enzymes, gastric acid, etc. under physiological conditions in vivo.

[0030] The present invention includes, but is not limited to, hydrates, various solvates, and crystalline polymorphs of the aminohydroxybenzoic acid ester derivatives or salts thereof of the present invention, and may include any single crystalline form or a mixture of crystalline forms. Furthermore, the present invention includes isotopes (e.g., 2 H, 3 H, 14 C. 35 S, 125 Also included are compounds labeled with .I.

[0031] The aminohydroxybenzoic acid ester derivative or a salt thereof of the present invention can be produced, for example, by the following synthesis scheme 1 or 2, which can be appropriately modified depending on the type of substituents, etc., and can be produced by any method suitable for the situation. The starting materials for each step are commercially available or can be produced by methods known in the art.

[0032] Compound (Ia) of general formula (I), in which R1 is an alkyl group or an aralkyl group, can be obtained by reacting compound (1) with an aldehyde or ketone (2) in a suitable solvent in the presence of a hydride reducing agent according to the Boch reductive amination reaction, as shown below. <Synthetic Scheme 1>

[0033] [ka]

[0034] (wherein R2 is the same as above)

[0035] The solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include hydrocarbons (benzene, toluene, xylene, etc.), halogenated hydrocarbons (chloroform, 1,2-dichloroethane, etc.), nitriles (acetonitrile, etc.), ethers (tetrahydrofuran (THF), diethyl ether, dioxane, t-butyl methyl ether, diglyme, etc.), alcohols (methanol, ethanol, etc.), aprotic polar solvents (N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoramide, etc.), water, or mixed solvents thereof.

[0036] Examples of hydride reducing agents include NaBH(OAc)3, NaBH4, Borane-2-Methylpyridine Complex, LiAlH4, LiBH4, LiBH(C2H5)3, NaBH3CN, Pd / C+H2, Pd / C+Et3SiH, and DIBAL-H.

[0037] In this reaction, an acid may be added to accelerate the reaction, and examples of the acid include organic acids such as acetic acid, trifluoroacetic acid (TFA), formic acid, and p-toluenesulfonic acid, and Lewis acids such as aluminum chloride (III), diethylaluminum chloride, and trifluoroborane ether complex.

[0038] The amount of the aldehyde or ketone (2) used is usually 1 to 3 moles per mole of the compound (1).

[0039] The reaction is usually carried out at room temperature or under cooling, preferably at room temperature of 23°C for 24 hours or more.

[0040] Compound (Ib), in which R1 in general formula (I) is an aryl group, can be obtained by the Buchwald-Hartwig cross-coupling reaction of compound (1) with aryl halide (3) in an appropriate solvent in the presence of a metal catalyst, a ligand, and a base, as shown below. <Synthetic Scheme 2>

[0041] [ka]

[0042] (wherein R2 is the same as above).

[0043] The aryl halide (3) may be, for example, a chloride, a bromide, an iodide, a sulfonylalkoxy compound such as trifluoromethanesulfonate, or an arylborane.

[0044] The solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include the same solvents as those mentioned above. However, hydrocarbons (hexane, benzene, toluene, xylene, etc.), ethers (tetrahydrofuran (THF), diethyl ether, 1,4-dioxane, t-butyl methyl ether, diglyme, etc.), and halogenated carbons (dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane) are preferred.

[0045] Examples of the metal catalyst include palladium catalysts such as tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3), PdCl2 (palladium chloride), and Pd(OAc)2 (palladium acetate), and monovalent and divalent copper catalysts such as CuCl (copper(I) chloride), CuBr (copper(I) bromide), CuI (copper(I) iodide), and Cu(OAc)2 (copper(II) acetate).

[0046] Examples of the ligand include tBuXPhos (2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl), BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl), DPPF (1,1'-bis(diphenylphosphino)ferrocene), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos).

[0047] Examples of the base include metal hydrides such as lithium hydride and sodium hydride; metal alkoxides such as sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide; metal amides such as lithium amide and lithium diisopropylamide; and tripotassium phosphate.

[0048] The amount of the aryl halide (3) used is usually 1 to 3 moles per mole of the compound (1).

[0049] The reaction is preferably carried out at 80-120°C for 24-48 hours.

[0050] The aminohydroxybenzoic acid ester derivative of the present invention thus obtained can be isolated and purified by known separation and purification means such as concentration, solvent extraction, filtration, recrystallization, column chromatography, etc.

[0051] As shown in the Examples below, the aminohydroxybenzoic acid ester derivatives of the present invention not only have excellent antioxidant activity but also exhibit high stability in solution and excellent solubility in fat-soluble solvents. Therefore, the aminohydroxybenzoic acid ester derivatives or salts thereof of the present invention can be used as antioxidants and can prevent deterioration of the quality of various substances due to oxidation.

[0052] The aminohydroxybenzoic acid ester derivative or its salt of the present invention can be blended into, for example, a polymer composition, a detergent, a rust inhibitor, a dye, a lubricating oil, a gasoline fuel, an engine oil, a fat or oil, a pharmaceutical (including quasi-drugs), a fragrance, a cosmetic, a food, an agricultural chemical, etc. Examples of the polymer composition include a plastic composition, a rubber composition, an adhesive composition, etc. The aminohydroxybenzoic acid ester derivative or a salt thereof can be used in combination with known antioxidant components, other additives, etc., within the scope of not impairing the effects of the present invention.

[0053] When the antioxidant of the present invention is used by blending it with the above-mentioned composition to prevent its oxidation, the amount of antioxidant used is preferably 0.5 to 3% by mass per part by mass of the composition.

[0054] In relation to the above-described embodiment, the present invention further discloses the following aspects.

[0055] <1> The following general formula (I)

[0056] [ka]

[0057] (In the formula, R1 represents an alkyl group, an aralkyl group, or an aryl group, and R2 represents an aryl group substituted with an alkyl group or a hydroxyalkyl group having 6 to 20 carbon atoms.) An aminohydroxybenzoic acid ester derivative represented by the formula (I) or a salt thereof.

[0058] <2> R1 is preferably an alkyl group having 1 to 10 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, or an aryl group having 6 to 14 carbon atoms, more preferably a branched or cyclic alkyl group having 3 to 10 carbon atoms, an aralkyl group having 7 to 9 carbon atoms, or an aryl group having 6 to 10 carbon atoms, and even more preferably a branched or cyclic alkyl group having 3 to 10 carbon atoms. <1> 1. The aminohydroxybenzoic acid ester derivative or a salt thereof according to claim 1. <3> R2 is preferably an alkyl group having 6 to 20 carbon atoms or a hydroxy group 1-6 an aryl group having 6 to 14 carbon atoms substituted with an alkyl group, more preferably an alkyl group having 8 to 18 carbon atoms, even more preferably an alkyl group having 12 to 16 carbon atoms, and still more preferably an n-hexadecyl group; <1> or <2> 1. The aminohydroxybenzoic acid ester derivative or a salt thereof according to claim 1. <4> The substitution position of the ester group of the formula -C(O)OR2 is preferably the 3- or 4-position, more preferably the 4-position, in the structure having the amino group. <1> ~ <3> 1. The aminohydroxybenzoic acid ester derivative or salt thereof according to any one of the above items. <5> The substitution position of the hydroxy group is preferably the 2- or 3-position, more preferably the 2-position, in the structure having the amino group. <1> ~ <4> 1. The aminohydroxybenzoic acid ester derivative or salt thereof according to any one of the above items.

[0059] <6> R1 is an alkyl group having 1 to 10 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, or an aryl group having 6 to 14 carbon atoms, and R2 is an alkyl group having 6 to 20 carbon atoms or a hydroxy group having 6 to 20 carbon atoms. 1-6 an aryl group having 6 to 14 carbon atoms substituted with an alkyl group; <1> 1. The aminohydroxybenzoic acid ester derivative or a salt thereof according to claim 1. <7> R1 is an alkyl group having 1 to 10 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, or an aryl group having 6 to 14 carbon atoms, and R2 is an alkyl group having 8 to 18 carbon atoms. <1> 1. The aminohydroxybenzoic acid ester derivative or a salt thereof according to claim 1. <8> R1 is a branched or cyclic alkyl group having 3 to 10 carbon atoms, an aralkyl group having 7 to 9 carbon atoms, or an aryl group having 6 to 10 carbon atoms, and R2 is an alkyl group having 8 to 18 carbon atoms. <1> 1. The aminohydroxybenzoic acid ester derivative or a salt thereof according to claim 1. <9> R1 is a branched or cyclic alkyl group having 3 to 10 carbon atoms, and R2 is an alkyl group having 8 to 18 carbon atoms. <1> 1. The aminohydroxybenzoic acid ester derivative or a salt thereof according to claim 1. <10> An aminohydroxybenzoic acid ester derivative or a salt thereof selected from the following: hexadecyl 3-hydroxy-4-((4-methylpentan-2-yl)amino)benzoate, hexadecyl 3-hydroxy-4-(phenylamino)benzoate, hexadecyl 3-hydroxy-4-isopropylaminobenzoate, hexadecyl 3-hydroxy-4-sec-butylaminobenzoate, hexadecyl 3-hydroxy-4-pentan-3ylaminobenzoate, hexadecyl 3-hydroxy-4-((3-methylbutan-2-yl)amino)benzoate, hexadecyl 3-hydroxy-4-(octan-2-ylamino)benzoate, hexadecyl 3-hydroxy-4-((5-methylhexan-2-yl)amino)benzoate, hexadecyl 3-hydroxy-4-cyclohexylaminobenzoate, hexadecyl 3-hydroxy-4-((1-phenylethyl)amino)benzoate, Hexadecyl 3-hydroxy-4-(3,3-dimethylbutan-2-ylamino)benzoate Octyl 3-hydroxy-4-((4-methylpentan-2-yl)amino)benzoate, hexadecyl 4-hydroxy-3-((4-methylpentan-2-yl)amino)benzoate.

[0060] <11> <1> ~ <10> 1. An antioxidant comprising the aminohydroxybenzoic acid ester derivative or salt thereof according to any one of the above items. <12> <1> ~ <10> 1. A composition comprising the aminohydroxybenzoic acid ester derivative or salt thereof according to any one of the above items. <13> Preferably it is a polymer composition, <12> The composition described in [Example]

[0061] Example 1 Hexadecyl 3-hydroxy-4-((4-methylpentan-2-yl)amino)benzoate (AHB C16 -DMB) manufacturing AHB can be produced from 4-amino-3-hydroxybenzoic acid by the following steps: C16 -DMB was synthesized.

[0062] [ka]

[0063] (1) Synthesis of Hexadecyl 4-amino-3-hydroxybenzoate Under an argon atmosphere, 4-amino-3-hydroxybenzoic acid (50 g, 33 mmol) was placed in a 200 mL round-bottom flask, and 1-hexadecanol (157 g, 65 mmol) was added. The mixture was heated to 150 °C and stirred to obtain a brown suspension. Subsequently, concentrated sulfuric acid (19.2 mL, 36 mmol) was slowly added dropwise, followed by stirring for 3 hours. After the reaction, the mixture was cooled to 60 °C, and then chloroform (750 mL) and triethylamine (100 mL) were added and stirred for 30 minutes. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure using an evaporator. The resulting residue was then redissolved in chloroform (250 mL) and stirred at 37 °C for 30 minutes. After stirring, hexane (1250 mL) was added, and the mixture was recrystallized to obtain 4-amino-3-hydroxybenzoic acid hexadecyltriethylamine salt (122 g, 79% yield) as a white solid.

[0064] 1 H-NMR(600MHz,CDCl3)δ 7.49(d,J=1.9Hz,1H),7.46(dd,J=8.1,1.9Hz,1H),6.63(d,J=8.2Hz,1H),4.21(t,J=6.7Hz,2H),3. 0(q,J=7.2Hz,6H),1.73-1.68(m,2H),1.42-1.37(m,2H),1.32-1.25(m,33H),0.87(t,J=6.8Hz,3H)

[0065] (2) Synthesis of Hexadecyl 3-hydroxy-4-((4-methylpentan-2-yl)amino)benzoate Under an argon atmosphere, 4-amino-3-hydroxybenzoic acid hexadecyltriethylamine salt (15 g, 31 mmol) was placed in a 2000 mL round-bottom flask, and dehydrated 1,2-dichloroethane (945 mL), acetic acid (9.45 mL), and 4-methyl-2-pentanone (15 mL, 80 mmol) were added and stirred to obtain a suspension. Subsequently, 80% pure sodium triacetoxyborohydride (25.2 g, 95 mmol) was added and stirred at room temperature for 24 hours. After the reaction, methanol (500 mL) was added and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure using an evaporator, and the resulting residue was purified by silica gel chromatography (eluent: chloroform-ethyl acetate (100:0 ⇒ 95:5, v / v) to obtain hexadecyl 3-hydroxy-4-((4-methylpentan-2-yl)amino)benzoate (10.8 g, yield 75%) as a white compound.

[0066] 1 H-NMR(600MHz,CDCl3) δ 7.59(dd,J=8.4,1.7Hz,1H),7.48(d,J=1.8Hz,1H),6.55(d,J=8.5Hz,1H),4.25(d,J=6.6Hz,2H),3.66-3.59(m,1H),1.78-1.69(m,3H),1.54- 1.50(m,1H),1.44-1.39(m,1H),1.35-1.25(m,25H),1.20(d,J=6.2Hz,3H),0.95(d,J=6.5Hz,3H),0.90(d,J=6.5Hz,3H),0.87(t,J=7.0Hz,3H) Melting point: 45℃

[0067] Example 2 Hexadecyl 3-hydroxy-4-(phenylamino)benzoate (AHB C16 -Ph) AHB can be produced from 4-amino-3-hydroxybenzoic acid by the following steps: C16 -Ph was synthesized.

[0068] [ka]

[0069] (1) Synthesis of Hexadecyl 4-amino-3-hydroxybenzoate In the same manner as in Example 1, hexadecyltriethylamine 4-amino-3-hydroxybenzoate was obtained from 4-amino-3-hydroxybenzoic acid.

[0070] (2) Synthesis of Hexadecyl 3-hydroxy-4-(phenylamino)benzoate Under an argon atmosphere, a 100 mL round-bottom flask was charged with 4-amino-3-hydroxybenzoic acid hexadecyltriethylamine salt (1 g, 2 mmol), bromobenzene (400 μL, 18 mmol), tris(dibenzylideneacetone)dipalladium(0) (490 mg, 0.53 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (260 mg, 0.53 mmol), and sodium tert-butoxide (350 mg, 3.6 mmol). Toluene (15 mL) was added and the mixture was stirred to obtain a suspension. The reaction mixture was degassed with argon, then heated to 110 °C and stirred for 19 hours. After the reaction, the mixture was diluted with chloroform, washed with water, dried over sodium sulfide, and concentrated under reduced pressure using an evaporator. Next, the obtained residue was purified by silica gel chromatography (elution solvent: chloroform-ethyl acetate (100:0⇒95:5, v / v)) to obtain hexadecyl 3-hydroxy-4-(phenylamino)benzoate (306 mg, yield 32%) as a brown compound.

[0071] 1 H-NMR(600MHz,CDCl3) δ 7.62(d,J=1.9Hz,1H),7.57(dd,J=8.3,1.8Hz,1H),7.32(t,J=7.4Hz,2H),7.22(d,J=8.4Hz,1H),7.13(d,J=7.6Hz,2H)7.03(t ,J=7.4Hz,1H),4.27(t,J=6.7Hz,2H),1.76-1.72(m,2H),1.45-1.40(m,2H),1.35-1.25(m,24H),0.87(t,J=6.5Hz,6.9Hz,3H) Melting point: 81℃

[0072] In the same manner as in Example 1, the following compounds were synthesized from 4-amino-3-hydroxybenzoic acid.

[0073] [ka]

[0074] Example 3 Hexadecyl 3-hydroxy-4-isopropylaminobenzoate (AHB C16 Synthesis of -IPR) Under an argon atmosphere, hexadecyl 4-amino-3-hydroxybenzoate triethylamine salt (1 g, 2 mmol) was placed in a 100 mL round-bottom flask, and dehydrated 1,2-dichloroethane (20 mL), acetic acid (1 mL), and acetone (1 mL, 13.6 mmol) were added and stirred to obtain a suspension. Subsequently, 80% pure sodium triacetoxyborohydride (1.3 g, 4.9 mmol) was added and stirred at room temperature for 24 hours. After the reaction, methanol (20 mL) was added and stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure using an evaporator, and the resulting residue was purified by silica gel chromatography (eluent: chloroform-ethyl acetate (100:0 to 95:5, v / v)) to obtain hexadecyl 3-hydroxy-4-isopropylaminobenzoate (610 mg, 70% yield) as a pale pink compound.

[0075] 1 H-NMR(600MHz,CDCl3) δ7.58(d,J=8.4Hz,1H),7.54(s,1H), 6.55(d,J=8.4Hz,1H),4.24(t,J=6.8Hz,2H),3.72-3.68(m,1H),1.74-1 .70(m,2H),1.44-1.39(m,2H),1.35-1.25(m,30H),0.87(t,J=7.3Hz,3H)

[0076] Example 4 Hexadecyl 3-hydroxy-4-sec-butylaminobenzoate (AHB C16 Synthesis of -MPR Under an argon atmosphere, 4-amino-3-hydroxybenzoic acid hexadecyltriethylamine salt (1 g, 2 mmol) was placed in a 100 mL round-bottom flask, and dehydrated 1,2-dichloroethane (20 mL), acetic acid (239 μL), and butanone (558 μL, 6.2 mmol) were added and stirred to obtain a suspension. Subsequently, 80% pure sodium triacetoxyborohydride (1.32 g, 5.0 mmol) was added and stirred at room temperature for 17 hours. After the reaction, methanol (20 mL) was added and stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure using an evaporator, and the resulting residue was purified by silica gel chromatography (eluent: chloroform-ethyl acetate (100:0 to 95:7, v / v)) to obtain hexadecyl 3-hydroxy-4-sec-butylaminobenzoate (699 mg, 77% yield) as a white compound.

[0077] 1 H-NMR(600MHz,CDCl3) δ7.56(dd,J=8.4,1.6Hz,1H),7.55(d,J=1.5Hz,1H), 6.53(d,J=8.4Hz,1H),4.24(t,J=6.5Hz,2H),3.49-3.47(m,1H),1.74-1.71(m,2H),1.67-1.61(m,1H),1.57-1.5 0(m,1H)1.44-1.39(m,2H)1.36-1.25(m,24H),1.21(d,J=6.5Hz,3H),0.96(t,J=7.3Hz,3H),0.87(t,J=7.3Hz,3H)

[0078] Example 5 Hexadecyl 3-hydroxy-4-pentan-3ylaminobenzoate (AHB C16 Synthesis of -EPR Under an argon atmosphere, 4-amino-3-hydroxybenzoic acid hexadecyltriethylamine salt (1 g, 2 mmol) was placed in a 100 mL round-bottom flask, and dehydrated 1,2-dichloroethane (20 mL), acetic acid (239 μL), and 3-pentanone (659 μL, 6.2 mmol) were added and stirred to obtain a suspension. Subsequently, 80% pure sodium triacetoxyborohydride (1.32 g, 5.0 mmol) was added and stirred at room temperature for 17 hours. After the reaction, methanol (20 mL) was added and stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure using an evaporator, and the resulting residue was purified by silica gel chromatography (eluent: chloroform-ethyl acetate (100:0 to 95:7, v / v)) to obtain hexadecyl 3-hydroxy-4-pentan-3ylaminobenzoate (695 mg, 74% yield) as a pale pink compound.

[0079] 1 H-NMR (600MHz, CDCl3) δ7.56(d,J=7.0Hz,1H),7.53(s,1H), 6.52(d,J=8.3Hz,1H),4.24(t,J=6.5Hz,2H),3.32-3.31(m,1H),1.74-1.69(m,2H),1.67-1.61(m,2H), 1.55-1.48(m,2H),1.44-1.39(m,2H),1.35-1.25(m,24H),0.93(t,J=7.3Hz,6H),0.87(t,J=6.8Hz,3H)

[0080] Example 6 Hexadecyl 3-hydroxy-4-((3-methylbutan-2-yl)amino)benzoate (AHB C16 Synthesis of -DPR) Under an argon atmosphere, 4-amino-3-hydroxybenzoic acid hexadecyltriethylamine salt (1 g, 2 mmol) was placed in a 100 mL round-bottom flask, and dehydrated 1,2-dichloroethane (20 mL), acetic acid (239 μL), and methyl isopropyl ketone (565 μL, 5.3 mmol) were added and stirred to obtain a suspension. Subsequently, 80% pure sodium triacetoxyborohydride (1.32 g, 4.9 mmol) was added and stirred at room temperature for 17 hours. After the reaction, methanol (20 mL) was added and stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure using an evaporator, and the resulting residue was purified by silica gel chromatography (eluent: chloroform-ethyl acetate (100:0 to 95:7, v / v)) to obtain hexadecyl 3-hydroxy-4-((3-methylbutan-2-yl)amino)benzoate (710 mg, 76% yield) as a pale pink compound.

[0081] 1 H-NMR(600MHz, CDCl3) δ7.58(s,1H),7.56(d,J=8.3Hz,1H),6.52(d,J=8.4Hz,1H),4.25(t,J=6.5Hz,2H),3.42-3.41(m,1H),1.90-1.84(m,1H),1.74-1.70(m ,2H),1.44-1.39(m,2H),1.34-1.25(m,24H),1.14(d,J=6.5Hz,3H),0.98(d,J=6.9Hz,3H),0.93(d,J=6.5Hz,3H),0.87(t,J=6.9Hz,3H)

[0082] In the same manner as in Example 1, the following compounds were synthesized from 4-amino-3-hydroxybenzoic acid.

[0083] [ka]

[0084] Example 7 Hexadecyl 3-hydroxy-4-(octan-2-ylamino)benzoate (AHB C16 Synthesis of -MHP Under an argon atmosphere, 4-amino-3-hydroxybenzoic acid hexadecyltriethylamine salt (1 g, 2 mmol) was placed in a 100 mL round-bottom flask, and dehydrated 1,2-dichloroethane (20 mL), acetic acid (239 μmL), and 2-octanone (972 μL, 6.3 mmol) were added and stirred to obtain a suspension. Subsequently, 80% pure sodium triacetoxyborohydride (1.3 g, 4.9 mmol) was added and stirred at room temperature for 17 hours. After the reaction, methanol (20 mL) was added and stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure using an evaporator, and the resulting residue was purified by silica gel chromatography (eluent: chloroform-ethyl acetate (100:0 to 95:5, v / v)) to obtain hexadecyl 3-hydroxy-4-(octan-2-ylamino)benzoate (626 mg, 61% yield) as a pale pink compound.

[0085] 1 H-NMR(600MHz,CDCl3) δ7.58-7.56(m,2H),6.53(d,J=8.4Hz,1H), 4.25(t,J=6.5Hz,2H),3.53(m,1H),1.74-1.70(m,2H),1.63-1.55(m,1H),1 .51-1.45(m,1H),1.44-1.25(m,34H),1.21(d,6.5Hz,3H),0.88-0.86(m,6H)

[0086] Example 8 Hexadecyl 3-hydroxy-4-((5-methylhexan-2-yl)amino)benzoate (AHB C16 Synthesis of -DPN) Under an argon atmosphere, 4-amino-3-hydroxybenzoic acid hexadecyltriethylamine salt (1 g, 2 mmol) was placed in a 100 mL round-bottom flask, and dehydrated 1,2-dichloroethane (20 mL), acetic acid (239 μmL), and 5-methyl-2-hexanone (972 μL, 6.3 mmol) were added and stirred to obtain a suspension. Subsequently, 80% pure sodium triacetoxyborohydride (1.3 g, 4.9 mmol) was added and stirred at room temperature for 17 hours. After the reaction, methanol (20 mL) was added and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure using an evaporator, and the resulting residue was purified by silica gel chromatography (eluent: chloroform-ethyl acetate (100:0⇒95:5, v / v)) to obtain hexadecyl 3-hydroxy-4-((5-methylhexan-2-yl)amino)benzoate (813 mg, yield 82%) as a pale pink compound.

[0087] 1 H-NMR(600MHz, CDCl3) δ7.57(dd,J=8.0,1.5Hz,1H),7.52(d,J=1.6Hz,1H),6.52(d,d=8.8Hz,1H),4.24(t,J=6.9Hz,2H),3.52-3.48( m,1H),1.74-1.70(m,2H),1.64-1.39(m,5H),1.36-1.19(m,30H),0.88(t,d=6.5Hz,3H),0.87(t,d=7.3Hz,6H)

[0088] Example 9 Hexadecyl 3-hydroxy-4-cyclohexylaminobenzoate (AHB C16 Synthesis of -CHX Under an argon atmosphere, 4-amino-3-hydroxybenzoic acid hexadecyltriethylamine salt (1 g, 2 mmol) was placed in a 100 mL round-bottom flask, and dehydrated 1,2-dichloroethane (20 mL), acetic acid (239 μmL), and cyclohexanone (649 μL, 6.3 mmol) were added and stirred to obtain a suspension. Subsequently, 80% pure sodium triacetoxyborohydride (1.3 g, 4.9 mmol) was added and stirred at room temperature for 17 hours. After the reaction, methanol (20 mL) was added and stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure using an evaporator, and the resulting residue was purified by silica gel chromatography (eluent: chloroform-ethyl acetate (100:0 to 93:7, v / v)) to obtain hexadecyl 3-hydroxy-4-cyclohexylaminobenzoate (802 mg, 84% yield) as a pale pink compound.

[0089] 1 H-NMR(600MHz, CDCl3) δ7.57(dd,J=8.4,1.6,1H),7.47(d,J=1.1Hz,1H),6.56(d,J=8.4Hz,1H),4.24(t,J=6.9Hz,2H),3 .35-3.31(m,1H),2.07-2.04(m,2H),1.79-1.64(m,5H),1.43-1.25(m,31H),0.87(t,J=7.1HZ,3H)

[0090] Example 10 Hexadecyl 3-hydroxy-4-((1-phenylethyl)amino)benzoate (AHB C16 Synthesis of -MBN Under an argon atmosphere, 4-amino-3-hydroxybenzoic acid hexadecyltriethylamine salt (1 g, 2 mmol) was placed in a 100 mL round-bottom flask, and dehydrated 1,2-dichloroethane (20 mL), acetic acid (239 μmL), and acetophenone (733 μL, 6.3 mmol) were added and stirred to obtain a suspension. Subsequently, 80% pure sodium triacetoxyborohydride (1.3 g, 4.9 mmol) was added and stirred at room temperature for 17 hours. After the reaction, methanol (20 mL) was added and stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure using an evaporator, and the resulting residue was purified by silica gel chromatography (eluent: chloroform-ethyl acetate (100:0 to 95:5, v / v)) to obtain hexadecyl 3-hydroxy-4-((1-phenylethyl)amino)benzoate (363 mg, 36% yield) as a pale pink compound.

[0091] 1 H-NMR(600MHz,CDCl3) δ7.60(d,J=1.9Hz,1H),7.32(dd,J=8.4,1.9Hz,1H), 7.34-7.29(m,4H),7.24-7.21(m,1H),6.29(d,8.4Hz,1H),4.58-4.56(m,1H),4.24-4.20(m,2H),1. 71-1.66(m,2H),1.57(d,J=6.5Hz,3H),1.41-1.36(m,2H),1.32-1.24(m,24H),0.87(d,J=6.8Hz,3H)

[0092] Example 11 Hexadecyl 3-hydroxy-4-(3,3-dimethylbutan-2-ylamino)benzoate (AHB C16 Synthesis of -TPR) Under an argon atmosphere, 4-amino-3-hydroxybenzoic acid hexadecyltriethylamine salt (1 g, 2 mmol) was placed in a 100 mL round-bottom flask, and dehydrated 1,2-dichloroethane (20 mL), acetic acid (239 μmL), and 3,3-dimethylbutanone (777 μL, 6.2 mmol) were added and stirred to obtain a suspension. Subsequently, 80% pure sodium triacetoxyborohydride (1.3 g, 4.9 mmol) was added and stirred at room temperature for 17 hours. After the reaction, methanol (20 mL) was added and stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure using an evaporator, and the resulting residue was purified by silica gel chromatography (eluent: chloroform-ethyl acetate (100:0 to 95:5, v / v)) to obtain hexadecyl 3-hydroxy-4-(3,3-dimethylbutan-2-ylamino)benzoate (273 mg, 28% yield) as a pale yellow compound. 1 H-NMR(600MHz, CDCl3) δ7.57(dd,J=8.4,1.5Hz,1H),7.50(d,J=1.5Hz,1H),6.56(d,J=8.8Hz,1H),4.25(t,J=6.9Hz,2H),3.36-3.31(m,1H) ,1.74-1.69(m,2H),1.42-1.39(m,2H),1.36-1.25(m,24H),1.13(d,J=6.5Hz,3H),0.98(s,9H),0.87(t,J=6.9Hz,3H)

[0093] Example 12 Octyl 3-hydroxy-4-((4-methylpentan-2-yl)amino)benzoate (AHB C8 -DMB) manufacturing AHB can be produced from 4-amino-3-hydroxybenzoic acid by the following steps: C8 -DMB was synthesized.

[0094] [ka]

[0095] (1) Synthesis of Octyl 4-amino-3-hydroxybenzoate Under an argon atmosphere, 4-amino-3-hydroxybenzoic acid (2 g, 13 mmol) was placed in a 20 mL round-bottom flask, and n-octanol (4.1 mL, 26 mmol) was added. The mixture was stirred under reflux to obtain a brown suspension. Subsequently, concentrated sulfuric acid (770 μL, 14 mmol) was slowly added dropwise, followed by stirring for 3 hours. After the reaction, the mixture was cooled to room temperature, and then chloroform (40 mL) and triethylamine (4 mL) were added and stirred for 30 minutes. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure using an evaporator. Next, the mixture was concentrated under reduced pressure using an evaporator, and the resulting residue was purified by silica gel chromatography (elution solvent: chloroform-ethyl acetate (95:5, v / v)) to obtain octyl 4-amino-3-hydroxybenzoate (2.6 g, 74% yield) as a pale pink compound.

[0096] 1 H-NMR(600MHz, CDCl3) δ7.52(d,J=1.9Hz,1H),7.51(dd,J=8.0,1.9Hz,1H),6.67(d,J=8.0Hz,1H),4.25(t,J=6. 8Hz,2H),1.75-1.70(m,2H),1.43-1.39(m,2H),1.35-1.26(m,8H),0.88(d,J=6.8Hz,1H)

[0097] (2) Synthesis of Octyl 3-hydroxy-4-((4-methylpentan-2-yl)amino)benzoate Under an argon atmosphere, octyl 4-amino-3-hydroxybenzoate (500 mg, 1.9 mmol) was placed in a 100 mL round-bottom flask, and dehydrated 1,2-dichloroethane (19 mL), acetic acid (943 μL), and 4-methyl-2-pentanone (709 μL, 5.4 mmol) were added and stirred to obtain a suspension. Subsequently, 80% pure sodium triacetoxyborohydride (1.2 g, 4.6 mmol) was added and stirred at room temperature for 19 hours. After the reaction, methanol (19 mL) was added and stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure using an evaporator, and the resulting residue was purified by silica gel chromatography (eluent: chloroform-ethyl acetate (100:0 to 95:5, v / v) to obtain octyl 3-hydroxy-4-((4-methylpentan-2-yl)amino)benzoate (730 mg, 78% yield) as a pale pink compound.

[0098] 1 H-NMR(600MHz, CDCl3) δ7.59(dd,J=8.0,1.5Hz,1H),7.44(d,J=1.9Hz,1H),6.55(d,J=8.4Hz,1H),4.24(t,J=6.5Hz,2H),3.60(m,1H),1.77-1.69(m,3H),1.55-1 .50(m,1H),1.43-1.39(m,2H),1.35-1.23(m,9H),1.2(d,J=6.1Hz,3H),0.95(d,J=6.5Hz,3H),0.90(d,J=6.5Hz,3H),0.88(t,J=6.8Hz,3H) Melting point: 63℃

[0099] Example 13 Hexadecyl 4-hydroxy-3-((4-methylpentan-2-yl)amino)benzoate (isoAHB C16 -DMB) manufacturing The following steps will convert 3-amino-4-hydroxybenzoic acid to isoAHB: C8 -DMB was synthesized.

[0100] [ka]

[0101] (1) Synthesis of Hexadecyl 3-amino-4-hydroxybenzoate Under an argon atmosphere, 3-amino-4-hydroxybenzoic acid (2 g, 13 mmol) was placed in a 50 mL round-bottom flask, and 1-hexadecanol (6.3 g, 26 mmol) was added. The mixture was heated to 150 °C and stirred to obtain a brown suspension. Subsequently, concentrated sulfuric acid (770 μL, 14 mmol) was slowly added dropwise, followed by stirring for 3 hours. After the reaction, the mixture was cooled to 60 °C, and then chloroform (750 mL) and triethylamine (100 mL) were added and stirred for 30 minutes. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure using an evaporator. Next, the mixture was concentrated under reduced pressure using an evaporator, and the resulting residue was purified by silica gel chromatography (elution solvent: chloroform-ethyl acetate (95:5, v / v)) to obtain hexadecyl 3-amino-4-hydroxybenzoate (1.9 g, 40% yield) as a white compound.

[0102] 1 H-NMR(600MHz,CDCl3) δ 7.46(d,J=1.9Hz,1H),7.43(d,J=8.4,2.3Hz,1H),6.74(d,J=8.0Hz,1H),4.25(t,J=6.5 Hz,2H),1.74-1.71(m,2H),1.41-1.40(m,2H),1.34-1.25(m,23H),0.87(t,J=7.2Hz,2H)

[0103] (2) Synthesis of Hexadecyl 4-hydroxy-3-((4-methylpentan-2-yl)amino)benzoate Under an argon atmosphere, octyl 4-amino-3-hydroxybenzoate (500 mg, 1.8 mmol) was placed in a 100 mL round-bottom flask, and dehydrated 1,2-dichloroethane (13 mL), acetic acid (663 μL), and 4-methyl-2-pentanone (397 μL, 3.0 mmol) were added and stirred to obtain a suspension. Subsequently, 80% pure sodium triacetoxyborohydride (843 mg, 3.2 mmol) was added and stirred at room temperature for 19 hours. After the reaction, methanol (13 mL) was added and stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure using an evaporator, and the resulting residue was purified by silica gel chromatography (eluent: chloroform-ethyl acetate (100:0 to 95:5, v / v) to obtain hexadecyl 4-hydroxy-3-((4-methylpentan-2-yl)amino)benzoate (362 mg, 59% yield) as a white compound.

[0104] 1 H-NMR(600MHz, CDCl3) δ7.40-7.37(m,2H),7.37(d,J=8.0Hz,1H),4.26(t,J=6.1Hz,2H),4.53-4.50(m,1H),1.77-1.71(m,3H),1.52-1.49(m,1H),1. 43-1.39(m,2H),1.36-1.25(m,28H)1.16(d,J=6.1Hz,3H),0.96(d,J=6.9Hz,3H),0.92(d,J=6.5Hz,3H),0.87(t,J=7.3Hz,3H) Melting point: 64℃

[0105] Comparative Example 1 Ethyl 3-hydroxy-4-((4-methylpentan-2-yl)amino)benzoate (AHB C2 -DMB) manufacturing AHB can be produced from 4-amino-3-hydroxybenzoic acid by the following steps: C2 -DMB was synthesized.

[0106] [ka]

[0107] (1) Synthesis of Ethyl 4-amino-3-hydroxybenzoate Under an argon atmosphere, 4-amino-3-hydroxybenzoic acid (3 g, 20 mmol) was placed in a 100 mL round-bottom flask, ethanol (22 mL, 37 mmol) was added, and the mixture was stirred under reflux to obtain a brown suspension. Subsequently, concentrated sulfuric acid (1.1 mL, 20 mmol) was slowly added dropwise, and the mixture was stirred for 23 hours. After the reaction, the mixture was cooled to room temperature, and then chloroform (60 mL) and triethylamine (6 mL) were added and stirred for 30 minutes. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure using an evaporator. Next, the mixture was concentrated under reduced pressure using an evaporator, and the resulting residue was purified by silica gel chromatography (elution solvent: chloroform-ethyl acetate (84:16, v / v)) to obtain ethyl 4-amino-3-hydroxybenzoate (2.6 g, yield 73%) as a white compound.

[0108] 1 H-NMR(600MHz,CDCl3) δ 7.64(d,J=1.9Hz,1H),7.50(dd,J=8.0,1.9Hz,1H),6.66(d,J=8.4Hz,1H),4.33(q,J=7.3Hz,2H),1.36(t,J=6.8Hz,3H)

[0109] (2) Synthesis of Ethyl 3-hydroxy-4-((4-methylpentan-2-yl)amino)benzoate Under an argon atmosphere, ethyl 4-amino-3-hydroxybenzoate (500 mg, 2.8 mmol) was placed in a 100 mL round-bottom flask, and dehydrated 1,2-dichloroethane (13 mL), acetic acid (690 μL), and 4-methyl-2-pentanone (1.0 mL, 7.7 mmol) were added and stirred to obtain a suspension. Subsequently, 80% pure sodium triacetoxyborohydride (1.8 g, 6.6 mmol) was added and stirred at room temperature for 19 hours. After the reaction, methanol (13 mL) was added and stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure using an evaporator, and the resulting residue was purified by silica gel chromatography (eluent: chloroform-ethyl acetate (100:0 to 85:15, v / v) to obtain ethyl 3-hydroxy-4-((4-methylpentan-2-yl)amino)benzoate (730 mg, 100% yield) as a white compound.

[0110] 1 H-NMR(600MHz, CDCl3) δ7.59-7.57(m,2H),6.54(d,J=8.4Hz,1H),4.31(q,J=6.9Hz,2H),3.62-3.59(m,1H),1.77-1.72(m,1H),1.54-1.50( m,1H),1.35(t,J=6.9Hz,3H),1.35-1.30(m,1H),1.19(d,J=6.5Hz,3H),0.95(d,J=6.8Hz,3H),0.90(d,J=6.5Hz,3H) Melting point: 175℃

[0111] Test Example 1 Evaluation of antioxidant activity In this test, antioxidant activity was evaluated using a DPPH Antioxidant Assay Kit (manufactured by Dojin Chemical Research Institute). A 96-well plate for colorimetric measurement was prepared according to the following conditions (final sample concentration: 20 μg / mL), and 200 μL of each solution was dispensed into each well. The plate was then gently shaken and stirred, and allowed to stand at room temperature for 30 minutes. The absorbance at 490 nm was then measured using a SPARK10M (Tecan Japan). The absorbance was calculated as the difference Δ from the blank absorbance, and the results are shown in Figures 1 and 2.

[0112] [Table 1]

[0113] As shown in Figures 1 and 2, it was confirmed that the aminohydroxybenzoic acid ester derivatives of the present invention have superior antioxidant activity compared to the control.

[0114] Test Example 2: Stability test To evaluate the stability of the target substance, it was dissolved in dimethyl sulfoxide (DMSO) at a concentration of 1 mg / mL and the resulting solution was allowed to stand at 50°C for 1 and 7 days. After standing, the solution was diluted and its stability was measured using HPLC (Figure 3, left). The area values ​​obtained were quantified using a calibration curve. Furthermore, 200 μL of the undiluted solution was dispensed into a 96-well plate for colorimetric measurement, and colorimetric measurements were performed at a wavelength of 450 nm using a SPARK10M (Tecan Japan). The absorbance values ​​obtained were shown as the differential absorbance Δ from the absorbance value of the blank (pre-test sample solution) in Figure 3 (Figure 3, right).

[0115] As shown in FIG. 3, it was confirmed that the aminohydroxybenzoic acid ester derivatives of the present invention exhibit excellent substance stability.

Claims

1. The following general formula (I) 【Chemistry 1】 (In the formula, R 1 represents an alkyl group, an aralkyl group, or an aryl group; R 2 represents an aryl group substituted with an alkyl group or a hydroxyalkyl group having 6 to 20 carbon atoms. An aminohydroxybenzoic acid ester derivative represented by the formula (I) or a salt thereof.

2. R 1 is an alkyl group having 1 to 10 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, or an aryl group having 6 to 14 carbon atoms, and R 2 The aminohydroxybenzoic acid ester derivative or a salt thereof according to claim 1, wherein is an alkyl group having 8 to 18 carbon atoms.

3. An aminohydroxybenzoic acid ester derivative or a salt thereof selected from the following: hexadecyl 3-hydroxy-4-((4-methylpentan-2-yl)amino)benzoate, hexadecyl 3-hydroxy-4-(phenylamino)benzoate, hexadecyl 3-hydroxy-4-isopropylaminobenzoate, hexadecyl 3-hydroxy-4-sec-butylaminobenzoate, hexadecyl 3-hydroxy-4-pentan-3ylaminobenzoate, hexadecyl 3-hydroxy-4-((3-methylbutan-2-yl)amino)benzoate, hexadecyl 3-hydroxy-4-(octan-2-ylamino)benzoate, hexadecyl 3-hydroxy-4-((5-methylhexan-2-yl)amino)benzoate, hexadecyl 3-hydroxy-4-cyclohexylaminobenzoate, hexadecyl 3-hydroxy-4-((1-phenylethyl)amino)benzoate, Hexadecyl 3-hydroxy-4-(3,3-dimethylbutan-2-ylamino)benzoate Octyl 3-hydroxy-4-((4-methylpentan-2-yl)amino)benzoate, hexadecyl 4-hydroxy-3-((4-methylpentan-2-yl)amino)benzoate.

4. An antioxidant comprising the aminohydroxybenzoic acid ester derivative or its salt according to any one of claims 1 to 3.

5. A composition comprising the aminohydroxybenzoic acid ester derivative or its salt according to any one of claims 1 to 3.

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