Polyunsaturated fatty acid and method for producing same

Abstract

Provided is a method for producing a polyunsaturated fatty acid by: reacting a compound (2) and a compound (3) in the co-presence of an organic solvent, a base soluble in the organic solvent, and a monovalent copper salt, deprotecting the obtained reaction product, and subsequently repeating the abovementioned reaction and deprotection reaction n - 1 times (n being an integer of 1 or greater) by using the obtained intermediate and the compound (3) so as to thereby synthesize a compound (13), then synthesizing a compound (12) by either reacting the compound (13) and a compound (4) in the same manner as described above, or reacting, in the same manner as described above, the compound (2) and the compound (4) without using the compound (3), and further synthesizing a compound (11) through a homogeneous catalytic hydrogen transfer reaction with respect to the compound (12), thereby obtaining a polyunsaturated fatty acid (1) from the compound (11).

Description

Polyunsaturated fatty acids and their production method

[0001] The present invention relates to polyunsaturated fatty acids and methods for producing the same. This application claims priority based on Japanese Patent Application No. 2024-054041, filed on March 28, 2024, the contents of which are incorporated herein by reference.

[0002] Polyunsaturated fatty acids are fatty acids with a linear unsaturated hydrocarbon skeleton containing two or more double bonds between carbon atoms, and are important biomolecules that play a variety of functions in vivo, such as energy storage and signal transduction, and the formation and regulation of biological membranes. Because polyunsaturated fatty acids can exhibit different actions based on subtle differences in their chemical structures, obtaining polyunsaturated fatty acids is an important challenge for clarifying their functions.

[0003] Until now, polyunsaturated fatty acids have primarily been obtained by extraction from natural resources, but they are often difficult to obtain because some naturally occurring polyunsaturated fatty acids exist only in trace amounts and require a great deal of effort for extraction. Therefore, in order to easily obtain naturally occurring polyunsaturated fatty acids and novel non-naturally occurring polyunsaturated fatty acids, attempts have been made to produce them by chemical synthesis. In general, novel non-naturally occurring derivatives obtained by modifying part of the structure of naturally occurring compounds that are useful to living organisms may exhibit stronger effects than naturally occurring compounds or may exhibit effects different from those of naturally occurring compounds, making them extremely important. This importance is also true for polyunsaturated fatty acids.

[0004] However, in conventional chemical synthesis, polyunsaturated fatty acids have been produced by a commonly used method. That is, polyunsaturated fatty acids have been produced by obtaining the target product by a liquid phase synthesis method in which a chemical reaction is carried out in an organic solvent, then performing post-treatment on the reaction solution as necessary, extracting the target product, and further purifying it as necessary. However, such conventional production methods involve many steps, requiring a long time and a great deal of labor.

[0005] On the other hand, other than polyunsaturated fatty acids, nucleic acids, peptides, proteins, and sugars are well known as compounds useful to living organisms. These compounds were also initially produced by conventional liquid-phase synthesis, but there was a strong desire for efficient acquisition, and as a result of extensive research, solid-phase synthesis using solid supports was developed. These solid-phase synthesis methods have been refined through successive improvements, and it has become possible to obtain the desired products in an extremely short time and with high yields. As a result, research on the functions of these compounds in living organisms has made great progress, as is well known.

[0006] A production method employing solid-phase synthesis has also been reported for polyunsaturated fatty acids (see Non-Patent Document 1). The synthesis reaction in this production method is outlined below, along with the reaction schemes for each step. Specifically, this production method first uses a starting compound having a structure in which a carboxylic acid having an ethynyl group at the molecular terminal is ester-bonded to a solid-phase support. Then, in an organic solvent, the starting compound is reacted with 4-chloro-2-butyn-1-ol in the presence of copper(I) iodide, sodium iodide, and potassium carbonate to bond a 2-butyn-1-ol-4-yl group to the ethynyl group of the starting compound, thereby extending the unsaturated hydrocarbon chain containing a carbon atom triple bond (C≡C) in the starting compound and obtaining an intermediate having a hydroxyl group at the molecular terminal. Next, the hydroxyl groups of this intermediate are substituted with bromine atoms, and then the intermediate is reacted with 2-propyn-1-ol in the presence of copper(I) iodide, sodium iodide, and potassium carbonate in an organic solvent, as described above, to elongate the unsaturated hydrocarbon chain containing a triple bond between carbon atoms in the intermediate, thereby obtaining a new intermediate having a hydroxyl group at the molecular end. Thereafter, the substitution of the hydroxyl groups of this intermediate with bromine atoms and the elongation of the unsaturated hydrocarbon chain are repeated, and finally, the elongation of the unsaturated hydrocarbon chain is completed by reacting a hydrocarbon having an ethynyl group in place of 2-propyn-1-ol. Next, a polyunsaturated fatty acid having multiple triple bonds between carbon atoms is excised from the solid support, and this unsaturated fatty acid is subjected to a hydrogenation reaction using a liquid-phase synthesis method to obtain the desired polyunsaturated fatty acid having multiple double bonds between carbon atoms (C=C).

[0007]

[0008] Solid-Phase Synthesis of Anandamide Analogues, Longwu Qi, Michael M. Meijler, Sang-Hyeup Lee, Chengzao Sun, and Kim D. Janda, Org. Lett. 2004, 6, 1673-1675

[0009] In the production method described in Non-Patent Document 1, even though solid-phase synthesis was employed, a single elongation reaction of an unsaturated hydrocarbon chain containing a triple bond between carbon atoms for the starting compound and each intermediate required a long time of three days or more. Furthermore, the hydrogenation reaction of polyunsaturated fatty acids having multiple triple bonds between carbon atoms could not be performed by solid-phase synthesis, but was performed by liquid-phase synthesis, which limited the options for the hydrogenation reaction. Thus, conventional production methods for polyunsaturated fatty acids using solid-phase synthesis required a long time and required the use of liquid-phase synthesis in combination to obtain the target product, resulting in the problem that polyunsaturated fatty acids could not be obtained efficiently.

[0010] An object of the present invention is to provide a method for producing polyunsaturated fatty acids, which can produce polyunsaturated fatty acids in a short time by solid-phase synthesis without using liquid-phase synthesis in combination.

[0011] In order to solve the above problems, the present invention employs the following configuration: [1] A method for producing polyunsaturated fatty acids using a solid phase carrier, comprising:

[0012] (In the formula, Z １ is a solid support; G １ is a divalent group; X １ is an alkylene group which may have a substituent; and m is 0 or 1.) and a compound having an ethynyl group at a molecular terminal, represented by the following general formula (3):

[0013] (In the formula, L １ is a leaving group; E １is a silicon atom-containing protecting group.) is reacted with a compound represented by the formula (I) in the presence of an organic solvent, a base soluble in the organic solvent, and a monovalent copper salt, and then the E １ is replaced with a hydrogen atom, thereby synthesizing an intermediate having an ethynyl group at the molecular end, and further reacting the intermediate with the compound represented by the general formula (3) in the presence of an organic solvent, a base soluble in the organic solvent, and a monovalent copper salt, and １ is replaced with a hydrogen atom, ０ −1(n ０ is an integer of 1 or more.) times,

[0014] (In the formula, Z １ , G １ , X １ , m and n ０ are the same as above.) A compound represented by the general formula (13) is synthesized, and a compound represented by the following general formula (4) is synthesized.

[0015] (In the formula, L ２ is a leaving group; R １ is an alkyl group, one or more hydrogen atoms in the alkyl group may be substituted with a substituent, and one or more non-adjacent methylene groups in the alkyl group may be substituted with an oxygen atom, an ethylene oxide-1,2-diyl group, or a furan-2,5-diyl group.) in the co-presence of an organic solvent, a base soluble in the organic solvent, and a monovalent copper salt, or without using the compound represented by general formula (3), by reacting the compound represented by general formula (2) with the compound represented by general formula (4) in the co-presence of an organic solvent, a base soluble in the organic solvent, and a monovalent copper salt,

[0016] (In the formula, Z １ , G １ , X １ , m and R １is the same as above; and n is an integer of 1 or more.) A compound represented by the following general formula (11) is synthesized by subjecting the compound represented by the general formula (12) to a homogeneous catalytic hydrogen transfer reaction:

[0017] (In the formula, Z １ , G １ , X １ , m, n and R １ are the same as above.) When a hydrogen atom in the alkyl group is substituted with a hydroxyl group protected by a silicon atom-containing protecting group as the substituent, the silicon atom-containing protecting group may then be removed to obtain a new compound represented by the general formula (11). By cleaving the bond between the carbonyl group in the compound represented by the general formula (11) and the oxygen atom adjacent to the carbonyl group, a compound represented by the following general formula (1):

[0018] (In the formula, G １ , X １ , m, n and R １ (wherein the formula (I) is the same as above).

[0019] [2] A method for producing polyunsaturated fatty acids using a solid phase carrier, comprising:

[0020] (In the formula, Z １ is a solid support; G １ is a divalent group; X １ is an alkylene group which may have a substituent; and m is 0 or 1.) and a compound having an ethynyl group at a molecular terminal, represented by the following general formula (3):

[0021] (In the formula, L １ is a leaving group; E １ is a silicon atom-containing protecting group.) A protected intermediate is synthesized by reacting a compound represented by the formula (I) with an organic solvent, a base soluble in the organic solvent, and a monovalent copper salt, and further, １with a hydrogen atom, and reacting the resulting deprotection reaction product with the compound represented by the general formula (3) in the presence of an organic solvent, a base soluble in the organic solvent, and a monovalent copper salt, １０ −1(n １０ is an integer of 1 or more.) times,

[0022] (In the formula, Z １ , G １ , X １ , m, n １０ and E １ is the same as above.) and then subjecting the compound represented by the general formula (16) to a homogeneous catalytic hydrogen transfer reaction to obtain a compound represented by the following general formula (110):

[0023] (In the formula, Z １ , G １ , X １ , m and n １０ is the same as above.) and synthesizing a compound represented by the following general formula (10):

[0024] (In the formula, G １ , X １ , m and n １０ (wherein the formula (I) is the same as above).

[0025] [3] The method for producing a polyunsaturated fatty acid according to [1] or [2], wherein the organic solvent-soluble base is one or more selected from the group consisting of tetramethylguanidine, 1,5-diazabicyclo[4.3.0]-5-nonene, 1,8-diazabicyclo[5.4.0]-7-undecene, 2,2,6,6-tetramethylpiperidine, and N,N-diisopropylethylamine. [4] The method for producing a polyunsaturated fatty acid according to any one of [1] to [3], wherein the homogeneous catalytic hydrogen transfer reaction is carried out in the presence of [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]copper(I) tert-butoxide, an alcohol, and a hydrosilane. [5] The method for producing a polyunsaturated fatty acid according to any one of [1] to [4], wherein the alkylene group is a linear alkylene group having 2 to 10 carbon atoms. [6] The method for producing a polyunsaturated fatty acid according to any one of [1] to [5], wherein the alkyl group is a chain alkyl group having 1 to 12 carbon atoms. [7] The method for producing a polyunsaturated fatty acid according to any one of [1] and [3] to [5], wherein n is 1 to 10. [8] The method for producing a polyunsaturated fatty acid according to any one of [1] and [3] to [5], wherein n is 1 to 10. １０ [9] The method for producing a polyunsaturated fatty acid according to any one of [2] to [6], wherein the formula (1A) is a carboxylic acid represented by the following general formula (1A):

[0026] (In the formula, X １１ is a chain alkylene group having 2, 3, 4 or 8 carbon atoms; n １１ is X １１ is an alkylene group having 2 carbon atoms, it is 1, 2 or 3; １１ is an integer of 1 to 3 when X is a chain alkylene group having 3 carbon atoms; １１ is a chain alkylene group having 4 carbon atoms, it is 1, 2 or 3; １１ is an integer of 1 to 4 when R is a chain alkylene group having 8 carbon atoms; １１ is X １１ is an alkylene group having 2 carbon atoms, X is a chain alkyl group having 1 or 8 carbon atoms; １１is a chain alkylene group having 3 carbon atoms, it is a hydrogen atom, a methyl group, an ethyl group, or a substituted alkyl group having a structure in which one methylene group in a chain alkyl group having 4 carbon atoms is substituted with an ethyleneoxide-1,2-diyl group or a furan-2,5-diyl group, and X １１ is a chain alkylene group having 4 carbon atoms, it is a methyl group or an ethyl group, １１ is a chain alkylene group having 8 carbon atoms, it is a hydrogen atom or a chain alkyl group having 1 to 5 carbon atoms.) (excluding (5Z,8Z,11Z,14Z)-16-(3-ethyloxiran-2-yl)hexadeca-5,8,11,14-tetraenoic acid, (10Z,13Z)-hexadeca-10,13-dienoic acid, (10Z,13Z,16Z,19Z)-docosa-10,13,16,19-tetraenoic acid, and (10Z,13Z,16Z,19Z)-pentacosa-10,13,16,19-tetraenoic acid).

[10] The polyunsaturated fatty acid represented by the general formula (1A) is

[0027] (In the formula, n １１１ is an integer from 1 to 3; R １１１ is a methyl group, an ethyl group, or the above-mentioned substituted alkyl group, or a polyunsaturated fatty acid represented by the following general formula (1A)-2

[0028] (In the formula, X １１２ is a chain alkylene group having 2, 4 or 8 carbon atoms; n １１２ is X １１２ is an alkylene group having 2 carbon atoms, it is 1, 2 or 3; １１２ is a chain alkylene group having 4 carbon atoms, it is 1, 2 or 3; １１２ is an integer of 1 to 4 when R is a chain alkylene group having 8 carbon atoms; １１２ is X １１２ is an alkylene group having 2 carbon atoms, X is a chain alkyl group having 1 or 8 carbon atoms; １１２ is a chain alkylene group having 4 carbon atoms, it is a methyl group or an ethyl group, １１２is a chain alkylene group having 8 carbon atoms, it is a chain alkyl group having 1, 2 or 5 carbon atoms.) or a polyunsaturated fatty acid represented by the following general formula (1A)-3

[0029] (In the formula, X １１３ is a chain alkylene group having 3 or 8 carbon atoms; n １１３ is X １１３ is an alkylene group having 3 carbon atoms, the value is 3; １１３ is a chain alkylene group having 8 carbon atoms, the value is 1.) The polyunsaturated fatty acid according to [9] (excluding (5Z,8Z,11Z,14Z)-16-(3-ethyloxiran-2-yl)hexadeca-5,8,11,14-tetraenoic acid, (10Z,13Z)-hexadeca-10,13-dienoic acid, (10Z,13Z,16Z,19Z)-docosa-10,13,16,19-tetraenoic acid, and (10Z,13Z,16Z,19Z)-pentacosa-10,13,16,19-tetraenoic acid).

[0030] According to the present invention, there is provided a method for producing polyunsaturated fatty acids, which can produce polyunsaturated fatty acids in a short time by solid phase synthesis without using liquid phase synthesis in combination.

[0031] In this specification, when a specific compound is assumed to have a structure in which one or more hydrogen atoms are substituted with a group other than a hydrogen atom, the compound having such a substituted structure is referred to as a "derivative" of the specific compound. In this specification, unless otherwise specified, the term "group" includes not only an atomic group formed by bonding multiple atoms but also a single atom.

[0032] Method for Producing Polyunsaturated Fatty Acids (First Embodiment) A method for producing polyunsaturated fatty acids according to one embodiment of the present invention is a method using a solid phase carrier,

[0033] (In the formula, Z １ is a solid support; G １ is a divalent group; X １is an alkylene group which may have a substituent; and m is 0 or 1.) A compound having an ethynyl group at a molecular terminal represented by the following general formula (3) (sometimes referred to as "compound (2)" in this specification)

[0034] (In the formula, L １ is a leaving group; E １ is a silicon atom-containing protecting group.) (hereinafter, this may be referred to as “compound (3)”) is reacted with an organic solvent, a base soluble in the organic solvent, and a monovalent copper salt, and then the E in the resulting reaction product is １ is replaced with a hydrogen atom, thereby synthesizing an intermediate having an ethynyl group at the molecular end, and further reacting the intermediate with the compound represented by the general formula (3) in the presence of an organic solvent, a base soluble in the organic solvent, and a monovalent copper salt, and １ is replaced with a hydrogen atom, ０ −1(n ０ is an integer of 1 or more.) times,

[0035] (In the formula, Z １ , G １ , X １ , m and n ０ are the same as above.) (hereinafter, sometimes referred to as "compound (13)") is synthesized, and the compound represented by the general formula (13) and the compound represented by the following general formula (4)

[0036] (In the formula, L ２ is a leaving group; R １is an alkyl group, one or more hydrogen atoms in the alkyl group may be substituted with a substituent, and one or more non-adjacent methylene groups in the alkyl group may be substituted with an oxygen atom, an ethylene oxide-1,2-diyl group, or a furan-2,5-diyl group.) is reacted with a compound represented by the following general formula (12) (sometimes referred to as "compound (4)" in this specification) in the coexistence of an organic solvent, a base soluble in the organic solvent, and a monovalent copper salt, or without using the compound represented by the general formula (3), by reacting a compound represented by the general formula (2) with a compound represented by the general formula (4) in the coexistence of an organic solvent, a base soluble in the organic solvent, and a monovalent copper salt,

[0037] (In the formula, Z １ , G １ , X １ , m and R １ is the same as above; and n is an integer of 1 or more.) A compound represented by the following general formula (11) (sometimes referred to as "compound (12)" in this specification) is synthesized, and the compound represented by the general formula (12) is subjected to a homogeneous catalytic hydrogen transfer reaction to obtain a compound represented by the following general formula (11):

[0038] (In the formula, Z １ , G １ , X １ , m, n and R １ are the same as above.) (in this specification, this may be referred to as "compound (11)"), and when a hydrogen atom in the alkyl group is substituted with a hydroxyl group protected by a silicon-containing protecting group as the substituent, the silicon-containing protecting group may then be removed, and a compound represented by the following general formula (11) is obtained by cleaving the bond between the carbonyl group in the compound represented by the general formula (11) and the oxygen atom adjacent to the carbonyl group:

[0039] (In the formula, G １ , X １ , m, n and R １are the same as above.) (Herein, this embodiment may be referred to as "first embodiment.") According to the production method of the first embodiment, polyunsaturated fatty acids can be produced in a short time by solid-phase synthesis without using liquid-phase synthesis in combination.

[0040] In the production method of the first embodiment, compound (2) is reacted with compound (3) in the presence of an organic solvent, a base soluble in the organic solvent, and a monovalent copper salt, and then a deprotection reaction is carried out by treating the resulting reaction product with a deprotecting agent capable of removing (deprotecting) the silicon atom-containing protecting group. Next, the reaction of the deprotected reaction product with compound (3) in the presence of an organic solvent, a base soluble in the organic solvent, and a monovalent copper salt, and the deprotection reaction of the resulting reaction product are carried out in the following manner: ０ This step is repeated once, and then a step of reacting the resulting reactant with compound (4) in the presence of an organic solvent, a base soluble in the organic solvent, and a monovalent copper salt is adopted; or a step of reacting compound (2) with compound (4) in the presence of an organic solvent, a base soluble in the organic solvent, and a monovalent copper salt is adopted without using compound (3); then, the reactant obtained in either of these steps is subjected to a homogeneous catalytic hydrogen transfer reaction; if a hydrogen atom in the alkyl group in compound (4) is substituted with a hydroxyl group protected by a silicon-containing protecting group, then, a deprotection reaction may be performed on the resulting reactant by treating it with a deprotecting agent capable of removing (deprotecting) the silicon-containing protecting group; then, polyunsaturated fatty acid (1) is obtained by cleaving the polyunsaturated fatty acid (1) from the resulting reactant from the solid phase support; all reactions are performed on the solid phase support.

[0041] <<Polyunsaturated Fatty Acid (1)>> First, we will explain the polyunsaturated fatty acid (1), which is the target product of the production method of the first embodiment. The polyunsaturated fatty acid (1) is represented by the general formula (1) above and is a fatty acid having a chain unsaturated hydrocarbon skeleton with two or more double bonds (C=C) between carbon atoms.

[0042] In the general formula (1), m is 0 or 1, and the general formula "-C(=O)-G １ In the polyunsaturated fatty acid (1), X １ When m is 0, a terminal hydroxyl group (-OH) is bonded to the carbonyl group (-C(=O)-) bonded to G １ are bonded.

[0043] That is, when m is 0, the polyunsaturated fatty acid (1) is represented by the following general formula (1α):

[0044] (In the formula, X １ , n and R １ is the same as above.) (In this specification, this polyunsaturated fatty acid (1) may be referred to as "polyunsaturated fatty acid (1α)"). On the other hand, when m is 1, the polyunsaturated fatty acid (1) is represented by the following general formula (1β):

[0045] (In the formula, G １ , X １ , n and R １ is the same as above.) (In this specification, this polyunsaturated fatty acid (1) may be referred to as "polyunsaturated fatty acid (1β)").

[0046] Polyunsaturated fatty acids (1β) have a structure in which the hydroxyl group (—OH) in the carboxy group (—C(═O)—OH) in polyunsaturated fatty acids (1α) is substituted, and can be said to be analogs of polyunsaturated fatty acids (1α). However, since they share a common structure with polyunsaturated fatty acids (1α) in that they both have two or more double bonds and a carboxy group, they are categorized as polyunsaturated fatty acids (1) together with polyunsaturated fatty acids (1α).

[0047] In general formula (1), G １ is a divalent group, and is not particularly limited as long as it can bond two adjacent carbonyl groups together. １ Examples of the group include a group that constitutes an amino acid residue together with the carbonyl group marked with the symbol m. １(the amino acid residue) has an imino group (—NH—), and the imino group is １ It is bonded to a carbonyl group that is bonded to

[0048] The amino acid that becomes the amino acid residue is not particularly limited. １ The amino group (-NH ２ ), when the amino acid further has an amino group in addition to the imino group, one or two hydrogen atoms in this amino group may or may not be substituted with a substituent other than a hydrogen atom. When the amino acid has an imino group other than the imino group, the hydrogen atom in this imino group may or may not be substituted with a substituent other than a hydrogen atom. The substituent substituting the hydrogen atom in the amino group or imino group may be a protecting group. When the amino acid has a carboxy group (—COOH), this carboxy group may form a carboxylic acid ester (protected with a protecting group). Up to this point, we have explained cases in which the amino group, imino group, or carboxy group in an amino acid is protected with a protecting group or modified with a group other than a protecting group, but other functional groups that do not fall into the category of an amino group, imino group, or carboxy group may be protected with a protecting group or modified with a group other than a protecting group.

[0049] In general formula (1), X １ represents an alkylene group which may have a substituent. １ The alkylene group in X may be any of linear, branched, and cyclic, and may have both a linear structure (linear or branched) and a cyclic structure, but is preferably linear (linear or branched), and more preferably linear. １ The number of carbon atoms in the alkylene group is not particularly limited, but is preferably 1 to 10, and more preferably 2 to 10.

[0050] Examples of the chain alkylene group having 1 to 10 carbon atoms include straight-chain alkylene groups such as a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group, a hexamethylene group, a heptamethylene group, an octamethylene group, a nonamethylene group, and a decamethylene group; Propylene group (methylethylene group), 1-methyltrimethylene group, 2-methyltrimethylene group, 1,2-dimethylethylene group, 1,1-dimethylethylene group, ethylethylene group, 1-methyltetramethylene group, 2-methyltetramethylene group, 1,1-dimethyltrimethylene group, 1,2-dimethyltrimethylene group, 1,3-dimethyltrimethylene group, 1-ethyltrimethylene group, 2-ethyltrimethylene group, 1-methyl-2-ethylethylene group, n-propylethylene group, 1-methylpentamethylene group, 2-methylpentamethylene group, 3-methylpentamethylene group, 1,1-dimethyltetramethylene group branched alkylene groups such as a 1,2-dimethyltetramethylene group, a 1,3-dimethyltetramethylene group, a 1,4-dimethyltetramethylene group, a 2,3-dimethyltetramethylene group, a 2,2-dimethyltetramethylene group, a 1-ethyltetramethylene group, a 2-ethyltetramethylene group, a 1-methyl-2-ethyltrimethylene group, a 1-methyl-3-ethyltrimethylene group, a 2-methyl-3-ethyltrimethylene group, a 1-methyl-1-ethyltrimethylene group, a 2-methyl-2-ethyltrimethylene group, a 1,2,3-trimethyltrimethylene group, and a 1,1,2,2-tetramethylethylene group; and the like.

[0051] X １ The number of carbon atoms in the alkylene group in the formula (I) is more preferably 2 to 8, and may be, for example, 2 to 6, 2 to 4, 4 to 8, or 6 to 8. １ Polyunsaturated fatty acids (1) having the formula (I) are particularly useful and can be produced more easily.

[0052] In this specification, the number of carbon atoms of an alkylene group means the number of carbon atoms including the number of carbon atoms of the substituent, when the alkylene group has a substituent described below.

[0053] X １The alkylene group in the formula (I) is preferably a chain alkylene group, more preferably a chain alkylene group having 2 to 10 carbon atoms (a linear alkylene group having 2 to 10 carbon atoms, or a branched alkylene group having 3 to 10 carbon atoms), and even more preferably a linear alkylene group having 2 to 10 carbon atoms.

[0054] X １ In the above formula, the alkylene group having a substituent means that one or more hydrogen atoms (—H) in the alkylene group have been substituted with a group (substituent) other than a hydrogen atom.

[0055] Examples of the substituent that the alkylene group has include halogen atoms such as a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom; and a hydroxyl group.

[0056] The number of substituents that the alkylene group has is preferably 0 to 3, and may be, for example, 0 to 2 or 0 to 1. When the number of substituents that the alkylene group has is 2 or more, the two or more substituents may be the same or different from each other, and when the two or more substituents are different from each other, the combination of these substituents is not particularly limited.

[0057] In this specification, without being limited to the case of substituents possessed by the alkylene group, "two or more substituents may be the same or different" means that all the substituents may be the same, or all the substituents may be different, or, when the number of substituents is three or more, only some of the substituents may be the same.

[0058] In particular, it is preferable that the number of substituents on the alkylene group is 0, that is, the alkylene group has no substituents. １ Polyunsaturated fatty acids (1) having the formula (I) are easier to prepare.

[0059] X １is a chain alkylene group having 2 to 10 carbon atoms, or a substituted alkylene group in which 1 to 3 hydrogen atoms in a chain alkylene group having 2 to 10 carbon atoms have been substituted with halogen atoms or hydroxyl groups, and when 2 to 3 hydrogen atoms have been substituted with halogen atoms or hydroxyl groups, the 2 to 3 substituents may be the same or different, preferably a chain alkylene group having 2 to 10 carbon atoms.

[0060] In general formula (1), n ​​is an integer of 1 or more, and n-1 is the same as the number of times the carbon chain having a triple bond between carbon atoms is extended by the reaction of the intermediate with compound (3), as described below. In other words, n is the same as the total number of times the carbon chain having a triple bond between carbon atoms is extended using compound (3).

[0061] n is preferably 1 to 10, more preferably 1 to 7, and even more preferably 1 to 5, and may be, for example, any of 1 to 3, 2 to 4, and 3 to 5. Many polyunsaturated fatty acids (1) in which n is in such a range are particularly useful and can be produced more easily.

[0062] In general formula (1), R １ is an alkyl group, and the alkyl group may be linear, branched, or cyclic, and may have both a chain structure (linear or branched) and a cyclic structure. When the alkyl group has a cyclic structure, including when the alkyl group is cyclic, the cyclic structure may be either monocyclic or polycyclic.

[0063] R １ The alkyl group in the formula (I) preferably has 1 to 12 carbon atoms, more preferably 1 to 10 carbon atoms, and even more preferably 1 to 8 carbon atoms.

[0064] In this specification, the number of carbon atoms of an alkyl group means the number of carbon atoms including the number of carbon atoms of the substituent, when the alkyl group has a substituent as described below.

[0065] The linear or branched alkyl group preferably has 1 to 12 carbon atoms. Examples of such chain alkyl groups include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, a 1-methylbutyl group, an n-hexyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 2,2-dimethylbutyl group, a 2,3-dimethylbutyl group, an n-heptyl group, a 2-methylhexyl group, a 3-methylhexyl group, a 2,2-dimethylpentyl group, a 2,3-dimethylpentyl group, a 2,4-dimethylpentyl group, a 3,3-dimethylpentyl group, a 3-ethylpentyl group, a 2,2,3-trimethylbutyl group, an n-octyl group, an isooctyl group, a 2-ethylhexyl group, a nonyl group, a decyl group, an undecyl group, and a dodecyl group. The chain alkyl group more preferably has 1 to 10 carbon atoms, and even more preferably has 1 to 8 carbon atoms, and may have, for example, 1 to 4, 3 to 6, or 5 to 8 carbon atoms.

[0066] The number of carbon atoms in the alkyl group having a cyclic structure, such as a cyclic alkyl group (cycloalkyl group), is preferably 3 to 12. Examples of such cyclic alkyl groups include monocyclic or polycyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, isobornyl, 1-adamantyl, 2-adamantyl, and tricyclodecyl. Examples of such alkyl groups having both a chain structure and a cyclic structure include monovalent groups having a structure in which one or more hydrogen atoms in the above-mentioned linear or branched alkyl group are substituted with the above-mentioned cyclic alkyl group. The number of carbon atoms in the alkyl group having a cyclic structure is more preferably 3 to 10, even more preferably 3 to 8, and may be, for example, 5 to 8.

[0067] R １The alkyl group in the formula (I) is preferably a chain alkyl group, more preferably a chain alkyl group having 1 to 12 carbon atoms (a linear alkyl group having 1 to 12 carbon atoms, or a branched alkyl group having 3 to 12 carbon atoms), and even more preferably a linear alkyl group having 1 to 12 carbon atoms.

[0068] R １ One or more hydrogen atoms in the alkyl group in the formula (I) may be substituted with a substituent. When the number of substituents substituting hydrogen atoms is two or more, the two or more substituents may be the same or different, and when the two or more substituents are different, the combination of these substituents is not particularly limited.

[0069] Examples of the substituent with which a hydrogen atom is substituted include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom; a hydroxyl group; and a hydroxyl group protected by a silicon-containing protecting group. More specifically, the hydroxyl group protected by a silicon-containing protecting group is a hydroxyl group represented by the general formula "-OE ２ " is a group represented by E ２ , i.e., silicon atom-containing protecting groups, will be described in detail later.

[0070] The position of the carbon atom to which the substituent substituting the hydrogen atom is bonded is not particularly limited, and examples thereof include R １ It may be a terminal carbon atom in the alkylene group, or a non-terminal carbon atom.

[0071] The number of the substituents substituting the hydrogen atoms is preferably 0 to 3, and may be, for example, either 0 to 2 or 0 to 1.

[0072] R １ In the alkyl group, one or two or more non-adjacent methylene groups (—CH ２ -) may be substituted with an oxygen atom (-O-), an ethylene oxide-1,2-diyl group (also known as an oxirane-1,2-diyl group), or a furan-2,5-diyl group. ３) is considered to contain a methylene group (a hydrogen atom is bonded to the methylene group). When the number of substituents substituting the methylene group is two or more, the two or more substituents may be the same or different, and when the two or more substituents are different, the combination of these substituents is not particularly limited.

[0073] The number of the substituents substituting the methylene group is preferably 0 to 2, and may be, for example, 0 to 1.

[0074] The substituted alkyl group in which a methylene group is substituted with the substituent is preferably an alkyl group in which one methylene group is substituted with an ethyleneoxide-1,2-diyl group, an alkyl group in which one methylene group is substituted with a furan-2,5-diyl group, or an alkyl group in which one or two non-adjacent methylene groups are substituted with an oxygen atom.

[0075] R １ is preferably a chain alkyl group having 1 to 12 carbon atoms, a substituted alkyl group in which 1 to 3 hydrogen atoms in a chain alkyl group having 1 to 12 carbon atoms have been substituted with halogen atoms, hydroxyl groups, or hydroxyl groups protected with silicon-containing protecting groups, or a substituted alkyl group in which one or two non-adjacent methylene groups in a chain alkyl group having 3 to 12 carbon atoms have been substituted with ethylene oxide-1,2-diyl groups, furan-2,5-diyl groups, or oxygen atoms, and when two to three hydrogen atoms have been substituted with halogen atoms, hydroxyl groups, or hydroxyl groups protected with silicon-containing protecting groups, the two to three substituents may be the same or different, and when two methylene groups have been substituted with ethylene oxide-1,2-diyl groups, furan-2,5-diyl groups, or oxygen atoms, the two substituents may be the same or different.

[0076] The polyunsaturated fatty acid (1) is represented by the following general formula (1)-1

[0077] (wherein m is the same as above; G １１ is a divalent group having an imino group, and the imino group is １１ is bonded to a carbonyl group bonded to X １１represents a chain alkylene group having 2 to 10 carbon atoms, and 1 to 3 hydrogen atoms in the alkylene group may be substituted with a halogen atom or a hydroxyl group; n １１ is an integer from 1 to 10; R １１ is a chain alkyl group having 1 to 12 carbon atoms, in which 1 to 3 hydrogen atoms may be substituted with a halogen atom, a hydroxyl group, or a hydroxyl group protected by a silicon atom-containing protecting group, and one or two non-adjacent methylene groups in the alkyl group having 3 to 12 carbon atoms may be substituted with an oxygen atom, an ethylene oxide-1,2-diyl group, or a furan-2,5-diyl group.

[0078] That is, when m is 0, the polyunsaturated fatty acid (1)-1 is represented by the following general formula (1α)-1

[0079] (In the formula, X １１ , n １１ and R １１ On the other hand, when m is 1, the polyunsaturated fatty acid (1)-1 is represented by the following general formula (1β)-1

[0080] (In the formula, G １１ , X １１ , n １１ and R １１ is the same as above.)

[0081] In general formula (1)-1, G １１ is a divalent group having an imino group, and the imino group is １１ It is bonded to a carbonyl group bonded to G １ That is, G １１ together with the carbonyl group marked with the symbol m constitute an amino acid residue.

[0082] X in general formula (1)-1 １１ The chain alkylene group having 2 to 10 carbon atoms in X １Among the alkylene groups in the above formula, it is the same as the chain alkylene group having 2 to 10 carbon atoms. １１ In the above formula (I), 1 to 3 hydrogen atoms in the alkylene group may be substituted with a halogen atom or a hydroxyl group. When the number of substituents substituting hydrogen atoms is 2 or more (2 to 3), the 2 or more (2 to 3) substituents may be the same or different from each other, and when the 2 or more substituents are different from each other, the combination of these substituents is not particularly limited.

[0083] In general formula (1)-1, n １１ is an integer of 1 to 10, preferably 1 to 7, more preferably 1 to 5, and may be, for example, any of 1 to 3, 2 to 4, and 3 to 5.

[0084] R in general formula (1)-1 １１ The chain alkyl group having 1 to 12 carbon atoms in R １ Among the alkyl groups in the above, R is the same as the chain alkyl group having 1 to 12 carbon atoms. １１ In the above formula, 1 to 3 hydrogen atoms in the alkyl group may be substituted with a halogen atom, a hydroxyl group, or a hydroxyl group protected with a silicon-containing protecting group. When the number of substituents substituting hydrogen atoms is 2 or more (2 to 3), the 2 or more (2 to 3) substituents may be the same or different, and when the 2 or more substituents are different, the combination of these substituents is not particularly limited. When the alkyl group has 3 or more (3 to 12) carbon atoms, one or two non-adjacent methylene groups in the alkyl group having 3 to 12 carbon atoms may be substituted with an oxygen atom, an ethylene oxide-1,2-diyl group, or a furan-2,5-diyl group. When the number of substituents substituting methylene groups is 2, the two substituents may be the same or different, and when the two substituents are different, the combination of these substituents is not particularly limited.

[0085] Next, the raw materials used in the production of the polyunsaturated fatty acid (1) will be described.

[0086] <<Compound (2)>> Compound (2) is represented by the general formula (2) and has an ethynyl group at one molecular end. １ , X １ and m is G in general formula (1). １ , X １ and m, so detailed description of them will be omitted here.

[0087] In general formula (2), Z １ is a solid support. １ The oxygen atom bonded to the carbonyl group marked with m may or may not be part of the solid support, and is the reaction site for ultimately cleaving the polyunsaturated fatty acid (1) from the solid support. For example, Z １ When the group has a functional group capable of reacting with carboxy, such as a hydroxyl group, Z １ The oxygen atom bonded to the solid support is, strictly speaking, a part of the solid support, and is shown separately for the sake of convenience in order to facilitate understanding of the reaction. １ The moiety represented by "-O-" is, for example, a moiety represented by the general formula "Z １ The solid phase carrier is represented by "Z -OH". １ constitutes a solid phase support together with the oxygen atom bonded thereto. １ has a functional group capable of reacting with carboxy, such as a chlorine atom, Z １ The oxygen atom attached to is not part of the solid support.

[0088] The solid phase support is not particularly limited as long as it has a functional group capable of reacting with a carboxylic acid, and known solid phase supports can be used. Examples of the functional group include, but are not limited to, a chlorine atom and a hydroxyl group. The resin that is the main constituent material may be a known resin such as a polystyrene-divinylbenzene copolymer. The solid phase support may be, for example, a solid phase support used in solid-phase peptide synthesis.

[0089] <<Compound (3)>> Compound (3) is represented by the general formula (3) and is a structural unit (building block) used when extending a carbon chain having a triple bond between carbon atoms in compound (2).

[0090] In general formula (3), L １ is a leaving group and may be any known group. １ More specifically, examples of the alkyl group include halogen atoms such as a chlorine atom (—Cl), a bromine atom (—Br), and an iodine atom (—I); a trifluoromethanesulfonyloxy group (CF ３ SO ３ fluorinated alkylsulfonyloxy groups such as p-toluenesulfonyloxy groups (CH ３ C ６ H ４ SO ３ -) and other arylsulfonyloxy groups; methanesulfonyloxy groups (CH ３ SO ３ Among these, the alkylsulfonyloxy group L １ is preferably a bromine atom or an iodine atom.

[0091] In general formula (3), E １ is a silicon atom-containing protecting group, which may be a known group. １ Examples of the protecting group include a silyl protecting group that can be used as a protecting group for a hydroxyl group. １ More specifically, for example, a trimethylsilyl group (TMS, (CH ３ ) ３ Si-), triethylsilyl group (TES, (CH ３ CH ２ ) ３ Si-), tert-butyldimethylsilyl group (TBS, (CH ３ ) ３ CH (CH ３ ) ２ Si-), triisopropylsilyl group (TIPS, ((CH ３ ) ２ CH) ３ Si-), dimethyl n-propylsilyl group (CH ３ CH２ CH ２ (CH ３ ) ２ Si-), ethyldimethylsilyl group (CH ３ CH ２ (CH ３ ) ２ Si-), n-butyldimethylsilyl group (CH ３ (CH ２ ) (CH ３ ) ２ Si-), diethylisopropylsilyl group ((CH ３ CH ２ ) ２ (CH ３ ) ２ trialkylsilyl groups such as CHSi-; tert-butyldiphenylsilyl groups (TBDPS, (CH ３ ) ３ CH(C ６ H ５ ) ２ Monoalkyldiarylsilyl groups such as benzyldimethylsilyl groups (C ６ H ５ CH ２ (CH ３ ) ２ Si-), and dialkylmonoaralkylsilyl groups.

[0092] <<Compound (4)>> Compound (4) is represented by the general formula (4) and is a structural unit (building block) that extends a carbon chain having a triple bond between carbon atoms in compound (13) and terminates the extension of the carbon chain.

[0093] L in general formula (4) ２ is a leaving group, and L in general formula (3) １ The R in the general formula (4) is the same as the R in the general formula (4), and a detailed description thereof will be omitted here. １ represents R in general formula (1). １ Therefore, detailed description thereof will be omitted here.

[0094] Next, each step in the production of polyunsaturated fatty acid (1) will be described. The production method of the first embodiment includes a production method in which compound (3) is used to synthesize compound (12) via compound (13) (this production method may be referred to as "production method (I)" in this specification), and a production method in which compound (12) is synthesized without using compound (3) and without going through compound (13) (this production method may be referred to as "production method (II)" in this specification). First, the synthesis of compound (12) in production method (I) will be described below.

[0095] In the case of production method (I), <<Reaction of compound (2) with compound (3) (elongation of carbon chain having a triple bond between carbon atoms, synthesis of protected intermediate (15))>> The reaction of compound (2) with compound (3) is carried out in the presence of an organic solvent, a base soluble in the organic solvent, and a monovalent copper salt. This reaction elongates the carbon chain of compound (2) having a triple bond between carbon atoms, thereby producing a compound represented by the following general formula (15):

[0096] (In the formula, Z １ , G １ , X １ , m and E １ is the same as above.) １ A protected intermediate having the general formula (15) (sometimes referred to as "protected intermediate (15)" in this specification) is synthesized. １ , G １ , X １ , m and E １ are the same as above.

[0097] <Organic Solvent> The organic solvent used in the reaction of compound (2) with compound (3) is preferably one capable of dissolving compound (3). More specific examples of the organic solvent include amides (compounds having an amide bond) such as N,N-dimethylformamide (DMF). In terms of increasing the reaction rate of compound (2) with compound (3), the organic solvent is preferably a dry organic solvent (a dehydrated organic solvent) or a degassed organic solvent (an organic solvent from which an operation to remove gases such as air and oxygen gas has been performed).

[0098] The organic solvent used in the reaction of compound (2) and compound (3) may be one kind or two or more kinds. When two or more kinds are used, the combination and ratio thereof can be arbitrarily selected depending on the purpose.

[0099] The amount of organic solvent used is preferably an amount that results in a concentration of compound (3) in the reaction solution of 0.01 to 3 mol / L, more preferably an amount that results in 0.1 to 1 mol / L. When the amount of organic solvent used is equal to or greater than the lower limit, the reaction proceeds more easily. When the amount of organic solvent used is equal to or less than the upper limit, excessive use of organic solvent is suppressed.

[0100] <Base> The base used in the reaction of compound (2) with compound (3) is not particularly limited as long as it is soluble in the organic solvent. By using such a soluble base, the solid-phase reaction of compound (2) with compound (3) proceeds in a shorter time than conventional methods.

[0101] The base is preferably an organic base. The base may be, for example, any of a chain aliphatic amine, aromatic amine, nitrogen atom-containing aliphatic heterocyclic compound (a compound having a nitrogen atom as a hetero atom constituting an aliphatic heterocyclic skeleton), and nitrogen atom-containing aromatic heterocyclic compound (a compound having a nitrogen atom as a hetero atom constituting an aromatic heterocyclic skeleton). The base may be, for example, any of a secondary amine and a tertiary amine.

[0102] As used herein, "aliphatic" means not aromatic (non-aromatic). As used herein, "chain" means not having a cyclic structure.

[0103] Among the bases, examples of the chain aliphatic secondary amine include diisopropylamine ( ｉ Pr ２ NH); alkylpiperidines (piperidines having a structure in which one or more hydrogen atoms bonded to a carbon atom are substituted with alkyl groups) such as 2,2,6,6-tetramethylpiperidine (TMP). Among the bases, examples of aliphatic tertiary amines include alkylguanidines (guanidines having a structure in which two hydrogen atoms in an amino group are substituted with alkyl groups) such as 1,1,3,3-tetramethylguanidine (TMG); N,N-diisopropylethylamine ( ｉ Pr ２ Among the bases, examples of the nitrogen atom-containing aliphatic heterocyclic compounds include 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), 1,5-diazabicyclo[4.3.0]-5-nonene (DBN), and 2,2,6,6-tetramethylpiperidine.

[0104] The amount of base used is preferably 1 to 50 times, and more preferably 5 to 20 times, the molar amount of ethynyl groups in compound (2) relative to the amount (mol) of ethynyl groups in compound (2). When the amount of base used is equal to or greater than the lower limit, the reaction rate between compound (2) and compound (3) becomes higher. When the amount of base used is equal to or less than the upper limit, excessive use of base is suppressed.

[0105] The base used in the reaction of compound (2) and compound (3) may be one type only, or two or more types may be used. When two or more types are used, the combination and ratio thereof can be arbitrarily selected depending on the purpose.

[0106] In terms of increasing the reaction rate of the compound (2) and the compound (3), the base is preferably a base with low nucleophilicity, more preferably a secondary amine or a tertiary amine, and even more preferably a chain aliphatic secondary amine, an aliphatic tertiary amine, or a nitrogen atom-containing aliphatic heterocyclic compound, and diisopropylamine ( ｉ Pr ２NH), 2,2,6,6-tetramethylpiperidine (TMP), 1,1,3,3-tetramethylguanidine (TMG), N,N-diisopropylethylamine ( ｉ Pr ２ It is more preferable that the base is one or more selected from the group consisting of tetramethylguanidine, 1,5-diazabicyclo[4.3.0]-5-nonene (DBU), and 1,5-diazabicyclo[4.3.0]-5-nonene (DBN). Of these, the base is preferably a strong base, and is particularly preferably one or more selected from the group consisting of tetramethylguanidine, 1,5-diazabicyclo[4.3.0]-5-nonene, 1,8-diazabicyclo[5.4.0]-7-undecene, 2,2,6,6-tetramethylpiperidine, and N,N-diisopropylethylamine, with 1,1,3,3-tetramethylguanidine being the most preferable.

[0107] <Monovalent Copper Salt> The monovalent copper salt (sometimes simply referred to as "copper salt" in this specification) used in the reaction of compound (2) with compound (3) is preferably one that can convert an ethynyl group into copper(I) acetylide. More specific examples of the copper salt include copper(I) halides such as copper(I) iodide (CuI), copper(I) bromide (CuBr), and copper(I) chloride (CuCl).

[0108] The copper salt used in the reaction of compound (2) with compound (3) may be one kind or two or more kinds. When two or more kinds are used, the combination and ratio thereof can be arbitrarily selected depending on the purpose.

[0109] The amount of copper salt used is preferably 1 to 50 times, and more preferably 5 to 20 times, the molar amount of ethynyl groups in compound (2) relative to the molar amount (moles). When the amount of copper salt used is equal to or greater than the lower limit, the reaction rate between compound (2) and compound (3) is increased. When the amount of copper salt used is equal to or less than the upper limit, excessive use of base is suppressed.

[0110] <Iodine-containing salt> Compound (3) is L １When a compound (2) is a chlorine atom or a bromine atom, it is preferable to further use an iodine-containing salt (a salt having iodine as a constituent element) when reacting compound (2) with compound (3). By doing so, halogen exchange occurs in compound (3) to produce iodide (L １ is an iodine atom, and since the reactivity of this iodide is high, the reaction between compound (2) and compound (3) proceeds more easily, thereby making it possible to further shorten the reaction time. Examples of the iodine-containing salt include alkali metal iodides such as sodium iodide (NaI) and potassium iodide (KI); alkaline earth metal iodides; and iodide salts of organic compounds.

[0111] The iodine-containing salt used in the reaction of compound (2) with compound (3) may be one type only or two or more types. When two or more types are used, the combination and ratio thereof can be arbitrarily selected depending on the purpose.

[0112] The amount of the iodine-containing salt used is preferably 1 to 3 times, and more preferably 1 to 2 times, the amount (mol) of compound (3) used. When the amount of the iodine-containing salt used is equal to or greater than the lower limit, the effect of using the iodine-containing salt is more pronounced. When the amount of the iodine-containing salt used is equal to or less than the upper limit, excessive use of the iodine-containing salt is suppressed.

[0113] <Other Components> When reacting compound (2) with compound (3), other components that do not fall under any of compound (2), compound (3), organic solvent, base, copper salt, and iodine-containing salt may or may not be used. The type of the other components is not particularly limited as long as it does not impair the effects of the present invention, and can be selected arbitrarily depending on the purpose. The other components used may be one type only, or two or more types, and when two or more types are used, the combination and ratio thereof can be selected arbitrarily depending on the purpose. The amount of the other components used can also be selected arbitrarily depending on the purpose, and is not particularly limited.

[0114] <Other Conditions> The reaction of compound (2) with compound (3) may be carried out in an air atmosphere or an inert gas atmosphere, and is preferably carried out in an inert gas atmosphere in order to increase the yield of the protected intermediate (15). Examples of the inert gas include nitrogen gas, helium gas, and argon gas.

[0115] The reaction temperature during the reaction of compound (2) and compound (3) is preferably 10 to 35°C, more preferably 10 to 30°C, and may be, for example, room temperature. When the reaction temperature is equal to or higher than the lower limit, the reaction proceeds more easily. When the reaction temperature is equal to or lower than the upper limit, the effect of suppressing side reactions is enhanced, and the yield of protected intermediate (15) is increased.

[0116] In this specification, "room temperature" means a temperature that is neither particularly cold nor hot, that is, an ordinary temperature, and examples thereof include temperatures of 15 to 25°C.

[0117] The reaction time during the reaction of compound (2) and compound (3) may be, for example, 24 hours or less, 13 hours or less, 7 hours or less, or 4 hours or less, but is preferably 2 hours or less, and more preferably 1.5 hours or less. By keeping the reaction time at or below the upper limit, excessive reaction time is prevented. In particular, the shorter the reaction time, the more pronounced the effect of the present invention, that is, the ability to obtain polyunsaturated fatty acid (1) in a short time by solid-phase synthesis. On the other hand, in terms of a higher yield of protected intermediate (15), the reaction time is preferably 20 minutes or more.

[0118] The reaction of compound (2) with compound (3) is preferably carried out while stirring the reaction solution by, for example, shaking the reaction vessel.

[0119] After the reaction of compound (2) with compound (3), it is preferable to remove the liquid (i.e., reaction residue) and then wash the reaction product (i.e., protected intermediate (15)) with a solvent once or twice or more times by a known method. The solvent used for washing is preferably an organic solvent, and may be the same organic solvent as that used in the reaction. Furthermore, in addition to the same organic solvent, washing may be performed once or twice or more times with other organic solvents, such as alcohols such as methanol, ethanol, and 2-propanol; halogenated hydrocarbons such as dichloromethane and chloroform; etc. However, the organic solvent used for washing (the same organic solvent or other organic solvent) does not have to be a dried organic solvent or a degassed organic solvent. The washed protected intermediate (15) may be dried by drying under reduced pressure or the like before use in the next reaction, or it may be subjected to a final wash with the organic solvent to be used in the next reaction and then used directly in the next reaction without drying.

[0120] When reacting compound (2) with compound (3), it is preferable to prepare a mixture of compound (2), a copper salt, and, if necessary, an iodine-containing salt, and then add a mixture of compound (3), an organic solvent, and a base to the mixture to initiate the reaction.

[0121] It is presumed that during the reaction between compound (2) and compound (3), the ethynyl group (—C≡CH) in compound (2) first converts to copper(I) acetylide (—C≡CCu) through a reaction between compound (2), a copper salt, and a base, and compound (2) in this state reacts with compound (3) to produce protected intermediate (15). In the production method of the first embodiment, the formation of copper(I) acetylide on the side of compound (2) containing the solid phase support facilitates the reaction between compound (2) and compound (3). In contrast, when copper(I) acetylide is formed on the side of the compound not containing the solid phase support, the desired reaction tends to proceed less smoothly. This is presumed to be because copper(I) acetylide molecules, which are relatively free to move in the reaction solution, tend to approach each other, interacting in the reaction solution and, in some cases, forming a precipitate, making them less likely to contribute to the reaction. In contrast, in the first embodiment, it is presumed that the copper(I) acetylides formed on the compound (2) side and immobilized on the solid support are less likely to approach each other, and therefore more likely to contribute to the reaction with compound (3).

[0122] <<Deprotection of Protected Intermediate (15) (Synthesis of Intermediate (14))>> In the production method (1), after the reaction of compound (2) with compound (3), the E １ is subjected to a deprotection reaction to replace the group with a hydrogen atom.

[0123] (In the formula, Z １ , G １ , X １ and m are the same as above.) An intermediate having an ethynyl group at the molecular end (sometimes referred to as "intermediate (14)" in this specification) is synthesized. １ , G １ , X １ and m are the same as above.

[0124] The deprotection of the protected intermediate (15) can be carried out by a known method.

[0125] <Deprotecting Agent> The deprotection of the protected intermediate (15) can be carried out well, for example, by using a deprotecting agent. Examples of the deprotecting agent include salts having fluorine as a constituent element (sometimes referred to as "fluorine-containing salts" in this specification). Examples of the fluorine-containing salts include triethylamine trihydrofluoride (Et ３ salts of bases and hydrofluoric acid, such as tetrabutylammonium fluoride (TBAF, (CH ３ (CH ２ ) ３ ) ４ N ＋ F － ), tetrabutylammonium difluorotriphenylsilicate (also known as TBAT, (CH ３ (CH ２ ) ３ ) ４ N ＋ CSi － F ３ (C ６ H ５ ) ３ ) and tetraalkylammonium salts containing fluoride ions or fluorinated silicate as anions.

[0126] The amount of the deprotecting agent used is preferably 1 to 50 times, and more preferably 5 to 20 times, the molar amount (moles) of ethynyl groups in compound (2). When the amount of the deprotecting agent used is equal to or greater than the lower limit, the reaction rate of the deprotection reaction of protected intermediate (15) becomes higher. When the amount of the deprotecting agent used is equal to or less than the upper limit, excessive use of the deprotecting agent is suppressed.

[0127] <Organic Solvent> The deprotection of the protected intermediate (15) is preferably carried out in the presence of an organic solvent. The organic solvent used in this case may be the same as the organic solvent used in the reaction of compound (2) with compound (3), and may be the same type of organic solvent used in the reaction of compound (2) with compound (3). However, the organic solvent used in this case does not have to be either a dry organic solvent or a degassed organic solvent. The organic solvent used in this case may be one type only or two or more types, and when two or more types are used, the combination and ratio thereof can be selected as desired depending on the purpose.

[0128] The amount of organic solvent used is preferably an amount that results in a deprotection agent concentration in the reaction solution of 0.01 to 3 mol / L, more preferably an amount that results in 0.1 to 1 mol / L. When the amount of organic solvent used is equal to or greater than the lower limit, the reaction proceeds more easily. When the amount of organic solvent used is equal to or less than the upper limit, excessive use of organic solvent is suppressed.

[0129] <Other Components> When deprotecting the protected intermediate (15), other components that do not fall under any of the protected intermediate (15), the deprotecting agent, and the organic solvent may or may not be used. The type of the other components is not particularly limited as long as it does not impair the effects of the present invention, and can be selected arbitrarily depending on the purpose. The other components used may be one type only, or two or more types, and when two or more types are used, the combination and ratio thereof can be selected arbitrarily depending on the purpose. The amount of the other components used can also be selected arbitrarily depending on the purpose, and is not particularly limited.

[0130] <Other Conditions> The deprotection of the protected intermediate (15) may be carried out in an air atmosphere or an inert gas atmosphere, and is preferably carried out in an inert gas atmosphere in terms of increasing the yield of the protected intermediate (15). Examples of the inert gas include nitrogen gas, helium gas, and argon gas.

[0131] The reaction temperature during deprotection of the protected intermediate (15) is preferably 10 to 35°C, more preferably 15 to 30°C, and may be, for example, room temperature. When the reaction temperature is equal to or higher than the lower limit, the reaction proceeds more easily. When the reaction temperature is equal to or lower than the upper limit, the effect of suppressing side reactions is enhanced, and the yield of the intermediate (14) is increased.

[0132] The reaction time during deprotection of the protected intermediate (15) may be, for example, 24 hours or less, but is preferably 2 hours or less, and more preferably 1.5 hours or less. By keeping the reaction time at or below the upper limit, excessive reaction time is prevented. In particular, the shorter the reaction time, the more remarkable the effect of the present invention, that is, the ability to obtain polyunsaturated fatty acid (1) in a short time by solid-phase synthesis. On the other hand, in terms of a higher yield of the protected intermediate (15), the reaction time is preferably 30 minutes or more.

[0133] The deprotection of the protected intermediate (15) is preferably carried out while stirring the reaction solution in the same manner as in the reaction of the compound (2) with the compound (3) described above.

[0134] After deprotection of the protected intermediate (15), it is preferable to remove the liquid (i.e., reaction residue) and then wash the reaction product (i.e., intermediate (14)) with a solvent once or twice or more times by a known method. The solvent used for washing is preferably an organic solvent, and may be the same organic solvent as that used in the reaction. The intermediate (14) may further be washed once or twice or more times with another organic solvent, as in the case of the above-mentioned protected intermediate (15). The washed intermediate (14) may or may not be dried, as in the case of the above-mentioned protected intermediate (15).

[0135] <<Elongation of a Carbon Chain Having a Triple Bond Between Carbon Atoms, and Deprotection (Synthesis of Compound (13))>> In the production method (1), after deprotection of the protected intermediate (15), the resulting intermediate (intermediate (14), and in some cases an intermediate different from the intermediate (14)) is reacted with compound (3) in the presence of an organic solvent, a base, and a monovalent copper salt (i.e., elongation of a carbon chain having a triple bond between carbon atoms), and the E １ is replaced with a hydrogen atom, ０ That is, in the production method (1), the carbon chain elongation (synthesis of a protected intermediate) by the compound (3) and the deprotection are each repeated n times in total. ０ This is carried out twice to synthesize compound (13).

[0136] In general formula (13), n ０ is an integer of 1 or more. ０ For example, in order to relatively easily produce a wide variety of useful polyunsaturated fatty acids (1), the upper limit of n ０ is preferably 9 or less.

[0137] n ０ is an integer of 1 or more, so that in the production method (I), the intermediate (14) may not be subjected to the carbon chain elongation and deprotection.

[0138] n ０ The carbon chain extension is repeated once, and the target of the reaction of compound (3) is different from compound (2), and further, n ０ The carbon chain elongation reaction can be carried out in the same manner as described above, except for the differences depending on the number of repetitions. Even during these repeated carbon chain elongations, copper(I) acetylide is formed on the intermediate having the solid phase support, which facilitates the carbon chain elongation reaction. ０ The deprotection repeated once is also performed when the target compound is different from the protected intermediate (15) and further, ０The repeated carbon chain elongation and deprotection can be carried out in the same manner as described above, except for the differences depending on the number of times. Therefore, further detailed description of these repeated carbon chain elongation and deprotection will be omitted.

[0139] <<Reaction of Compound (13) with Compound (4) (Elongation and Termination of Carbon Chain Having a Triple Bond Between Carbon Atoms, Synthesis of Compound (12))>> The reaction of compound (13) with compound (4) is carried out in the presence of an organic solvent, a base soluble in the organic solvent, and a monovalent copper salt. This reaction elongates the carbon chain having a triple bond between carbon atoms of compound (13) and terminates further elongation of the carbon chain, thereby synthesizing compound (12).

[0140] In the compound (12) (general formula (12)) obtained by the reaction of the compound (13) with the compound (4), n≧2 and n−1=n ０ is.

[0141] Carbon chain elongation using compound (4) can be carried out in the same manner as the carbon chain elongation using compound (3) described above. That is, the reaction between compound (13) and compound (4) can be carried out in the same manner as the reaction between compound (2) and compound (3) described above, except that compound (13) is used instead of compound (2) and compound (4) is used instead of compound (3). During this carbon chain elongation, copper(I) acetylide is formed on the side of compound (13) having a solid phase support, which facilitates the carbon chain elongation reaction. Therefore, further detailed explanation of carbon chain elongation will be omitted here.

[0142] Next, the synthesis of compound (12) in production method (II) will be described.

[0143] Production Method (II) <<Reaction of Compound (2) with Compound (4) (Elongation and Termination of Carbon Chain Having a Triple Bond Between Carbon Atoms, Synthesis of Compound (12))>> The reaction of Compound (2) with Compound (4) is carried out in the presence of an organic solvent, a base soluble in the organic solvent, and a monovalent copper salt. This reaction elongates the carbon chain of Compound (2) having a triple bond between carbon atoms, and terminates further elongation of the carbon chain, thereby synthesizing Compound (12).

[0144] In the compound (12) (general formula (12)) obtained by the reaction of the compound (2) with the compound (4), n=1.

[0145] Carbon chain elongation using compound (4) can be carried out in the same manner as the carbon chain elongation using compound (3) described above. That is, the reaction between compound (2) and compound (4) can be carried out in the same manner as the reaction between compound (2) and compound (3) described above, except that compound (4) is used instead of compound (3). During this carbon chain elongation, copper (I) acetylide is formed on the side of compound (2) having a solid support, which facilitates the carbon chain elongation reaction. Therefore, further detailed explanation of carbon chain elongation will be omitted here.

[0146] Common to Production Method (I) and Production Method (II) As explained above, in both Production Method (I) and Production Method (II), the carbon chain elongation proceeds via the formation of copper(I) acetylide on the solid-phase support-containing compound side, which is advantageous in that the carbon chain elongation reaction proceeds easily. Next, the further reaction will be explained.

[0147] <<Homogeneous catalytic hydrogen transfer reaction of compound (12) (synthesis of compound (11))>> The hydrogen transfer reaction of compound (12) is carried out using a homogeneous catalyst. This reaction hydrogenates the triple bond (C≡C) between carbon atoms in compound (12) to form a double bond (C≡C), thereby synthesizing compound (11). Compound (11) has a structure in which the target polyunsaturated fatty acid (1) is bound to a solid support. According to the production method of the first embodiment, unlike conventional production methods of polyunsaturated fatty acids that employ solid-phase synthesis, by applying a homogeneous catalytic hydrogen transfer reaction to compound (12), hydrogenation can be carried out by solid-phase synthesis rather than liquid-phase synthesis.

[0148] The homogeneous catalytic hydrogen transfer reaction (sometimes simply referred to as "hydrogen transfer reaction" in this specification) of compound (12) can be carried out by a known method. For example, the hydrogen transfer reaction can be carried out by referring to the method described in "Monophasic Catalytic System for the Selective Semireduction of Alkynes, Aaron M Whittaker and Gojko Lalic, Org. Lett. 2013, 15, 1112-1115."

[0149] In the hydrogen transfer reaction, it is preferable to use either or both of an alcohol and a hydrosilane as the hydrogen source, and it is more preferable to use both. By using them in this way, the reaction rate of the hydrogen transfer reaction becomes higher. Examples of the alcohol include monohydric alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol (also known as isobutyl alcohol), and 2-methyl-2-propanol (also known as tert-butyl alcohol). Examples of the hydrosilane include poly(methylhydrosiloxane) (PMHS).

[0150] The amounts of the alcohol and hydrosilane used are each independently preferably 10 to 200 times, and more preferably 100 to 140 times, the molar amount of ethynyl groups in compound (12) relative to the number (moles) of ethynyl groups. When the amounts of the alcohol and hydrosilane used are equal to or greater than the lower limit, the reaction rate of the hydrogen transfer reaction is increased. When the amounts of the alcohol and hydrosilane used are equal to or less than the upper limit, excessive use of these is suppressed. When both the alcohol and hydrosilane are used, the alcohol and hydrosilane may be used in the same molar amount or in different molar amounts depending on the purpose.

[0151] The hydrogen transfer reaction was carried out using [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]copper(I) tert-butoxide ( ｉ PrCuO ｔ In this case, it is preferable to use a hydrogen transfer reaction catalyst such as HCl, which is a fluorine-containing compound, to obtain a hydrogen transfer reaction.

[0152] The amount of [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]copper(I) tert-butoxide used is preferably 5 to 200 mol %, and more preferably 30 to 100 mol %, based on the number (moles) of ethynyl groups in compound (2). When the amount of [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]copper(I) tert-butoxide used is equal to or greater than the lower limit, the reaction rate of the hydrogen transfer reaction is increased. When the amount of [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]copper(I) tert-butoxide used is equal to or less than the upper limit, excessive use of [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]copper(I) tert-butoxide is suppressed.

[0153] [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]copper(I) tert-butoxide is, for example, [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]copper(I) chloride ( ｉPrCuCl) and sodium tert-butoxide (NaO ｔ Bu). When using the [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]copper(I) tert-butoxide obtained in this manner, sodium chloride, a by-product of the above reaction, may be removed before use, or, to simplify the process, it may be used as a mixture with sodium chloride without removing sodium chloride. When using a mixture of [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]copper(I) tert-butoxide and sodium chloride, the amount of sodium chloride used is preferably 0.8 to 1.2 times, and more preferably 0.9 to 1.1 times, the molar amount of [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]copper(I) tert-butoxide.

[0154] It is particularly preferable that the hydrogen transfer reaction be carried out in the presence of [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]copper(I) tert-butoxide, an alcohol, and a hydrosilane, which results in a particularly high reaction rate of the hydrogen transfer reaction.

[0155] The hydrogen transfer reaction is preferably carried out in the presence of an organic solvent. Examples of the organic solvent used in this case include aromatic hydrocarbons such as toluene and xylene (o-xylene, m-xylene, p-xylene). In order to increase the reaction rate of the hydrogen transfer reaction, the organic solvent is preferably a dry organic solvent or a degassed organic solvent. The organic solvent used in this case may be one type only, or two or more types, and when two or more types are used, the combination and ratio thereof can be selected as desired depending on the purpose.

[0156] The amount of organic solvent used is preferably 10 to 200 mL, more preferably 30 to 70 mL, per 1 g of compound (12). When the amount of organic solvent used is equal to or greater than the lower limit, the reaction proceeds more easily. When the amount of organic solvent used is equal to or less than the upper limit, excessive use of the organic solvent is suppressed.

[0157] The hydrogen transfer reaction is preferably carried out under an inert gas atmosphere, such as nitrogen gas, helium gas, or argon gas, in order to obtain a higher yield of compound (11).

[0158] The reaction temperature during the hydrogen transfer reaction is preferably 40 to 60°C, more preferably 45 to 55°C. When the reaction temperature is equal to or higher than the lower limit, the reaction proceeds more easily. When the reaction temperature is equal to or lower than the upper limit, the effect of suppressing side reactions is enhanced, and the yield of compound (11) is increased.

[0159] The reaction time during the hydrogen transfer reaction is preferably 10 to 120 minutes, more preferably 10 to 60 minutes, and may be, for example, 10 to 40 minutes. When the reaction time is equal to or greater than the lower limit, the yield of compound (11) is increased. When the reaction time is equal to or less than the upper limit, excessive reaction time is prevented.

[0160] The hydrogen transfer reaction is preferably carried out while stirring the reaction solution in the same manner as in the reaction between compound (2) and compound (3) described above.

[0161] After the hydrogen transfer reaction, it is preferable to remove the liquid (i.e., reaction residue) and then wash the reaction product (i.e., compound (11)) with a solvent once or twice or more times by a known method. The solvent used for washing is preferably an organic solvent, and may be the same organic solvent as that used in the reaction, or another organic solvent. Examples of the other organic solvent include ethers such as tetrahydrofuran (THF); alcohols such as methanol, ethanol, and 2-propanol; and halogenated hydrocarbons such as dichloromethane and chloroform. However, the organic solvent used for washing (the same organic solvent or another organic solvent) does not have to be either a dry organic solvent or a degassed organic solvent.

[0162] <<Removal of Silicon Atom-Containing Protective Group>> １That is, one or more hydrogen atoms of the alkyl group are substituted with a hydroxyl group protected with a silicon atom-containing protecting group (i.e., a group represented by the general formula "-OE ２ " (wherein E ２ is a silicon atom-containing protecting group. After the hydrogen transfer reaction, the silicon atom-containing protecting group (E ２ ) may be removed for deprotection, thereby obtaining a new, different compound (11) (compound (11) having a hydroxyl group as the substituent).

[0163] The above E ２ The silicon atom-containing protecting group in １ The silicon atom-containing protecting groups are the same as those in the above.

[0164] R １ The deprotection in (15) can be carried out in the same manner as in the deprotection of the protected intermediate (15).

[0165] <<Cleaving the bond between the carbonyl group in compound (11) and the oxygen atom adjacent to the carbonyl group (cleavage of polyunsaturated fatty acid (1))>> The bond (ester bond) between the carbonyl group in compound (11) and the oxygen atom adjacent to the carbonyl group can be cleaved by a known method. This allows the polyunsaturated fatty acid (1) to be cleaved from the solid phase support, thereby obtaining the desired polyunsaturated fatty acid (1).

[0166] The polyunsaturated fatty acid (1) is preferably separated using an acid, more preferably using a weak acid. By using an acid, particularly a weak acid, it is possible to suppress side reactions and increase the yield of the polyunsaturated fatty acid (1). Examples of the acid include 1,1,1,3,3,3-hexafluoropropan-2-ol ((CF ３ ) ２ fluorinated alcohols (alcohols having a structure in which one or more hydrogen atoms are substituted with fluorine atoms) such as CHOH and HFIP.

[0167] The amount of acid used is preferably 1 to 100 mL, more preferably 10 to 20 mL, per 1 g of compound (11). When the amount of acid used is equal to or greater than the lower limit, the reaction proceeds more easily. When the amount of acid used is equal to or less than the upper limit, excessive use of acid is suppressed.

[0168] The polyunsaturated fatty acid (1) is preferably excised in the presence of an organic solvent, and more preferably in a state in which the compound (11) is swollen with the organic solvent. When excising the polyunsaturated fatty acid (1), it is preferable to use an acid solution in which an acid is dissolved in an organic solvent. Examples of the organic solvent in the acid solution include halogenated hydrocarbons such as dichloromethane and chloroform. The organic solvent used in this case may be one type only, or two or more types. When two or more types are used, the combination and ratio thereof can be selected as desired depending on the purpose. The acid concentration in the acid solution may be, for example, 10 to 40% by mass.

[0169] The reaction temperature during excision of the polyunsaturated fatty acid (1) is preferably 10 to 35°C, more preferably 10 to 30°C, and may be, for example, room temperature. When the reaction temperature is equal to or higher than the lower limit, the reaction proceeds more easily. When the reaction temperature is equal to or lower than the upper limit, the effect of suppressing side reactions is enhanced, and the yield of the polyunsaturated fatty acid (1) is increased.

[0170] The reaction time during excision of the polyunsaturated fatty acid (1) is preferably 10 to 120 minutes, more preferably 10 to 90 minutes, and may be, for example, 10 to 60 minutes. When the reaction time is equal to or greater than the lower limit, the yield of the polyunsaturated fatty acid (1) is increased. When the reaction time is equal to or less than the upper limit, excessive reaction time is prevented.

[0171] The polyunsaturated fatty acid (1) is preferably separated by stirring the reaction solution in the same manner as in the reaction of the compound (2) with the compound (3) described above.

[0172] After the polyunsaturated fatty acid (1) is separated, the liquid material (e.g., a solution) containing the polyunsaturated fatty acid (1) can be subjected to post-treatment procedures such as filtration, washing, extraction, pH adjustment, dehydration, and concentration, either alone or in combination, as needed, using known techniques, and the polyunsaturated fatty acid (1) can be isolated by concentration, crystallization, reprecipitation, column chromatography, high performance liquid chromatography, etc. The isolated polyunsaturated fatty acid (1) can be further purified, as needed, by performing one or more operations, such as column chromatography, high performance liquid chromatography, crystallization, extraction, and stirring and washing with a solvent, either alone or in combination. Alternatively, the liquid material containing the polyunsaturated fatty acid (1) can be used directly for the intended purpose without isolating the polyunsaturated fatty acid (1).

[0173] The structure of the polyunsaturated fatty acid (1) obtained by the production method of the first embodiment can be confirmed by known techniques such as nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry (MS), and infrared spectroscopy (IR).

[0174] According to the production method of the first embodiment, each step of the solid-phase synthesis can be completed in a shorter time than conventional methods, and the process up to the excision of the polyunsaturated fatty acid (1) can be carried out solely by solid-phase synthesis without using liquid-phase synthesis in combination. Therefore, the polyunsaturated fatty acid (1) can be produced efficiently in a short time. Furthermore, since each step is highly versatile, polyunsaturated fatty acids (1) of various structures can be produced. For example, not only naturally occurring polyunsaturated fatty acids (1) but also novel polyunsaturated fatty acids not derived from natural sources can be easily produced as the polyunsaturated fatty acids (1).

[0175] Method for Producing Polyunsaturated Fatty Acids (Second Embodiment) A method for producing polyunsaturated fatty acids according to one embodiment of the present invention is a production method using a solid phase carrier,

[0176] (In the formula, Z １ is a solid support; G １ is a divalent group; X １is an alkylene group which may have a substituent; and m is 0 or 1.) and a compound having an ethynyl group at a molecular terminal (compound (2)) represented by the following general formula (3):

[0177] (In the formula, L １ is a leaving group; E １ is a silicon atom-containing protecting group.) in the presence of an organic solvent, a base soluble in the organic solvent, and a monovalent copper salt, to synthesize a protected intermediate; and １ with a hydrogen atom, and reacting the resulting deprotection reaction product with the compound represented by the general formula (3) in the presence of an organic solvent, a base soluble in the organic solvent, and a monovalent copper salt, １０ −1(n １０ is an integer of 1 or more.) times,

[0178] (In the formula, Z １ , G １ , X １ , m, n １０ and E １ are the same as above.) (hereinafter, this may be referred to as "compound (16)"), and the compound represented by the general formula (16) is subjected to a homogeneous catalytic hydrogen transfer reaction to obtain a compound represented by the following general formula (110):

[0179] (In the formula, Z １ , G １ , X １ , m and n １０ are the same as above.) (hereinafter, sometimes referred to as "compound (110)") is synthesized, and the bond between the carbonyl group in the compound represented by general formula (110) and the oxygen atom adjacent to the carbonyl group is cleaved to obtain a compound represented by the following general formula (10):

[0180] (In the formula, G １ , X １ , m and n １０are the same as above.) (Herein, this embodiment may be referred to as "second embodiment.") According to the production method of the second embodiment, as in the case of the production method of the first embodiment, polyunsaturated fatty acids can be produced in a short time by solid-phase synthesis without using liquid-phase synthesis in combination.

[0181] The production method of the second embodiment includes reacting compound (2) with compound (3) in the presence of an organic solvent, a base soluble in the organic solvent, and a monovalent copper salt, and then reacting the resulting reaction product with a deprotecting agent capable of removing (deprotecting) the silicon atom-containing protecting group to perform a deprotection reaction, and then reacting the resulting deprotected reaction product with compound (3) in the presence of an organic solvent, a base soluble in the organic solvent, and a monovalent copper salt, as a reaction product of n １０ The reaction mixture is then subjected to a homogeneous catalytic hydrogen transfer reaction, and the resulting reaction mixture is then cleaved from the solid support to obtain polyunsaturated fatty acid (2), all of which are carried out on the solid support.

[0182] <<Polyunsaturated fatty acid (10)>> First, we will explain the polyunsaturated fatty acid (10), which is the target product of the production method of the second embodiment. The polyunsaturated fatty acid (10) is represented by the general formula (10) and is a fatty acid having a chain unsaturated hydrocarbon skeleton with two or more double bonds (C=C) between carbon atoms.

[0183] G in general formula (10) １ , X １ and m are each G in the general formula (1). １ , X １ and m are the same as those in the formula (10). That is, when m is 0, the polyunsaturated fatty acid (10) is represented by the following general formula (10α):

[0184] (In the formula, X １ and n １０is the same as above.) (In this specification, this polyunsaturated fatty acid (10) may be referred to as "polyunsaturated fatty acid (10α)"). On the other hand, when m is 1, the polyunsaturated fatty acid (10) is represented by the following general formula (10β):

[0185] (In the formula, G １ , X １ and n １０ is the same as above.) (In this specification, this polyunsaturated fatty acid (10) may be referred to as "polyunsaturated fatty acid (10β)").

[0186] Polyunsaturated fatty acids (10β) have a structure in which the hydroxyl group (—OH) in the carboxy group (—C(═O)—OH) in the polyunsaturated fatty acid (10α) is substituted, and can be said to be analogs of polyunsaturated fatty acids (10α). However, since they share a common structure with polyunsaturated fatty acids (10α) in that they both have two or more double bonds and a carboxy group, they are categorized as polyunsaturated fatty acids (10) together with polyunsaturated fatty acids (10α).

[0187] X in general formula (10) １ The alkylene group in the formula (I) is preferably a chain alkylene group, more preferably a chain alkylene group having 2 to 10 carbon atoms (a linear alkylene group having 2 to 10 carbon atoms, or a branched alkylene group having 3 to 10 carbon atoms), and even more preferably a linear alkylene group having 2 to 10 carbon atoms.

[0188] n １０ is preferably 1 to 10, more preferably 1 to 7, and even more preferably 1 to 5, and may be, for example, any of 1 to 3, 2 to 4, and 3 to 5. １０ However, polyunsaturated fatty acids (10) within this range are often particularly useful and can be produced more easily.

[0189] The polyunsaturated fatty acid (10) is represented by the following general formula (10)-1

[0190] (wherein m is the same as above; G １１ is a divalent group having an imino group, and the imino group is１１ is bonded to a carbonyl group bonded to X １１ represents a chain alkylene group having 2 to 10 carbon atoms, and 1 to 3 hydrogen atoms in the alkylene group may be substituted with a halogen atom or a hydroxyl group; n １０１ is an integer of 1 to 10) (sometimes referred to herein as "polyunsaturated fatty acid (10)-1").

[0191] That is, when m is 0, the polyunsaturated fatty acid (10)-1 is represented by the following general formula (10α)-1

[0192] (In the formula, X １１ and n １０１ On the other hand, when m is 1, the polyunsaturated fatty acid (10)-1 is represented by the following general formula (10β)-1

[0193] (In the formula, G １１ , X １１ and n １０１ is the same as above.)

[0194] G in general formula (10)-1 １１ and X １１ are G in the general formula (1)-1. １１ and X １１ is the same as

[0195] In general formula (10)-1, n １０１ is an integer of 1 to 10, preferably 1 to 7, more preferably 1 to 5, and may be, for example, any of 1 to 3, 2 to 4, and 3 to 5.

[0196] The compounds (2) and (3) used in the production of the polyunsaturated fatty acid (10) are the same as the compounds (2) and (3) used in the production of the polyunsaturated fatty acid (1), respectively.

[0197] Next, each step in the production of the polyunsaturated fatty acid (10) will be described.

[0198] <<Reaction of Compound (2) with Compound (3) (Extending the Carbon Chain Having a Triple Bond Between Carbon Atoms, Synthesis of Protected Intermediate (15))>> The reaction of Compound (2) with Compound (3) in the production method of the second embodiment is the same as the reaction of Compound (2) with Compound (3) in the production method of the first embodiment. As in the first embodiment, protected intermediate (15) is synthesized by this reaction. In the production method of the second embodiment, the preferred compounds (2) and (3) are both the same as in the production method of the first embodiment.

[0199] In the production method of the second embodiment, as in the production method of the first embodiment, it is preferable to wash the protected intermediate (15) with a solvent once or twice or more times, and the washed protected intermediate (15) may be dried by drying under reduced pressure or the like before being used in the next reaction, or may be subjected to a final washing with the organic solvent to be used in the next reaction and then used directly in the next reaction without being dried.

[0200] <<Deprotection of Protected Intermediate, Reaction of Deprotected Reactant with Compound (3) (Extending Carbon Chain Having a Triple Bond Between Carbon Atoms, Synthesis of Protected Intermediate)>> In the production method of the second embodiment, after synthesizing the protected intermediate (15), the E １ with a hydrogen atom, and the resulting deprotection product (intermediate (14), or in some cases a deprotection product different from intermediate (14)) is reacted with compound (3) in the presence of an organic solvent, a base soluble in the organic solvent, and a monovalent copper salt (i.e., elongation of a carbon chain having a triple bond between carbon atoms). １０ That is, in the production method of the second embodiment, deprotection is repeated n times in total. １０ -1 times, and the carbon chain extension (synthesis of a protected intermediate) by compound (3) is carried out a total of n １０ Do this n times. １０ is an integer of 1 or more, so in the production method of the second embodiment, the protected intermediate (15) may not be subjected to the deprotection and carbon chain elongation.

[0201] In the production method of the second embodiment, deprotection of protected intermediate (15) and deprotection of a protected intermediate other than protected intermediate (15) can be carried out in the same manner as in the deprotection in embodiment 1. In the production method of the second embodiment, the reaction between intermediate (14) and compound (3) and the reaction between a deprotected reactant other than intermediate (14) and compound (3) can be carried out in the same manner as in the reaction between an intermediate and compound (3) in the production method of the first embodiment.

[0202] In this way, only the synthesis of the protected intermediate (15) is carried out, or further, the compound (16) is synthesized by repeating the deprotection and carbon chain elongation of the protected intermediate.

[0203] Z in general formula (16) １ , G １ , X １ and m is Z in the general formula (2). １ , G １ , X １ and m are the same as those in the general formula (16). １ represents E in the general formula (3). １ The n in the general formula (16) is the same as １０ is the same as above and is an integer of 1 or more.

[0204] In the production method of the second embodiment, after deprotection of the protected intermediate (15) and after deprotection of a protected intermediate different from the protected intermediate (15), the deprotection reaction product is preferably washed once or twice or more times with a solvent, as in the production method of the first embodiment. The deprotection reaction product after washing may be dried by drying under reduced pressure or the like before being used in the next reaction, or may be subjected to a final wash with the organic solvent to be used in the next reaction and then used directly in the next reaction without being dried.

[0205] <<Homogeneous catalytic hydrogen transfer reaction of compound (16) (synthesis of compound (110))>> In the production method of the second embodiment, the hydrogen transfer reaction of compound (16) can be carried out in the same manner as the hydrogen transfer reaction of compound (12) in the first embodiment, except that compound (16) is used instead of compound (12). １In the production method of the second embodiment, similarly to the production method of the first embodiment, it is preferable to wash the obtained compound (110) with a solvent once or twice or more times.

[0206] <<Cleaving the bond between the carbonyl group in compound (110) and the oxygen atom adjacent to the carbonyl group (excision of polyunsaturated fatty acid (10))>> In the production method of the second embodiment, the cleavage of the bond (ester bond) between the carbonyl group in compound (110) and the oxygen atom adjacent to the carbonyl group can be carried out in the same manner as the cleavage of the bond between the carbonyl group in compound (11) and the oxygen atom adjacent to the carbonyl group in compound (11) in the production method of the first embodiment, except that compound (110) is used instead of compound (11). This allows the polyunsaturated fatty acid (10) to be excised from the solid phase support, thereby obtaining the desired polyunsaturated fatty acid (10).

[0207] After the polyunsaturated fatty acid (10) is separated, the polyunsaturated fatty acid (10) can be extracted in the same manner as in the case of the polyunsaturated fatty acid (1). If necessary, the extracted polyunsaturated fatty acid (10) may be further purified in the same manner as in the case of the polyunsaturated fatty acid (1), or the liquid material containing the polyunsaturated fatty acid (10) may be used as is for the intended purpose without extracting the polyunsaturated fatty acid (10).

[0208] The structure of the polyunsaturated fatty acid (10) obtained by the production method of the second embodiment can be confirmed by known techniques such as nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry (MS), and infrared spectroscopy (IR).

[0209] According to the production method of the second embodiment, each step of the solid-phase synthesis can be completed in a shorter time than conventional methods, and the process up to the excision of the polyunsaturated fatty acid (10) can be carried out solely by solid-phase synthesis without using liquid-phase synthesis in combination. Therefore, the polyunsaturated fatty acid (10) can be produced efficiently in a short time. Furthermore, since each step is highly versatile, polyunsaturated fatty acids (10) with various structures can be produced. For example, not only naturally occurring polyunsaturated fatty acids (10) but also novel polyunsaturated fatty acids that are not naturally occurring can be easily produced as the polyunsaturated fatty acids (10).

[0210] Polyunsaturated Fatty Acids The polyunsaturated fatty acids according to one embodiment of the present invention are represented by the following general formula (1A):

[0211] (In the formula, X １１ is a chain alkylene group having 2, 3, 4 or 8 carbon atoms; n １１ is X １１ is an alkylene group having 2 carbon atoms, it is 1, 2 or 3; １１ is an integer of 1 to 3 when X is a chain alkylene group having 3 carbon atoms; １１ is a chain alkylene group having 4 carbon atoms, it is 1, 2 or 3; １１ is an integer of 1 to 4 when R is a chain alkylene group having 8 carbon atoms; １１ is X １１ is an alkylene group having 2 carbon atoms, X is a chain alkyl group having 1 or 8 carbon atoms; １１ is a chain alkylene group having 3 carbon atoms, it is a hydrogen atom, a methyl group, an ethyl group, or a substituted alkyl group having a structure in which one methylene group in a chain alkyl group having 4 carbon atoms is substituted with an ethyleneoxide-1,2-diyl group or a furan-2,5-diyl group, and X １１ is a chain alkylene group having 4 carbon atoms, it is a methyl group or an ethyl group, １１is a chain alkylene group having 8 carbon atoms, and the chain alkyl group having 1 to 5 carbon atoms is a hydrogen atom.) (excluding (5Z,8Z,11Z,14Z)-16-(3-ethyloxiran-2-yl)hexadeca-5,8,11,14-tetraenoic acid, (10Z,13Z)-hexadeca-10,13-dienoic acid, (10Z,13Z,16Z,19Z)-docosa-10,13,16,19-tetraenoic acid, and (10Z,13Z,16Z,19Z)-pentacosa-10,13,16,19-tetraenoic acid) (In this specification, this polyunsaturated fatty acid may be referred to as "polyunsaturated fatty acid (1A)"). The polyunsaturated fatty acid (1A) is included in the above-mentioned polyunsaturated fatty acid (1) or polyunsaturated fatty acid (10). １１ is not a hydrogen atom can be produced by the production method of the first embodiment of the present invention. １１ The compound in which is a hydrogen atom can be produced by the production method according to the second embodiment of the present invention.

[0212] In general formula (1A), X １１ is a chain alkylene group having 2, 3, 4 or 8 carbon atoms, and the above-mentioned X １ Among the alkylene groups in the above, the alkylene groups are the same as the chain alkylene groups having 2, 3, 4 or 8 carbon atoms.

[0213] In general formula (1A), n １１ and R １１ is X １１ That is, X １１ When is an alkylene group having 2 carbon atoms (ethylene group), n １１ is 1, 2 or 3, and R １１ is a chain alkyl group having 1 or 8 carbon atoms. １１ The chain alkyl group having 1 or 8 carbon atoms in １ Among the alkyl groups in the above, the alkyl groups are the same as the chain alkyl groups having 1 or 8 carbon atoms.

[0214] X １１ is a chain alkylene group having 3 carbon atoms (trimethylene group, propylene group (methylethylene group)), n１１ is an integer from 1 to 3, and R １１ is a hydrogen atom, a methyl group, an ethyl group, or a substituted alkyl group having a structure in which one methylene group in a chain alkyl group having 4 carbon atoms is substituted with an ethyleneoxide-1,2-diyl group or a furan-2,5-diyl group. １１ The chain alkyl group having 4 carbon atoms before substitution is the same as the above-mentioned R １ In the substituted alkyl group, the position of the methylene group substituted with the ethyleneoxide-1,2-diyl group or the furan-2,5-diyl group is not particularly limited, but may be any position in the alkyl group chain having 4 carbon atoms, such as R １１ is preferably a methylene group at the β-position or γ-position (other than at a non-terminal position) relative to the carbon atom forming the double bond (C═C) to which the carbon atom is bonded.

[0215] X １１ When is a chain alkylene group having 4 carbon atoms, n １１ is 1, 2 or 3, and R １１ is a methyl group or an ethyl group.

[0216] X １１ When is a chain alkylene group having 8 carbon atoms, n １１ is an integer from 1 to 4, and R １１ is a hydrogen atom or a chain alkyl group having 1 to 5 carbon atoms. １１ The chain alkyl group having 1 to 5 carbon atoms in １ Among the alkyl groups in the above, the alkyl groups are the same as the chain alkyl groups having 1 to 5 carbon atoms.

[0217] However, (5Z,8Z,11Z,14Z)-16-(3-ethyloxiran-2-yl)hexadeca-5,8,11,14-tetraenoic acid, (10Z,13Z)-hexadeca-10,13-dienoic acid, (10Z,13Z,16Z,19Z)-docosa-10,13,16,19-tetraenoic acid, and (10Z,13Z,16Z,19Z)-pentacosa-10,13,16,19-tetraenoic acid, which can be represented by general formula (1A), are excluded from polyunsaturated fatty acids (1A).

[0218] The polyunsaturated fatty acid (1A) is represented by the following general formula (1A)-1

[0219] (In the formula, n １１１ is an integer from 1 to 3; R １１１ is a methyl group, an ethyl group, or the above-mentioned substituted alkyl group.) (Hereinafter, this may be referred to as "polyunsaturated fatty acid (1A)-1"), or a polyunsaturated fatty acid represented by the following general formula (1A)-2

[0220] (In the formula, X １１２ is a chain alkylene group having 2, 4 or 8 carbon atoms; n １１２ is X １１２ is an alkylene group having 2 carbon atoms, it is 1, 2 or 3; １１２ is a chain alkylene group having 4 carbon atoms, it is 1, 2 or 3; １１２ is an integer of 1 to 4 when R is a chain alkylene group having 8 carbon atoms; １１２ is X １１２ is an alkylene group having 2 carbon atoms, X is a chain alkyl group having 1 or 8 carbon atoms; １１２ is a chain alkylene group having 4 carbon atoms, it is a methyl group or an ethyl group, １１２ is a chain alkylene group having 8 carbon atoms, it is a chain alkyl group having 1, 2 or 5 carbon atoms.)

[0221] (In the formula, X １１３ is a chain alkylene group having 3 or 8 carbon atoms; n １１３ is X １１３ is an alkylene group having 3 carbon atoms, the value is 3; １１３ is a chain alkylene group having 8 carbon atoms, the value is 1.) (Herein, this may be referred to as "polyunsaturated fatty acid (1A)-3").

[0222] The polyunsaturated fatty acids (1A)-1 and (1A)-2 can be produced by the production method of the first embodiment of the present invention described above, and are included in the polyunsaturated fatty acids (1). The polyunsaturated fatty acid (1A)-3 can be produced by the production method of the second embodiment of the present invention described above, and is included in the polyunsaturated fatty acids (10).

[0223] In general formula (1A)-1, R １１１ The substituted alkyl group in R １１ The substituted alkyl group is the same as the substituted alkyl group in the above formula. １１１ is any of 1 to 3, the substituted alkyl group R １１１ In the formula (I), the position of the methylene group substituted with the ethyleneoxide-1,2-diyl group or the furan-2,5-diyl group is not particularly limited, but may be any of R １１１ is preferably a methylene group at the β-position or γ-position (other than at a non-terminal position) relative to the carbon atom forming the double bond (C═C) to which the carbon atom is bonded.

[0224] However, (5Z,8Z,11Z,14Z)-16-(3-ethyloxiran-2-yl)hexadeca-5,8,11,14-tetraenoic acid, which can be represented by the general formula (1A)-1, is excluded from the polyunsaturated fatty acids (1A)-1.

[0225] More specific examples of the polyunsaturated fatty acid (1A)-1 include (5Z,8Z,11Z)-13-(3-ethyloxiran-2-yl)trideca-5,8,11-trienoic acid, (5Z,8Z,11Z,14Z)-16-(5-ethylfuran-2-yl)hexadeca-5,8,11,14-tetraenoic acid, (5Z,8Z)-10-(5-ethylfuran-2-yl)deca-5,8-dienoic acid, (5Z,8Z)-deca-5,8-dienoic acid, (5Z,8Z)-undeca-5,8-dienoic acid, and (5Z,8Z,11Z)-trideca-5,8,11-trienoic acid, which are described in the Examples below.

[0226] In general formula (1A)-2, X １１２ is a chain alkylene group having 2, 4 or 8 carbon atoms, and the above-mentioned X １Among the alkylene groups in the above, the alkylene groups are the same as the chain alkylene groups having 2, 4 or 8 carbon atoms.

[0227] In general formula (1A)-2, n １１２ and R １１２ is X １１２ That is, X １１２ When is an alkylene group having 2 carbon atoms (ethylene group), n １１２ is 1, 2 or 3, and R １１２ is a chain alkyl group having 1 or 8 carbon atoms. １１２ The chain alkyl group having 1 or 8 carbon atoms in １１ It is the same as the chain alkyl group having 1 or 8 carbon atoms in the above formula.

[0228] X １１２ When is a chain alkylene group having 4 carbon atoms, n １１２ is 1, 2 or 3, and R １１２ is a methyl group or an ethyl group.

[0229] X １１２ When is a chain alkylene group having 8 carbon atoms, n １１２ is an integer from 1 to 4, and R １１２ is a chain alkyl group having 1, 2 or 5 carbon atoms. １１２ The chain alkyl group having 1, 2 or 5 carbon atoms in １ Among the alkyl groups in the above, the alkyl groups are the same as the chain alkyl groups having 1, 2 or 5 carbon atoms.

[0230] However, (10Z,13Z)-hexadeca-10,13-dienoic acid, (10Z,13Z,16Z,19Z)-docosa-10,13,16,19-tetraenoic acid, and (10Z,13Z,16Z,19Z)-pentacosa-10,13,16,19-tetraenoic acid, which can be represented by general formula (1A)-2, are excluded from polyunsaturated fatty acids (1A)-2.

[0231] More specifically, examples of the polyunsaturated fatty acid (1A)-2 include (4Z,7Z)-hexadeca-4,7-dienoic acid, (10Z,13Z)-pentadeca-10,13-dienoic acid, (10Z,13Z,16Z)-octadeca-10,13,16-trienoic acid, (10Z,13Z,16Z)-nonadeca-10,13,16-trienoic acid, (10Z,13Z,16Z,19Z)-heneicosa-10,13,16,19-tetraenoic acid, (10Z,13Z,16Z,19Z)-heneicosa-10,13,16,19-tetraenoic acid, (10Z,13Z,16Z,19Z)-hexadeca-4,7-dienoic acid, (10Z,13Z,16Z)-pentadeca-10,13-dienoic acid, (10Z,13Z,16Z)-octadeca-10,13,16-trienoic acid, (10Z,13Z,16Z,19Z)-hexadeca-10,13,16,19-tetra ... (4Z,16Z,19Z,22Z)-tetracosa-10,13,16,19,22-pentaenoic acid, (4Z,7Z,10Z,13Z)-pentadeca-4,7,10,13-tetraenoic acid, (6Z,9Z,12Z)-tetradeca-6,9,12-trienoic acid, (6Z,9Z,12Z,15Z)-heptadeca-6,9,12,15-tetraenoic acid, (4Z,7Z,10Z)-dodeca-4,7,10-trienoic acid, and (6Z,9Z)-dodeca-6,9-dienoic acid.

[0232] In general formula (1A)-3, X １１３ is a chain alkylene group having 3 or 8 carbon atoms, and the above-mentioned X １ Among the alkylene groups in the above, the alkylene groups are the same as the chain alkylene groups having 3 or 8 carbon atoms.

[0233] In general formula (1A)-3, n １１３ is X １１３ That is, X １１３ When is an alkylene group having 3 carbon atoms, n １１３ is 3 and X １１３ When is a chain alkylene group having 8 carbon atoms, n １１３ is 1.

[0234] More specific examples of the polyunsaturated fatty acid (1A)-3 include (5Z,8Z,11Z)-pentadeca-5,8,11,14-tetraenoic acid and (Z)-tetradeca-10,13-dienoic acid, which are described in the Examples below.

[0235] The present invention will be described in more detail below with reference to specific examples, although the present invention is not limited to the examples shown below.

[0236] In the following examples, unless otherwise specified, post-reaction work-up and purification procedures were carried out in an air atmosphere.

[0237] In the following examples, the amount of each raw material used in the reaction is based on the amount of ethynyl groups in compound (2), unless otherwise specified.

[0238] The structure of the target polyunsaturated fatty acid (1) is: １ H NMR (400 MHz, CDCl ３ , 25°C), １３ C NMR (101 MHz, CDCl ３ , 25°C) or MS.

[0239] <<Production of Polyunsaturated Fatty Acid (1)>> [Example 1] 2-chlorotrityl chloride resin (Watanabe Chemical Industry Co., Ltd., "Cl-Trt(2-Cl)-Resin 200-400 mesh, 1% DVB") was placed in a fritted plastic syringe (6 mL) and swelled with dehydrated dichloromethane. After that, a dichloromethane solution of 5-hexynoic acid and diisopropylethylamine was added, and the mixture was shaken and stirred at room temperature for 2 hours to carry out a reaction. The reaction product was then washed with dichloromethane and dried to obtain compound (2)-101, which had a structure in which 5-hexynoic acid was bound to a resin.

[0240] The compound (2)-101 obtained above (36.6 mg, 20.0 μmol as the 5-hexynoic acid residue), copper(I) iodide (76.2 mg, 400 μmol, 20 equiv), and potassium iodide (66.4 mg, 400 μmol, 20 equiv) were placed in a fritted plastic syringe (6 mL) (hereinafter, sometimes simply referred to as "syringe"). After filling the syringe with nitrogen gas, the atmosphere inside the syringe was replaced with nitrogen gas by repeating evacuation and filling with nitrogen gas three times. A solution of 3-(trimethylsilyl)propargyl bromide (65.3 μL, 400 μmol, 20 equiv) and 1,1,3,3-tetramethylguanidine (TMG) (50.1 μL, 400 μmol, 20 equiv) dissolved in N,N-dimethylformamide (DMF) (1 mL) was added to the syringe. The syringe was shaken and stirred at room temperature for 30 minutes, and after removing the reaction solution, the resin was washed three times with DMF. In this way, a protected intermediate was obtained by extending the carbon chain containing a triple bond between the carbon atoms of the 5-hexynoic acid residue.

[0241] Next, DMF (1 mL) and triethylamine trihydrofluoride (Et ３ N·3HF) (69.3 μL, 400 μmol, 20 equiv) was added. The syringe was shaken and stirred at room temperature for 1 hour to carry out a deprotection reaction of the protected intermediate. After removing the reaction solution, the resin was washed three times with DMF, three times with methanol, and three times with dichloromethane, and then dried under reduced pressure. As a result, a deprotected intermediate was obtained.

[0242] Furthermore, this intermediate was reacted with the above-mentioned 3-(trimethylsilyl)propargyl bromide and Et ３ The carbon chain elongation and deprotection, that is, deprotection of the trimethylsilyl group with N·3HF, were repeated twice (three times in total) to obtain compound (13)-101.

[0243] Furthermore, carbon chain elongation was carried out on compound (13)-101 in the same manner as above, except that 1-bromo-2-pentyne (53.1 μL, 400 μmol, 20 equiv) was used instead of 3-(trimethylsilyl)propargyl bromide. After removing the reaction solution, the resin was washed three times with DMF, three times with methanol, and three times with dichloromethane. The resulting product was transferred to a glass (5 mL) LibraTube (registered trademark) (LibraTube, manufactured by HiPep Laboratories, hereinafter referred to as "tube") and dried under reduced pressure. In this manner, compound (12)-101 was obtained.

[0244] The tube was charged with 11.7 mg (20 μmol, 100 mol%) of [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]copper(I) tert-butoxide (containing the same molar amount of sodium chloride, a by-product of its preparation). The tube was then filled with nitrogen gas, and the atmosphere inside the tube was then replaced with nitrogen gas by repeatedly evacuating and filling the tube with nitrogen gas three times. A solution of tert-butyl alcohol (190 μL, 2 mmol, 140 equiv) and poly(methylhydrosiloxane) (PMH) (168 μL, 2.8 mmol, 140 equiv) dissolved in dehydrated toluene (1 mL) was added to the tube. The hydrogen transfer reaction was carried out by shaking and stirring the tube at 50°C for 20 minutes. After removing the reaction solution, the resin was washed three times with tetrahydrofuran (THF), three times with methanol, and three times with dichloromethane, and then dried under reduced pressure. This reaction and washing process was then repeated once more. As a result, compound (11)-101 was obtained.

[0245] The resulting compound (11)-101 was transferred to a fritted plastic syringe (6 mL) and allowed to swell in dichloromethane for 10 minutes. A 30% by volume solution of 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) in dichloromethane (1 mL) was added to the syringe, and the syringe was shaken and stirred at room temperature for 15 minutes. The reaction solution was filtered, and the filtrate was collected. Furthermore, a dichloromethane solution of HFIP was added to the syringe, and the syringe was shaken and stirred at room temperature for 15 minutes. The reaction solution was filtered, and the filtrate was collected. This procedure was repeated three times, and the resulting filtrates were combined. The filtrate was concentrated under reduced pressure, and the resulting concentrate was subjected to silica gel column chromatography. The mobile phase was changed from n-hexane / ethyl acetate (10 / 1, volume ratio) to n-hexane / ethyl acetate (4 / 1, volume ratio) by gradually increasing the ethyl acetate ratio. The eluate was collected and concentrated under reduced pressure to obtain the target product, (5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenoic acid (also known as EPA, polyunsaturated fatty acid (1)-101), as a colorless oil (yield: 82%). This oil was then purified by reversed-phase high-performance liquid chromatography (reverse-phase HPLC) for use in biological assays. The mobile phase was changed from acetonitrile / water (50 / 50, volume ratio) to acetonitrile / water (99 / 1, volume ratio) with gradually increasing acetonitrile ratios. This resulted in the purified polyunsaturated fatty acid (1)-101 (EPA).

[0246] The obtained polyunsaturated fatty acid (1)-101 １ The H NMR spectrum data is shown below. 1 H NMR (400 MHz, CDCl3)δ5.43-5.28 (m, 10H), 2.89-2.78 (m, 8H), 2.34 (t, J = 7.6 Hz, 2H), 2.17-2.04 (m, 4H), 1.74-1.66 (m, 2H), 0.97 (t, J = 7.6, 3H).

[0247] During the ceremony, Z １０１is 2-chlorotrityl chloride resin or a part thereof. This also applies to the other examples below.

[0248] Example 2 (4Z,7Z,10Z,13Z,16Z)-nonadeca-4,7,10,13,16-pentaenoic acid (polyunsaturated fatty acid (1)-102) was obtained in the same manner as in Example 1, except that the same number of moles of 4-pentynoic acid was used instead of 5-hexynoic acid (yield: 48%). １ The H NMR spectrum data is shown below. 1 H NMR (400 MHz, CDCl3)δ5.46-5.28 (m, 10H), 2.88-2.80 (m, 8H), 2.44-2.40 (m, 4H), 2.12-2.04 (m, 2H), 0.98 (t, J = 7.6 Hz, 3H).

[0249]

[0250] [Example 3] Instead of 5-hexynoic acid, the same number of moles of 4-pentynoic acid was used, and the reaction of the intermediate with 3-(trimethylsilyl)propargyl bromide and Et ３ The carbon chain elongation and deprotection, i.e., deprotection of the trimethylsilyl group with N·3HF, was repeated three times (four times in total) instead of two times (three times in total) in the same manner as in Example 1, except that (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-4-hexaenoic acid (also known as DHA, polyunsaturated fatty acid (1)-103) was obtained (yield 45%). １ The H NMR spectrum data is shown below. 1 H NMR (400 MHz, CDCl3)δ5.46-5.28 (m, 12H), 2.88-2.80 (m, 10H), 2.42-2.39 (m, 4H), 2.11-2.04 (m, 2H), 0.97 (t, J = 7.6 Hz, 3H).

[0251]

[0252] Example 4: (5Z,8Z,11Z,14Z)-heptadeca-5,8,11,14-tetraenoic acid (polyunsaturated fatty acid (1)-104) was obtained (yield 81%) in the same manner as in Example 1, except that the carbon chain elongation and deprotection of the intermediate was repeated once (two times in total) instead of twice (three times in total). １ The H NMR spectrum data is shown below. 1 H NMR (400 MHz, CDCl3)δ5.45-5.28 (m, 8H), 2.85-2.80 (m, 6H), 2.37 (t, J = 7.6 Hz, 2H), 2.16-2.04 (m, 4H), 1.72 (qui, J = 7.4 Hz, 2H), 0.98 (t, J = 7.6 Hz, 3H).

[0253]

[0254] Example 5: (5Z,8Z,11Z,14Z,17Z,20Z)-tricosa-5,8,11,14,17,20-hexanoic acid (polyunsaturated fatty acid (1)-105) was obtained in the same manner as in Example 1, except that the carbon chain elongation and deprotection of the intermediate was repeated three times (four times in total) instead of two times (three times in total). １ The H NMR spectrum data is shown below. 1 H NMR (400 MHz, CDCl3)δ5.44-5.28 (m, 12H), 2.89-2.80 (m, 10H), 2.36 (t, J = 7.6 Hz, 2H), 2.17-2.04 (m, 4H), 1.75-1.68 (m, 2H), 0.97 (t, J = 7.6, 3H).

[0255]

[0256] Example 6 (6Z,9Z,12Z,15Z,18Z)-heneicosa-6,9,12,15,18-pentaenoic acid (polyunsaturated fatty acid (1)-106) was obtained in the same manner as in Example 1, except that the same number of moles of 6-heptynoic acid was used instead of 5-hexynoic acid (yield: 68%). １ The H NMR spectrum data is shown below. 1 H NMR (400 MHz, CDCl3)δ5.44-5.28 (m, 10H), 2.88-2.80 (m, 8H), 2.36 (t, J = 7.6 Hz, 2H), 2.12-2.04 (m, 4H), 1.70-1.62 (m, 2H), 1.46-1.38 (m, 2H), 0.98 (t, J = 7.6 Hz, 3H).

[0257]

[0258] Example 7 (6Z,9Z,12Z,15Z,18Z,21Z)-tetracosa-6,9,12,15,18,21-hexaenoic acid (polyunsaturated fatty acid (1)-107) was obtained (yield 25%) in the same manner as in Example 1, except that the same number of moles of 6-heptynoic acid was used instead of 5-hexynoic acid, and the carbon chain elongation and deprotection of the intermediate was repeated three times (four times in total) instead of two times (three times in total). １ The H NMR spectrum data is shown below. 1 H NMR (400 MHz, CDCl3)δ5.43-5.28 (m, 12H), 2.88-2.80 (m, 10H), 2.36 (t, J = 7.6 Hz, 2H), 2.12-2.04 (m, 4H), 1.70-1.63 (m, 2H), 1.46-1.39 (m, 2H), 0.98 (t, J = 7.6 Hz, 3H).

[0259]

[0260] [Example 8] (5Z,8Z,11Z,14Z)-eicosa-5,8,11,14-tetraenoic acid (also known as arachidonic acid, polyunsaturated fatty acid (1)-108) was obtained (yield 70%) in the same manner as in Example 1, except that the carbon chain elongation and deprotection of the intermediate was repeated once (two times in total) instead of twice (three times in total) and the same number of moles of 1-bromo-2-octyne was used instead of 1-bromo-2-pentyne. １ The H NMR spectrum data is shown below. 1 H NMR (400 MHz, CDCl3)δ5.45-5.30 (m, 8H), 2.85-2.80 (m, 6H), 2.37 (t, J = 7.7 Hz, 2H), 2.16-2.11 (m, 2H), 2.08-2.03 (m, 2H), 1.72 (qui, J = 7.4 Hz, 2H), 1.40-1.24 (m, 6H), 0.89 (t, J = 7.0 Hz, 3H).

[0261]

[0262] Example 9 (5Z,8Z,11Z)-eicosa-5,8,11-trienoic acid (also known as mead acid, polyunsaturated fatty acid (1)-109) was obtained (yield 89%) in the same manner as in Example 1, except that the carbon chain elongation and deprotection of the intermediate were not carried out and the same number of moles of 1-bromo-2-undecyne was used instead of 1-bromo-2-pentyne. １ The H NMR spectrum data is shown below. 1 H NMR (400 MHz, CDCl3)δ5.45-5.30 (m, 6H), 2.82-2.79 (m, 4H), 2.37 (t, J = 7.6 Hz, 2H), 2.16-2.11 (m, 2H), 2.08-2.03 (m, 2H), 1.76-1.68 (m, 2H), 1.39-1.20 (m, 12H), 0.88 (t, J = 7.1 Hz, 3H).

[0263]

[0264] [Example 10] (5Z,8Z,11Z,14Z)-16-(3-ethyloxiran-2-yl)hexadeca-5,8,11,14-tetraenoic acid (also known as 17,18-EpETE, polyunsaturated fatty acid (1)-110) was obtained (yield 31%) in the same manner as in Example 1, except that the carbon chain elongation and deprotection of the intermediate was repeated once (twice in total) instead of twice (three times in total), 2-(4-bromobut-2-yn-1-yl)-3-ethyloxirane was used in place of 1-bromo-2-pentyne in a molar ratio of 1 / 4, the amounts of copper(I) iodide, potassium iodide, TMG, and DMF used were reduced to 1 / 4, and the reaction time was set to 1 hour. １ The H NMR spectrum data is shown below. 1 H NMR (400 MHz, CDCl3)δ5.56-5.33 (m, 8H), 3.03-2.99 (m, 1H), 2.96-2.92 (m, 1H), 2.88-2.75 (m, 6H), 2.50-2.43 (m, 1H), 2.33 (brs, 2H), 2.25-2.17 (m, 1H), 2.14-2.06 (m, 2H), 1.74-1.49 (m, 4H), 1.05 (t, J = 7.6 Hz, 3H).

[0265]

[0266] Example 11 The novel compound (5Z,8Z,11Z)-13-(3-ethyloxiran-2-yl)trideca-5,8,11-trienoic acid (polyunsaturated fatty acid (1)-111) was obtained (yield 32%) in the same manner as in Example 1, except that the carbon chain elongation and deprotection of the intermediate were not performed, 1 / 4 the molar amount of 2-(4-bromobut-2-yn-1-yl)-3-ethyloxirane was used instead of 1-bromo-2-pentyne, the amounts of copper(I) iodide, potassium iodide, TMG, and DMF used were reduced to 1 / 4, and the reaction time was set to 1 hour. １ The H NMR spectrum data is shown below.1 H NMR (400 MHz, CDCl3)δ5.56-5.33 (m, 6H), 3.04-2.99 (m, 1H), 2.98-2.94 (m, 1H), 2.91-2.76 (m, 4H), 2.52-2.44 (m, 1H), 2.36 (t, J = 7.2 Hz, 2H), 2.25-2.18 (m, 1H), 2.17-2.11 (m, 2H), 1.75 1.50 (m, 4H), 1.06 (t, J = 7.6 Hz, 3H).

[0267]

[0268] Example 12 Compound (13)-101 was obtained in the same manner as in Example 1. Next, compound (12)-112 was obtained by carrying out the reaction in the same manner as in Example 1, except that 1-bromo-2-pentyne was replaced with half the molar amount of (5-bromo-3-pentyn-1-yl)oxytert-butyldimethylsilane and the reaction time was changed to 1 hour. Compound (12)-1121 was obtained in the same manner as in Example 1, except that compound (12)-112 was used instead of compound (12)-101. The reaction product in the LibraTube (registered trademark) was then transferred to a fritted plastic syringe (6 mL) and swelled with THF (1 mL) for 10 minutes. After removing the solution, a 0.5 mol / L solution of tetrabutylammonium fluoride (TBAF) in TFH (1 mL) was added, and the mixture was stirred at room temperature for 2 hours. The resulting product was then washed three times with THF, three times with methanol, and three times with dichloromethane, and dried under reduced pressure. Furthermore, this reaction and washing were repeated once more. As a result, the tert-butyldimethylsilyl group was removed (deprotected) from compound (11)-1121 to obtain compound (11)-1122. Next, (5Z,8Z,11Z,14Z,17Z)-20-hydroxyeicosa-5,8,11,14,17-pentaenoic acid (also known as 20-HEPE, polyunsaturated fatty acid (1)-112) was obtained (yield 45%) in the same manner as in Example 1, except that compound (11)-1122 was used instead of compound (11)-101.１ The H NMR spectrum data is shown below. 1 H NMR (400 MHz, CDCl3)δ5.60-5.54 (m, 1H), 5.45-5.34 (m, 9H), 3.69 (t, J = 6.2 Hz, 2H), 2.98-2.94 (m, 1H),2.91-2.76 (m, 4H), 2.52-2.44 (m, 1H), 2.36 (t, J = 7.2 Hz, 2H), 2.88-2.78 (m, 8H), 2.40-2.34 (m, 4H), 2.17-2.11 (m, 2H), 1.74-1.67 (m, 2H).

[0269]

[0270] Example 13 Compound (13)-104 was obtained in the same manner as in Example 1, except that carbon chain elongation and deprotection of the intermediate was repeated once (twice in total) instead of twice (three times in total). Then, the reaction was carried out in the same manner as in Example 1, except that 1-bromo-2-pentyne was replaced with half the mole number of (5-bromo-3-octyn-1-yl)oxytert-butyldimethylsilane, to obtain compound (12)-113. Then, compound (11)-1131 was obtained in the same manner as in Example 1, except that compound (12)-113 was used instead of compound (12)-101. Next, the reaction product in the LibraTube (registered trademark) was transferred into a fritted plastic syringe (6 mL) and swelled with THF (1 mL) for 10 minutes. After removing the solution, a 0.5 mol / L TBAF solution in TFH (1 mL) was added and stirred at room temperature for 2 hours. The resulting product was then washed three times with THF, three times with methanol, and three times with dichloromethane, and dried under reduced pressure. This reaction and washing process was then repeated one more time. As a result, the tert-butyldimethylsilyl group in compound (11)-1131 was removed (deprotected) to obtain compound (11)-1132. Next, (5Z,8Z,11Z,14Z)-20-hydroxyeicosa-5,8,11,14-tetraenoic acid (also known as 20-HETE, polyunsaturated fatty acid (1)-113) was obtained in the same manner as in Example 1, except that compound (11)-1132 was used instead of compound (11)-101 (yield 72%). １ The H NMR spectrum data is shown below. 1 H NMR (400 MHz, CDCl3)δ5.45-5.33 (m, 8H), 3.67 (t, J = 6.4 Hz, 2H), 2.88-2.78 (m, 6H), 2.38-2.34 (m, 2H), 2.16-2.06 (m, 4H), 1.75-1.68 (m, 2H), 1.60-1.55 (m, 2H), 1.40-1.35 (m, 4H).

[0271]

[0272] [Example 14] The carbon chain elongation and deprotection of the intermediate was repeated once (twice in total) instead of twice (three times in total), 1-bromo-2-pentyne was replaced by 1 / 4 the molar amount of 2-(4-bromo-2-butyn-1-yl)-5-ethylfuran, the amounts of copper(I) iodide, potassium iodide, TMG, and DMF used were reduced to half, and the reaction time was set to one hour. The novel compound (5Z,8Z,11Z,14Z)-16-(5-ethylfuran-2-yl)hexadeca-5,8,11,14-tetraenoic acid (polyunsaturated fatty acid (1)-114) was obtained (yield 59%) in the same manner as in Example 1. The obtained polyunsaturated fatty acid (1)-114 １ The H NMR spectrum data is shown below. 1 H NMR (400 MHz, CDCl3)δ5.87 (d, J = 3.0 Hz, 1H), 5.85 (d, J = 3.0 Hz, 1H), 5.62-5.48 (m,2H), 5.44-5.33 (m, 6H), 3.38 (d, J = 7.1 Hz, 2H), 2.89 (t, J = 6.3 Hz, 2H), 2.85-2.79 (m, 4H), 2.60 (q, J = 7.6 Hz, 2H), 2.35 (t, J = 7.6 Hz, 2H), 2.15-2.10 (m, 2H), 1.75-1.67 (m, 2H), 1.21 (t, J = 7.6 Hz, 3H).

[0273]

[0274] Example 15: Instead of 3-(trimethylsilyl)propargyl bromide, 1 / 4 moles of 2-(4-bromo-2-butyn-1-yl)-5-ethylfuran was used relative to compound (2)-101, and the amounts of copper(I) iodide, potassium iodide, TMG, and DMF used were reduced to 1 / 2. The reaction time was set to 1 hour, and the procedure was the same as in Example 1, except that the intermediate was not synthesized. Thus, a novel compound, (5Z,8Z)-10-(5-ethylfuran-2-yl)deca-5,8-dienoic acid (polyunsaturated fatty acid (1)-115) was obtained (yield 87%). The obtained polyunsaturated fatty acid (1)-115 １ The H NMR spectrum data is shown below. 1 H NMR (400 MHz, CDCl3)δ5.87 (d, J = 3.1 Hz, 1H), 5.85 (d, J = 3.0 Hz, 1H), 5.61-5.34 (m, 4H), 3.37 (d, J = 6.9 Hz, 2H), 2.85 (t, J = 6.8 Hz, 2H), 2.60 (q, J = 7.6 Hz, 2H), 2.36 (t, J = 7.0 Hz, 2H), 2.15-2.10 (m, 2H), 1.74-1.67 (m, 2H), 1.21 (t, J = 7.6 Hz, 3H).

[0275]

[0276] Example 16 The novel compound (4Z,7Z)-hexadeca-4,7-dienoic acid (polyunsaturated fatty acid (1)-116) was obtained (yield 42%) in the same manner as in Example 1, except that the same number of moles of 4-pentynoic acid was used instead of 5-hexynoic acid, that the reaction was carried out using the same number of moles of 1-bromo-2-undecyne instead of 3-(trimethylsilyl)propargyl bromide for compound (2)-102, thereby avoiding the synthesis of the intermediate, that methanol was used instead of tert-butyl alcohol during the hydrogen transfer reaction, and that reverse-phase HPLC was used instead of silica gel column chromatography when isolating the target product. １The H NMR spectrum data is shown below. 1 H NMR (400 MHz, CDCl3)δ5.45-5.28 (m, 4H), 2.80 (t, J = 6.9 Hz, 2H), 2.41 (brs, 4H), 2.07-2.02 (m, 2H), 1.40-1.19 (m, 12H), 0.88 (t, J = 6.9Hz, 3H).

[0277]

[0278] Example 17: The novel compound (10Z,13Z)-pentadeca-10,13-dienoic acid (polyunsaturated fatty acid (1)-117) was obtained (yield 72%) in the same manner as in Example 1, except that the same number of moles of 10-undecynoic acid was used instead of 5-hexynoic acid, that the reaction was carried out using the same number of moles of 1-bromo-2-butyne instead of 3-(trimethylsilyl)propargyl bromide for compound (2)-104, thereby avoiding the synthesis of the intermediate, that methanol was used instead of tert-butyl alcohol during the hydrogen transfer reaction, and that reverse-phase HPLC was used instead of silica gel column chromatography when isolating the target product. １ The H NMR spectrum data is shown below. 1 H NMR (400 MHz, CDCl3)δ5.50-5.30 (m, 4H), 2.80-2.77 (m, 2H), 2.37 (brs, 2H), 2.08-2.03 (m, 2H), 1.65-1.63 (m, 3H), 1.38-1.22 (m, 12H).

[0279]

[0280] Example 18: The novel compound (10Z,13Z)-nonadeca-10,13-dienoic acid (also known as DHA, polyunsaturated fatty acid (1)-118) was obtained (yield 17%) in the same manner as in Example 1, except that the same number of moles of 10-undecynoic acid was used instead of 5-hexynoic acid, the same number of moles of 1-bromo-2-octyne was used instead of 3-(trimethylsilyl)propargyl bromide for compound (2)-104, thereby avoiding the synthesis of the intermediate, the use of methanol instead of tert-butyl alcohol in the hydrogen transfer reaction, and reverse-phase HPLC instead of silica gel column chromatography for isolation of the target product. １ The H NMR spectrum data is shown below. 1 H NMR (400 MHz, CDCl3)δ5.42-5.29 (m, 4H), 2.79-2.76 (m, 2H), 2.35 (t, J = 7.3 Hz, 2H), 2.05 (q, J = 6.9 Hz, 4H), 1.67-1.60 (m, 2H), 1.39-1.24 (m, 16H), 0.89 (t, J = 6.9 Hz, 3H).

[0281]

[0282] Example 19: The novel compound (10Z,13Z,16Z)-octadeca-10,13,16-trienoic acid (polyunsaturated fatty acid (1)-119) was obtained (yield 15%) in the same manner as in Example 1, except that the same number of moles of 10-undecynoic acid was used instead of 5-hexynoic acid, the carbon chain elongation and deprotection of the intermediate were not performed, the same number of moles of 1-bromo-2-butyne was used instead of 1-bromo-2-pentyne, methanol was used instead of tert-butyl alcohol during the hydrogen transfer reaction, and reversed-phase HPLC was used instead of silica gel column chromatography when isolating the target product. １ The H NMR spectrum data is shown below. 1H NMR (400 MHz, CDCl3)δ5.52-5.31 (m, 6H), 2.86-2.78 (m, 4H), 2.36 (brs, 2H), 2.08-2.03 (m, 2H), 1.69-1.58 (m, 5H), 1.40-1.24 (m, 10H).

[0283]

[0284] Example 20 The novel compound (10Z,13Z,16Z)-nonadeca-10,13,16-trienoic acid (polyunsaturated fatty acid (1)-120) was obtained (yield 6%) in the same manner as in Example 1, except that the same number of moles of 10-undecynoic acid was used instead of 5-hexynoic acid, the carbon chain elongation and deprotection of the intermediate were not performed, methanol was used instead of tert-butyl alcohol during the hydrogen transfer reaction, and reverse-phase HPLC was used instead of silica gel column chromatography when isolating the target product. １ The H NMR spectrum data is shown below. 1 H NMR (400 MHz, CDCl3)δ5.43-5.28 (m, 6H), 2.82-2.79 (m, 4H), 2.38-2.34 (m, 2H), 2.10-2.03 (m, 4H), 1.40-1.24 (m, 12H), 0.98 (t, J = 7.3Hz, 3H).

[0285]

[0286] Example 21: The novel compound (10Z,13Z,16Z,19Z)-heneicosa-10,13,16,19-tetraenoic acid (polyunsaturated fatty acid (1)-121) was obtained (yield 13%) in the same manner as in Example 1, except that the same number of moles of 10-undecynoic acid was used instead of 5-hexynoic acid, the carbon chain elongation and deprotection of the intermediate was repeated once (twice in total) instead of twice (three times in total), the same number of moles of 1-bromo-2-butyne was used instead of 1-bromo-2-pentyne, methanol was used instead of tert-butyl alcohol during the hydrogen transfer reaction, and reverse-phase HPLC was used instead of silica gel column chromatography when isolating the target product. １ The H NMR spectrum data is shown below. 1 H NMR (400 MHz, CDCl3)δ5.52-5.30 (m, 8H), 2.87-2.80 (m, 6H), 2.35 (t, J = 7.4 Hz, 2H), 2.05 (q, J = 6.8 Hz, 2H), 1.67-1.60 (m, 5H), 1.40-1.25 (m, 10H).

[0287]

[0288] Example 22 The novel compound (10Z,13Z,16Z,19Z,22Z)-tetracosa-10,13,16,19,22-pentaenoic acid (polyunsaturated fatty acid (1)-122) was obtained (yield 4%) in the same manner as in Example 1, except that the same number of moles of 10-undecynoic acid was used instead of 5-hexynoic acid, the same number of moles of 1-bromo-2-butyne was used instead of 1-bromo-2-pentyne, methanol was used instead of tert-butyl alcohol during the hydrogen transfer reaction, and reverse-phase HPLC was used instead of silica gel column chromatography when isolating the target product. １ The H NMR spectrum data is shown below. 1H NMR (400 MHz, CDCl3)δ5.52-5.30 (m, 10H), 2.88-2.77 (m, 8H), 2.35 (t, J = 7.4 Hz, 2H), 2.05 (q, J = 6.9 Hz, 2H), 1.65-1.60 (m, 5H), 1.38-1.28 (m, 10H).

[0289]

[0290] [Example 23] Instead of 5-hexynoic acid, the same number of moles of 4-pentynoic acid was used, and the intermediate was reacted with 3-(trimethylsilyl)propargyl bromide and Et ３ (4Z,7Z,10Z)-hexadeca-4,7,10-trienoic acid (polyunsaturated fatty acid (1)-123) was obtained (yield 52%) in the same manner as in Example 1, except that the carbon chain elongation and deprotection, i.e., deprotection of the trimethylsilyl group with N·3HF, was not performed, the same number of moles of 1-bromo-2-octyne was used instead of 1-bromo-2-pentyne, methanol was used instead of tert-butyl alcohol during the hydrogen transfer reaction, and reversed-phase HPLC was used instead of silica gel column chromatography when isolating the target product. １ The H NMR spectrum data is shown below. 1 H NMR (400 MHz, CDCl3)δ5.46-5.30 (m, 6H), 2.86-2.79 (m, 4H), 2.42 (brs, 4H), 2.08-2.03 (m, 2H), 1.39-1.24 (m, 6H), 0.89 (t, J = 6.9 Hz, 3H).

[0291]

[0292] Example 24 (4Z,7Z,10Z)-nonadeca-4,7,10-trienoic acid (polyunsaturated fatty acid (1)-124) was obtained (yield 27%) in the same manner as in Example 1, except that the same number of moles of 4-pentynoic acid was used instead of 5-hexynoic acid, the carbon chain elongation and deprotection of the intermediate were not performed, the same number of moles of 1-bromo-2-undecyne was used instead of 1-bromo-2-pentyne, methanol was used instead of tert-butyl alcohol during the hydrogen transfer reaction, and reverse-phase HPLC was used instead of silica gel column chromatography when isolating the target product. １ The H NMR spectrum data is shown below. 1 H NMR (400 MHz, CDCl3)δ5.46-5.30 (m, 6H), 2.86-2.79 (m, 4H), 2.43 (brs, 4H), 2.08-2.03 (m, 2H), 1.40-1.21 (m, 12H), 0.88 (t, J = 6.9 Hz, 3H).

[0293]

[0294] Example 25: (4Z,7Z,10Z,13Z)-hexadeca-4,7,10,13-tetraenoic acid (polyunsaturated fatty acid (1)-125) was obtained (yield 42%) in the same manner as in Example 1, except that the same number of moles of 4-pentynoic acid was used instead of 5-hexynoic acid, the carbon chain elongation and deprotection of the intermediate was repeated once (two times in total) instead of twice (three times in total), methanol was used instead of tert-butyl alcohol during the hydrogen transfer reaction, and reverse-phase HPLC was used instead of silica gel column chromatography when isolating the target product. １ The H NMR spectrum data is shown below. 1 H NMR (400 MHz, CDCl3)δ5.47-5.28 (m, 8H), 2.88-2.80 (m,6H), 2.42 (brs, 4H), 2.12-2.04 (m, 2H), 0.98 (t, J = 7.6 Hz, 3H).

[0295]

[0296] Example 26 Compound (2)-101 was reacted with the same number of moles of 1-bromo-2-undecyne instead of 3-(trimethylsilyl)propargyl bromide, and the intermediate was not synthesized. The procedure was the same as in Example 1, except that methanol was used instead of tert-butyl alcohol during the hydrogen transfer reaction, and reverse-phase HPLC was used instead of silica gel column chromatography when isolating the target product. (5Z,8Z)-heptadeca-5,8-dienoic acid (polyunsaturated fatty acid (1)-126) was obtained (yield 48%). １ The H NMR spectrum data is shown below. 1 H NMR (400 MHz, CDCl3)δ5.44-5.28 (m, 4H), 2.79-2.75 (m, 2H), 2.39-2.35 (m, 2H), 2.16-2.11 (m, 2H), 2.07-2.02 (m, 2H), 1.72 (qui, J = 7.3 Hz, 2H), 1.41-1.20 (m, 12H), 0.88 (t, J = 6.9 Hz, 3H).

[0297]

[0298] Example 27 (5Z,8Z,11Z)-heptadeca-5,8,11-trienoic acid (polyunsaturated fatty acid (1)-127) was obtained (yield 27%) in the same manner as in Example 1, except that the carbon chain elongation and deprotection of the intermediate were not carried out, the same number of moles of 1-bromo-2-octyne was used instead of 1-bromo-2-pentyne, methanol was used instead of tert-butyl alcohol during the hydrogen transfer reaction, and reversed-phase HPLC was used instead of silica gel column chromatography when isolating the target product. １ The H NMR spectrum data is shown below. 1H NMR (400 MHz, CDCl3)δ5.45-5.30 (m, 6H), 2.82-2.79 (m, 4H), 2.37 (t, J = 7.6 Hz, 2H), 2.16-2.11 (m, 2H), 2.08-2.03 (m, 2H), 1.72 (qui, J = 7.3 Hz, 2H), 1.40-1.24 (m, 6H), 0.89 (t, J = 6.9 Hz, 3H).

[0299]

[0300] Example 28: (5Z,8Z,11Z,14Z)-hexadeca-5,8,11,14-tetraenoic acid (polyunsaturated fatty acid (1)-128) was obtained (yield 19%) in the same manner as in Example 1, except that the carbon chain elongation and deprotection of the intermediate was repeated once (twice in total) instead of twice (three times in total), the same number of moles of 1-bromo-2-butyne was used instead of 1-bromo-2-pentyne, methanol was used instead of tert-butyl alcohol during the hydrogen transfer reaction, and reversed-phase HPLC was used instead of silica gel column chromatography when isolating the target product. １ The H NMR spectrum data is shown below. 1 H NMR (400 MHz, CDCl3)δ5.52-5.30 (m, 8H), 2.89-2.72 (m, 6H), 2.40-2.36 (m, 2H), 2.17-2.11 (m, 2H), 1.72 (qui, J = 7.3 Hz, 2H), 1.65 (d, J = 6.4 Hz, 3H).

[0301]

[0302] Example 29 (5Z,8Z,11Z,14Z,17Z)-nonadeca-5,8,11,14,17-pentaenoic acid (polyunsaturated fatty acid (1)-129) was obtained (yield 52%) in the same manner as in Example 1, except that the same number of moles of 1-bromo-2-butyne was used instead of 1-bromo-2-pentyne, methanol was used instead of tert-butyl alcohol during the hydrogen transfer reaction, and reverse-phase HPLC was used instead of silica gel column chromatography when isolating the target product. １ The H NMR spectrum data is shown below. 1 H NMR (400 MHz, CDCl3)δ5.52-5.33 (m, 10H), 2.89-2.80 (m, 8H), 2.36 (t, J = 7.6 Hz, 2H), 2.16-2.11 (m, 2H), 1.75-1.68 (m, 2H), 1.65-1.63 (m, 3H).

[0303]

[0304] Example 30: (6Z,9Z)-octadeca-6,9-dienoic acid (polyunsaturated fatty acid (1)-130) was obtained (yield 42%) in the same manner as in Example 1, except that the same number of moles of 6-heptynoic acid was used instead of 5-hexynoic acid, that the reaction was carried out using the same number of moles of 1-bromo-2-undecyne instead of 3-(trimethylsilyl)propargyl bromide for compound (2)-103, thereby avoiding the synthesis of the intermediate, that methanol was used instead of tert-butyl alcohol during the hydrogen transfer reaction, and that reverse-phase HPLC was used instead of silica gel column chromatography when isolating the target product. １ The H NMR spectrum data is shown below. 1H NMR (400 MHz, CDCl3)δ5.42-5.29 (m, 4H), 2.79-2.76 (m, 2H), 2.36 (t, J = 7.3 Hz, 2H), 2.11-2.02 (m, 4H), 1.46-1.41 (m, 2H), 1.35-1.20 (m, 12H), 0.88 (t, J = 6.9 Hz, 3H).

[0305]

[0306] Example 31: (6Z,9Z,12Z,15Z)-octadeca-6,9,12,15-tetraenoic acid (polyunsaturated fatty acid (1)-131) was obtained (yield 76%) in the same manner as in Example 1, except that the same number of moles of 6-heptynoic acid was used instead of 5-hexynoic acid, the carbon chain elongation and deprotection of the intermediate was repeated once (two times in total) instead of twice (three times in total), and methanol was used instead of tert-butyl alcohol during the hydrogen transfer reaction. １ The H NMR spectrum data is shown below. 1 H NMR (400 MHz, CDCl3)δ5.44-5.28 (m, 8H), 2.85-2.78 (m, 6H), 2.36 (t, J = 7.3 Hz, 2H), 2.12-2.04 (m, 4H),1.66 (qui, J = 7.7 Hz, 2H), 1.46-1.39 (m, 2H), 0.98 (t, J = 7.5 Hz, 3H).

[0307]

[0308] Example 32 (10Z,13Z)-hexadeca-10,13-dienoic acid (polyunsaturated fatty acid (1)-132) was obtained (yield 12%) in the same manner as in Example 1, except that the same number of moles of 10-undecynoic acid was used instead of 5-hexynoic acid, the same number of moles of 1-bromo-2-pentyne was used instead of 3-(trimethylsilyl)propargyl bromide for compound (2)-104, and thus the intermediate was not synthesized, methanol was used instead of tert-butyl alcohol during the hydrogen transfer reaction, and reverse-phase HPLC was used instead of silica gel column chromatography when isolating the target product. １ The H NMR spectrum data is shown below. 1 H NMR (400 MHz, CDCl3)δ5.42-5.27 (m, 4H), 2.77 (t, J = 6.7 Hz, 2H), 2.35 (t, J = 7.6 Hz, 2H), 2.11-2.02 (m, 4H), 1.67-1.60 (m, 2H), 1.39-1.26 (m, 10H), 0.97 (t, J = 7.3 Hz, 3H).

[0309]

[0310] <<Consideration of Bases>> [Experimental Example 1] As in Example 1, compound (2)-101, copper(I) iodide (20 equiv), and potassium iodide (20 equiv) were placed in a reaction vessel, and the atmosphere in the reaction vessel was replaced with nitrogen gas. Then, a solution of 3-(trimethylsilyl)propargyl bromide (20 equiv) and 1,1,3,3-tetramethylguanidine (TMG) (20 equiv) dissolved in N,N-dimethylformamide (DMF) was added to the reaction vessel. The reaction vessel was then shaken and stirred at room temperature for 20 hours, thereby extending the carbon chain of compound (2)-101 having a triple bond between carbon atoms, and the protected intermediate was obtained. The protected intermediate was １ The product was analyzed by H NMR, and the spectral data confirmed that the protected intermediate was indeed obtained, and the yield of the protected intermediate was calculated. The results are shown in Table 1.

[0311] [Experimental Examples 2 to 6] Instead of TMG as a base, the same number of moles of N,N-diisopropylethylamine ( ｉ Pr ２ NEt, Experimental Example 2), diisopropylamine ( ｉ Pr ２ The protected intermediate was obtained in the same manner as in Experimental Example 1, except that 2,2,6,6-tetramethylpiperidine (TMP, Experimental Example 4), 1,8-diazabicyclo[5.4.0]-7-undecene (DBU, Experimental Example 5), or 1,5-diazabicyclo[4.3.0]-5-nonene (DBN, Experimental Example 6) was used. １ The product was analyzed by H NMR, and the spectral data confirmed that the protected intermediate was indeed obtained, and the yield of the protected intermediate was calculated. The results are shown in Table 1.

[0312]

[0313]

[0314] All of the bases shown in Table 1 were soluble in organic solvents, and as is clear from Table 1, all of these bases were usable for synthesizing the protected intermediate. That is, all of these bases can be used to repeatedly extend the carbon chain having a triple bond between carbon atoms in the intermediate, and it was confirmed that they can be used as bases in the method for producing polyunsaturated fatty acid (1) of this embodiment.

[0315] <<Study on Reaction Time>> [Experimental Example 7] As in Example 1, compound (2)-101, copper(I) iodide (20 equiv), and potassium iodide (20 equiv) were placed in a reaction vessel, and the atmosphere in the reaction vessel was replaced with nitrogen gas. Then, a solution of 3-(trimethylsilyl)propargyl bromide (20 equiv) and 1,1,3,3-tetramethylguanidine (TMG) (20 equiv) dissolved in N,N-dimethylformamide (DMF) was added to the reaction vessel. The reaction vessel was then shaken and stirred at room temperature for 12 hours to elongate the carbon chain of compound (2)-101 having a triple bond between carbon atoms, thereby obtaining the protected intermediate. The protected intermediate was１ The product was analyzed by H NMR, and the spectral data confirmed that the protected intermediate was indeed obtained, and the yield of the protected intermediate was calculated. The results are shown in Table 2.

[0316] [Experimental Examples 8 to 15] The protected intermediate was obtained in the same manner as in Experimental Example 7, except that the reaction time (the time for shaking and stirring the reaction vessel) was changed from 12 hours to 8 hours (Experimental Example 8), 4 hours (Experimental Example 9), 3 hours (Experimental Example 10), 2 hours (Experimental Example 11), 1 hour (Experimental Example 12), 40 minutes (Experimental Example 13), or 20 minutes (Experimental Example 14). The protected intermediate was obtained in the same manner as in Experimental Example 7, except that the reaction time was changed from 12 hours to 30 minutes, and the atmosphere in the reaction vessel was replaced with air instead of nitrogen gas (Experimental Example 15). １ The product was analyzed by H NMR, and the spectral data confirmed that the protected intermediate was indeed obtained, and the yield of the protected intermediate was calculated. The results are shown in Table 2.

[0317]

[0318]

[0319] As is clear from Table 1, the reaction was almost complete 20 minutes after the start of the reaction, and the yield of the protected intermediate was significantly higher when the reaction time was within 3 hours. In other words, the production method of this embodiment enables the carbon chain of the intermediate to be extended with a triple bond between carbon atoms in a very short time, demonstrating that polyunsaturated fatty acid (1) can be obtained in a short time. Meanwhile, as is clear from Experimental Example 15, the carbon chain extension was also possible in an air atmosphere in the production method of this embodiment.

[0320] <<Study on Deprotecting Agents>> [Experimental Example 16] As in Example 1, compound (2)-101, copper(I) iodide (20 equiv), and potassium iodide (20 equiv) were placed in a reaction vessel, and the atmosphere in the reaction vessel was replaced with nitrogen gas. Then, a solution of 3-(trimethylsilyl)propargyl bromide (20 equiv) and 1,1,3,3-tetramethylguanidine (TMG) (20 equiv) dissolved in N,N-dimethylformamide (DMF) was added to the reaction vessel. The reaction vessel was then shaken and stirred at room temperature for 20 hours to elongate the carbon chain of compound (2)-101 having a triple bond between carbon atoms, thereby obtaining the protected intermediate. Next, a deprotection reaction was carried out in the same manner as in Example 1, except that tetrahydrofuran (THF) was used instead of DMF and tetrabutylammonium difluorotriphenylsilicate (TBAT, 20 equiv) was used instead of triethylamine trihydrofluoride, followed by washing and drying under reduced pressure to obtain the intermediate in which the carbon chain having a triple bond between carbon atoms was extended from compound (2)-101 via the protected intermediate. １ The product was analyzed by H NMR, and the spectral data confirmed that the intermediate was indeed obtained, and the yield of the intermediate was calculated. The results are shown in Table 3.

[0321] [Experimental Example 17] The intermediate was obtained in the same manner as in Experimental Example 16, except that tetrabutylammonium fluoride (TBAF, 20 equiv) and 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP, 5% by volume relative to THF) were used instead of tetrabutylammonium difluorotriphenylsilicate (TBAT). １ The product was analyzed by H NMR, and the spectral data confirmed that the intermediate was indeed obtained, and the yield of the intermediate was calculated. The results are shown in Table 3.

[0322]

[0323]

[0324] As is clear from the above results, it was possible to deprotect the trimethylsilyl group using a general-purpose deprotecting agent other than triethylamine trihydrofluoride. In other words, it was confirmed that these deprotecting agents can be used to perform the deprotection reaction of the protected intermediate and the deprotection reaction that occurs during the elongation of the carbon chain having a triple bond between carbon atoms, and can be used as deprotecting agents in the production method of polyunsaturated fatty acid (1) of this embodiment.

[0325] Example 33 In place of compound (2)-101, the same mole number of compound (2)-105, which has a structure in which a modified 5-hexynoic acid in which the carboxy group of 5-hexynoic acid is amidated with N-Boc tryptophan, is bound to a resin, was used in the same manner as in Example 1, except that 1-(tert-butoxycarbonyl)-N α -((5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenoyl)-L-tryptophan (polyunsaturated fatty acid (1)-133) was obtained (yield: 7%). １ The H NMR spectrum data is shown below. 1 H NMR (500 MHz, CDCl3)δ8.10 (brs, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.44 (s, 1H), 7.31 (t, J = 7.9 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 6.05 (d, J = 6.4Hz, 1H), 5.43-5.28 (m, 10H), 4.88-4.85 (m, 1H), 3.34 (dd, J =15.0, 5.8 Hz, 1H), 3.24 (dd, J = 15.0, 6.1 Hz, 1H), 2.86-2.71 (m, 8H), 2.16 (t, J = 7.9 Hz, 2H), 2.09-2.03 (m, 4H), 1.69-1.63 (m, 11H), 0.97 (t, J = 7.6 Hz, 3H).

[0326]

[0327] It was confirmed that the polyunsaturated fatty acid (1) in which m is 1 can be produced by the production method of this embodiment in the same way as the polyunsaturated fatty acid (1) in which m is 0.

[0328] Example 34 The novel compound (4Z,7Z,10Z,13Z)-pentadeca-4,7,10,13-tetraenoic acid (polyunsaturated fatty acid (1)-134) was obtained (yield 9%) in the same manner as in Example 1, except that the same number of moles of 4-pentynoic acid was used instead of 5-hexynoic acid, the carbon chain elongation and deprotection of the intermediate was repeated once (twice in total) instead of twice (three times in total), the same number of moles of 1-bromo-2-butyne was used instead of 1-bromo-2-pentyne, methanol was used instead of tert-butyl alcohol during the hydrogen transfer reaction, and reversed-phase HPLC was used instead of silica gel column chromatography when isolating the target product. １ The H NMR spectrum data is shown below. 1 H NMR (400 MHz, CDCl3)δ5.52-5.33 (m, 8H), 2.86-2.81 (m, 6H), 2.46-2.38 (m, 4H), 1.67-1.64 (m, 3H).

[0329]

[0330] Example 35: The novel compound (6Z,9Z,12Z)-tetradeca-6,9,12-trienoic acid (polyunsaturated fatty acid (1)-135) was obtained (yield 11%) in the same manner as in Example 1, except that the same number of moles of 6-heptynoic acid was used instead of 5-hexynoic acid, the carbon chain elongation and deprotection of the intermediate were not performed, the same number of moles of 1-bromo-2-butyne was used instead of 1-bromo-2-pentyne, methanol was used instead of tert-butyl alcohol during the hydrogen transfer reaction, and reverse-phase HPLC was used instead of silica gel column chromatography when isolating the target product. １ The H NMR spectrum data is shown below. 1H NMR (400 MHz, CDCl3)δ5.53-5.26 (m, 6H), 2.83-2.80 (m, 4H), 2.37 (t, J = 7.3 Hz, 2H), 2.12-2.07 (m, 2H), 1.70-1.63 (m, 4H), 1.47-1.39 (m, 2H).

[0331]

[0332] Example 36 The novel compound (6Z,9Z,12Z,15Z)-heptadeca-6,9,12,15-tetraenoic acid (polyunsaturated fatty acid (1)-136) was obtained (yield 11%) in the same manner as in Example 1, except that the same number of moles of 6-heptynoic acid was used instead of 5-hexynoic acid, the carbon chain elongation and deprotection of the intermediate was repeated once (twice in total) instead of twice (three times in total), the same number of moles of 1-bromo-2-butyne was used instead of 1-bromo-2-pentyne, methanol was used instead of tert-butyl alcohol during the hydrogen transfer reaction, and reverse-phase HPLC was used instead of silica gel column chromatography when isolating the target product. １ The H NMR spectrum data is shown below. 1 H NMR (400 MHz, CDCl3)δ5.52-5.30 (m, 8H), 2.89-2.74 (m, 6H), 2.39-2.35 (m, 2H), 2.12-2.07 (m, 2H), 1.70-1.61 (m, 4H), 1.47-1.39 (m, 2H).

[0333]

[0334] Example 37 (6Z,9Z,12Z)-pentadeca-6,9,12-trienoic acid (polyunsaturated fatty acid (1)-137) was obtained (yield 31%) in the same manner as in Example 1, except that the same number of moles of 6-heptynoic acid was used instead of 5-hexynoic acid, the carbon chain elongation and deprotection of the intermediate were not performed, methanol was used instead of tert-butyl alcohol during the hydrogen transfer reaction, and reverse-phase HPLC was used instead of silica gel column chromatography when isolating the target product. １ The H NMR spectrum data is shown below. 1 H NMR (400 MHz, CDCl3)δ5.43-5.28 (m, 6H), 2.82-2.79 (m, 4H), 2.39 (brs, 2H), 2.13-2.02 (m, 4H), 1.71-1.64 (m, 2H), 1.47-1.39 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H).

[0335]

[0336] [Example 38] Compound (16)-101 was obtained in the same manner as in Example 1, except that the carbon chain elongation and deprotection of the intermediate was repeated once (twice in total) instead of twice (three times in total). Then, a novel compound, (5Z,8Z,11Z)-pentadeca-5,8,11,14-tetraenoic acid (polyunsaturated fatty acid (10)-101), was obtained (yield 26%) in the same manner as in Example 1, except that the same number of moles of compound (16)-101 was used instead of compound (12)-101, methanol was used instead of tert-butyl alcohol during the hydrogen transfer reaction, and reversed-phase HPLC was used instead of silica gel column chromatography when isolating the target product. １ The H NMR spectrum data is shown below. 1H NMR (400 MHz, CDCl3)δ5.87-5.77 (m, 1H), 5.46-5.31 (m, 6H), 5.08-5.02 (m, 1H), 5.01-4.96 (m, 1H), 2.85-2.72 (m, 6H), 2.39-2.36 (m, 2H), 2.17-2.11 (m, 2H), 1.76-1.69 (m, 2H).

[0337]

[0338] Example 39: Protected intermediate (15)-101 was obtained by carrying out a reaction using 3-(trimethylsilyl)propargyl bromide in the same manner as in Example 1, except that the same number of moles of 10-undecynoic acid was used instead of 5-hexynoic acid. Then, a novel compound, (Z)-tetradeca-10,13-dienoic acid (polyunsaturated fatty acid (10)-102), was obtained (yield 17%) in the same manner as in Example 1, except that the same number of moles of protected intermediate (15)-101 was used instead of compound (12)-101, that methanol was used instead of tert-butyl alcohol during the hydrogen transfer reaction, and that reverse-phase HPLC was used instead of silica gel column chromatography when extracting the target product. １ The H NMR spectrum data is shown below. 1 H NMR (400 MHz, CDCl3)δ5.86-5.76 (m, 1H), 5.45-5.35 (m, 2H), 5.06-5.01 (m, 1H), 4.99-4.95 (m, 1H), 2.81-2.77 (m, 2H), 2.05-2.00 (m, 2H), 1.64 (brs, 2H), 1.38-1.21 (m, 12H).

[0339]

[0340] Example 40: (4Z,7Z)-deca-4,7-dienoic acid (polyunsaturated fatty acid (1)-138) was obtained (yield 36%) in the same manner as in Example 1, except that the same moles of 4-pentynoic acid were used instead of 5-hexynoic acid, and the same moles of 1-bromo-2-pentyne were used instead of 3-(trimethylsilyl)propargyl bromide for compound (2)-102, thereby avoiding the synthesis of the intermediate, that methanol was used instead of tert-butyl alcohol during the hydrogen transfer reaction, and that reverse-phase HPLC was used instead of silica gel column chromatography when isolating the target product. The resulting polyunsaturated fatty acid (1)-138 was analyzed by mass spectrometry (MS) in negative mode, revealing that the m / z was 167.1, confirming that the target product was obtained.

[0341]

[0342] Example 41: Compound (2)-101 was reacted with the same number of moles of 1-bromo-2-butyne instead of 3-(trimethylsilyl)propargyl bromide, thereby avoiding the synthesis of the intermediate, using methanol instead of tert-butyl alcohol during the hydrogen transfer reaction, and using reverse-phase HPLC instead of silica gel column chromatography to isolate the target compound, in the same manner as in Example 1. This resulted in the production of a novel compound, (5Z,8Z)-deca-5,8-dienoic acid (polyunsaturated fatty acid (1)-139) (yield 13%). The resulting polyunsaturated fatty acid (1)-139 was analyzed by MS in negative mode, revealing that the m / z was 167.1, confirming that the target compound had been obtained.

[0343]

[0344] Example 42: (4Z,7Z)-trideca-4,7-dienoic acid (polyunsaturated fatty acid (1)-140) was obtained (yield 37%) in the same manner as in Example 1, except that the same moles of 4-pentynoic acid were used instead of 5-hexynoic acid, and the same moles of 1-bromo-2-octyne were used instead of 3-(trimethylsilyl)propargyl bromide for compound (2)-102, thereby avoiding the synthesis of the intermediate, that methanol was used instead of tert-butyl alcohol during the hydrogen transfer reaction, and that reverse-phase HPLC was used instead of silica gel column chromatography when isolating the target product. The resulting polyunsaturated fatty acid (1)-140 was analyzed by MS in negative mode, revealing that the m / z was 209.1, confirming that the target product had been obtained.

[0345]

[0346] Example 43: Compound (2)-101 was reacted with the same molar amount of 1-bromo-2-pentyne instead of 3-(trimethylsilyl)propargyl bromide, thereby avoiding the synthesis of the intermediate, using methanol instead of tert-butyl alcohol during the hydrogen transfer reaction, and using reverse-phase HPLC instead of silica gel column chromatography to isolate the target compound, in the same manner as in Example 1. This resulted in the production of a novel compound, (5Z,8Z)-undeca-5,8-dienoic acid (polyunsaturated fatty acid (1)-141) (yield 38%). The resulting polyunsaturated fatty acid (1)-141 was analyzed by MS in negative mode, revealing that the m / z was 181.1, confirming that the target compound had been obtained.

[0347]

[0348] [Example 44] Instead of 5-hexynoic acid, the same number of moles of 4-pentynoic acid was used, and the intermediate was reacted with 3-(trimethylsilyl)propargyl bromide and Et ３The novel compound (4Z,7Z,10Z)-dodeca-4,7,10-trienoic acid (polyunsaturated fatty acid (1)-142) was obtained (yield 27%) in the same manner as in Example 1, except that the carbon chain elongation and deprotection, i.e., deprotection of the trimethylsilyl group with N·3HF, was not performed, the same number of moles of 1-bromo-2-butyne was used instead of 1-bromo-2-pentyne, methanol was used instead of tert-butyl alcohol during the hydrogen transfer reaction, and reverse-phase HPLC was used instead of silica gel column chromatography when isolating the target product. The resulting polyunsaturated fatty acid (1)-142 was analyzed by MS in negative mode, and the m / z was 193.1, confirming that the target product had been obtained.

[0349]

[0350] Example 45 Compound (2)-101 was reacted with the same molar amount of 1-bromo-2-octyne instead of 3-(trimethylsilyl)propargyl bromide, thereby avoiding the synthesis of the intermediate, using methanol instead of tert-butyl alcohol in the hydrogen transfer reaction, and using reverse-phase HPLC instead of silica gel column chromatography to isolate the target product, in the same manner as in Example 1 to obtain (5Z,8Z)-tetradeca-5,8-dienoic acid (polyunsaturated fatty acid (1)-143) (yield 36%). Analysis of the resulting polyunsaturated fatty acid (1)-143 by MS in negative mode revealed that the m / z was 223.1, confirming that the target product had been obtained.

[0351]

[0352] [Example 46] Instead of 5-hexynoic acid, the same number of moles of 4-pentynoic acid was used, and the intermediate was reacted with 3-(trimethylsilyl)propargyl bromide and Et ３(4Z,7Z,10Z)-trideca-4,7,10-trienoic acid (polyunsaturated fatty acid (1)-144) was obtained (42% yield) in the same manner as in Example 1, except that the carbon chain elongation and deprotection, i.e., deprotection of the trimethylsilyl group with N·3HF, was not performed, methanol was used instead of tert-butyl alcohol during the hydrogen transfer reaction, and reverse-phase HPLC was used instead of silica gel column chromatography when isolating the target product. The resulting polyunsaturated fatty acid (1)-144 was analyzed by MS in negative mode, and the m / z was 207.1, confirming that the target product was obtained.

[0353]

[0354] Example 47 A novel compound, (5Z,8Z,11Z)-trideca-5,8,11-trienoic acid (polyunsaturated fatty acid (1)-145), was obtained (yield 29%) in the same manner as in Example 1, except that the intermediate was not subjected to carbon chain elongation and deprotection, and the same number of moles of 1-bromo-2-butyne was used instead of 1-bromo-2-pentyne. The obtained polyunsaturated fatty acid (1)-145 was analyzed by MS in negative mode, and the m / z was 207.1, confirming that the target product was obtained.

[0355]

[0356] Example 48: The same moles of 4-pentynoic acid were used instead of 5-hexynoic acid; the carbon chain elongation and deprotection of the intermediate was repeated once (twice in total) instead of twice (three times in total); the same moles of 1-bromo-2-octyne were used instead of 1-bromo-2-pentyne; methanol was used instead of tert-butyl alcohol during the hydrogen transfer reaction; and reverse-phase HPLC was used instead of silica gel column chromatography when the target product was isolated. The procedure was the same as in Example 1, except that (4Z,7Z,10Z,13Z)-nonadeca-4,7,10,13-tetraenoic acid (polyunsaturated fatty acid (1)-146) was obtained (yield 23%). The resulting polyunsaturated fatty acid (1)-146 was analyzed by MS in negative mode, revealing that the m / z was 289.2, confirming that the target product had been obtained.

[0357]

[0358] Example 49: (10Z,13Z,16Z,19Z)-docosa-10,13,16,19-tetraenoic acid (polyunsaturated fatty acid (1)-147) was obtained (38% yield) in the same manner as in Example 1, except that the same moles of 10-undecynoic acid were used instead of 5-hexynoic acid, the carbon chain elongation and deprotection of the intermediate were repeated once (twice in total) instead of twice (three times in total), methanol was used instead of tert-butyl alcohol during the hydrogen transfer reaction, and reverse-phase HPLC was used instead of silica gel column chromatography when isolating the target product. The resulting polyunsaturated fatty acid (1)-147 was analyzed by MS in negative mode, and the m / z was 331.2, confirming that the target product was obtained.

[0359]

[0360] Example 50: The procedure was the same as in Example 1, except that the same moles of 6-heptynoic acid were used instead of 5-hexynoic acid, and the same moles of 1-bromo-2-pentyne were used instead of 3-(trimethylsilyl)propargyl bromide for compound (2)-103, thereby preventing the synthesis of the intermediate, that methanol was used instead of tert-butyl alcohol during the hydrogen transfer reaction, and that reverse-phase HPLC was used instead of silica gel column chromatography when isolating the target product. The novel compound (6Z,9Z)-dodeca-6,9-dienoic acid (polyunsaturated fatty acid (1)-148) was obtained (yield 28%). The resulting polyunsaturated fatty acid (1)-148 was analyzed by MS in negative mode, and the m / z was 195.1, confirming that the target product was obtained.

[0361]

[0362] Example 51: (10Z,13Z,16Z,19Z)-pentacosa-10,13,16,19-tetraenoic acid (polyunsaturated fatty acid (1)-149) was obtained (yield 19%) in the same manner as in Example 1, except that the same moles of 10-undecynoic acid were used instead of 5-hexynoic acid, the carbon chain elongation and deprotection of the intermediate was repeated once (twice in total) instead of twice (three times in total), the same moles of 1-bromo-2-octyne were used instead of 1-bromo-2-pentyne, methanol was used instead of tert-butyl alcohol during the hydrogen transfer reaction, and reverse-phase HPLC was used instead of silica gel column chromatography when isolating the target product. The resulting polyunsaturated fatty acid (1)-149 was analyzed by MS in negative mode, revealing that the m / z was 373.3, confirming that the target product was obtained.

[0363]

[0364] Example 52: Instead of 5-hexynoic acid, the same number of moles of 6-heptynoic acid was used; instead of 3-(trimethylsilyl)propargyl bromide, the same number of moles of 1-bromo-2-octyne was used to react with compound (2)-103, thereby preventing the synthesis of the intermediate; instead of tert-butyl alcohol, methanol was used in the hydrogen transfer reaction; and reverse-phase HPLC was used instead of silica gel column chromatography when isolating the target product. The procedure was the same as in Example 1, except that (6Z,9Z)-pentadeca-6,9-dienoic acid (polyunsaturated fatty acid (1)-150) was obtained (yield 42%). The resulting polyunsaturated fatty acid (1)-150 was analyzed by MS in negative mode, revealing that the m / z was 237.1, confirming that the target product had been obtained.

[0365]

[0366] Example 53: The same moles of 6-heptynoic acid were used instead of 5-hexynoic acid; the carbon chain elongation and deprotection of the intermediate was repeated once (twice in total) instead of twice (three times in total); the same moles of 1-bromo-2-octyne were used instead of 1-bromo-2-pentyne; methanol was used instead of tert-butyl alcohol during the hydrogen transfer reaction; and reverse-phase HPLC was used instead of silica gel column chromatography to isolate the target product. The procedure was the same as in Example 1, except that (6Z,9Z,12Z,15Z)-heneicosa-6,9,12,15-tetraenoic acid (polyunsaturated fatty acid (1)-151) was obtained (yield 13%). The resulting polyunsaturated fatty acid (1)-151 was analyzed by MS in negative mode, revealing that the m / z was 317.2, confirming that the target product had been obtained.

[0367]

[0368] Example 54 A novel compound, (6Z,9Z,12Z)-tetradeca-6,9,12-trienoic acid (polyunsaturated fatty acid (1)-135), was obtained (yield 38%) in the same manner as in Example 35, except that tert-butyl alcohol was used instead of methanol during the hydrogen transfer reaction. The obtained polyunsaturated fatty acid (1)-135 was analyzed by MS in negative mode, and the m / z was 221.1, confirming that the target product was obtained.

[0369]

[0370] The present invention can be used to produce polyunsaturated fatty acids using a solid phase carrier.

Claims

1. A method for producing polyunsaturated fatty acids using a solid phase carrier, comprising: (In the formula, Z １ is a solid support; G １ is a divalent group; X １ is an alkylene group which may have a substituent; and m is 0 or 1.) and a compound having an ethynyl group at a molecular terminal, represented by the following general formula (3): (In the formula, L １ is a leaving group; E １ is a silicon atom-containing protecting group.) is reacted with a compound represented by the formula (I) in the presence of an organic solvent, a base soluble in the organic solvent, and a monovalent copper salt, and then the E １ is replaced with a hydrogen atom, thereby synthesizing an intermediate having an ethynyl group at the molecular end, and further reacting the intermediate with the compound represented by the general formula (3) in the presence of an organic solvent, a base soluble in the organic solvent, and a monovalent copper salt, and １ is replaced with a hydrogen atom, ０ −1(n ０ is an integer of 1 or more.) times, (In the formula, Z １ , G １ , X １ , m and n ０ are the same as above.) A compound represented by the general formula (13) is synthesized, and a compound represented by the following general formula (4) is synthesized. (In the formula, L ２ is a leaving group; R １ is an alkyl group, one or more hydrogen atoms in the alkyl group may be substituted with a substituent, and one or more non-adjacent methylene groups in the alkyl group may be substituted with an oxygen atom, an ethylene oxide-1,2-diyl group, or a furan-2,5-diyl group.) in the co-presence of an organic solvent, a base soluble in the organic solvent, and a monovalent copper salt, or without using the compound represented by general formula (3), by reacting the compound represented by general formula (2) with the compound represented by general formula (4) in the co-presence of an organic solvent, a base soluble in the organic solvent, and a monovalent copper salt, (In the formula, Z １ , G １ , X １ , m and R １ is the same as above; and n is an integer of 1 or more.) A compound represented by the following general formula (11) is synthesized by subjecting the compound represented by the general formula (12) to a homogeneous catalytic hydrogen transfer reaction: (In the formula, Z １ , G １ , X １ , m, n and R １ are the same as above.) When a hydrogen atom in the alkyl group is substituted with a hydroxyl group protected by a silicon atom-containing protecting group as the substituent, the silicon atom-containing protecting group may then be removed to obtain a new compound represented by the general formula (11). By cleaving the bond between the carbonyl group in the compound represented by the general formula (11) and the oxygen atom adjacent to the carbonyl group, a compound represented by the following general formula (1): (In the formula, G １ , X １ , m, n and R １ (wherein the formula (I) is the same as above).

2. A method for producing polyunsaturated fatty acids using a solid phase carrier, comprising: (In the formula, Z １ is a solid support; G １ is a divalent group; X １ is an alkylene group which may have a substituent; and m is 0 or 1.) and a compound having an ethynyl group at a molecular terminal, represented by the following general formula (3): (In the formula, L １ is a leaving group; E １ is a silicon atom-containing protecting group.) A protected intermediate is synthesized by reacting a compound represented by the formula (I) with an organic solvent, a base soluble in the organic solvent, and a monovalent copper salt, and further, １ with a hydrogen atom, and reacting the resulting deprotection reaction product with the compound represented by the general formula (3) in the presence of an organic solvent, a base soluble in the organic solvent, and a monovalent copper salt, １０ −1(n １０ is an integer of 1 or more.) times, (In the formula, Z １ , G １ , X １ , m, n １０ and E １ is the same as above.) and then subjecting the compound represented by the general formula (16) to a homogeneous catalytic hydrogen transfer reaction to obtain a compound represented by the following general formula (110): (In the formula, Z １ , G １ , X １ , m and n １０ is the same as above.) and synthesizing a compound represented by the following general formula (10): (In the formula, G １ , X １ , m and n １０ (wherein the formula (I) is the same as above).

3. The method for producing polyunsaturated fatty acids according to claim 1 or 2, wherein the organic solvent-soluble base is one or more selected from the group consisting of tetramethylguanidine, 1,5-diazabicyclo[4.3.0]-5-nonene, 1,8-diazabicyclo[5.4.0]-7-undecene, 2,2,6,6-tetramethylpiperidine, and N,N-diisopropylethylamine.

4. The method for producing polyunsaturated fatty acids according to claim 1 or 2, wherein the homogeneous catalytic hydrogen transfer reaction is carried out in the presence of [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]copper(I) tert-butoxide, an alcohol, and a hydrosilane.

5. The method for producing polyunsaturated fatty acids according to claim 1 or 2, wherein the alkylene group is a chain alkylene group having 2 to 10 carbon atoms.

6. The method for producing polyunsaturated fatty acids according to claim 1, wherein the alkyl group is a chain alkyl group having 1 to 12 carbon atoms.

7. The method for producing polyunsaturated fatty acids according to claim 1, wherein n is 1 to 10.

8. The above n １０ The method for producing polyunsaturated fatty acids according to claim 2, wherein is 1 to 10.

9. The following general formula (1A): (In the formula, X １１ is a chain alkylene group having 2, 3, 4 or 8 carbon atoms; n １１ is X １１ is an alkylene group having 2 carbon atoms, it is 1, 2 or 3; １１ is an integer of 1 to 3 when X is a chain alkylene group having 3 carbon atoms; １１ is a chain alkylene group having 4 carbon atoms, it is 1, 2 or 3; １１ is an integer of 1 to 4 when R is a chain alkylene group having 8 carbon atoms; １１ is X １１ is an alkylene group having 2 carbon atoms, X is a chain alkyl group having 1 or 8 carbon atoms; １１ is a chain alkylene group having 3 carbon atoms, it is a hydrogen atom, a methyl group, an ethyl group, or a substituted alkyl group having a structure in which one methylene group in a chain alkyl group having 4 carbon atoms is substituted with an ethyleneoxide-1,2-diyl group or a furan-2,5-diyl group, and X １１ is a chain alkylene group having 4 carbon atoms, it is a methyl group or an ethyl group, １１ is a chain alkylene group having 8 carbon atoms, and is a hydrogen atom or a chain alkyl group having 1 to 5 carbon atoms.) 10. The polyunsaturated fatty acid represented by the general formula (1A) is represented by the following general formula (1A)-1 (In the formula, n １１１ is an integer from 1 to 3; R １１１ is a methyl group, an ethyl group, or the above-mentioned substituted alkyl group, or a polyunsaturated fatty acid represented by the following general formula (1A)-2 (In the formula, X １１２ is a chain alkylene group having 2, 4 or 8 carbon atoms; n １１２ is X １１２ is an alkylene group having 2 carbon atoms, it is 1, 2 or 3; １１２ is a chain alkylene group having 4 carbon atoms, it is 1, 2 or 3; １１２ is an integer of 1 to 4 when R is a chain alkylene group having 8 carbon atoms; １１２ is X １１２ is an alkylene group having 2 carbon atoms, X is a chain alkyl group having 1 or 8 carbon atoms; １１２ is a chain alkylene group having 4 carbon atoms, it is a methyl group or an ethyl group, １１２ is a chain alkylene group having 8 carbon atoms, it is a chain alkyl group having 1, 2 or 5 carbon atoms.) or a polyunsaturated fatty acid represented by the following general formula (1A)-3 (In the formula, X １１３ is a chain alkylene group having 3 or 8 carbon atoms; n １１３ is X １１３ is an alkylene group having 3 carbon atoms, the value is 3; １１３ is a chain alkylene group having 8 carbon atoms, the value is 1.) The polyunsaturated fatty acid according to claim 9 (excluding (5Z,8Z,11Z,14Z)-16-(3-ethyloxiran-2-yl)hexadeca-5,8,11,14-tetraenoic acid, (10Z,13Z)-hexadeca-10,13-dienoic acid, (10Z,13Z,16Z,19Z)-docosa-10,13,16,19-tetraenoic acid, and (10Z,13Z,16Z,19Z)-pentacosa-10,13,16,19-tetraenoic acid).

Images