Method for producing aromatic-substituted polyunsaturated fatty acid derivative and method for producing aromatic-substituted polyunsaturated fatty acid

Abstract

To provide a method for producing an aromatic-substituted polyunsaturated fatty acid derivative in which an aromatic group is position-specifically introduced only into a double bond at a specific position in a polyunsaturated fatty acid derivative containing two or more carbon-carbon double bonds in the molecule, and to provide a method for producing an aromatic-substituted polyunsaturated fatty acid.SOLUTION: A polyunsaturated fatty acid derivative having a specific structure is reacted with Ar-I (wherein Ar is an aromatic group) in the presence of a palladium catalyst and a hydrosilane to give an aromatic-substituted polyunsaturated fatty acid derivative in which the aromatic group is position-specifically introduced only into the carbon-carbon double bond nearest to the 8-quinolylamino group.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for producing an aromatic-substituted polyunsaturated fatty acid derivative and a method for producing an aromatic-substituted polyunsaturated fatty acid. [Background technology]

[0002] In recent years, it has been suggested that structural differences in the fatty acids that make up lipid molecules are related to the mechanisms of various inflammation and metabolic diseases. To advance lipid research, it is essential to build a compound library containing diverse fatty acid derivatives and develop synthetic methods that enable quantitative supply. However, due to their simple structure, functionalization of fatty acids is extremely difficult, and it is necessary to synthesize the corresponding raw materials separately for each target compound.

[0003] The present inventors have been working on the development of an efficient and comprehensive method for synthesizing fatty acid derivatives, and have previously reported the reductive Heck reaction of monounsaturated fatty acid derivatives containing one unsaturated bond in the molecule (e.g., Non-Patent Document 1). [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] J.Org.Chem.,2024,89,2787-2793 Summary of the Invention [Problem to be solved by the invention]

[0005] However, there have been no reports of the reductive Heck reaction of polyunsaturated fatty acid derivatives containing two or more double bonds in the molecule, due to the occurrence of side reactions such as double bond isomerization, decomposition, and double bond migration due to chain walking reactions.

[0006] An object of one aspect of the present invention is to provide a method for producing an aromatic-substituted polyunsaturated fatty acid derivative in which an aromatic group is regiospecifically introduced only into double bonds at specific positions in a polyunsaturated fatty acid derivative containing two or more carbon-carbon double bonds in the molecule, and a method for producing an aromatic-substituted polyunsaturated fatty acid. [Means for solving the problem]

[0007] In order to solve the above problems, the present invention includes the following aspects.

[0008] [1] A polyunsaturated fatty acid derivative represented by the following formula (1):

[0009] [ka]

[0010] (In formula (1), n ​​is an integer of 1 to 4, and R 1 is a hydrocarbon group containing 1 to 10 carbon-carbon double bonds, -(CH2) n -CH=CH-R 1 at least one hydrogen atom contained in may be substituted with at least one substituent selected from the group consisting of an alkyl group having 1 to 12 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, an aryl group, an amino group, an amido group, and an imino group); Ar-I, where Ar is an aromatic group, reacting in the presence of a palladium catalyst and a hydrosilane; The method for producing an aromatic substituted polyunsaturated fatty acid derivative, wherein Ar-I may be substituted with an additional substituent in addition to the iodo group.

[0011] [2] In the polyunsaturated fatty acid derivative represented by formula (1), the hydrogen atom bonded to the carbon atom in the carbon-carbon double bond closest to the 8-quinolylamino group is substituted with the substituent; The method for producing an aromatic-substituted polyunsaturated fatty acid derivative according to [1], wherein an aromatic-substituted quaternary carbon is constructed at the position where the substituent is bonded.

[0012] [3] Furthermore, polyunsaturated fatty acids represented by the following formula (2)

[0013] [ka]

[0014] (In formula (2), n is an integer of 1 to 4, and R 1 is a hydrocarbon group containing 1 to 10 carbon-carbon double bonds, -(CH2) n -CH=CH-R 1 wherein at least one hydrogen atom contained in the above formula (I) may be substituted with at least one substituent selected from the group consisting of an alkyl group having 1 to 12 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, an aryl group, an amino group, an amido group, and an imino group) with 8-aminoquinoline.

[0015] [4] A method for producing an aromatic-substituted polyunsaturated fatty acid, comprising a step of removing an aminoquinoline group from an aromatic-substituted polyunsaturated fatty acid derivative obtained by the production method according to any one of [1] to [3]. [Effects of the Invention]

[0016] According to one aspect of the present invention, it is possible to provide a method for producing an aromatic-substituted polyunsaturated fatty acid derivative in which an aromatic group is regiospecifically introduced only into double bonds at specific positions in a polyunsaturated fatty acid derivative containing two or more carbon-carbon double bonds in the molecule, and a method for producing an aromatic-substituted polyunsaturated fatty acid. DETAILED DESCRIPTION OF THE INVENTION

[0017] Hereinafter, embodiments of the present invention will be described in detail. However, the present invention is not limited to these, and various modifications are possible within the scope of the description. Embodiments obtained by appropriately combining the technical means disclosed in different embodiments are also included in the technical scope of the present invention. In addition, unless otherwise specified in this specification, "A to B" representing a numerical range means "greater than or equal to A and less than or equal to B."

[0018] As used herein, "polyunsaturated fatty acid derivative" refers to an unsaturated fatty acid derivative containing two or more carbon-carbon double bonds in the molecule, and "polyunsaturated fatty acid" refers to an unsaturated fatty acid containing two or more carbon-carbon double bonds in the molecule. The two or more carbon-carbon double bonds contained in "polyunsaturated fatty acid derivatives" and "polyunsaturated fatty acids" are preferably inactive carbon-carbon double bonds. Here, "inactive carbon-carbon double bond" refers to a carbon-carbon double bond with little electronic imbalance between the two carbon atoms forming the double bond.

[0019] 1. Method for producing aromatic-substituted polyunsaturated fatty acid derivatives The present inventors have conducted studies to solve the above-mentioned problems, and as a result, have found that when a polyunsaturated fatty acid derivative having a specific structure, in which the hydroxyl group of the carboxyl group of a polyunsaturated fatty acid is substituted with an 8-quinolylamino group, is reacted with Ar-I (wherein Ar is an aromatic group) in the presence of a palladium catalyst and a hydrosilane, an aromatic-substituted polyunsaturated fatty acid derivative is obtained in which an aromatic group is regiospecifically introduced only into the carbon-carbon double bond closest to the 8-quinolylamino group, and have thus completed the present invention.

[0020] That is, a method for producing an aromatic-substituted polyunsaturated fatty acid derivative according to one embodiment of the present invention comprises producing a polyunsaturated fatty acid derivative represented by the following formula (1):

[0021] [ka]

[0022] (In formula (1), n ​​is an integer of 1 to 4, and R 1 is a hydrocarbon group containing 1 to 10 carbon-carbon double bonds, -(CH2) n -CH=CH-R 1 (wherein at least one hydrogen atom may be substituted with at least one substituent selected from the group consisting of an alkyl group having 1 to 12 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, an aryl group, an amino group, an amido group, and an imino group) with Ar-I (wherein Ar is an aromatic group) in the presence of a palladium catalyst and a hydrosilane (hereinafter sometimes referred to as "Step I" in this specification), wherein Ar-I may be substituted with an additional substituent in addition to an iodo group. Note that, although the polyunsaturated fatty acid derivative represented by formula (1) may have cis-trans isomerism at the carbon-carbon double bond in formula (1), the structure of formula (1) is intended to include both the cis form and the trans form.

[0023] When a monounsaturated fatty acid derivative is reacted with Ar-I in the presence of a palladium catalyst and a hydrosilane, an aromatic group and a hydrogen atom are introduced into the carbon-carbon double bond by a reductive Heck reaction. By using a polyunsaturated fatty acid derivative having the structure described above as the substrate, an aromatic-substituted polyunsaturated fatty acid derivative can be obtained in which an aromatic group and a hydrogen atom are regiospecifically introduced only into the carbon-carbon double bond closest to the 8-quinolylamino group. The obtained aromatic-substituted polyunsaturated fatty acid derivative can be an aromatic-substituted polyunsaturated fatty acid derivative in which a hydrogen atom is regiospecifically introduced into the carbon atom on the 8-quinolylamino group side of the carbon-carbon double bond closest to the 8-quinolylamino group, and an aromatic group is regiospecifically introduced into the carbon atom on the other side of the carbon-carbon double bond.

[0024] (Polyunsaturated fatty acid derivatives) The polyunsaturated fatty acid derivative may have a structure represented by formula (1). In formula (1), n ​​may be an integer of 1 to 4, more preferably an integer of 1 to 3, even more preferably 1 or 2, and particularly preferably 2. When n is an integer of 1 to 4, a hydrogen atom and an aromatic group can be suitably introduced into a carbon-carbon double bond at a specific position.

[0025] In formula (1), R 1 R may be any hydrocarbon group containing 1 to 10 carbon-carbon double bonds. 1 may be a hydrocarbon group containing 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 carbon-carbon double bonds. According to one embodiment of the present invention, even when the molecule contains two or more carbon-carbon double bonds, it is possible to obtain an aromatic-substituted polyunsaturated fatty acid derivative in which an aromatic group is regiospecifically introduced only into the carbon-carbon double bond closest to the 8-quinolylamino group.

[0026] R 1 The number of carbon atoms contained in R is not particularly limited. 1 R may have, for example, 1 to 40, 1 to 30, 1 to 20, or 1 to 10 carbon atoms. 1 may be a straight-chain hydrocarbon group or a branched hydrocarbon group, but is more preferably a straight-chain hydrocarbon group.

[0027] R 1 Examples of the hydrocarbon group include hydrocarbon groups represented by the following formula (3). -[(CH2) c -CH=CH-(CH2) d ] m -H (3) In formula (3), m is preferably an integer of 1 to 10, and may be, for example, an integer of 1 to 5, 1 to 4, 1 to 3, or 1 to 2; c is preferably, independently in each repeating unit, an integer of 0 to 10, and may be, for example, an integer of 1 to 10 or 2 to 10; and d is preferably, independently in each repeating unit, an integer of 0 to 10, and may be, for example, an integer of 1 to 10 or 2 to 10.

[0028] In formula (1), -(CH2) n -CH=CH-R 1 At least one hydrogen atom contained in -(CH2) may be substituted with at least one substituent selected from the group consisting of an alkyl group having 1 to 12 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, an aryl group, an amino group, an amido group, and an imino group. n -CH=CH-R 1 At least one hydrogen atom bonded to a carbon atom forming a carbon-carbon double bond in the above formula (I) may be substituted with at least one substituent selected from the group consisting of an alkyl group having 1 to 12 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, an aryl group, an amino group, an amide group, and an imino group. In other words, the polyunsaturated fatty acid derivative may contain a tri-substituted alkene. Unsaturated fatty acid derivatives containing a tri-substituted alkene are more stable than unsaturated fatty acid derivatives containing only di-substituted alkenes, and it has been difficult to introduce an aromatic group and a hydrogen atom into the tri-substituted carbon-carbon double bond by reductive Heck reaction. Furthermore, it was thought to be even more difficult to regiospecifically introduce an aromatic group and a hydrogen atom into only a double bond at a specific position in a polyunsaturated fatty acid derivative containing a tri-substituted alkene. However, according to one embodiment of the present invention, it has surprisingly been found that even when the polyunsaturated fatty acid derivative contains a tri-substituted alkene, it is possible to obtain an aromatic-substituted polyunsaturated fatty acid derivative in which a hydrogen atom and an aromatic group are introduced into the carbon-carbon double bond closest to the 8-quinolylamino group. -(CH2) n -CH=CH-R 1When at least one hydrogen atom bonded to a carbon atom forming a carbon-carbon double bond in the above formula (I) is substituted with the aforementioned substituent, the hydrogen atom bonded to any of the carbon atoms may be substituted. In the carbon-carbon double bond closest to the 8-quinolylamino group, the hydrogen atom bonded to the carbon atom may be substituted with the aforementioned substituent. Even in such a case, a hydrogen atom and an aromatic group can be introduced into the carbon-carbon double bond closest to the 8-quinolylamino group. This allows a quaternary carbon to be regioselectively constructed at the position of the carbon-carbon double bond closest to the 8-quinolylamino group. For example, when the hydrogen atom bonded to the carbon atom farthest from the 8-quinolylamino group in the carbon-carbon double bond closest to the 8-quinolylamino group is substituted with the aforementioned substituent, a quaternary carbon with an aromatic group introduced into that carbon atom can be constructed.

[0029] That is, the method for producing an aromatic-substituted polyunsaturated fatty acid derivative according to one embodiment of the present invention can be a method for producing an aromatic-substituted polyunsaturated fatty acid derivative in which the hydrogen atom bonded to the carbon atom in the carbon-carbon double bond closest to the 8-quinolylamino group of the polyunsaturated fatty acid derivative represented by formula (1) is substituted with the substituent, and an aromatic-substituted quaternary carbon is constructed at the position where the substituent is bonded.

[0030] The alkyl group having 1 to 12 carbon atoms may be linear or branched, and examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a t-butyl group, a hexyl group, an octyl group, and a decyl group. Examples of a cycloalkyl group having 3 to 8 carbon atoms include a cyclopropyl group, a cyclopentyl group, and a cyclohexyl group. Examples of an aralkyl group having 7 to 12 carbon atoms include a benzyl group and a phenethyl group. Examples of an aryl group include a phenyl group, a naphthyl group, an anthracenyl group, a phenanthrenyl group, a pyridyl group, a quinolyl group, a thienyl group, a thiazolyl group, and an indolyl group.

[0031] In formula (1), -(CH2) n -CH=CH-R1 The number of hydrogen atoms substituted with the alkyl group contained in -(CH2) is not particularly limited, but is, for example, 0 to 10, or 0 to 5. n -CH=CH-R 1 The number of hydrogen atoms bonded to the carbon atoms forming the carbon-carbon double bond substituted with the alkyl group is not particularly limited, but is, for example, 0 to 10, or 0 to 5.

[0032] (Ar-I) The Ar-I is not particularly limited. Examples of Ar (aromatic group) include carbocyclic aromatic groups such as a phenyl group, a naphthyl group, an anthracenyl group, and a phenanthrenyl group; and heterocyclic aromatic groups such as a pyridyl group, a quinolyl group, a thienyl group, a thiazolyl group, and an indolyl group.

[0033] The Ar-I may be substituted with an additional substituent in addition to the iodo group. That is, in the Ar-I, a hydrogen atom of the aromatic group may be further substituted with a substituent in addition to the iodo group represented by "-I" in the formula. When the Ar-I has an additional substituent, the number of the additional substituents is not particularly limited and may be one, two, or more. In addition, the position at which the substituent is introduced is not particularly limited. For example, when the Ar-I is iodobenzene, the substituent may be introduced at the ortho position, meta position, para position, or any combination of these positions relative to the iodo group.

[0034] The substituents can include a wide range of functional groups, from water-soluble to oil-soluble, such as alkyl groups having 1 to 12 carbon atoms, alkoxy groups having 1 to 12 carbon atoms, haloalkyl groups having 1 to 12 carbon atoms, cyano groups, nitro groups, halogeno groups, amino groups, and hydroxyl groups. The alkyl groups having 1 to 12 carbon atoms may be linear or branched, and examples thereof include methyl groups, ethyl groups, propyl groups, isopropyl groups, t-butyl groups, hexyl groups, octyl groups, and decyl groups. The alkoxy groups having 1 to 12 carbon atoms may be linear or branched, and examples thereof include methoxy groups, ethoxy groups, benzyloxy groups, cyclohexyloxy groups, and phenoxy groups. The haloalkyl group having 1 to 12 carbon atoms may be linear or branched, and examples thereof include a fluoromethyl group, a chloromethyl group, a bromomethyl group, a difluoromethyl group, a trifluoromethyl group, a 1-fluoroethyl group, a 2-fluoroethyl group, and a pentafluoroethyl group. Examples of the halogeno group include a fluoro group, a chloro group, a bromo group, and an iodo group. The substituents may be of one type or a combination of two or more types.

[0035] The amount of Ar-I used in step I is preferably 1 equivalent or more and 10 equivalents or less, more preferably 1 equivalent or more and 8 equivalents or less, and even more preferably 2 equivalents or more and 6 equivalents or less, relative to the compound represented by formula (1).

[0036] (Palladium catalyst) The palladium catalyst is not particularly limited as long as it contains palladium, and examples thereof include palladium organic acid salts such as palladium acetate (Pd(OAc)2, Pd2(OAc)3), palladium oxalate, palladium pivalate, palladium trifluoroacetate, bis(dibenzylideneacetone)palladium, and tris(dibenzylideneacetone)dipalladium; palladium halides such as palladium chloride and palladium bromide; palladium inorganic acid salts such as palladium nitrate and palladium sulfate; and palladium carbon and palladium alumina in which palladium is supported on a carrier such as carbon or alumina. Among these, palladium organic acid salts, particularly Pd(OAc)2, are more preferred.

[0037] The amount of the palladium catalyst used in Step I is preferably 1 mol % or more and 100 mol % or less, more preferably 2 mol % or more and 30 mol % or less, and even more preferably 5 mol % or more and 15 mol % or less, based on the compound represented by Formula (1).

[0038] (hydrosilane) The hydrosilane is not particularly limited as long as it is a compound having a SiH group, and examples thereof include polymethylhydrosiloxane (PMHS), trimethylsilane, triethylsilane, trimethoxysilane, triethoxysilane, diethoxymethylsilane, dimethoxymethylsilane, and ethoxydimethylsilane. Among these, polymethylhydrosiloxane is more preferred from the viewpoint of obtaining the target product in a high yield. One type of hydrosilane may be used alone, or two or more types may be used in combination.

[0039] The amount of the hydrosilane used in Step I is preferably 1 equivalent or more and 10 equivalents or less, more preferably 2.5 equivalents or more and 8 equivalents or less, and even more preferably 3 equivalents or more and 6 equivalents or less, relative to the amount of the compound represented by Formula (1).

[0040] The amount of the hydrosilane used is preferably 1 equivalent or more, more preferably 2.5 equivalents or more, because even when a side reaction between Ar-I and the hydrosilane competes with each other, the effect on the reaction between the polyunsaturated fatty acid derivative represented by formula (1) and Ar-I can be reduced. This makes it possible to suitably obtain an aromatic-substituted polyunsaturated fatty acid derivative in which a hydrogen atom and an aromatic group have been introduced into the carbon-carbon double bond, particularly when the polyunsaturated fatty acid derivative contains a trisubstituted alkene.

[0041] Since polymethylhydrosiloxane is classified as industrial waste, the reaction using polymethylhydrosiloxane as a reducing agent can be considered an environmentally friendly reaction. Therefore, the production method of the present disclosure using polymethylhydrosiloxane also contributes to the achievement of Goal 12 of the Sustainable Development Goals (SDGs) proposed by the United Nations, "Ensure sustainable consumption and production patterns."

[0042] (Activator for hydrosilanes) In step I, it is more preferable to react the polyunsaturated fatty acid derivative represented by formula (1) with Ar-I in the presence of a palladium catalyst, a hydrosilane, and an activator for the hydrosilane. The coexistence of a fluoride salt as the activator for the hydrosilane is preferable because fluoride ions are coordinated to the hydrosilane, thereby generating a highly reactive silicate.

[0043] The hydrosilane activator is not particularly limited, and examples thereof include fluoride salts such as cesium fluoride, potassium fluoride, sodium fluoride, rubidium fluoride, and potassium hydrogen fluoride. Among these, from the viewpoint of yield, the fluoride salt is more preferably cesium fluoride or potassium fluoride.

[0044] The amount of the hydrosilane activator used in Step I is preferably 0.1 equivalents or more and 8 equivalents or less, more preferably 0.5 equivalents or more and 5 equivalents or less, and even more preferably 1 equivalent or more and 3 equivalents or less, relative to the amount of the compound represented by Formula (1).

[0045] (solvent) In Step I, the reaction is carried out without a solvent, or by dissolving or suspending in a suitable solvent. Specific examples of the solvent include, but are not limited to, ethyl acetate, methyl acetate, butyl acetate, dichloromethane, tetrahydrofuran (THF), 2-methyl-THF, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 1,4-dioxane, toluene, 1,2-dimethoxyethane, cyclopentyl methyl ether, diethyl ether, chloroform, diethylene glycol dimethyl ether, and mixtures thereof.

[0046] (Operation and reaction conditions for step I) In step I, the order in which the polyunsaturated fatty acid derivative represented by formula (1), Ar-I, palladium catalyst, hydrosilane, etc. are added is not particularly limited, and for example, a method in which a hydrosilane is added to a mixture containing the polyunsaturated fatty acid derivative represented by formula (1), Ar-I, palladium catalyst, etc., and the reaction is carried out can be suitably used. The method for preparing a mixture containing the polyunsaturated fatty acid derivative represented by formula (1), Ar-I, palladium catalyst, etc. is also not particularly limited, and for example, a method in which Ar-I, a palladium catalyst, and, if necessary, an activator for the hydrosilane are mixed, and the polyunsaturated fatty acid derivative represented by formula (1) and, if necessary, a solvent are added to the obtained mixture can be used.

[0047] The method for adding hydrosilane to a mixture containing the polyunsaturated fatty acid derivative represented by formula (1), Ar-I, a palladium catalyst, and the like is not particularly limited, but it is more preferable to add hydrosilane dropwise to the mixture at a rate of, for example, 2 to 4 equivalents / h, more preferably 0.2 to 0.4 equivalents / h, relative to the polyunsaturated fatty acid derivative represented by formula (1). Adding hydrosilane over a long period of time is preferable because it makes it less likely for side reactions to occur.

[0048] The reaction time is, for example, 12 to 96 hours, more preferably 24 to 72 hours, from the start of addition of the hydrosilane. The reaction temperature is 0 to 40° C., more preferably 20 to 30° C. According to the production method of one embodiment of the present invention, the reductive Heck reaction can be carried out suitably even at room temperature, and an aromatic-substituted polyunsaturated fatty acid derivative can be obtained in which an aromatic group is regiospecifically introduced only into the carbon-carbon double bond closest to the 8-quinolylamino group.

[0049] After completion of the reaction, the target product can be isolated and / or purified from the reaction mixture by a separation means such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, or chromatography.

[0050] (aromatic substituted polyunsaturated fatty acid derivatives) According to the method for producing an aromatic-substituted polyunsaturated fatty acid derivative according to one embodiment of the present invention, an aromatic-substituted polyunsaturated fatty acid derivative represented by the following formula (4) can be produced.

[0051] [ka]

[0052] In formula (4), n and R 1 is the n and R in the above formula (1). 1 In addition, in formula (4), Ar is a group obtained by removing the iodo group from the above-mentioned Ar-I.

[0053] According to one embodiment of the present invention, as represented by formula (4), even when the molecule contains two or more carbon-carbon double bonds, it is possible to obtain an aromatic-substituted polyunsaturated fatty acid derivative in which an aromatic group is regiospecifically introduced only into the carbon-carbon double bond closest to the 8-quinolylamino group.

[0054] (Step of preparing a polyunsaturated fatty acid derivative represented by formula (1)) The polyunsaturated fatty acid derivative represented by formula (1) can be prepared by a conventional method. The polyunsaturated fatty acid derivative represented by formula (1) can be prepared, for example, from a polyunsaturated fatty acid represented by the following formula (2):

[0055] [ka]

[0056] (In formula (2), n is an integer of 1 to 4, and R 1 is a hydrocarbon group containing 1 to 10 carbon-carbon double bonds, -(CH2) n -CH=CH-R 1 (at least one hydrogen atom contained in the formula (2) may be substituted with at least one substituent selected from the group consisting of an alkyl group having 1 to 12 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, an aryl group, an amino group, an amido group, and an imino group) with 8-aminoquinoline. Note that the polyunsaturated fatty acid represented by formula (2) may have cis-trans isomerism at the carbon-carbon double bond in formula (2), but the structure of formula (2) is intended to include both the cis form and the trans form.

[0057] That is, the method for producing an aromatic-substituted polyunsaturated fatty acid derivative according to one embodiment of the present invention may include a step of reacting the polyunsaturated fatty acid represented by the formula (2) with 8-aminoquinoline (hereinafter, sometimes referred to as "step II" in this specification). 1 is the n and R in the above formula (1). 1The polyunsaturated fatty acid represented by formula (2) can be produced by a known method, or a commercially available product can be used.

[0058] The polyunsaturated fatty acid derivative represented by formula (1) can be prepared, for example, by reacting the polyunsaturated fatty acid represented by formula (2) with 8-aminoquinoline in an organic solvent in the presence of a base and a dehydration condensation agent.

[0059] Examples of the base include organic amines such as 4-dimethylaminopyridine (DMAP), triethylamine, pyridine, N,N-diisopropylethylamine (DIEA), imidazole, diazabicycloundecene (DBU), and diethylaniline.

[0060] Examples of the dehydration condensation agent include 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl), N,N'-dicyclohexylcarbodiimide (DCC), ethyl chlorocarbonate, isobutyl chlorocarbonate, and diphenyl chlorophosphate.

[0061] Specific examples of the organic solvent are the same as those described in "Step I."

[0062] In step II, the order in which the polyunsaturated fatty acid represented by formula (2), 8-aminoquinoline, base, dehydration condensing agent, etc. are added is not particularly limited. For example, a method in which the polyunsaturated fatty acid represented by formula (2) and 8-aminoquinoline are added to a mixture containing a base, a dehydration condensing agent, and a solvent, and then the mixture is reacted, can be suitably used.

[0063] The reaction time is, for example, 2 hours to 24 hours, and the reaction temperature is, for example, 0°C to 50°C.

[0064] After completion of the reaction, the target product can be isolated and / or purified from the reaction mixture by a separation means such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, or chromatography.

[0065] 2. Method for producing aromatic-substituted polyunsaturated fatty acids An aromatic-substituted polyunsaturated fatty acid can be obtained by eliminating the aminoquinoline group from the aromatic-substituted polyunsaturated fatty acid derivative obtained by the production method according to one embodiment of the present invention.

[0066] That is, a method for producing an aromatic-substituted polyunsaturated fatty acid according to one embodiment of the present invention includes a step of removing an aminoquinoline group from an aromatic-substituted polyunsaturated fatty acid derivative obtained by the above-mentioned production method. The method for removing the aminoquinoline group from the aromatic-substituted polyunsaturated fatty acid derivative obtained by the above-mentioned production method may be performed according to a conventional method. For example, the aminoquinoline group can be removed from the aromatic-substituted polyunsaturated fatty acid derivative by a conversion reaction to a carboxylic acid by acidic hydrolysis, basic hydrolysis, or the like, or by direct conversion to an ester using a nickel catalyst. More specifically, for example, see Chemistry A European Journal, Volume 27, Issue 33, Pages 8411-8436 (June 10, 2021), A Guide to Directing Group Removal: 8-Aminoquinoline doi.org / 10.1002 / chem.202100093, etc., can be used. [Example]

[0067] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0068] [Production Example 1: Synthesis of polyunsaturated fatty acid derivative 1] Under a nitrogen atmosphere, 0.86 g (7 mmol, 1.4 equiv.) of 4-dimethylaminopyridine (DMAP), 1.25 g (6.5 mmol, 1.3 equiv.) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), and 10 mL of dichloromethane were placed in a reaction vessel equipped with a mechanical stirrer. The reaction vessel was cooled to 0 °C in an ice bath, and 1.26 g (5 mmol, 1.0 equiv.) of (E)-5,9-dimethyldeca-4,8-dienoic acid (synthesized as described in Science, 375, 745-752 (2022)) was added. The resulting mixture was stirred for 1 hour, after which 0.76 g (5.25 mmol, 1.05 equiv.) of 8-aminoquinoline was added. The ice bath was removed, and the reaction mixture was stirred at room temperature (23 °C) for 12 hours. After stirring for 12 hours, 50 mL of water was added to the reaction mixture and extracted with dichloromethane (3 x 50 mL). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate: 93 / 7) to obtain the polyunsaturated fatty acid derivative 1 ((E)-5,9-dimethyl-N-(quinolin-8-yl)deca-4,8-dienamide) represented by the following formula as a pale yellow oil. Yield: 1.62 g (100%).

[0069] [ka]

[0070] 1 H NMR(500MHz,CDCl3)δ9.81(brs,1H),8.83-8.76(m,2H),8.15(dd,J=8.2,1.7Hz,1H),7.56-7.47(m,2H),7.44(ddd,J=8.2,4.3,1.0Hz,1H),5.28-5.20( m,1H),5.11-5.03(m,1H),2.64-2.57(m,2H),2.56-2.44(m,2H),2.11-2.02 (m,2H),2.02-1.94(m,2H),1.67(s,3H),1.64(d,J=1.3Hz,3H),1.55(s,3H). 13C NMR(126MHz,CDCl3)δ171.6,148.2,138.5,137.2,136.5,134.7,131.5,128.1,12 7.6,124.3,122.5,121.7,121.4,116.6,39.8,38.5,26.8,25.8,24.3,17.8,16.3. HRMS(ESI + )(m / z):Calcd. for C 21 H 26 N2NaO + [M+Na] + 345.1937,Found 345.1934.

[0071] Example 1: Synthesis of aromatic-substituted polyunsaturated fatty acid derivative 3a Under a nitrogen atmosphere, 175.5 mg (0.75 mmol, 3.0 equivalents) of 4-iodoanisole, 25.6 mg (0.025 mmol, 10 mol%) of Pd(OAc), and 76 mg (0.50 mmol, 2.0 equivalents) of CsF were placed in a 6.0 mL test tube equipped with a stirrer. The test tube was sealed with a lid, and 1.2 mL of ethyl acetate and 76 μL (0.25 mmol, 1.0 equivalents) of the polyunsaturated fatty acid derivative 1 obtained in Example 1 were added sequentially. After stirring the mixture at room temperature (23°C), 61 μL (1.0 mmol, 4.1 equivalents) of polymethylhydrosiloxane were added over 12 hours using a syringe pump. The mixture was stirred at room temperature (23°C) for 48 hours from the start of the addition of the polymethylhydrosiloxane. The reaction mixture was then filtered through a glass filter filled with Celite and washed with ethyl acetate (×5). The filtrate was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (hexane / toluene / ethyl acetate: 88 / 8 / 4). As a result, aromatic-substituted polyunsaturated fatty acid derivative 3a (5-(4-methoxyphenyl)-5,9-dimethyl-N-(quinolin-8-yl)dec-8-enamide) represented by the following formula was obtained as a clear pale yellow oil. Yield: 77.0 mg (72%).

[0072] [ka]

[0073] 1 H NMR(500MHz,CDCl3)δ9.72(s,1H),8.81-8.73(m,2H),8.15(dd,J=8.3,1.7Hz,1H),7.56-7.47(m,2H),7.45(dd,J=8.2,4.2Hz,1H ),7.24-7.18(m,2H),6.85-6.79(m,2H),5.16-4.91(m,1H),3.77(s,3H),2.45(t,J=7.2Hz,2H),1.86-1.44(m,14H),1.33(s,3H). 13 C NMR(126MHz, CDCl3)δ171.8,157.4,148.2,139.6,138.5,136.5,134.7,131.2,128.1,127.6,127. 4,125.0,121.7,121.4,116.5,113.5,55.3,43.4,43.2,40.4,38.9,25.8,24.0,23.1,20.8,17.7. HRMS(ESI + )(m / z):Calcd. for C 28 H 35 N2O2 + [M+H] + 431.2693,Found 431.2691.

[0074] Example 2: Synthesis of aromatic-substituted polyunsaturated fatty acid derivative 3b The same amounts of palladium catalyst, CsF, polyunsaturated fatty acid derivative 1, and polymethylhydrosiloxane as in Example 1 were used, except that 232.6 mg (0.75 mmol, 3.0 equivalents) of 1-benzyloxy-4-iodobenzene was used as Ar-I. The same procedure as in Example 1 was carried out to obtain aromatic-substituted polyunsaturated fatty acid derivative 3a ((5-(4-(benzyloxy)phenyl)-5,9-dimethyl-N-(quinolin-8-yl)dec-8-enamide) represented by the following formula. Aromatic-substituted polyunsaturated fatty acid derivative 3b was obtained as a pale yellow oil in a yield of 95.0 mg (75%).

[0075] [ka]

[0076] 1 H NMR(500MHz, CDCl3)δ9.73(brs,1H),8.82-8.74(m,2H),8.15(dd,J=8.3,1.7Hz,1H),7.56-7.46(m,2H),7.46-7.40(m,3H),7.38(dd, J=8.5,6.7Hz,2H),7.35-7.27(m,1H),7.26-7.19(m,2H),6.94-6.87(m,2H),5.06-5.00(m,3H),2.46(t,J=7.2Hz,2H),1.87-1.43(m, 14H),1.34(s,3H). 13 C NMR (126MHz, CDCl3) δ171.8,156.7,148.2,139.9,138.4,137.4,136.5,134.7,131.2,128.7,128.1,128.0,127. 7,127.6,127.5,125.0,121.7,121.4,116.5,114.4,70.1,43.4,43.2,40.4,38.9,25.8,24.0,23.1,20.8,17.7. HRMS (ESI) + (m / z):Calcd. for C 34 H 39 N2O2 + [M+H] + 507.3006, Found 507.3007.

[0077] [Example 3: Synthesis of aromatic substituted polyunsaturated fatty acid inducer 3c] The same amounts of palladium catalyst, CsF, polyunsaturated fatty acid derivative 1, and polymethylhydrosiloxane were used as in Example 1, except that 163.5 mg (0.75 mmol, 3.0 equivalents) of 4-iodotoluene was used as Ar-I. The same procedures as in Example 1 were followed, including purification by silica gel column chromatography. As a result, an inseparable mixture of aromatic-substituted polyunsaturated fatty acid derivative 3c (5,9-dimethyl-N-(quinolin-8-yl)-5-(p-tolyl)dec-8-enamide) represented by the following formula and polyunsaturated fatty acid derivative 1 was obtained as a clear oil in a 90% yield (93.3 mg). The estimated yield of 3c was 70% (the ratio of 3c to polyunsaturated fatty acid derivative 1 in the inseparable mixture, 3c:polyunsaturated fatty acid derivative 1, was 3.5:1.0).

[0078] [ka]

[0079] 1 H NMR(3c)+(1)(500MHz,CDCl3)δ9.82(brs,0.3H(1H1)),9.72(brs,1H(1H3c)),8.83-8.73(m,2H(2H3c)+0.6H(2H1)),8.18-8.12(m,1H(1) H3c)+0.3H(1H1)),7.57-7.41(m,3H(3H3c)+0.9H(3H1)),7.20(d,J=8.0Hz,2H(2H3c)),7.09(d,J=7.9Hz,2H(2H3c)),5.33-5.19(m,0.3H (1H1)),5.11-5.01(m,1H(1H3c)+0.3H(1H1)),2.66-2.57(m,0.6H(2H1)),2.56-2.49(m,0.6H(2H1)),2.45(t,J=7.2 Hz,2H(2H3c)),2.29(s,3H),2.12-1.95(m,1.2H(4H1)),1.88-1.41(m,14H(14H3c)+2.7H(9H1)),1.34(s,3H(3H3c)). 13C NMR(3c)+(1)(126MHz,CDCl3)δ171.8,171.6,148.2,148.2,144.5,138.5,138.4, 137.2,136.5,134.8,134.7,134.7,131.5,131.2,128.9,128.1,128.0,127.6,12 6.3, 125.0, 124.3, 122.5, 121.7, 121.4, 121.4, 116.6, 116.5, 43.2, 43.1, 40.6, 39.8, 38.9, 38.5, 26.8, 25.8, 25.8, 24.3, 24.0, 23.1, 21.0, 20.8, 17.8, 17.7, 16.3. HRMS(ESI + )(m / z):Calcd. for C 28 H 35 N2O + [M+H] + 415.2744,Found 415.2744.

[0080] Example 4: Synthesis of aromatic-substituted polyunsaturated fatty acid derivative 3d The same amounts of palladium catalyst, CsF, polyunsaturated fatty acid derivative 1, and polymethylhydrosiloxane as in Example 1 were used, except that 108 μL (0.75 mmol, 3.0 equivalents) of 4-iodobenzenetrifluoride was used as Ar-I. The same procedure as in Example 1 was carried out to obtain aromatic-substituted polyunsaturated fatty acid derivative 3d (5,9-dimethyl-N-(quinolin-8-yl)-5-(4-(trifluoromethyl)phenyl)dec-8-enamide) represented by the following formula. Aromatic-substituted polyunsaturated fatty acid derivative 3d was obtained as a colorless oil. Yield: 105.6 mg (90%).

[0081] [ka]

[0082] 1H NMR(500MHz,CDCl3)δ9.73(brs,1H),8.81-8.70(m,2H),8.16(dd,J=8.2,1.7Hz,1H),7.56 -7.39(m,7H),5.08-4.90(m,1H),2.47(t,J=7.2Hz,2H),1.92-1.41(m,14H),1.39(s,3H). 13 C NMR(126MHz,CDCl3)δ171.5,151.9,148.2,138.4,136.5,134.6,131.6,128.1,127.9(q, J(CF)=32.3Hz),127.6,126.9,125.2(q,J(CF)=4.2Hz),124.5(q,J(CF)=271.7Hz) ,124.5,121.7,121.5,116.5,43.3,42.9,41.4,38.6,25.8,23.7,23.0,20.6,17.6. 19 FNMR (471 MHz, CDCl3) δ -65.4. HRMS(ESI + )(m / z):Calcd. for C 28 H 32 F3N2O + [M+H] + 469.2461,Found 469.2458.

[0083] Example 5: Synthesis of aromatic-substituted polyunsaturated fatty acid derivative 3e The same procedures as in Example 1 were carried out using the same amounts of palladium catalyst, CsF, polyunsaturated fatty acid derivative 1, and polymethylhydrosiloxane as in Example 1, except that 171.8 mg (0.75 mmol, 3.0 equivalents) of 4-iodobenzonitrile was used as Ar-I, and purification was carried out by silica gel column chromatography (hexane / ethyl acetate: 88 / 12). This afforded aromatic-substituted polyunsaturated fatty acid derivative 3e (5-(4-cyanophenyl)-5,9-dimethyl-N-(quinolin-8-yl)dec-8-enamide) represented by the following formula. Aromatic-substituted polyunsaturated fatty acid derivative 3e was obtained as an orange oil in a yield of 104.0 mg (98%).

[0084] [ka]

[0085] 1 H NMR(500MHz,CDCl3)δ9.70(brs,1H),8.81-8.71(m,2H),8.16(dd,J=8.2,1.7Hz,1H),7.59-7.43(m,5 H),7.41(d,J=8.2Hz,2H),5.01-4.94(m,1H),2.47(t,J=7.2Hz,2H),1.94-1.40(m,14H),1.37(s,3H). 13 C NMR(126MHz, CDCl3)δ171.3,153.5,148.2,138.4,136.6,134.5,132.1,131.8,128.1,127.5,127. 4,124.2,121.8,121.6,119.2,116.5,109.5,43.2,42.6,41.7,38.4,25.7,23.4,23.0,20.5,17.6. HRMS(ESI + )(m / z):Calcd. for C 28 H 32 N3O + [M+H] + 426.2540,Found 426.2541.

[0086] Example 6: Synthesis of aromatic-substituted polyunsaturated fatty acid derivative 3f The same procedures as in Example 1 were carried out using the same amounts of palladium catalyst, CsF, polyunsaturated fatty acid derivative 1, and polymethylhydrosiloxane as in Example 1, except that 186.8 mg (0.75 mmol, 3.0 equivalents) of 1-iodo-4-nitrobenzene was used as Ar-I. The ethyl acetate volume was changed from 1.2 mL to 2.4 mL, and purification was performed by silica gel column chromatography (hexane / ethyl acetate: 75 / 25). Aromatically substituted polyunsaturated fatty acid derivative 3f (5,9-dimethyl-5-(4-nitrophenyl)-N-(quinolin-8-yl)dec-8-enamide) was obtained as shown below. Aromatically substituted polyunsaturated fatty acid derivative 3f was obtained as a yellow oil. Yield: 57.0 mg (51%).

[0087] [ka]

[0088] 1 H NMR(500MHz,CDCl3)δ9.70(brs,1H),8.76(dd,J=4.2,1.7Hz,1H),8.74(dd,J=7.3,1.7Hz,1H),8.16(dd,J=8.2,1.7Hz,1 H),8.13-8.08(m,2H),7.56-7.41(m,5H),5.16-4.90(m,1H),2.55-2.41(m,2H),1.92-1.51(m,10H),1.50-1.36(m,7H). 13 C NMR(126MHz,CDCl3)δ171.3,155.8,148.2,146.0,138.4,136.5,134.5,131.8,128.1,127.5,1 27.4,124.1,123.4,121.8,121.6,116.5,43.3,42.7,41.9,38.4,25.7,23.6,23.0,20.6,17.6. HRMS(ESI + )(m / z):Calcd. for C 27 H 32 N3O3 + [M+H] + 446.2438,Found 446.2433.

[0089] Example 7: Synthesis of aromatic-substituted polyunsaturated fatty acid derivative 3g The same amounts of palladium catalyst, CsF, polyunsaturated fatty acid derivative 1, and polymethylhydrosiloxane as in Example 1 were used, except that 86.7 μL (0.75 mmol, 3.0 equivalents) of 1-fluoro-4-iodobenzene was used as the substituted Ar-I. The same procedure as in Example 1 was carried out, except that the crude product was purified by column chromatography (hexane / toluene / ethyl acetate: 87 / 8 / 4), to obtain 3 g of an aromatic-substituted polyunsaturated fatty acid derivative represented by the following formula (5-(4-fluorophenyl)-5,9-dimethyl-N-(quinolin-8-yl)dec-8-enamide). The aromatic-substituted polyunsaturated fatty acid derivative 3 g was obtained as a yellow oil. Yield: 98.6 mg (94%).

[0090] [ka]

[0091] 1 H NMR(500MHz,CDCl3)δ9.72(brs,1H),8.81-8.72(m,2H),8.16(dt,J=8.3,1.8Hz,1H),7.56-7.48(m,2H),7.48-7.42(m, 1H),7.28-7.21(m,2H),7.00-6.91(m,2H),5.05-4.98(m,1H),2.46(t,J=7.2Hz,2H),1.88-1.39(m,14H),1.34(s,3H). 13 C NMR(126MHz,CDCl3)δ171.7,161.0(d,J(CF)=244.0Hz),148.2,143.1(d,J(CF)=3.8Hz),138.4,136.5,134.6,131.4,128.1,128.0(d ,J(CF)=7.5Hz),127.6,124.7,121.7,121.5,116.5,114.8(d,J(CF)=20.1Hz),43.5,43.1,40.7,38.7,25.8,23.9,23.0,20.7,17.6. 19 F NMR (471MHz, CDCl3)δ-121.7. HRMS(ESI + )(m / z):Calcd. for C 27 H 32 FN2O + [M+H] + 419.2493,Found 419.2489.

[0092] Example 8: Synthesis of aromatic-substituted polyunsaturated fatty acid derivative 3h The same procedures as in Example 1 were carried out using the same amounts of palladium catalyst, CsF, polyunsaturated fatty acid derivative 1, and polymethylhydrosiloxane as in Example 1, except that 178.8 mg (0.75 mmol, 3.0 equivalents) of 1-chloro-4-iodobenzene was used as the substituted Ar-I, and purification was carried out by silica gel column chromatography (hexane / toluene / ethyl acetate: 83 / 8 / 9). Aromatic-substituted polyunsaturated fatty acid derivative 3h (5-(4-chlorophenyl)-5,9-dimethyl-N-(quinolin-8-yl)dec-8-enamide) represented by the following formula was obtained. Aromatic-substituted polyunsaturated fatty acid derivative 3h was obtained as a colorless oil. Yield: 108.0 mg (99%).

[0093] [ka]

[0094] 1 H NMR(500MHz,CDCl3)δ9.72(brs,1H),8.81-8.72(m,2H),8.15(dd,J=8.3,1.7Hz,1H),7.55-7.47(m,2H),7.45(dd, J=8.3,4.2Hz,1H),7.25-7.19(m,4H),5.10-4.89(m,1H),2.46(t,J=7.1Hz,2H),1.92-1.38(m,14H),1.34(s,3H). 13 C NMR(126MHz,CDCl3)δ171.6,148.2,146.1,138.4,136.5,134.6,131.5,131.3,128.3,128.1,1 28.0,127.6,124.6,121.7,121.5,116.5,43.3,43.0,40.8,38.7,25.8,23.7,23.0,20.6,17.7. HRMS(ESI + )(m / z):Calcd. for C 27 H 32 ClNO + [M+H]+ 435.2198,Found 435.2201.

[0095] Example 9: Synthesis of aromatic-substituted polyunsaturated fatty acid derivative 3i The same procedures as in Example 1 were carried out using the same amounts of palladium catalyst, CsF, polyunsaturated fatty acid derivative 1, and polymethylhydrosiloxane as in Example 1, except that 212.2 mg (0.75 mmol, 3.0 equivalents) of 1-bromo-4-iodobenzene was used as the substituted Ar-I, and purification was carried out by silica gel column chromatography (hexane / toluene / ethyl acetate: 83 / 8 / 9). This afforded aromatic-substituted polyunsaturated fatty acid derivative 3i (5-(4-bromophenyl)-5,9-dimethyl-N-(quinolin-8-yl)dec-8-enamide) represented by the following formula. Aromatic-substituted polyunsaturated fatty acid derivative 3i was obtained as a dark green oil in a yield of 74.5 mg (62%).

[0096] [ka]

[0097] 1 H NMR(500MHz,CDCl3)δ9.72(brs,1H),8.81-8.72(m,2H),8.15(dd,J=8.3,1.7Hz,1H),7.58-7.48(m,2H),7.45(dd,J=8.2,4. 2Hz,1H),7.41-7.33(m,2H),7.21-7.13(m,2H),5.04-4.97(m,1H),2.46(t,J=7.1Hz,2H),1.91-1.40(m,14H),1.33(s,3H). 13 C NMR(126MHz,CDCl3)δ171.6,148.2,146.6,138.4,136.5,134.6,131.5,131.2,128.4,128.1,1 27.6,124.6,121.7,121.5,119.5,116.5,43.3,42.9,40.9,38.7,25.8,23.7,23.0,20.7,17.7. HRMS(ESI +)(m / z):Calcd. for C 27 H 32 BrNO + [M+H] + 479.1693,Found 479.1695.

[0098] Example 10: Synthesis of aromatic-substituted polyunsaturated fatty acid 4a 240 mg of sodium hydroxide (93% content) and 1.0 mL of ethanol were placed in a 20 mL pressure test tube. 20.0 mg (0.046 mmol, 1.0 equivalent) of the aromatic-substituted polyunsaturated fatty acid derivative 3a obtained in Example 1 was dissolved in 3.0 mL of ethanol and added. A stirring device was placed in the pressure test tube, the tube was sealed with a lid, and the contents were stirred in an oil bath at 130°C for 39.5 hours. After the reaction was completed, the reaction mixture was cooled to room temperature. The reaction mixture was then diluted with 20 mL of ethyl acetate, and the organic layer was washed four times with 6 mL of 1N hydrochloric acid by a separation operation. The washed organic layer was dried over sodium sulfate and concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate: 4 / 1) to obtain aromatic-substituted polyunsaturated fatty acid 4a as a yellow oil. Yield: 14.1 mg (84%).

[0099] [ka]

[0100] 1 H NMR(500MHz,CDCl3)δ7.22-7.14(m,2H),6.87-6.80(m,2H),5.07-4.99(m,1H),3.79(s,3H),2.2 4(t,J=7.3Hz,2H),1.85-1.74(m,1H),1.72-1.60(m,5H),1.57-1.45(m,5H),1.36-1.23(m,6H). 13C NMR (126MHz, CDCl3) δ178.9,157.4,139.4,131.3,127.4,124.9,113.5,55.3,43.4,43.0,40.3,34.5,25.8,24.0,23.1,19.8,17.7. HRMS(ESI + )(m / z):Calcd. for C 19 H 28 O3 + [M+Na] + 327.1930,Found 327.1931.

[0101] Example 11: Synthesis of aromatic-substituted polyunsaturated fatty acid ester 5a 7.4 mg (0.0174 mmol, 0.23 equivalents) of bis(2,2,6,6-tetramethyl-3,5-heptanedionate)nickel(II) and 0.6 mL of methanol were placed in a 20 mL pressure test tube. Then, 32.0 mg (0.074 mmol, 1.0 equivalents) of the aromatic-substituted polyunsaturated fatty acid derivative 3a obtained in Example 1 was dissolved in 1.8 mL of methanol and added. A stirring device was placed in the pressure test tube, the tube was sealed with a lid, and the contents were stirred in an oil bath at 100°C for 40.5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was then diluted with diethyl ether and concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by silica gel column chromatography (hexane / ether: 8 / 1) to obtain aromatic-substituted polyunsaturated fatty acid ester 5a as a yellow oil. Yield: 23.9 mg (100%).

[0102] [ka]

[0103] 1H NMR(500MHz,CDCl3)δ7.22-7.15(m,2H),6.87-6.80(m,2H),5.15-4.91(m,1H),3.79(s,3H),3.63(s,3 H),2.20(t,J=7.3Hz,2H),1.86-1.72(m,1H),1.71-1.59(m,6H),1.57-1.36(m,4H),1.35-1.18(m,6H). 13 C NMR (126MHz, CDCl3) δ174.2,157.4,139.5,131.3,127.4,124.9,113.5,55.3,51.6,43.4,43.1,40.3,34.8,25.8,24.0,23.1,20.1,17.7. HRMS(ESI + )(m / z):Calcd. for C 20 H 30 O3 + [M+Na] + 341.2087,Found 341.2089.

[0104] Example 12: Synthesis of aromatic-substituted polyunsaturated fatty acid 4a from aromatic-substituted polyunsaturated fatty acid ester 5a 200 mg of sodium hydroxide (93%) and 2.4 mL of methanol were placed in a 6.0 mL test tube. Next, fatty acid ester 5a (13.9 mg, 0.044 mmol, 1.0 equiv.) dissolved in 2.0 mL of methanol was added, and a stirrer was added. The test tube was sealed with a lid and stirred at room temperature. After 2 days, the reaction was stopped by adding 5 mL of 2N hydrochloric acid. The reaction mixture was transferred to a separatory funnel, 50 mL of water was added, and extraction was performed with 20 mL of diethyl ether. Extraction of the carboxylic acid into the organic layer was repeated four times with diethyl ether (a total of five times). The resulting organic layer was dried over sodium sulfate and concentrated under reduced pressure using a rotary evaporator to obtain aromatic-substituted polyunsaturated fatty acid 4a as a yellow oil. Yield: 16.0 mg (100%). [Industrial Applicability]

[0105] According to the present invention, it is possible to produce aromatic-substituted polyunsaturated fatty acid derivatives in which aromatic groups are regiospecifically introduced only into double bonds at specific positions in a polyunsaturated fatty acid derivative containing two or more carbon-carbon double bonds in the molecule. Therefore, it is possible to synthesize fatty acids with diverse functions depending on the aromatic ring introduced, and it is possible to synthesize rare polyunsaturated fatty acid derivatives that do not exist in nature. It is also possible to synthesize functional fatty acids and to improve the physical properties of known products by modifying the fatty acids.

Claims

1. A polyunsaturated fatty acid derivative represented by the following formula (1): 【Chemistry 1】 (In formula (1), n ​​is an integer of 1 to 4, and R １ is a hydrocarbon group containing 1 to 10 carbon-carbon double bonds, and —(CH ２ ) ｎ -CH=CH-R １ at least one hydrogen atom contained in may be substituted with at least one substituent selected from the group consisting of an alkyl group having 1 to 12 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, an aryl group, an amino group, an amido group, and an imino group); Ar-I, where Ar is an aromatic group, reacting in the presence of a palladium catalyst and a hydrosilane; The method for producing an aromatic substituted polyunsaturated fatty acid derivative, wherein Ar-I may be substituted with an additional substituent in addition to the iodo group.

2. In the polyunsaturated fatty acid derivative represented by formula (1), in the carbon-carbon double bond closest to the 8-quinolylamino group, a hydrogen atom bonded to the carbon atom is substituted with the substituent, The method for producing an aromatic-substituted polyunsaturated fatty acid derivative according to claim 1, wherein an aromatic-substituted quaternary carbon is constructed at the position where the substituent is bonded.

3. Furthermore, polyunsaturated fatty acids represented by the following formula (2) 【Chemistry 2】 (In formula (2), n is an integer of 1 to 4, and R １ is a hydrocarbon group containing 1 to 10 carbon-carbon double bonds, and —(CH ２ ) ｎ -CH=CH-R １ wherein at least one hydrogen atom contained in the formula (I) may be substituted with at least one substituent selected from the group consisting of an alkyl group having 1 to 12 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, an aryl group, an amino group, an amido group, and an imino group), with 8-aminoquinoline.

4. A method for producing an aromatic-substituted polyunsaturated fatty acid, comprising a step of removing an aminoquinoline group from the aromatic-substituted polyunsaturated fatty acid derivative obtained by the production method according to any one of claims 1 to 3.

Images