Method for producing aromatic β-hydroxy acid

Abstract

The purpose of the present invention is to provide a method by which an aromatic β-hydroxy acid can be efficiently produced. A method for producing an aromatic β-hydroxy acid according to the present invention is characterized by comprising a step for bringing carbon dioxide into contact with a composition that contains an aromatic compound having a phenolic hydroxyl group, a strong base, and an aliphatic thiol compound.

Description

Method for producing aromatic β-hydroxy acid

[0001] The present invention relates to a method capable of efficiently producing an aromatic β-hydroxy acid.

[0002] Aromatic β-hydroxy acids such as 2-hydroxybenzoic acid, so-called salicylic acid, etc. are skeletons widely found in useful substances such as pharmaceuticals, agricultural chemicals, cosmetics, functional foods, and luxury goods. Salicylic acid itself has an anti-inflammatory and analgesic effect and a skin keratolytic effect. Its derivatives such as acetylsalicylic acid and methyl salicylate are widely used as anti-inflammatory and analgesic agents.

[0003] Also, cannabis-derived components containing salicylic acid in their partial structure are collectively called acidic cannabinoids. Acidic cannabinoids are known to have diverse and attractive pharmacological effects. When decarboxylation occurs due to heat, light, metabolism, etc., they lose the carboxy group and become something other than salicylic acid. The resulting group of compounds is collectively called neutral cannabinoids, and these also become useful substances. For example, cannabidiolic acid is an acidic cannabinoid, and like cannabidiol, which is a neutral cannabinoid, it is not only a useful cannabis component in pharmaceuticals, functional foods, and luxury goods, but can also be a synthetic raw material for other useful substances.

[0004] As a typical chemical synthesis method for aromatic β-hydroxy acids, the Kolbe-Schmitt (hereinafter referred to as "Kolbe-Schmitt") reaction for introducing a carboxy group at the β-position of a phenolic hydroxyl group can be mentioned. In this reaction, the metal salt of an aromatic β-hydroxy acid produced by reacting carbon dioxide with a metal salt of a phenol compound under high temperature and high pressure is neutralized with a strong acid to liberate the aromatic β-hydroxy acid. Since this reaction was discovered in 1885, due to its practicality, it has been applied to the industrial-scale production of various aromatic β-hydroxy acids.

[0005] However, for the implementation of the Kolbe-Schmitt reaction and its improved methods, high-pressure carbon dioxide is essential. For the implementation of a reaction involving pressurization, a pressure vessel for pressurization is required. In addition, the manufacturing process involving pressurization has risks associated with a wide range of hazards. Therefore, the development of a Kolbe-Schmitt type reaction that does not require high pressure is required.

[0006] Several Kolbe-Schmidt type reactions that can be carried out under atmospheric pressure have been reported to date. The Mechoulam method, the Yamada method, and the Larrosa method are examples of methods that show a relatively wide range of applicability, but each has problems that hinder their practical use. For example, the Mechoulam method (Non-Patent Literature 1) requires the use of expensive Styles reagent (magnesium methyl carbonate). Furthermore, it is known that the yield will be significantly lower if the starting compound does not have a 3-hydroxyphenol (hereinafter referred to as "resorcinol") structure.

[0007] The Yamada method (Non-Patent Literature 2) also suffers from the problem of its applicability, as the starting compound must have a resorcinol structure. Furthermore, since there are very few experimental examples under atmospheric pressure, the usefulness of the Yamada method under atmospheric pressure is largely unknown. For example, Patent Literature 1 reports that the Yamada method can be used to produce cannabidiolic acid, but it describes carrying out the reaction under carbon dioxide at 24 to 36 bar.

[0008] The Larrosa process (Non-Patent Literature 3) has the advantages of not requiring the use of solvents and yielding aromatic β-hydroxy acids in good yield even if the starting compounds do not have a resorcinol structure. However, the Larrosa process requires homogenizing the starting compounds in the reaction vessel by grinding them down in a facility or space filled with inert gas, such as a glove box. Therefore, the Larrosa process is unsuitable for large-scale industrial production. Furthermore, 2,4,6-trimethylphenol (hereinafter referred to as "meshitol"), which is necessary for the Larrosa process, is relatively expensive. Moreover, separating meshitol from the target compound, the aromatic β-hydroxy acid, after the reaction requires column chromatography, which is unsuitable for large-scale implementation.

[0009] Furthermore, Patent Document 2 describes a method for producing a sulfurized aliphatic hydrocarbon-substituted metal salicylate, which involves sulfurizing an aliphatic hydrocarbon-substituted phenol with sulfur halides such as sulfur or sulfur chloride, and then converting it to an alkali metal salicylate using an alkali metal hydroxide and carbon dioxide. However, the chemical structure of the target compound, the sulfurized aliphatic hydrocarbon-substituted metal salicylate, remains unclear. In addition, high-pressure carbon dioxide at 14 bar is used.

[0010] Furthermore, Patent Documents 3 and 4 describe a method for producing a mixture of salicylic acids and alkaline earth metal salts of phenols, which involves reacting phenols, dihydric alcohols, and alkaline earth metal reagents such as calcium oxide, then reacting with carbon dioxide, and finally adding dihydric alcohols and sulfur to carry out a sulfidation reaction. However, since high-pressure carbon dioxide of 5 atm or 3 atm is used, these methods are also not suitable for large-scale implementation. It should be noted that a Kolbe-Schmidt type reaction is carried out until the reaction with sulfur, and sulfur is used for adjusting the hue, so it is thought that sulfur is not involved in the carboxyl group introduction reaction.

[0011] International Publication No. 2023 / 205298 Pamphlet Japanese Patent Publication No. Sho 61-24562 Japanese Patent Publication No. Hei 6-211779 Japanese Patent Publication No. Hei 6-211780

[0012] Mechoulam, R. et al., J. Chem. Soc. D. , 1969, pp. 343-344 Yamada, T. et al., Chem. Commun. , 2019, 55, p. 9837 Larrosa, I. et al., Chem. Eur. J. , 2016, 22, p. 6798

[0013] As mentioned above, various methods have been developed to produce aromatic β-hydroxy acids from aromatic compounds having phenolic hydroxyl groups, but these methods are unsuitable for large-scale industrial implementation, for example, because they require the use of high-pressure carbon dioxide. Therefore, the present invention aims to provide a method for efficiently producing aromatic β-hydroxy acids.

[0014] In order to solve the above problems, the present inventors have conducted intensive studies. As a result, they have found that by using a relatively inexpensive aliphatic thiol compound, a carboxy group can be introduced into an aromatic compound having a phenolic hydroxyl group without using high-pressure carbon dioxide, and thus completed the present invention. Hereinafter, the present invention will be described.

[0015] [1] A method for producing an aromatic β-hydroxy acid, comprising a step of contacting a composition containing an aromatic compound having a phenolic hydroxyl group, a strong base, and an aliphatic thiol compound with carbon dioxide. [2] The method according to [1], wherein a metal hydride is used as the strong base. [3] The method according to [1] or [2], wherein an C 2-14 alkanethiol is used as the aliphatic thiol compound. [4] The aromatic compound may have, in addition to the phenolic hydroxyl group, a C 1-20 alkyl group which may have a substituent α, a C 2-20 alkenyl group which may have a substituent α, a C 2-20 alkynyl group which may have a substituent α, a C 1-6 alkoxy group, a phenoxy group which may have a substituent β, a sulfhydryl group, a C 1-6 alkylthio group which may have a substituent α, a phenylthio group which may have a substituent β, a carboxy group, a (C 1-6 alkyl)oxycarbonyl group, an amide group, a formyl group, an amino group, a halogeno group, a C 6-12 aryl-C 1-6 alkyl group, an oxo group, a methylidene group, a nitro group, and a cyano group, and may have a substituent selected from the group consisting of: Substituent α is a C 1-6 alkoxy group, a C 1-6 alkylthio group, a hydroxyl group, a sulfhydryl group, a carboxy group, an amino group, a halogeno group, an ester group, a nitro group, and a cyano group, and represents one or more substituents selected therefrom; Substituent β is a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 1-6 alkoxy group, a C 1-6The method according to any one of the above [1] to [3], wherein the substituent is selected from alkylthio group, hydroxyl group, sulfhydryl group, amino group, halogeno group, nitro group, and cyano group. [5] The aromatic compound is a carboxyl group, (C 1-6 The method according to any one of [1] to [3], wherein the substituent is selected from alkyl)oxycarbonyl group, amide group, formyl group, halogeno group, nitro group, and cyano group. [6] The method according to any one of [1] to [5], wherein the composition is brought into contact with carbon dioxide at 80°C or higher. [7] The method according to any one of [1] to [6], wherein the aliphatic thiol compound is used in a ratio of 1 mole to 5 moles relative to the phenolic hydroxyl group. [8] The method according to any one of [1] to [7], wherein the strong base is used in a ratio of 1 mole to 10 moles relative to the phenolic hydroxyl group.

[0016] According to the present invention, it is not necessary to use high-pressure carbon dioxide, and it is possible to introduce a carboxyl group to the β-position of the phenolic hydroxyl group of an aromatic compound. Furthermore, the aliphatic thiol compound used in the present invention is relatively inexpensive. Therefore, the present invention is industrially excellent as a technology that can be applied to the large-scale industrial production of useful aromatic β-hydroxy acids.

[0017] The following describes a method for producing aromatic β-hydroxy acids according to the present invention, but the present invention is not limited to the following specific examples. Hereinafter, "compound (x)" means "compound represented by formula (x)".

[0018] 1. Anionization process of phenolic hydroxyl groups and aliphatic thiol compounds In this process, an aromatic compound having at least a phenolic hydroxyl group, a strong base, and an aliphatic thiol compound are mixed to neutralize the aromatic compound having a phenolic hydroxyl group and obtain a phenoxide anion and a thiolate anion.

[0019] (1) Aromatic compounds having a phenolic hydroxyl group Aromatic compounds are cyclic unsaturated organic compounds that exhibit aromaticity, and include aromatic hydrocarbon compounds and heterocyclic aromatic compounds.

[0020] Examples of aromatic hydrocarbon compounds include C 6-22 Aromatic hydrocarbon compounds can be used. 6-22 Aromatic hydrocarbon compounds are compounds having 6 or more carbon atoms and 22 or less carbon atoms. Examples include benzene, indene, naphthalene, dihydronaphthalene, tetrahydronaphthalene, biphenyl, dihydrobiphenyl, tetrahydrobiphenyl, biphenylene, fluorene, phenalene, phenanthrene, anthracene, pyrene, chrysene, naphthacene, pentaphene, and pentacene. Aromatic hydrocarbon compounds include C 6-12 Aromatic hydrocarbon compounds are preferred, benzene and naphthalene are more preferred, and benzene is even more preferred. Note that cycloalkyl rings such as dihydrobiphenyl and tetrahydrobiphenyl, and cycloalkenyl rings may also be bicyclic systems having a cross-linking structure, such as a bicycloheptenyl group.

[0021] Heterocyclic aromatic compounds refer to five-membered heterocyclic aromatic compounds, six-membered heterocyclic aromatic compounds, or fused heterocyclic aromatic compounds having at least one heteroatom such as N, O, and / or S. Examples include five-membered heterocyclic aromatic compounds such as pyrrole, imidazole, pyrazole, thiophene, furan, oxazole, isoxazole, thiazole, isothiazole, and thiadiazole; six-membered heterocyclic aromatic compounds such as pyridine, pyrazine, pyrimidine, pyridazine, and pyran; and condensed heterocyclic aromatic compounds such as indole, isoindole, quinoline, isoquinoline, benzofuran, isobenzofuran, chroman, isochroman, chromene, isochromene, thianthrene, xanthene, phenoxazine, purine, acridine, benzoxepin, dihydrobenzoxepin, tetrahydrobenzoxepin, dibenzochromene, tetrahydrodibenzochromene, hexahydrobenzochromene, dibenzoquinoline, tetrahydrodibenzoquinoline, hexahydrobenzoquinoline, and octahydro-oxabenzoanthracene.

[0022] The number of phenolic hydroxyl groups in the aromatic compound is preferably two or less, and more preferably one. In the method of the present invention, a carboxyl group is introduced on the carbon adjacent to the phenolic hydroxyl group, i.e., at the β position.

[0023] Aromatic compounds may have substituents other than phenolic hydroxyl groups, as long as they do not inhibit the reaction. Examples of substituents other than phenolic hydroxyl groups include C, which may have substituent α. 1-20 C may have an alkyl group or substituent α. 2-20 C may have an alkenyl group and a substituent α. 2-20 C may have an alkynyl group and a substituent α. 1-6 An alkoxy group, a phenoxy group which may have a substituent β, a sulfhydryl group, or a C which may have a substituent α 1-6 Alkylthio group, phenylthio group which may have a substituent β, carboxyl group, (C 1-6 C may have an alkyl)oxycarbonyl group, an amide group, a formyl group, an amino group, a halogeno group, or a substituent β. 6-12 Aryl-C 1-6 Examples of substituents include alkyl groups, oxo groups, methylidene groups, nitro groups, and cyano groups.

[0024] C 1-20 Alkyl groups are monovalent saturated aliphatic hydrocarbon groups having 1 to 20 carbon atoms, in a linear, branched, or cyclic configuration. Examples include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, s-butyl, t-butyl, cyclobutyl, n-pentyl, cyclopentyl, n-hexyl, cyclohexyl, dimethylpentyl, dimethylheptyl, dimethylhexyl, dimethylheptyl, dimethyloctyl, dimethylnonyl, hexylcyclobutyl, adamantyl, etc. Preferably C 1-10 It is an alkyl group, more preferably C 1-6 It is an alkyl group. A cyclic alkyl group may also be a spiro ring group.

[0025] C 2-20An alkenyl group is a monounsaturated aliphatic hydrocarbon group having 2 to 20 carbon atoms and possessing at least one carbon-carbon double bond, in a linear, branched, or cyclic configuration. Examples include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-butenyl, 3-butenyl, isobutenyl, 3-methyl-2-butenyl (prenyl), pentenyl, 4-methyl-3-pentenyl, hexenyl, heptenyl, 3,6-dimethyl-2,5-heptadienyl, 3,7-dimethyl-2,6-octadienyl (geranyl), 3,7,11-trimethyl-2,6,10-octatriene, 3-methyl-6-(2-propenyl)-2-cyclohexenyl (farnesyl), 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenyl (geranylgeranyl), etc. Preferably C 2-10 It is an alkenyl group. The cyclic alkenyl group may also be a spiro ring group.

[0026] C 2-20 An alkynyl group is a linear, branched, or cyclic monounsaturated aliphatic hydrocarbon group having 2 to 20 carbon atoms and at least one carbon-carbon triple bond. Examples include ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, pentynyl, hexynyl, etc. Preferably C 2-10 An alkynyl group, more preferably C 2-3 It is an alkynyl group.

[0027] C 1-6 An alkoxy group is a linear or branched saturated aliphatic hydrocarbon oxy group having 1 to 6 carbon atoms. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentoxy, n-hexoxy, etc., preferably C 1-4 It is an alkoxy group, more preferably C 1-2 It is an alkoxy group, and more preferably a methoxy group.

[0028] C 1-6Alkylthio groups refer to linear or branched saturated aliphatic hydrocarbon thio groups having 1 to 6 carbon atoms. Examples include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, t-butylthio, n-pentylthio, n-hexylthio, etc., preferably C 1-4 It is an alkylthio group, more preferably C 1-2 It is an alkylthio group, and more preferably a methylthio group.

[0029] In addition to the carbamoyl group (-CONH2), the amide group also includes mono(C) 1-6 Alkyl)aminocarbonyl group, di(C) 1-6 The compounds also include alkyl)aminocarbonyl groups, monoarylaminocarbonyl groups, and monoheteroarylcarbonyl groups. The aryl group refers to a monovalent aromatic hydrocarbon group corresponding to the aromatic hydrocarbon compound, and the heteroaryl group refers to a monovalent aromatic hydrocarbon group corresponding to the heteroaryl group. The aryl group and heteroaryl group may have the substituent β. That is, the amide group may be, for example, a carbamoyl group (-CONH2); mono(C)aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, isobutylaminocarbonyl, s-butylaminocarbonyl, t-butylaminocarbonyl, n-pentylaminocarbonyl, isopentylaminocarbonyl, n-hexylaminocarbonyl, isohexylaminocarbonyl, etc. 1-6 Alkyl)aminocarbonyl group; such as dimethylaminocarbonyl, diethylaminocarbonyl, ethylmethylaminocarbonyl, dipropylaminocarbonyl, methylpropylaminocarbonyl, ethylpropylaminocarbonyl, etc. 1-6 Examples include alkyl)aminocarbonyl groups; monoarylaminocarbonyl groups such as phenylaminocarbonyl; and monoheteroarylaminocarbonyl groups such as pyridylamino.

[0030] The amino group includes not only the -NH2 group in the narrow sense, but also mono(C) 1-6 Alkyl)amino group, di(C) 1-6Alkyl)amino group, monoarylamino group, diarylamino group, monoheteroaryl group, diheteroaryl group, C 1-6 Alkylarylamino group, and C 1-6 Alkyl heteroarylamino groups are also included. The aryl and heteroaryl groups may have the substituent β. That is, the amino group may be, for example, -NH2; mono(C) such as methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, s-butylamino, t-butylamino, n-pentylamino, isopentylamino, n-hexylamino, isohexylamino, etc. 1-6 Alkyl)amino group; such as dimethylamino, diethylamino, ethylmethylamino, dipropylamino, methylpropylamino, ethylpropylamino, etc. 1-6 Alkyl)amino groups; monoarylamino groups such as phenylamino; diarylamino groups such as diphenylamino; monoheteroarylamino groups such as pyridylamino; diheteroarylamino groups such as dipyridylamino; C groups such as N-methyl-N-phenylamino and N-ethyl-N-phenylamino. 1-6 Alkylarylamino groups; and C groups such as N-methyl-N-pyridylamino and N-ethyl-Npyridylamino. 1-6 Examples include alkyl heteroarylamino groups.

[0031] Examples of halogen groups include fluoro, chloro, bromo, and iodine, with chloro, bromo, and / or iodine being preferred, and chloro and / or bromo being more preferred.

[0032] C 6-12 Aryl-C 1-6 An alkyl group refers to an alkyl group having 1 to 6 carbon atoms that is substituted with one aromatic hydrocarbon group having 6 to 12 carbon atoms. Examples include benzyl, phenethyl, phenylpropyl, naphthylmethyl, naphthylethyl, and biphenylmethyl, with benzyl and phenethyl being preferred.

[0033] The oxo group can be substituted onto the methylene group (-CH2-) of a fused ring heterocyclic aromatic compound to form a carbonyl group (-C(=O)-). Similarly, the methylidene group can be substituted onto the methylene group (-CH2-) of a fused ring heterocyclic aromatic compound to form a >C=CH2 group.

[0034] As a substituent α, C 1-6 Alkoxy group, C 1-6 Examples include one or more substituents selected from alkylthio groups, hydroxyl groups, sulfhydryl groups, carboxyl groups, amino groups, halogeno groups, ester groups, nitro groups, and cyano groups, and the substituent β is C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Examples include one or more substituents selected from alkylthio groups, hydroxyl groups, sulfhydryl groups, amino groups, halogeno groups, nitro groups, and cyano groups.

[0035] The number of substituents is not particularly limited as long as they are substituted. However, in this invention, since a carboxyl group is introduced at the β-position of the phenolic hydroxyl group, at least one of the β-positions of the phenolic hydroxyl group must be free of substituents. The number of substituents other than the phenolic hydroxyl group is preferably 4 or less, preferably 3 or less, and more preferably 1 or 2. After a carboxyl group is introduced at the β-position of the phenolic hydroxyl group, the electron density of the aromatic compound decreases due to the electron-withdrawing carboxyl group, thus reducing its nucleophilicity. Therefore, it is considered difficult to substitute with two or more carboxyl groups. However, if the first carboxyl group is introduced into 2-hydroxyphenol (catechol) or 4-hydroxyphenol compounds, the hydroxyl group that did not participate in the reaction is not stabilized by the first introduced carboxyl group, so there is a possibility that a second carboxyl group may be introduced.

[0036] Two or more substituents may, together with the carbon atoms they substitute for, form a cyclic structure. For example, two adjacent carbon atoms in an aromatic compound may bond with the alkyl and / or alkenyl groups substituted on each carbon atom to form a cyclopropyl group, cyclohexyl group, cyclohexenyl group, methylcyclohexenyl group, and the like.

[0037] Carboxy group, (C 1-6 Electron-withdrawing groups such as alkyl)oxycarbonyl groups, amide groups, formyl groups, halogeno groups, nitro groups, and cyano groups tend to inactivate aromatic compounds, making it difficult to introduce carboxyl groups into aromatic compounds having these substituents using conventional methods. In contrast, according to the method of the present invention, as shown in the examples below, it is possible to introduce carboxyl groups into aromatic compounds substituted with electron-withdrawing groups in addition to hydroxyl groups.

[0038] (2) Strong base In this step, the phenolic hydroxyl group of the aromatic compound is neutralized with a strong base to obtain a phenoxide anion. Examples of strong bases include alkali metal hydrides such as sodium hydride and potassium hydride; group 2 metal hydrides such as calcium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; group 2 metal hydroxides such as calcium hydroxide, strontium hydroxide, and barium hydroxide; and metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium t-butoxide.

[0039] As a strong base, metal hydrides that do not produce water (H2O) upon neutralization are preferred. Alkali metal hydroxides are inexpensive and therefore preferred from a cost standpoint, but they do produce water upon neutralization. Furthermore, when using hydroxides, it is preferable to use a solvent with high solubility and affinity for the hydroxide. Suitable solvents include, for example, alcohol solvents such as methanol, ethanol, and 2-propanol. Therefore, when using hydroxides as a strong base, it is preferable to remove water or the alcohol solvent after neutralization. When using metal alkoxides, alcohol is produced upon neutralization, so it is preferable to remove the alcohol after neutralization.

[0040] The amount of strong base used should be adjusted appropriately within a range in which the phenolic hydroxyl groups of the aromatic compound are sufficiently neutralized. For example, the ratio of moles of strong base to (moles of phenolic hydroxyl groups of the aromatic compound) × (valence of strong base) can be set to 1 or more and 10 or less. Preferably, this ratio is 2 or more, more preferably 3 or more, preferably 8 or less, more preferably 7.5 or less or 7 or less, and even more preferably 6 or less. If the aromatic compound has substituents that react with the strong base in addition to phenolic hydroxyl groups, such as thiol groups or carboxyl groups, it is preferable to similarly adjust the ratio of moles of phenolic hydroxyl groups and such reactive substituents to the total to be 1 or more and 10 or less.

[0041] (3) Aliphatic Thiol Compounds In this step, aliphatic thiol compounds are used. Aliphatic thiol compounds are converted to thiolate anions by a strong base, and these thiolate anions react with carbon dioxide to form thiocarbonate anions. The thiocarbonate anions then reversibly bond with carbon dioxide to promote the reaction with phenoxide anions, or the thiocarbonate anions themselves act as carboxylating agents, potentially allowing the introduction of carboxyl groups into aromatic compounds even at atmospheric or near-atmospheric pressure. Furthermore, aliphatic thiols can be easily removed from the target compound, the aromatic β-hydroxy acid.

[0042] As for aliphatic thiols, C 2-14Alkanethiols are preferred. Ethanethiol, which has two carbon atoms, has a boiling point of 35°C at atmospheric pressure, and 1-tetradecanethiol, which has fourteen carbon atoms, has a melting point of 6-7°C. Since both are almost liquid at atmospheric pressure, if the alkanethiol has two or more carbon atoms and 14 or less, it is considered that the reaction solution will be liquid at least at the beginning of the reaction, even if a solvent is not required or only a small amount of solvent is used, and the reaction will proceed smoothly. In addition, generally speaking, the larger the number of carbon atoms in the aliphatic thiol, the easier it is to separate it from the target compound, the aromatic β-hydroxy acid. Therefore, the number of carbon atoms is preferably 6 or more, more preferably 8 or more, and even more preferably 10 or more. On the other hand, in order to be stably liquid and easy to use as a solvent, the number of carbon atoms in the aliphatic thiol is preferably 13 or less, and more preferably 12 or less.

[0043] The aliphatic hydrocarbon group of an aliphatic thiol may be substituted with substituents such as hydroxyl groups, amino groups, or pyridyl groups. Because aliphatic thiols with these substituents are highly water-soluble, they may be more easily separated from the target compound, the aromatic β-hydroxy acid. If the aliphatic thiol has an amino group or pyridyl group, it may also be a salt. Note that the amino group may be not only the -NH2 group in the narrow sense, as described above, but also a mono(C) group. 1-6 Alkyl)amino group and di(C) 1-6 Alkyl(amino) groups are also included.

[0044] Examples of aliphatic thiols include ethanediol, 1-propanethiol, 1-butanethiol, 1-pentanethiol, 1-hexanethiol, 1-heptanethiol, 1-octanthiol, 1-decanethiol, 1-undecanethiol, 1-dodecanethiol, 1-tetradecanethiol, 1-pentadecanethiol, 1-hexadecanethiol, 1-octadecanethiol, 1-docosathiol, 2-hydroxyethanethiol, 2-aminoethanethiol, 2-dimethylaminoethanethiol, and 2-diisopropylaminoethanethiol.

[0045] The amount of aliphatic thiol used can be adjusted as appropriate within a range that allows for the introduction of carboxyl groups into the aromatic compound under mild conditions. For example, the ratio of moles of aliphatic thiol to moles of phenolic hydroxyl groups in the aromatic compound can be 1 to 10 times. Preferably, this ratio is 1.2 times or more, more preferably 1.5 times or more, preferably 5 times or less, and more preferably 4 times or less or 2 times or less.

[0046] (4) Solvent In this step, it is preferable not to use a solvent because it is necessary to separate the target compound, the aromatic β-hydroxy acid. However, when hydroxide is used as the strong base, it is preferable to use an alcohol solvent as described above. In addition, when the aliphatic thiol is a gas or solid at room temperature and pressure, or when the aromatic compound is difficult to dissolve in the aliphatic thiol, for example, a nitrile solvent such as acetonitrile; an aromatic hydrocarbon solvent such as benzene, toluene, xylene, chlorobenzene, bromobenzene, dichlorobenzene, dibromobenzene; a halogenated hydrocarbon solvent such as dichloromethane, chloroform, carbon tetrachloride; an amide solvent such as dimethylformamide, dimethylacetamide; a sulfoxide solvent such as dimethyl sulfoxide; or an ether solvent such as diethyl ether, tetrahydrofuran, diglyme, triglyceride, tetraglyceride, polyethylene glycol may be used.

[0047] When using a solvent, it is preferable to minimize the amount of solvent used in order to suppress the inclusion of water as much as possible. For example, it is preferable to keep the ratio of the solvent to the total amount of the aromatic compound, strong base, aliphatic thiol compound, and solvent to 50% by mass or less. More preferably, this ratio is 20% by mass or less, and even more preferably 10% by mass or less or 5% by mass or less. There is no particular lower limit to this ratio, but it can be, for example, 1% by mass or more.

[0048] (5) Reaction conditions In this step, it is sufficient to mix at least an aromatic compound, a strong base, and an aliphatic thiol compound. It is believed that the phenolic hydroxyl group of the aromatic compound is rapidly neutralized by reacting the aromatic compound with the strong base in solution or suspension.

[0049] The reaction in this process is preferably carried out under an atmosphere of an inert gas such as nitrogen gas or argon gas in order to suppress the introduction of moisture into the system.

[0050] The reaction time in this step can be adjusted as appropriate within the range in which the phenolic hydroxyl groups of the aromatic compound are sufficiently neutralized. For example, it can be continued until the consumption of the aromatic compound is confirmed by thin-layer chromatography, or it can be determined by preliminary experiments. However, since this neutralization reaction generally proceeds rapidly, it can be set to, for example, 1 minute or more and 30 minutes or less. If an alkali metal hydride is used as the strong base, the reaction may be continued until the generation of hydrogen gas can no longer be confirmed. The reaction temperature can also be adjusted as appropriate. For example, it may be set to 0°C or more and 35°C or less, or the reaction may be carried out at room temperature. However, if the reaction solution contains insoluble components or if the viscosity of the reaction solution is high, the temperature may be heated to, for example, 50°C or more and 120°C or less to ensure that the reaction proceeds more reliably. The temperature may also be increased stepwise or continuously.

[0051] When a hydroxide is used as the base, water is generated by neutralization of the phenolic hydroxyl group, and when a metal alkoxide is used, alcohol is generated. It is preferable to remove the water and alcohol for the next step. There are no particular restrictions on the method of removing the water and alcohol, and any conventional method may be used, for example, by vacuum distillation or by adding anhydrous sodium sulfate or anhydrous magnesium sulfate and filtering.

[0052] 2. Carboxylate group introduction step In this step, a composition derived from step 1, which contains an aromatic compound having at least a neutralized phenolic hydroxyl group and an aliphatic thiol compound, is brought into contact with carbon dioxide to introduce a carboxylate group at the β position of the phenolic hydroxyl group of the aromatic compound, thereby obtaining an aromatic β-hydroxy acid.

[0053] Methods for contacting the composition with carbon dioxide include, for example, replacing the gas phase of the reaction system in step 1 with a carbon dioxide-containing gas in a closed system, or continuously supplying the carbon dioxide-containing gas to the gas phase. It is preferable that the carbon dioxide-containing gas is free of moisture or has its moisture content reduced by drying it beforehand by passing it through silica gel or the like, or by using carbon dioxide gas or a mixed gas of carbon dioxide and an inert gas. The carbon dioxide concentration in the carbon dioxide-containing gas is preferably 50 vol% or more, more preferably 70 vol% or more or 80 vol% or more, and even more preferably 90 vol% or more or 95 vol% or more. There is no particular upper limit to the concentration, but substantially 100 vol% is preferred.

[0054] Alternatively, a carbon dioxide-containing gas can be blown into the agitated composition. In this case, the reaction may proceed even if a carbon dioxide-containing gas with a relatively low carbon dioxide concentration is used. For example, air contains approximately 0.04 vol% carbon dioxide, and using air would offer significant cost advantages.

[0055] Conventional Kolbe-Schmidt reactions have used high-pressure carbon dioxide. In contrast, the method of the present invention does not require high-pressure carbon dioxide. However, the carbon dioxide-containing gas may be slightly pressurized for supplying the gas or in a closed system. For example, while atmospheric pressure is approximately 1013 hPa, a carbon dioxide-containing gas with a pressure of 1013 hPa or more and 1200 hPa or less may be used. The pressure is preferably 1150 hPa or less, and more preferably 1100 hPa or less.

[0056] The reaction temperature in this step can be appropriately adjusted within the range in which a carboxyl group is introduced at the β-position of the phenolic hydroxyl group, for example, it can be 80°C or higher and 250°C or lower. Preferably, the temperature is 100°C or higher or 120°C or higher, more preferably 150°C or higher, preferably 220°C or lower, and more preferably 200°C or lower. Similarly, the reaction time can be appropriately adjusted within the range in which a carboxyl group is introduced at the β-position of the phenolic hydroxyl group, for example, until the consumption of the neutralized aromatic compound is confirmed by thin-layer chromatography, or it can be determined by preliminary experiments, for example, it can be 1 hour or more and 20 hours or less. The temperature can also be increased stepwise or continuously. For example, after contacting the composition with carbon dioxide at room temperature, the reaction temperature can be increased stepwise or continuously.

[0057] 3. Post-processing step In this step, the target compound, aromatic β-hydroxy acid, is purified from the reaction solution after the reaction. For example, after it is confirmed that the aromatic compound having a phenolic hydroxyl group neutralized in step 2 has been consumed and / or that a carboxyl group has been sufficiently introduced into the aromatic compound, water is added to the reaction solution, for example, 10 to 30 times its volume, to stop the reaction, and then hydrochloric acid or the like is added to make the solution acidic. Next, the aromatic β-hydroxy acid is extracted with a water-insoluble organic solvent such as ethyl acetate or chloroform. As a result, water-soluble compounds derived from strong bases can be removed.

[0058] If the target compound, an aromatic β-hydroxy acid, is highly hydrophobic, it may be difficult to separate it from the aliphatic thiol compound. In such cases, water may be added to the reaction solution to stop the reaction, then a base such as an aqueous sodium hydroxide solution may be added to make the solution basic, and the aliphatic thiol compound may be extracted and removed with a water-insoluble organic solvent while the aromatic β-hydroxy acid remains in the aqueous phase. Subsequently, after making the aqueous phase acidic as described above, the aromatic β-hydroxy acid may be extracted with a water-insoluble organic solvent.

[0059] The obtained extract is dried with anhydrous sodium sulfate or anhydrous magnesium sulfate and concentrated. The target compound, aromatic β-hydroxy acid, has hydrophilic phenolic hydroxyl groups and carboxyl groups, and is therefore generally insoluble in aliphatic hydrocarbon solvents such as n-hexane. In contrast, aliphatic thiol compounds have a common structure of aliphatic hydrocarbon groups and therefore have a high affinity for aliphatic hydrocarbon solvents. Thus, by adding an aliphatic hydrocarbon solvent to the concentrated residue, separating the insoluble components from the liquid phase by filtration or centrifugation, and then washing with the aliphatic hydrocarbon solvent, the aliphatic thiol compounds can be removed, and aromatic β-hydroxy acid can be purified. As mentioned above, if the aromatic β-hydroxy acid is highly hydrophobic, the aliphatic thiol compounds can be removed from the basic aqueous phase, and washing of the crude aromatic β-hydroxy acid product with hexane may not be necessary. The aromatic β-hydroxy acid may be further purified by general methods such as acid-base extraction or recrystallization. Specifically, aromatic β-hydroxy acids, which are the target compounds, can generally be extracted into basic aqueous solutions due to their phenolic hydroxyl or carboxyl groups. In contrast, aliphatic thiol compounds, especially those with a large number of carbon atoms, are highly lipophilic and can therefore be separated from aqueous solutions of aromatic β-hydroxy acids. Furthermore, aromatic β-hydroxy acids can be extracted with organic solvents that are immiscible with water, such as chloroform or ethyl acetate, by making their basic aqueous solution acidic.

[0060] As described above, the present invention allows for the introduction of carboxyl groups into aromatic compounds having phenolic hydroxyl groups without the use of high-pressure carbon dioxide, thus eliminating the need for highly resistant manufacturing equipment or high-pressure carbon dioxide supply equipment. Furthermore, the reagents used, a strong base and aliphatic thiol compounds, are relatively inexpensive. Moreover, hydrophilic components derived from the strong base and aliphatic thiol compounds after the reaction can be easily removed from the target compound, aromatic β-hydroxy acid, without the need for purification methods unsuitable for large-scale mass production, such as column chromatography. Therefore, the present invention enables the efficient and low-cost production of aromatic β-hydroxy acids and is suitable for large-scale mass production.

[0061] This application claims the benefit of priority based on Japanese Patent Application No. 2024-177171, filed on 9 October 2024. The entire specification of Japanese Patent Application No. 2024-177171, filed on 9 October 2024, is incorporated herein by reference.

[0062] The present invention will be described in more detail below with reference to examples, but the present invention is not limited by the following examples, and it is certainly possible to implement it with appropriate modifications within the scope that is consistent with the spirit of the preceding and following descriptions, and all such modifications are included within the technical scope of the present invention.

[0063] Example 1: Synthesis of 3-methylsalicylic acid 2-Methylphenol (25.7 μL, 0.250 mmol, 1.00 equivalent), 1-Dodecanethiol (89.8 μL, 0.375 mmol, 1.50 equivalent), and sodium hydride (60% by mass, 50.0 mg, 1.25 mmol, 5.0 equivalent) were mixed under a nitrogen atmosphere at room temperature and reacted for 5 minutes. Subsequently, this mixture was reacted under a carbon dioxide atmosphere at room temperature for 5 minutes, and then reacted at 185°C for 2 hours. Next, the reaction was stopped by adding water (2 mL) to the mixture at room temperature, then acidified by adding 1 M hydrochloric acid (2 mL), and extracted three times with ethyl acetate (3 mL). Subsequently, the ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Subsequently, the obtained crude product was suspended in hexane (2 mL) and filtered. The obtained solid was then washed with hexane (8 mL) to obtain 3-methylsalicylic acid as a pale yellow solid (yield: 34.5 mg, 0.227 mmol, yield: 91%). 1 ¹H NMR (400 MHz, deuterated acetone) δ 11.42 (br s, 1H), 7.74 (dd, J=8.0, 1.3 Hz, 1H), 7.40 (br d, J=7.3 Hz, 1H), 6.84 (dd, J=8.0, 7.3 Hz, 1H), 2.22 (s, 3H)

[0064] Example 2: Synthesis of 3-ethyl salicylic acid 2-ethylphenol (29.4 μL, 0.250 mmol, 1.00 equivalent), 1-dodecanethiol (89.8 μL, 0.375 mmol, 1.50 equivalent), and sodium hydride (60% by mass, 50.0 mg, 1.25 mmol, 5.0 equivalent) were mixed under a nitrogen atmosphere at room temperature and reacted for 5 minutes. Subsequently, this mixture was reacted under a carbon dioxide atmosphere at room temperature for 5 minutes, and then reacted at 185°C for 2 hours. Next, the reaction was stopped by adding water (2 mL) to the mixture at room temperature, then acidified by adding 1 M hydrochloric acid (2 mL), and extracted three times with ethyl acetate (3 mL). Subsequently, the ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Subsequently, the obtained crude product was suspended in cold hexane (2 mL) and filtered. The obtained solid was then washed with cold hexane (4 mL) to obtain 3-ethylsalicylic acid as a white solid (yield: 32.6 mg, 0.196 mmol, yield: 78%). 1 H NMR (400 MHz, heavy acetone) δ11.45 (br s, 1H), 7.75 (dd, J=7.9, 1.5Hz, 1H), 7.42 (dd, J=7.5, 1.5Hz, 1H), 6.8 7 (dd, J=7.9, 7.5Hz, 1H), 2.66 (q, J=7.5Hz, 2H), 1.19 (t, J=7.5Hz, 3H)

[0065] Example 3: Synthesis of 4-methylsalicylic acid 3-Methylphenol (26.1 μL, 0.250 mmol, 1.00 equivalent), 1-Dodecanethiol (89.8 μL, 0.375 mmol, 1.50 equivalent), and sodium hydride (60% by mass, 50.0 mg, 1.25 mmol, 5.0 equivalent) were mixed under a nitrogen atmosphere at room temperature and reacted for 5 minutes. Subsequently, this mixture was reacted under a carbon dioxide atmosphere at room temperature for 5 minutes, followed by reaction at 185°C for 2 hours. Next, the reaction was stopped by adding water (2 mL) at room temperature, then acidified with 1 M hydrochloric acid (2 mL), and extracted three times with ethyl acetate (3 mL). The ethyl acetate layer was then washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was then suspended in hexane (2 mL) and filtered. The resulting solid was then washed with hexane (8 mL) to obtain a white solid. Subsequently, 1 ¹H NMR measurements confirmed that this white solid contained 4-methylsalicylic acid, the main product, as a mixture with 6-methylsalicylic acid, with an isomer purity of 99% (yield: 31.5 mg, 0.207 mmol, yield: 83%). 1 H NMR (400MHz, heavy acetone) δ11.05 (br s, 1H), 7.77 (d, J = 8.6Hz, 1H), 6.79-6.75 (m, 2H), 2.34 (s, 3H)

[0066] Example 4: Synthesis of 4-t-butylsalicylic acid 3-t-butylphenol (37.6 mg, 0.250 mmol, 1.00 equivalent), 1-dodecanethiol (89.8 μL, 0.375 mmol, 1.50 equivalent), and sodium hydride (60% by mass, 50.0 mg, 1.25 mmol, 5.0 equivalent) were mixed under a nitrogen atmosphere at room temperature and reacted for 5 minutes, followed by reaction at 100°C for 5 minutes. Subsequently, this mixture was reacted under a carbon dioxide atmosphere at room temperature for 5 minutes, followed by reaction at 185°C for 2 hours. Next, the reaction was stopped by adding water (2 mL) to the mixture at room temperature, then acidified by adding 1 M hydrochloric acid (2 mL), and extracted three times with ethyl acetate (3 mL). Subsequently, the ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Subsequently, the resulting crude product was suspended in hexane (2 mL) and filtered. The obtained solid was then washed with hexane (8 mL) to obtain 4-t-butylsalicylic acid as a white solid (yield: 31.5 mg, 0.162 mmol, yield: 65%). 1 ¹H NMR (400 MHz, deuterated acetone) δ 11.02 (br s, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.02 (dd, J=8.4, 1.8 Hz, 1H), 6.95 (d, J=1.8 Hz, 1H), 1.31 (s, 9H)

[0067] Example 5: Synthesis of 4-methoxysalicylic acid 3-Methoxyphenol (27.4 μL, 0.250 mmol, 1.00 equivalent), 1-Dodecanethiol (89.8 μL, 0.375 mmol, 1.50 equivalent), and sodium hydride (60% by mass, 50.0 mg, 1.25 mmol, 5.0 equivalent) were mixed under a nitrogen atmosphere at room temperature and reacted for 5 minutes. Subsequently, this mixture was reacted under a carbon dioxide atmosphere at room temperature for 5 minutes, and then reacted at 185°C for 2 hours. Next, the reaction was stopped by adding water (2 mL) to the mixture at room temperature, then acidified by adding 1 M hydrochloric acid (2 mL), and extracted three times with ethyl acetate (3 mL). Subsequently, the ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Subsequently, the obtained crude product was suspended in hexane (2 mL) and filtered. The obtained solid was then washed with hexane (8 mL) to obtain 4-methoxysalicylic acid as a pale yellow solid (yield: 39.0 mg, 0.232 mmol, yield: 93%). 1 ¹H NMR (400 MHz, deuterated acetone) δ 11.33 (br s, 1H), 7.80 (d, J=8.8 Hz, 1H), 6.51 (dd, J=8.8, 2.4 Hz, 1H), 6.46 (d, J=2.4 Hz), 3.86 (s, 3H)

[0068] Example 6: Synthesis of 4-dimethylaminosalicylic acid 3-dimethylaminophenol (34.3 mg, 0.250 mmol, 1.00 equivalent), 1-dodecanethiol (89.8 μL, 0.375 mmol, 1.50 equivalent), and sodium hydride (60% by mass, 50.0 mg, 1.25 mmol, 5.0 equivalent) were mixed under a nitrogen atmosphere at room temperature and reacted for 5 minutes, followed by reaction at 100°C for 5 minutes. Subsequently, this mixture was reacted under a carbon dioxide atmosphere at room temperature for 5 minutes, followed by reaction at 185°C for 2 hours. Next, the reaction was stopped by adding water (2 mL) to the mixture at room temperature, then acidified by adding 1 M hydrochloric acid (2 mL), and extracted three times with ethyl acetate (3 mL). Subsequently, the ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Subsequently, the resulting crude product was suspended in hexane (2 mL) and filtered. The obtained solid was then washed with hexane (8 mL) to obtain 4-dimethylaminosalicylic acid as a pale red solid (yield: 40.2 mg, 0.222 mmol, yield: 65%). 1 ¹H NMR (400 MHz, deuterated acetone) δ 11.25 (br s, 1H), 7.66 (d, J=9.0 Hz, 1H), 6.31 (dd, J=9.0, 2.5 Hz, 1H), 6.09 (d, J=2.5 Hz, 1H), 3.04 (s, 6H)

[0069] Example 7: Synthesis of 4-bromosalicylic acid 3-bromophenol (43.3 mg, 0.250 mmol, 1.00 equivalent), 1-dodecanethiol (89.8 μL, 0.375 mmol, 1.50 equivalent), and sodium hydride (60% by mass, 50.0 mg, 1.25 mmol, 5.0 equivalent) were reacted at room temperature under a nitrogen atmosphere for 5 minutes, followed by reaction at 100°C for 5 minutes. Subsequently, this mixture was reacted at room temperature under a carbon dioxide atmosphere for 5 minutes, followed by reaction at 185°C for 2 hours. Next, the reaction was stopped by adding water (2 mL) to the mixture at room temperature, then acidified by adding 1 M hydrochloric acid (2 mL), and extracted three times with ethyl acetate (3 mL). Subsequently, the ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Subsequently, the obtained crude product was suspended in hexane (2 mL) and filtered. Subsequently, the obtained solid was washed with hexane (8 mL) to obtain a white solid. Next, 1 ¹H NMR measurements confirmed that this white solid contained 4-bromosalicylic acid as a mixture with 6-bromosalicylic acid, with an isomer purity of 76% (yield: 42.4 mg, 0.195 mmol, yield: 78%). 1 ¹H NMR (400 MHz, deuterated acetone) δ 11.23 (br s, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.19 (d, J=1.9 Hz, 1H), 7.14 (dd, J=8.5, 1.9 Hz, 1H)

[0070] Example 8: Synthesis of 5-methylsalicylic acid 4-methylphenol (26.2 μL, 0.250 mmol, 1.00 equivalent), 1-dodecanethiol (89.8 μL, 0.375 mmol, 1.50 equivalent), and sodium hydride (60% by mass, 50.0 mg, 1.25 mmol, 5.0 equivalent) were mixed under a nitrogen atmosphere at room temperature and reacted for 5 minutes. Subsequently, this mixture was reacted under a carbon dioxide atmosphere at room temperature for 5 minutes, and then reacted at 185°C for 2 hours. Next, the reaction was stopped by adding water (2 mL) to the mixture at room temperature, then acidified by adding 1 M hydrochloric acid (2 mL), and extracted three times with ethyl acetate (3 mL). Subsequently, the ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Subsequently, the obtained crude product was suspended in hexane (2 mL) and filtered. The obtained solid was then washed with hexane (8 mL) to obtain 5-methylsalicylic acid as a white solid (yield: 17.2 mg, 0.113 mmol, yield: 45%). 1 ¹H NMR (400 MHz, deuterated chloroform) δ 10.21 (s, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.34 (dd, J=8.5, 2.2 Hz, 1H), 6.92 (d, J=8.5 Hz, 1H), 2.31 (s, 3H)

[0071] Example 9: Synthesis of 5-methylthiosalicylic acid 4-Methylthiophenol (35.1 mg, 0.250 mmol, 1.00 equivalent), 1-Dodecanethiol (89.8 μL, 0.375 mmol, 1.50 equivalent), and sodium hydride (60% by mass, 50.0 mg, 1.25 mmol, 5.0 equivalent) were mixed under a nitrogen atmosphere at room temperature and reacted for 5 minutes, followed by reaction at 100°C for 5 minutes. Subsequently, this mixture was reacted under a carbon dioxide atmosphere at room temperature for 5 minutes, followed by reaction at 185°C for 2 hours. Next, the reaction was stopped by adding water (2 mL) to the mixture at room temperature, then acidified by adding 1 M hydrochloric acid (2 mL), and extracted three times with ethyl acetate (3 mL). Subsequently, the ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Subsequently, the resulting crude product was suspended in hexane (2 mL) and filtered. The obtained solid was then washed with hexane (8 mL) to obtain 5-methylthiosalicylic acid as a white solid (yield: 15.9 mg, 0.0863 mmol, yield: 35%). 1 ¹H NMR (400 MHz, deuterated chloroform) δ 10.39 (br s, 1H), 7.86 (d, J=2.4 Hz, 1H), 7.50 (dd, J=8.7, 2.4 Hz, 1H), 6.97 (d, J=8.7 Hz, 1H), 2.48 (s, 3H)

[0072] Example 10: Synthesis of 3,4-dimethylsalicylic acid 2,3-dimethylphenol (30.5 mg, 0.250 mmol, 1.00 equivalent), 1-dodecanethiol (89.8 μL, 0.375 mmol, 1.50 equivalent), and sodium hydride (60% by mass, 50.0 mg, 1.25 mmol, 5.0 equivalent) were mixed under a nitrogen atmosphere at room temperature and reacted for 5 minutes, followed by reaction at 100°C for 5 minutes. Subsequently, this mixture was reacted under a carbon dioxide atmosphere at room temperature for 5 minutes, followed by reaction at 185°C for 2 hours. Next, the reaction was stopped by adding water (2 mL) to the mixture at room temperature, then acidified by adding 1 M hydrochloric acid (2 mL), and extracted three times with ethyl acetate (3 mL). Subsequently, the ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Subsequently, the resulting crude product was suspended in hexane (2 mL) and filtered. The obtained solid was then washed with hexane (8 mL) to obtain 3,4-dimethylsalicylic acid as a pale yellow solid (yield: 35.0 mg, 0.211 mmol, yield 84%). 1 ¹H NMR (400 MHz, deuterated acetone) δ 11.46 (br s, 1H), 7.64 (d, J=8.1 Hz, 1H), 6.75 (d, J=8.1 Hz, 1H), 2.29 (s, 3H), 2.14 (s, 3H)

[0073] Example 11: Synthesis of 3,5-dimethylsalicylic acid 2,4-dimethylphenol (30.2 μL, 0.250 mmol, 1.00 equivalent), 1-dodecanethiol (89.8 μL, 0.375 mmol, 1.50 equivalent), and sodium hydride (60% by mass, 50.0 mg, 1.25 mmol, 5.0 equivalent) were mixed under a nitrogen atmosphere at room temperature and reacted for 5 minutes. Subsequently, this mixture was reacted under a carbon dioxide atmosphere at room temperature for 5 minutes, and then reacted at 185°C for 2 hours. Next, the reaction was stopped by adding water (2 mL) to the mixture at room temperature, then acidified by adding 1 M hydrochloric acid (2 mL), and extracted three times with ethyl acetate (3 mL). Subsequently, the ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Subsequently, the obtained crude product was suspended in hexane (2 mL) and filtered. The obtained solid was then washed with hexane (8 mL) to obtain 3,5-dimethylsalicylic acid as a white solid (yield: 35.9 mg, 0.216 mmol, yield: 86%). 1 ¹H NMR (400 MHz, deuterated acetone) δ 11.20 (br s, 1H), 7.54 (d, J=0.8 Hz, 1H), 7.23 (d, J=0.8 Hz, 1H), 2.25 (s, 3H), 2.18 (s, 3H)

[0074] Example 12: Synthesis of 3-t-butyl-5-methoxysalicylic acid 2-t-butyl-4-methoxyphenol (45.1 mg, 0.250 mmol, 1.00 equivalent), 1-dodecanethiol (89.8 μL, 0.375 mmol, 1.50 equivalent), and sodium hydride (60% by mass, 50.0 mg, 1.25 mmol, 5.0 equivalent) were mixed under a nitrogen atmosphere at room temperature and reacted for 5 minutes, followed by reaction at 100°C for 5 minutes. Subsequently, this mixture was reacted under a carbon dioxide atmosphere at room temperature for 5 minutes, followed by reaction at 185°C for 2 hours. Next, the reaction was stopped by adding water (2 mL) to the mixture at room temperature, then acidified by adding 1 M hydrochloric acid (2 mL), and extracted three times with ethyl acetate (3 mL). Subsequently, the ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Subsequently, the resulting crude product was suspended in hexane (2 mL) and filtered. The obtained solid was then washed with hexane (8 mL) to obtain 3-t-butyl-5-methoxysalicylic acid as a white solid (yield: 4.9 mg, 0.227 mmol, yield: 8.74%). 1 ¹H NMR (400 MHz, deuterated chloroform) δ 11.00 (br s, 1H), 7.18 (d, J=3.2 Hz, 1H), 7.14 (d, J=3.2 Hz, 1H), 3.77 (s, 3H), 1.39 (s, 9H)

[0075] Example 13: Synthesis of 3-t-butyl-6-methylsalicylic acid 2-t-butyl-5-methylphenol (42.6 μL, 0.250 mmol, 1.00 equivalent), 1-dodecanethiol (89.8 μL, 0.375 mmol, 1.50 equivalent), and sodium hydride (60% by mass, 50.0 mg, 1.25 mmol, 5.0 equivalent) were mixed under a nitrogen atmosphere at room temperature and reacted for 5 minutes. Subsequently, this mixture was reacted under a carbon dioxide atmosphere at room temperature for 5 minutes, and then reacted at 185°C for 2 hours. Next, the reaction was stopped by adding water (2 mL) to the mixture at room temperature, then acidified by adding 1 M hydrochloric acid (2 mL), and extracted three times with ethyl acetate (3 mL). Subsequently, the ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Subsequently, the resulting crude product was suspended in hexane (2 mL) and filtered. The obtained solid was then washed with hexane (8 mL) to obtain 3-t-butyl-6-methylsalicylic acid as a white solid (yield: 2.3 mg, 0.0110 mmol, yield: 4%). 1 ¹H NMR (400 MHz, deuterated chloroform) δ 11.94 (br s, 1H), 7.38 (d, J=7.9 Hz, 1H), 6.67 (d, J=7.9 Hz, 1H), 2.56 (s, 3H), 1.40 (s, 9H)

[0076] Example 14: Synthesis of 4,6-dimethylsalicylic acid 3,5-dimethylphenol (30.5 mg, 0.250 mmol, 1.00 equivalent), 1-dodecanethiol (89.8 μL, 0.375 mmol, 1.50 equivalent), and sodium hydride (60% by mass, 50.0 mg, 1.25 mmol, 5.0 equivalent) were mixed under a nitrogen atmosphere at room temperature and reacted for 5 minutes, followed by reaction at 100°C for 5 minutes. Subsequently, this mixture was reacted under a carbon dioxide atmosphere at room temperature for 5 minutes, followed by reaction at 185°C for 2 hours. Next, the reaction was stopped by adding water (2 mL) to the mixture at room temperature, then acidified by adding 1 M hydrochloric acid (2 mL), and extracted three times with ethyl acetate (3 mL). Subsequently, the ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Subsequently, the resulting crude product was suspended in hexane (2 mL) and filtered. The obtained solid was then washed with hexane (8 mL) to obtain 4,6-dimethylsalicylic acid as a white solid (yield: 12.4 mg, 0.0746 mmol, yield: 30%). 1 H NMR (400MHz, heavy acetone) δ11.73 (br s, 1H), 6.62-6.60 (m, 2H), 2.54 (s, 3H), 2.26 (s, 3H)

[0077] Example 15: Synthesis of 1-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid 5,6,7,8-tetrahydro-1-naphthol (0.250 mmol, 1.00 equivalent), 1-dodecanethiol (89.8 μL, 0.375 mmol, 1.50 equivalent), and sodium hydride (60% by mass, 50.0 mg, 1.25 mmol, 5.0 equivalent) were mixed under a nitrogen atmosphere at room temperature and reacted for 5 minutes, followed by reaction at 100°C for 5 minutes. Subsequently, this mixture was reacted under a carbon dioxide atmosphere at room temperature for 5 minutes, followed by reaction at 185°C for 2 hours. Next, the reaction was stopped by adding water (2 mL) to the mixture at room temperature, then acidified by adding 1 M hydrochloric acid (2 mL), and extracted three times with ethyl acetate (3 mL). Subsequently, the ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Subsequently, the resulting crude product was suspended in hexane (10 mL) and filtered. The obtained solid was then washed with hexane (20 mL) to obtain 1-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid as a white solid (yield: 42.8 mg, 0.223 mmol, yield: 89%). 1 H NMR (400 MHz, heavy acetone) δ11.45 (br s, 1H), 7.61 (d, J = 8.1Hz, 1H), 6.65 (d, J = 8.1Hz, 1H), 2.75 (t, J = 5.8Hz, 2H), 2.63 (t, J = 6.0Hz, 2H), 1.82-1.71 (m, 4H)

[0078] Example 16: Synthesis of Amorphurtin A Crude product of 3-methoxy-5-(2-phenethyl)-2-prenylphenol synthesized from 3,5-dimethoxybenzyl bromide (23.1 g, 100 mmol, 1.00 equivalent), 1-dodecanethiol (71.9 mL, 300 mmol, 3.00 equivalent), and sodium hydride (60% by mass, 15.0 g, 375 mmol, 3.75 equivalent) were mixed under a nitrogen atmosphere while cooling the reaction vessel in an ice bath, and the mixture was reacted for approximately 1 minute until no more hydrogen gas was generated. Subsequently, sodium hydride (60% by mass, 15.0 g, 3.75 equivalent, total 30.0 g, total 750 mmol, total 7.5 equivalent) was added to this mixture, and the mixture was reacted for approximately 15 seconds until it solidified. After pulverizing the resulting solid, the reaction vessel was gradually filled with carbon dioxide while it remained cooled in an ice bath. Next, the reaction vessel was heated to 100°C under a carbon dioxide atmosphere and reacted for 10 minutes, after which the temperature of the heat source was gradually increased to 180°C over approximately 15 minutes. Subsequently, the reaction was carried out at 180°C under a carbon dioxide atmosphere for 3 hours, after which the reaction vessel was cooled in an ice bath. Next, the reaction was stopped by adding cold water (250 mL) to the reaction mixture, and then washed three times with hexane (250 mL). Next, the aqueous layer was made acidic by adding 4 M hydrochloric acid (250 mL), and then extracted three times with ethyl acetate (250 mL). Next, the ethyl acetate layer was washed with saturated brine, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. Next, the obtained brown solid was suspended in cold hexane (100 mL) and filtered. Next, the obtained solid was washed three times with cold hexane (50 mL) to obtain a brown solid. Next, this brown solid was suspended in cold methanol (50 mL), filtered, and then washed with cold methanol (80 mL) to obtain amorphurtin A as a pale yellow solid (yield: 11.3 g). Subsequently, the brown solid obtained by concentrating the filtrate was suspended in cold methanol (25 mL), filtered, and then washed with cold methanol (40 mL) to obtain amorphurtin A as a pale yellow solid (yield: 1.71 g, total yield: 13.0 g, 38.2 mmol, four-step yield from 3,5-dimethoxybenzyl bromide: 38%). 1H NMR (400MHz, deuterochloroform) δ11.68 (br s, 1H), 7.33-7.27 (m, 2H), 7.23-7.17 (m, 3H), 6.22 (s, 1H), 5.24-5.17 (m, 1H), 3.80 (s, 3H) ), 3.34 (d, J=7.0Hz, 2H), 3.29-3.21 (m, 2H), 2.97-2.87 (m, 2H), 1.79 (s, 3H), 1.68 (s, 3H)

[0079] Example 17: Synthesis of Amorphurtin B Crude product of 2-geranyl-3-methoxy-5-(2-phenethyl)phenol synthesized from 3,5-dimethoxybenzyl bromide (23.1 g, 100 mmol, 1.00 equivalent), 1-dodecanethiol (71.9 mL, 300 mmol, 3.00 equivalent), and sodium hydride (60% by mass, 15.0 g, 375 mmol, 3.75 equivalent) were mixed under a nitrogen atmosphere while cooling the reaction vessel in an ice bath, and the mixture was reacted for approximately 1 minute until no more hydrogen gas was generated. Subsequently, sodium hydride (60% by mass, 15.0 g, 3.75 equivalent, total 30.0 g, total 750 mmol, total 7.5 equivalent) was added to this mixture, and the mixture was reacted for approximately 15 seconds until it solidified. After pulverizing the resulting solid, the reaction vessel was gradually filled with carbon dioxide while it remained cooled in an ice bath. Next, the reaction was carried out at 100°C for 10 minutes under a carbon dioxide atmosphere, after which the temperature of the heat source was gradually increased to 180°C over approximately 15 minutes. Subsequently, the reaction was carried out at 180°C under a carbon dioxide atmosphere for 3 hours, after which the reaction vessel was cooled in an ice bath. Next, the reaction was stopped by adding cold water (250 mL) to the reaction mixture, and then washed three times with hexane (250 mL). Next, the aqueous layer was made acidic by adding 4 M hydrochloric acid (250 mL), and then extracted three times with ethyl acetate (250 mL). Next, the ethyl acetate layer was washed with saturated brine, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. Next, the obtained brown solid was suspended in cold hexane (100 mL) and filtered. Next, the obtained solid was washed with cold hexane (50 mL) to obtain amorphurtin B as a pale yellow solid (total yield: 11.8 g, 28.9 mmol, 4-step yield from 3,5-dimethoxybenzyl bromide: 29%). 1¹H NMR (400 MHz, deuterated chloroform) δ 11.64 (br s, 1H), 7.32-7.27 (m, 2H), 7.23-7.18 (m, 3H), 6.22 (s, 1H), 5.23-5.16 (m, 1H), 5.10-5.04 (m, 1H), 3.79 (s, 3H), 3.35 (d, J = 7.0Hz, 2H), 3.25 (dd, J=9.6, 6.4Hz, 2H), 2.92 (dd, J=9.6, 6.4Hz, 2H), 2.10-2.0 2 (m, 2H), 2.00-1.93 (m, 2H), 1.78 (s, 3H), 1.64 (s, 3H), 1.57 (s, 3H)

[0080] Example 18: Synthesis of monomethyl ether cannabigerolate Crude cannabigerol monomethyl ether synthesized from 3,5-dimethoxybenzaldehyde (0.831 g, 5.00 mmol, 1.00 equivalent), 1-dodecanethiol (3.59 mL, 15.0 mmol, 3.0 equivalent), and sodium hydride (60% by mass, 0.750 g, 18.8 mmol, 3.75 equivalent) were reacted under a nitrogen atmosphere for approximately 30 seconds while cooling the reaction vessel in a water bath until no more hydrogen gas was generated. Subsequently, sodium hydride (60% by mass, 0.750 g, total 1.50 g, total 37.5 mmol, total 7.0 equivalents) was added to this mixture and the reaction was carried out for approximately 10 seconds until solidification occurred. After pulverizing the resulting solid, the reaction vessel was gradually filled with carbon dioxide while cooling the vessel in an ice bath. Subsequently, the reaction was carried out at room temperature for 5 minutes under a carbon dioxide atmosphere. Next, the reaction was carried out at 100°C for 10 minutes under a carbon dioxide atmosphere, after which the temperature of the heat source was gradually increased to 180°C over approximately 10 minutes. Subsequently, the reaction was carried out at 180°C under a carbon dioxide atmosphere for 4 hours, after which the reaction vessel was cooled in a water bath. Next, the reaction was stopped by adding water (12 mL) to the reaction mixture at room temperature, then acidified by adding 4 M hydrochloric acid (15 mL), and extracted three times with ethyl acetate (25 mL). Subsequently, the ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Subsequently, the obtained crude product was purified by silica gel column chromatography (mobile phase: hexane / ethyl acetate = 5 / 1 to 0 / 1) to obtain monomethyl ether cannabigerolate as a pale brown solid (yield: 0.860 g, 2.30 mmol, 5-step yield from 3,5-dimethoxybenzaldehyde: 46%). 1 H NMR (400 MHz, deuterochloroform) δ11.64 (br s, 1H), 6.33 (s, 1H), 5.20 (t, J = 6.5Hz, 1H), 5.07 (t, J = 6.9Hz, 1H), 3.88 (s, 3H), 3.34 (d, J = 7.0Hz, 2H), 2.94 (t, J = 7.8Hz, 2 H), 2.09-1.92 (m, 4H), 1.78 (s, 3H), 1.64 (s, 3H), 1.61-1.55 (m, 2H), 1.57 (s, 3H), 1.39-1.32 (m, 4H), 0.91 (t, J = 6.8Hz, 3H)

[0081] Example 19: Synthesis of 4-methoxy-6-phenyl-3-prenylsalicylic acid 3-Hydroxy-5-methoxy-4-prenylbiphenyl (1.02 g, 3.80 mmol, 1.00 equivalent), 1-dodecanethiol (3.64 mL, 15.2 mmol, 4.00 equivalent), and sodium hydride (60% by mass, 0.570 g, 14.3 mmol, 3.75 equivalent) were reacted under a nitrogen atmosphere for approximately 10 minutes while cooling the reaction vessel in a water bath until no more hydrogen gas was generated. Subsequently, sodium hydride (60% by mass, 0.570 g, total 1.14 g, total 28.5 mmol, total 7.50 equivalents) was added to this mixture and the reaction was carried out for approximately 10 seconds until solidification occurred. After pulverizing the resulting solid, the reaction vessel was gradually filled with carbon dioxide while cooling the vessel in an ice bath. Subsequently, the reaction was carried out at room temperature for 10 minutes under a carbon dioxide atmosphere. Next, the reaction was carried out at 100°C for 10 minutes under a carbon dioxide atmosphere, after which the temperature of the heat source was gradually increased to 180°C over approximately 10 minutes. Subsequently, the reaction was carried out at 180°C under a carbon dioxide atmosphere for 4 hours, after which the reaction vessel was cooled in a water bath. Next, the reaction was stopped by adding water (10 mL) to the reaction mixture at room temperature, then acidified by adding 4 M hydrochloric acid (15 mL), and extracted three times with ethyl acetate (25 mL). Next, the ethyl acetate layer was washed with saturated brine, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. Next, the obtained crude product was dissolved in acetonitrile (20 mL). Next, this acetonitrile solution of the crude product was washed three times with hexane (5 mL). Next, the acetonitrile layer was concentrated under reduced pressure, and the resulting crude product was suspended in hexane (5 mL) and filtered. Next, the obtained solid was washed three times with hexane (3 mL) to obtain 4-methoxy-6-phenyl-3-prenylsalicylic acid as a pale yellow solid (yield: 0.325 g, 1.04 mmol, yield: 27%). 1H NMR (400 MHz, deuterochloroform) δ11.45 (br s, 1H), 7.41-7.37 (m, 3H), 7.31-7.27 (m, 2H), 6.32 (s, 1H), 5.27-5.21 (m, 1H), 3.85 (s, 3H), 3.39 (d, J=7.1Hz, 2H), 1.80 (s, 3H), 1.70 (s, 3H)

[0082] Example 20: Synthesis of 4-O-methylglyfolic acid Crude product of glyfoline monomethyl ether synthesized from 3,5-dimethoxytoluene (0.732 mL, 5.00 mmol, 1.00 equivalent), 1-dodecanethiol (3.59 mL, 15.0 mmol, 3.00 equivalent), and sodium hydride (60% by mass, 0.750 g, 18.8 mmol, 3.75 equivalent) were reacted under a nitrogen atmosphere for approximately 30 seconds while cooling the reaction vessel in a water bath until no more hydrogen gas was generated. Subsequently, sodium hydride (60% by mass, 0.750 g, total 1.50 g, total 37.5 mmol, total 7.0 equivalents) was added to this mixture and the reaction was carried out for approximately 10 seconds until solidification occurred. After pulverizing the resulting solid, the reaction vessel was gradually filled with carbon dioxide while cooling the reaction vessel in an ice water bath. Subsequently, the reaction was carried out at room temperature for 5 minutes under a carbon dioxide atmosphere. Next, the reaction was carried out at 100°C for 10 minutes under a carbon dioxide atmosphere, after which the temperature of the heat source was gradually increased to 180°C over approximately 10 minutes. Subsequently, the reaction was carried out at 180°C under a carbon dioxide atmosphere for 4 hours, after which the reaction vessel was cooled in a water bath. Next, the reaction was stopped and made acidic by adding 1 M hydrochloric acid (45 mL) to the reaction mixture at room temperature, and then extracted three times with ethyl acetate (25 mL). Subsequently, the ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Subsequently, the resulting crude product was partially purified by silica gel column chromatography (mobile phase: hexane / ethyl acetate = 5 / 1 to 0 / 1). Subsequently, the resulting crude product was suspended in hexane (5 mL) and filtered. Subsequently, the obtained solid was washed with hexane (20 mL) to obtain 4-O-methylglyfolic acid as a pale yellow solid (yield: 530 mg, 1.37 mmol, 3-step yield from 3,5-dimethoxytoluene 27%).1 H NMR (400MHz, deuterochloroform) δ11.62 (br s, 1H), 6.32 (s, 1H), 5.22-5.17 (m, 1H), 5.09-5.06 (m, 1H), 3.87 (s, 3H), 3.34 (d, J = 7.0Hz , 2H), 2.59 (s, 3H), 2.10-1.88 (m, 8H), 1.78 (s, 3H), 1.67 (s, 3H), 1.58 (s, 3H), 1.56 (s, 3H)

[0083] Example 21: Synthesis of (±)-Ladzlanin K (±)-Ladzlanin I (35.7 mg, 0.127 mmol, 1.00 equivalent), 1-Dodecanethiol (0.122 mL, 0.508 mmol, 4.00 equivalent), and sodium hydride (60% by mass, 38.1 mg, 0.953 mmol, 7.50 equivalent) were reacted for approximately 5 minutes under a nitrogen atmosphere while cooling the reaction vessel in a water bath. Subsequently, the reaction vessel was filled with carbon dioxide. Next, the reaction was carried out at room temperature under a carbon dioxide atmosphere for 5 minutes. Subsequently, the reaction was carried out at 180°C for 2 hours under a carbon dioxide atmosphere, after which the reaction vessel was cooled using a water bath. Next, the reaction was stopped by adding water (2 mL) to the reaction mixture at room temperature, then acidified by adding 1 M hydrochloric acid (2 mL), and extracted three times with ethyl acetate (3 mL). Subsequently, the ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Next, the crude product obtained was partially purified by silica gel column chromatography (mobile phase: hexane / ethyl acetate = 5 / 1 to 0 / 1). Subsequently, the resulting pale yellow solid was washed with hot hexane (2 mL) to obtain (±)-ladzlanin K as a white solid (yield: 23.4 mg, 0.0721 mmol, yield: 57%). 1H NMR (400 MHz, deuterated chloroform) δ 7.32 - 7.27 (m, 2H), 7.23 - 7.17 (m, 3H), 6.28 (s, 1H), 4.23 (d, J = 10.4 Hz, 1H), 3.73 (d, J = 10.4 Hz, 1H), 3.22 - 3.15 (m, 2H), 2.90 - 2.84 (m, 2H), 2.17 (dd, J = 8.5, 4.4 Hz, 1H), 1.27 (s, 3H), 1.06 (t, J = 4.4 Hz, 1H), 0.99 (dd, J = 8.5, 4.4 Hz, 1H)

[0084] Example 22: Synthesis of Cannabidiolic Acid Cannabidiol (78.6 mg, 0.250 mmol, 1.00 equivalent), 1-dodecanethiol (89.8 μL, 0.375 mmol, 1.50 equivalents), and sodium hydride (60 mass%, 60.0 mg, 1.50 mmol, 6.0 equivalents) were mixed at room temperature under a nitrogen atmosphere and reacted for 5 minutes, then reacted at 100 °C for 5 minutes. Subsequently, the mixture was reacted at room temperature for 5 minutes under a carbon dioxide atmosphere, then reacted at 100 °C for 30 minutes. Subsequently, the mixture was reacted at room temperature for 5 minutes under a carbon dioxide atmosphere, then reacted at 185 °C for 2 hours. Subsequently, the reaction was stopped by adding water (3 mL) to this mixture at room temperature, then acidified by adding 1 M hydrochloric acid (3 mL), and then extracted 3 times with ethyl acetate (5 mL). Subsequently, the ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Subsequently, trimethoxybenzene (42.0 mg, 0.250 mmol) was added to the obtained crude product as an internal standard for quantification 1 The yield of cannabidiolic acid was determined by H NMR (yield: 0.0825 mmol, yield 33%).

[0085] Example 23: Synthesis of Cannabinolic Acid Cannabinol (78.6 mg, 0.250 mmol, 1.00 equivalent), 1-dodecanethiol (89.8 μL, 0.375 mmol, 1.50 equivalent), and sodium hydride (60% by mass, 50.0 mg, 1.25 mmol, 5.0 equivalent) were mixed under a nitrogen atmosphere at room temperature and reacted for 5 minutes, followed by reaction at 100°C for 5 minutes. Subsequently, this mixture was reacted under a carbon dioxide atmosphere at room temperature for 5 minutes, followed by reaction at 100°C for 5 minutes. Next, this mixture was reacted under a carbon dioxide atmosphere at room temperature for 5 minutes, followed by reaction at 185°C for 2 hours. Subsequently, the reaction was stopped by adding water (3 mL) to this mixture at room temperature, then acidified by adding 1 M hydrochloric acid (3 mL), and extracted three times with ethyl acetate (3 mL). Subsequently, the ethyl acetate layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Next, triphenylmethane (61.1 mg, 0.250 mmol) was added to the obtained crude product as an internal standard, and quantification was performed. 1 The yield of cannabinolic acid was determined by 1H NMR (yield: 0.135 mmol, yield 54%).

[0086] Example 24: Synthesis of Cannabigerol Acid Cannabigerol (79.1 mg, 0.250 mmol, 1.00 equivalent), 1-dodecanethiol (89.8 μL, 0.375 mmol, 1.50 equivalent), and sodium hydride (60% by mass, 60.0 mg, 1.50 mmol, 6.00 equivalent) were mixed under a nitrogen atmosphere at room temperature and reacted for 5 minutes, followed by reaction at 100°C for 5 minutes. Subsequently, this mixture was reacted under a carbon dioxide atmosphere at room temperature for 5 minutes, followed by reaction at 100°C for 5 minutes. Next, this mixture was reacted under a carbon dioxide atmosphere at room temperature for 5 minutes, followed by reaction at 185°C for 2 hours. Subsequently, the reaction was stopped by adding water (3 mL) to this mixture at room temperature, then acidified by adding 1 M hydrochloric acid (3 mL), and extracted three times with ethyl acetate (3 mL). Subsequently, the ethyl acetate layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Next, triphenylmethane (61.1 mg, 0.250 mmol) was added to the obtained crude product as an internal standard, and the yield of cannabigerol acid was determined by quantitative 1H NMR (yield: 0.600 mmol, yield 24%).

[0087] Example 25: Synthesis of 6-formyl-3-methoxysalicylic acid 3-Hydroxy-4-methoxybenzaldehyde (38.0 mg, 0.250 mmol, 1.00 equivalent), 1-dodecanethiol (density 0.845, 89.8 μL, 0.375 mmol, 1.50 equivalent), and sodium hydride (60 wt%, 50.0 mg, 1.25 mmol, 5.0 equivalent) were mixed under a nitrogen atmosphere at room temperature and reacted for 5 minutes, followed by reaction at 100°C for 5 minutes. Subsequently, this mixture was reacted under a carbon dioxide atmosphere at room temperature for 5 minutes, followed by reaction at 185°C for 2 hours. Next, the reaction was stopped by adding water (2 mL) to the mixture at room temperature, then acidified by adding 1 M hydrochloric acid (2 mL), and extracted three times with ethyl acetate (3 mL). Subsequently, the ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Subsequently, the resulting crude product was suspended by adding hexane (2 mL), and the precipitate was filtered off. The obtained precipitate was washed with hexane (8 mL) to obtain the target compound as a pale yellow solid (yield 22.2 mg, 0.113 mmol, yield 45%). 1 H NMR (400MHz, deuterium chloroform) δ9.85 (s, 1H), 7.45 (d, J = 1.2Hz, 2H), 6.98 (d, J = 8.7Hz, 1H), 5.74 (s, 1H), 4.00 (s, 3H)

Claims

1. A method for producing an aromatic β-hydroxy acid, characterized by comprising the step of contacting a composition containing an aromatic compound having a phenolic hydroxyl group, a strong base, and an aliphatic thiol compound with carbon dioxide.

2. The method according to claim 1, wherein a metal hydride is used as the strong base.

3. As the aliphatic thiol compound, C 2-14 The method according to claim 1, which uses an alkanethiol.

4. In addition to the phenolic hydroxyl group, the aromatic compound may have a C substituent α 1-20 alkyl group, a C alkenyl group which may have substituent α 2-20 alkenyl group, a C alkynyl group which may have substituent α 2-20 alkynyl group, a C alkoxy group, a phenoxy group which may have substituent β, a sulfhydryl group, a C 1-6 alkylthio group, a phenylthio group which may have substituent β, a carboxy group, (C 1-6 alkyl) oxycarbonyl group, an amide group, a formyl group, an amino group, a halogeno group, a C 1-6 aryl-C alkyl group, an oxo group, a methylidene group, a nitro group, and a cyano group, and may have a substituent selected from the group consisting of: Substituent α is C 6-12 aryl-C alkyl group, an oxo group, a methylidene group, a nitro group, and a cyano group, and may have a substituent selected from the group consisting of: Substituent α is C 1-6 alkyl group, an oxo group, a methylidene group, a nitro group, and a cyano group, and may have a substituent selected from the group consisting of: Substituent α is C 1-6 alkoxy group, C 1-6 alkylthio group, hydroxyl group, sulfhydryl group, carboxy group, amino group, halogeno group, ester group, nitro group, and cyano group, and represents one or more substituents selected from the group consisting of: Substituent β is C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 alkoxy group, C 1-6 alkylthio group, hydroxyl group, sulfhydryl group, amino group, halogeno group, nitro group, and cyano group, and represents one or more substituents selected from the group consisting of: The method according to claim 1.

5. The aromatic compound has a carboxyl group, (C 1-6 The method according to claim 1, having a substituent selected from an alkyl)oxycarbonyl group, an amide group, a formyl group, a halogeno group, a nitro group, and a cyano group.

6. The method according to claim 1, wherein the composition is brought into contact with carbon dioxide at a temperature of 80°C or higher.

7. The method according to claim 1, wherein the aliphatic thiol compound is used in an amount of 1 molar or more and 5 molar or less relative to the phenolic hydroxyl group.

8. The method according to claim 1, wherein the strong base is used in an amount of 1 mole or more and 10 moles or less relative to the phenolic hydroxyl group.

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