Method for producing ultra-long chain polyunsaturated fatty acid

Abstract

According to the present invention, the preparation method of the ultra-long chain polyunsaturated fatty acid is provided, and the preparation method comprises: reacting a compound represented by a formula II with a formula III in a solvent to obtain a compound represented by a formula I, the formula II: R1-MgX1, the formula III: X2-(CH2) m-X, and the formula I: R1-(CH2) m-X.

Description

Technical Field

[0001] The present invention relates to a method for producing a very long chain polyunsaturated fatty acid. In addition, the present invention relates to a method for producing a very long chain polyunsaturated fatty acid for pharmaceutical use. Furthermore, the present invention relates to a method for producing a very long chain polyunsaturated fatty acid obtained by an environmentally friendly reaction. Background Art

[0002] It is known that natural resources contain long-chain polyunsaturated fatty acids (LC-PUFA) such as eicosapentaenoic acid (EPA) as an n-3 polyunsaturated fatty acid and arachidonic acid (ARA) as an n-6 polyunsaturated fatty acid. In addition, it is known that very long-chain polyunsaturated fatty acids (VLC-PUFA, for example, n-3 VLC-PUFA) having a longer carbon chain than LC-PUFA such as EPA are also contained, but their content is very small compared to LC-PUFA. In recent years, reports have been made on the biological activities of hydroxylated derivatives known as VLC-PUFA and elongatin (ELOVANOID) (Patent Documents 1 and 2, Non-Patent Document 1). It is known that polyunsaturated fatty acids (PUFA) such as LC-PUFA and VLC-PUFA have abundant double bonds or active methylene groups sandwiched by double bonds in their structures, and therefore are easily oxidized and isomerized. Therefore, it is necessary to consider the control of the above-mentioned side reactions in the chemical reactions of PUFA or the use of reactions that do not cause such side reactions.

[0003] As examples of VLC-PUFA synthesis, there are known methods for synthesizing C28:6n-3 from docosahexaenoic acid (DHA: C22:6n-3) (Patent Document 3) and a method for synthesizing C34:3n-3 methyl ester from a higher alcohol that is a reduced form of α-linolenic acid (ALA) (Non-Patent Document 2). In the above methods, there are many reaction steps from LC-PUFA to the synthesis of VLC-PUFA, and the yield is low. Due to this situation, there is a strong need to develop a method that can synthesize VLC-PUFA quickly and in large quantities. Prior art literature Patent Literature

[0004] Patent document 1: WO2016 / 130522A1 Patent document 2: WO2020 / 206448A1 Patent Document 3: WO2011 / 053892A1

[0005] Non-patent document 1: Bazan, NG, Molecular Aspects of Medicine 64 (2018) 18-33 Non-patent document 2: Kling, MR et al., J. Chem. Parkin Trans. 1993, 1183-1189 Summary of the invention Problems to be solved by the invention

[0006] Even with the existing technology, it is impossible to rapidly and massively synthesize ultra-long-chain polyunsaturated fatty acids from long-chain polyunsaturated fatty acids, and this method is not suitable for industrial-scale production. The purpose of the present invention is to provide a new method for producing ultra-long-chain polyunsaturated fatty acids. Technical Solution

[0007] The present inventors have invented a method for producing VLC-PUFA by preparing a Grignard reagent from LC-PUFA. The above method also improves the yield and is a more suitable production method than the prior art in terms of rapid and large-scale production of VLC-PUFA.

[0008] This application specification contains the following disclosures of the invention. [1] A method for producing a compound represented by formula I or a salt thereof. R 1 -(CH2) m -X(I) [Where R 1 It is a C containing 3 to 7 double bonds 18－30 hydrocarbon group, m is an integer selected from 1 to 19, and X is CO2H, CO2R a or CH2OR b , R a It is C 1－6 alkyl, R b is an ether-forming group, a silyl ether-forming group, or an ester-forming group]

[0009] [2] The method according to [1], wherein the method comprises: reacting a compound represented by formula II with a compound represented by formula III in a solvent to obtain a compound represented by formula I. R 1 -MgX 1 (II) [Wherein, X 1 is a halogen atom] X 2 -(CH2) m -X(III) [Wherein, X 2 selected from halogen atoms and sulfonyloxy groups]

[0010] [3] The method according to [2], wherein the reaction is carried out in the presence of a metal catalyst. [4] The method according to [2] or [3], wherein the reaction is carried out in the presence of an additive. [5] The method according to any one of [1] to [4], wherein R 1 It is a C containing 3 to 6 double bonds 18 , C 20 or C 22 Hydrocarbon.

[0011] [6] The method according to any one of [1] to [5], wherein R 1 It is a group represented by formula XI, or a group represented by formula XII. CH3-(CH2-CH=CH) a -(CH2) b -(XI) [wherein a is 5 and b is an integer selected from 2 to 14, or a is 6 and b is an integer selected from 1 to 11] CH3-(CH2)3-(CH2-CH=CH) c -(CH2) d -(XII) [wherein c is 3 and d is an integer selected from 5 to 17, or c is 4 and d is an integer selected from 2 to 14]

[0012] [7] The method according to [6], wherein R 1 is a group represented by formula XI, a is 5 and b is 4, or a is 6 and b is 3, or R 1 is a group represented by formula XII, c is 3 and d is 7, or c is 4 and d is 4.

[0013] [8] The method according to any one of [1] to [7], wherein R 1 All the double bonds contained are cis-form. [9] The method according to any one of [1] to [8], wherein m is 7, 9, 11 or 13.

[0014]

[10] The method according to any one of [3] to [9], wherein the metal catalyst is selected from a copper catalyst, a nickel catalyst, a palladium catalyst and an iron catalyst.

[11] The method according to any one of [3] to

[10] , wherein the metal catalyst is selected from Li2CuCl4, CuI, CuBr, CuCl, CuBr2, CuCl2, CuCN, CuCl2·2LiCl, CuCN·2LiCl, CuBr / CH3SCH3, Cu(acac)2, Cu(OAc)2, NiCl2, Ni(acac)2, Pd(OAc)2, Pd(PPh3)4, Pd(acac)2, PdCl2, Fe(acac)3 and FeCl3.

[0015]

[12] The method according to any one of [3] to

[11] , wherein the metal catalyst is Li2CuCl4.

[13] The method according to any one of [4] to

[12] , wherein the additive is selected from nitrogen-based additives, unsaturated hydrocarbon-based additives, and silyl-based additives, or a combination thereof.

[0016]

[14] The method according to any one of [4] to

[13] , wherein the additive is selected from NMP, DMPU, HMPA, HMTA, TMEDA, 1,3-butadiene, isoprene, 1-phenylpropyne and TMS-Cl, or a combination thereof.

[15] The method according to any one of [3] to

[14] , wherein the amount of the metal catalyst is 0.1 to 20 mol % relative to the compound represented by Formula III.

[0017]

[16] The method according to any one of [2] to

[15] , wherein the amount of the compound represented by formula II is 1 to 5 equivalents relative to the compound represented by formula III.

[17] The method according to any one of [4] to

[16] , wherein the amount of the additive is 0.1 to 10 equivalents relative to the compound represented by formula III.

[0018]

[18] The method according to any one of [2] to

[17] , wherein X 1 It is a bromine atom.

[19] The method according to any one of [1] to

[18] , wherein CH2OR b It represents an ether structure having 2 to 20 carbon atoms, a silyl ether structure having 4 to 20 carbon atoms, or an ester structure having 2 to 20 carbon atoms.

[0019]

[20] The method according to any one of [1] to

[19] , wherein R bSelected from tert-butyl, benzyl, p-methoxyphenylbenzyl, trityl, methoxymethyl, methoxyethoxymethyl, tetrahydropyranyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, acetyl, pivaloyl and benzoyl.

[0020]

[21] The method according to any one of [1] to

[20] , wherein X is CO2H, the compound represented by formula I is a very long chain polyunsaturated fatty acid having 20 to 50 carbon atoms and containing 3 to 7 double bonds, or X is CO2R a The compound shown in formula I is a C of a very long chain polyunsaturated fatty acid having 20 to 50 carbon atoms and containing 3 to 7 double bonds. 1－6 Alkyl esters.

[0021]

[22] The method according to any one of [1] to

[21] , wherein the compound represented by formula I is C 28－36 :5n-3、C 28－36 :4n-6、C 28－36 :6n-3 or C 28－36 : 3n-6 very long chain polyunsaturated fatty acids or their C 1－6 Alkyl esters.

[0022]

[23] The method according to any one of [1] to

[22] , wherein the compound represented by formula I is a very long chain polyunsaturated fatty acid of C32:4n-6, C34:4n-6, C32:5n-3, C34:5n-3, C32:6n-3, or C34:6n-3, or C34:6n-3 1－6 Alkyl esters.

[0023]

[24] The method according to any one of [1] to

[23] , wherein the compound represented by formula I is a C32:4n-6 or C34:5n-3 very long chain polyunsaturated fatty acid or its C 1－6 Alkyl esters.

[0024]

[25] The method according to any one of [2] to

[24] , wherein the reaction comprises: adding a mixture containing the compound represented by formula II to the compound represented by formula III in a solvent. X 2 -(CH2) m -X(III) R 1 -MgX 1 (II)

[0025]

[26] The method according to any one of [4] to

[25] , wherein the reaction is carried out in a solvent in the presence of a metal catalyst and an additive at a temperature of -20°C to 35°C.

[27] The method according to any one of [4] to

[26] , wherein the reaction comprises: adding a mixture comprising a compound represented by formula II to a compound represented by formula III in a solvent in the presence of a metal catalyst and an additive for a period of 5 to 80 minutes. X 2 -(CH2) m -X(III) R 1 -MgX 1 (II)

[0026]

[28] The method according to any one of [4] to

[27] , wherein the reaction comprises: adding a mixture comprising a compound represented by formula II to a compound represented by formula III at a rate of 0.1 to 1000 mL / min in a solvent in the presence of a metal catalyst and an additive. X 2 -(CH2) m -X(III) R 1 -MgX 1 (II)

[0027]

[29] The method according to any one of [2] to

[28] , wherein the method further comprises: converting the compound represented by Formula IIc into the compound represented by Formula II in a solvent. R 1 -X 1 (IIc) R 1 -MgX 1 (II)

[0028]

[30] The method according to

[29] , wherein the conversion comprises: adding a compound represented by formula IIc or a mixture containing the compound in a solvent in the presence of magnesium to convert the compound represented by formula IIc into the compound represented by formula II. R 1 -X 1 (IIc) R 1 -MgX 1 (II)

[0029]

[31] The method according to

[30] , wherein the conversion comprises: adding the compound represented by formula IIc or a mixture containing the compound over a period of 5 to 60 minutes. R 1 -X 1 (IIc)

[0030]

[32] The method according to

[30] or

[31] , wherein the conversion comprises: adding the compound represented by formula IIc or a mixture containing the compound at a rate of 0.1 to 1000 mL / min. R 1 -X 1 (IIc)

[0031]

[33] A method according to any one of [2] to

[32] , wherein the method further comprises: converting the compound represented by formula IIa into the compound represented by formula IIb; converting the compound represented by formula IIb into the compound represented by formula IIc; and converting the compound represented by formula IIc into the compound represented by formula II. R 1 -OH(IIa) R 1 -OX 3 (IIb) [Wherein, X 3 is sulfonyl] R 1 -X 1 (IIc) R 1 -MgX 1 (II)

[0032]

[34] The method according to any one of [1] to

[19] and

[21] to

[32] , wherein X is CH2OR b , the method further comprises: Converting the compound represented by Formula Ia into the compound represented by Formula V; and The compound represented by formula V is converted into the compound represented by formula Ib. R 1 -(CH2) m -CH2OR b (Ia) R 1 -(CH2) m -CH2OH(V) R 1 -(CH2) m -CO2H(Ib) The compound represented by formula Ib is a very long chain polyunsaturated fatty acid having 20 to 50 carbon atoms and 3 to 7 double bonds.

[0033]

[35] The method according to any one of [1] to

[34] , wherein the method further comprises: converting the very long chain polyunsaturated fatty acids into C 1－6 Alkyl esters.

[36] The compound of formula II is used to prepare very long chain polyunsaturated fatty acids or C 1－6 Uses of alkyl esters.

[0034]

[37] The compound of formula III is used to prepare a very long chain polyunsaturated fatty acid or its C 1－6 Uses of alkyl esters.

[0035]

[38] A method for producing a compound represented by formula I or a salt thereof, comprising: (1) converting the compound represented by formula IV into the compound represented by formula IIa; (2) converting the compound represented by formula IIa into the compound represented by formula IIb; (3) converting the compound represented by formula IIb into the compound represented by formula IIc; (4) converting the compound represented by Formula IIc into the compound represented by Formula II; and (5) reacting the compound represented by formula II with the compound represented by formula III to convert the compound represented by formula I. R 1 -(CH2) m -X(I) [Where R 1 It is a C containing 3 to 7 double bonds 18－30 hydrocarbon group, m is an integer selected from 1 to 19, and X is CO2H, CO2R a or CH2OR b ; R a It is C 1－6 alkyl; CH2OR b is an ether structure, a silyl ether structure or an ester structure] R 4 -CO2R 2 (IV) [Where R 4 It is a C containing 3 to 7 double bonds 17－29 Hydrocarbon, R 2 is a hydrogen atom or an ester-forming group] R 4 -CH2-OH(IIa) R 4 -CH2-OX 3 (IIb) [Wherein, X 3 is sulfonyl] R 4 -CH2-X 1 (IIc) [Wherein, X 1 is a halogen atom] R 4 -CH2-MgX 1 (II) X 2 -(CH2) m -X(III) [Wherein, X 2 selected from halogen atoms and sulfonyloxy groups]

[0036]

[39] The method according to

[38] , wherein the reaction of the compound represented by formula (5) II with the compound represented by formula (III) is carried out in a solvent in the presence of a metal catalyst.

[0037]

[40] The method according to

[38] , wherein the conversion of the compound represented by formula (1) IV comprises: reacting the compound represented by formula IV with a reducing agent in a solvent; The conversion of the compound represented by formula IIa (2) comprises: reacting the compound represented by formula IIa with a sulfonylating agent in a solvent in the presence of a base; The conversion of the compound represented by formula IIb (3) comprises: reacting the compound represented by formula IIb with a halogenating agent in a solvent; The conversion of the compound represented by formula IIc (4) comprises: reacting the compound represented by formula IIc with magnesium in a solvent; and The reaction of the compound represented by formula II with the compound represented by formula III (5) comprises: reacting the compound represented by formula II with the compound represented by formula III in a solvent in the presence of a metal catalyst.

[0038]

[41] The method according to any one of

[38] to

[40] , wherein the conversion of the compound represented by (2) Formula IIa and the conversion of the compound represented by (3) Formula IIb are performed by a one-pot synthesis.

[0039]

[42] The method according to any one of

[38] to

[41] , wherein the method comprises the one-pot synthesis of the compound represented by formula IIc in (3), wherein the one-pot synthesis comprises: (2) reacting the compound represented by Formula IIa with TsCl in a solvent in the presence of one or more amines to prepare the compound represented by Formula IIb; and (3) reacting the compound represented by Formula IIb with LiBr without isolating it to prepare the compound represented by Formula IIc. R 4 -CH2-OX 3 (IIb) [Wherein, X 3 is tosyl] R 4 -CH2-X 1 (IIc) [Wherein, X 1 is a bromine atom]

[0040]

[43] The method according to any one of

[38] to

[42] , wherein the conversion of the compound represented by formula IV (1) is carried out by reacting the compound represented by formula IV with sodium dihydrobis(2-methoxyethoxy)aluminate in a solvent.

[44] A method for treating long-chain polyunsaturated fatty acids or their C 1－6 The alkyl esters are converted to obtain very long chain polyunsaturated fatty acids or their C 1－6 A method for producing an alkyl ester, wherein: The long-chain polyunsaturated fatty acid has 18 to 30 carbon atoms and contains 3 to 7 double bonds, and the ultra-long-chain polyunsaturated fatty acid has 20 to 50 carbon atoms and contains 3 to 7 double bonds. The conversion step includes: 1－6 Alkyl ester-derived Grignard reagents and ω-halogenated C 2－20 Aliphatic acid or its C 1－6 Alkyl ester reaction to obtain the ultra-long chain polyunsaturated fatty acid or its C 1－6 Alkyl esters; The conversion step does not include one or more steps selected from the following steps: (a) a protection step of converting a compound having a hydroxyl group into a compound having a protected hydroxyl group; (b) a deprotection step of converting a compound having a protected hydroxyl group into a compound having a hydroxyl group; (c) an oxidation step of converting an alcohol into an aldehyde or a carboxylic acid; (d) an oxidation step of converting an aldehyde into a carboxylic acid; and (e) a step of converting an aldehyde into a carboxylic acid relative to the long-chain polyunsaturated fatty acid or its C 1－6 The step of producing a compound derived from an alkyl ester is carried out in the presence of a stoichiometric amount of a phosphorus compound.

[0041]

[45] A method for treating long-chain polyunsaturated fatty acids or their C 1－6 The alkyl esters are converted to obtain very long chain polyunsaturated fatty acids or their C 1－6 A method for producing an alkyl ester, wherein the long-chain polyunsaturated fatty acid has 18 to 30 carbon atoms and contains 3 to 7 double bonds, and the ultra-long-chain polyunsaturated fatty acid has 20 to 50 carbon atoms and contains 3 to 7 double bonds. In the conversion step, the long-chain polyunsaturated fatty acid or its C 1－6 Alkyl ester-derived Grignard reagents and ω-halogenated C 2－20 Aliphatic acid or its C 1－6The alkyl ester reacts in the presence of a metal catalyst to obtain the ultra-long chain polyunsaturated fatty acid or its C 1－6 Alkyl esters, The conversion step does not include one or more steps selected from the following steps: (a) converting a compound having a hydroxyl group into a compound having a C 1－20 Ether protecting group, C 3－20 Silyl ether protecting group or C 1－20 ester protecting group of the compound protection process; (b) having C 1－20 Ether protecting group, C 3－20 Silyl ether protecting group or C 1－20 (c) an oxidation step of a compound having a hydroxymethyl group to a compound having a formyl group or a carboxyl group; (d) an oxidation step of a compound having a formyl group to a compound having a carboxyl group; and (e) a step of removing a compound having an ester protecting group from a long-chain polyunsaturated fatty acid or its C 1－6 The process of producing a compound derived from an alkyl ester is carried out in the presence of a stoichiometric amount of triphenylphosphine or a triphenylphosphonium salt. Effects of the Invention

[0042] In one aspect of the present invention, a method for producing a very long chain polyunsaturated fatty acid is provided, which is suitable for efficient production on an industrial scale. In another aspect of the present invention, a method for producing a synthetic intermediate is provided, which is useful in the production of very long chain polyunsaturated fatty acids suitable for efficient production on an industrial scale. DETAILED DESCRIPTION

[0043] In this specification, the very long chain polyunsaturated fatty acid is not particularly limited as long as it is a fatty acid with 20 to 50 carbon atoms and 3 to 7 double bonds. In one aspect of the present invention, the very long chain polyunsaturated fatty acid is a fatty acid with 24 or more carbon atoms and 3 or more double bonds. In one aspect of the present invention, the number of carbon atoms of the very long chain polyunsaturated fatty acid is 24 to 42, 24 to 40, 26 to 40, 28 to 36, 28 to 40, 30 to 40, 24 to 38, 26 to 38, 28 to 38, or 30 to 38. In one embodiment of the present invention, the very long chain polyunsaturated fatty acid has 3 to 6 or 4 to 6 double bonds.

[0044] In one embodiment of the present invention, the very long chain polyunsaturated fatty acid has 3 to 6 double bonds arranged continuously with one methylene group. In one aspect of the present invention, each double bond is cis (Z configuration). In one embodiment of the present invention, the very long chain polyunsaturated fatty acid has the same chemical structure as docosahexaenoic acid, eicosapentaenoic acid, or arachidonic acid, and has 3 to 6 double bonds arranged continuously with one methylene group.

[0045] In one aspect of the present invention, the very long chain polyunsaturated fatty acid is an n3 or n6 very long chain polyunsaturated fatty acid (n3 VLC-PUFA, n6 VLC-PUFA) containing 24 to 42 carbon atoms (C24 to C42). 28－36 :5n-3(28~36 carbons, 5 double bonds, ω-3), C 28－36 :4n-6、C 28－36 :6n-3 and C 28－36 :3n-6. Specifically, C32:4n-6, C34:4n-6, C32:5n-3, C34:5n-3, 32:6n-3, and 34:6n-3 are mentioned. Preferably, C32:4n-6 and C34:5n-3 are mentioned.

[0046] In one aspect of the present invention, the ultra-long-chain polyunsaturated fatty acid, its salt or its ester is a compound represented by the following formula.

[0047] [Chemical formula 1]

[0048] [wherein, m1, m2, m3 and m4 are independently integers selected from 4 to 22, 4 to 20, 6 to 20, 8 to 20, 10 to 20, 4 to 18, 6 to 18, 8 to 18 or 10 to 18, and R is a hydrogen atom, a cation such as an alkali metal ion, or an ester-forming group such as a C1-6 alkyl group]

[0049] In one aspect of the present invention, the ultra-long chain polyunsaturated fatty acid can be converted into its ester. The ester conversion can be carried out by a commonly used method. Among them, the ester is not particularly limited, for example, it includes C 1－6 Alkyl esters, glycerides, etc. The glycerides may be triglycerides, diglycerides or monoglycerides, and at least one of the constituent fatty acids is a very long chain polyunsaturated fatty acid. In one embodiment, the ester of the very long chain polyunsaturated fatty acid is an ethyl ester.

[0050] In one aspect of the present invention, the very long chain polyunsaturated fatty acid can be converted into a salt thereof by treating with an alkali. Examples of the salt of the very long chain polyunsaturated fatty acid include alkali metal salts such as potassium salts and sodium salts.

[0051] In one aspect of the present invention, a method for producing a very long chain polyunsaturated fatty acid, an ester thereof, or a synthetic intermediate useful in the production thereof, namely, a compound represented by formula I, or a salt thereof is provided. R 1 -(CH2) m -X(I) [Where R 1 It is a C containing 3 to 7 double bonds 18－30 hydrocarbon group, m is an integer selected from 1 to 19, and X is CO2H, CO2R a or CH2OR b , R a It is C 1－6 Alkyl, R b is an ether-forming group, a silyl ether-forming group or an ester-forming group] The compound represented by formula I can be produced by the coupling reaction shown in the following method. The method is a method for preparing the compound shown in formula I, which comprises: reacting the compound shown in formula II with the compound shown in formula III to obtain the compound shown in formula I. R 1 -MgX 1 (II) [Wherein, X 1 is a halogen atom] X 2 -(CH2) m -X(III) [Wherein, X 2 selected from halogen atoms and sulfonyloxy groups]

[0052] In one aspect of the present invention, a method for producing a compound of formula I which is a very long chain polyunsaturated fatty acid or an ester thereof is provided. The compound of formula I can be produced by a coupling reaction as shown in the following method.

[0053] A method for preparing a compound represented by formula I comprises: reacting a compound represented by formula II with a compound represented by formula III in a solvent to obtain the compound represented by formula I. R 1 -(CH2) m -X(I) [Where R 1 It is a C containing 3 to 7 double bonds 18－30 Hydrocarbyl, m is an integer selected from 1 to 19, X is CO2H or CO2R a ; R a It is C 1－6 alkyl] R 1 -MgX 1(II) [Wherein, X 1 is a halogen atom] X 2 -(CH2) m -X(III) [Wherein, X 2 selected from halogen atoms and sulfonyloxy groups]

[0054] In one embodiment of the present invention, a method for preparing a very long chain polyunsaturated fatty acid or a C 1－6 Use of compounds of formula II as alkyl esters. In one embodiment of the present invention, a method for preparing a very long chain polyunsaturated fatty acid or a C 1－6 Use of compounds of formula III as alkyl esters. In one aspect of the present invention, in the very long chain polyunsaturated fatty acid or its C 1－6 The alkyl esters include compounds represented by formula I. R 1 -(CH2) m -X(I) [Where R 1 It is a C containing 3 to 7 double bonds 18－30 Hydrocarbyl, m is an integer selected from 1 to 19, X is CO2H or CO2R a ; R a It is C 1－6 alkyl]

[0055] In one aspect of the present invention, the compound of formula II includes the compound represented by formula II. R 1 -MgX 1 (II) [Wherein, X 1 is a halogen atom] In one aspect of the present invention, the compound of formula III includes the compound represented by formula III. X 2 -(CH2) m -X(III) [Wherein, X 2 selected from halogen atoms and sulfonyloxy groups]

[0056] In one aspect of the present invention, a method for producing a compound of formula Ia is provided, which is a synthetic intermediate useful in the production of very long chain polyunsaturated fatty acids. The compound of formula Ia can be produced by a coupling reaction as shown in the following method.

[0057] A method for preparing a compound represented by formula Ia comprises: reacting a compound represented by formula II with a compound represented by formula IIIa in a solvent to obtain the compound represented by formula Ia. R 1 -(CH2) m -CH2OR b (Ia) [Where R 1 It is a C containing 3 to 7 double bonds 18－30 hydrocarbon group, m is an integer selected from 1 to 19, R b is an ether-forming group, a silyl ether-forming group or an ester-forming group] R 1 -MgX 1 (II) [Wherein, X 1 is a halogen atom] X 2 -(CH2) m -CH2OR b (IIIa) [Wherein, X 2 selected from halogen atoms and sulfonyloxy groups]

[0058] In one embodiment of the present invention, R 1 It is a C containing 3 to 6 double bonds 18 , C 20 or C 22 For example, R 1 It is a straight chain hydrocarbon group. In one aspect of the present invention, R 1 It is a group represented by formula XI, or a group represented by formula XII. CH3-(CH2-CH=CH) a -(CH2) b -(XI) [wherein a is 5 and b is an integer selected from 2 to 14, or a is 6 and b is an integer selected from 1 to 11] CH3-(CH2)3-(CH2-CH=CH) c -(CH2) d -(XII) [wherein c is 3 and d is an integer selected from 5 to 17, or c is 4 and d is an integer selected from 2 to 14]

[0059] More specifically, R 1 It is a substituent represented by formula XI, or a group represented by formula XII. CH3-(CH2-CH=CH) a -(CH2)b -(XI) [wherein a is 5 and b is 4, or a is 6 and b is 3] CH3-(CH2)3-(CH2-CH=CH) c -(CH2) d -(XII) [wherein c is 3 and d is 7, or c is 4 and d is 4]

[0060] In one embodiment of the present invention, R 1 All double bonds contained in it are cis. In another embodiment of the present invention, R 1 is a hydrocarbon group selected from the following structures.

[0061] [Chemical formula 2]

[0062] [where · represents the bonding point, s1 is an integer selected from 2 to 14, s2 is an integer selected from 2 to 14, s3 is an integer selected from 1 to 11, s4 is an integer selected from 2 to 14]

[0063] In this specification, the bonding point refers to a point of bonding to other parts in a compound, and the bonding point does not include a methylene group (—CH 2 —). More specifically, R 1 is a hydrocarbon group selected from the following structures.

[0064] [Chemical formula 3]

[0065] [where · represents the bonding point] In one embodiment of the present invention, m is 3 to 17, 5 to 15, 7 to 15, or 7 to 13. In one aspect, m is an odd number. In one aspect, m is 7, 9, 11, or 13.

[0066] In this specification, CH2OR b It represents a structure selected from the group consisting of an ether structure, a silyl ether structure, and an ester structure.

[0067] Ether structure as CH2OR b As long as CH2OC(sp 3 ) structure, there is no particular limitation. The ether structure may include an acetal structure. As an ether structure, for example, the structure (CH2OR b) has a carbon number of 2 to 20. Specifically, the structure (CH2OR b ) has 2 to 20 carbon atoms, 1 to 5 oxygen atoms, and 0 to 3 heteroatoms selected from nitrogen atoms, fluorine atoms, phosphorus atoms, sulfur atoms, chlorine atoms, and bromine atoms. In one aspect of the present invention, R b It is an ether-forming group that forms an ether structure together with the adjacent CH2O. More specifically, as R b Examples thereof include a tert-butyl group, a benzyl group, a p-methoxyphenylbenzyl group, a trityl group, a methoxymethyl group, a methoxyethoxymethyl group and a tetrahydropyranyl group.

[0068] Silyl ether structure as CH2OR b There is no particular limitation as long as it has a CH2OSi structure. Examples of the silyl ether structure include the following structure (CH2OR b ) has 4 to 20 carbon atoms. Specifically, the structure (CH2OR b ) has 4 to 20 carbon atoms, 1 to 5 oxygen atoms, 1 to 2 silicon atoms, and 0 to 3 heteroatoms selected from nitrogen atoms, fluorine atoms, phosphorus atoms, sulfur atoms, chlorine atoms, and bromine atoms. In one aspect of the present invention, R b It is a silyl ether forming group which forms a silyl ether structure together with the adjacent CH2O. More specifically, as R b , examples include trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and tert-butyldiphenylsilyl.

[0069] Ester structure as CH2OR b There are no particular limitations as long as the ester structure has a CH2OC(=O) structure. Examples of the ester structure include the following structure (CH2OR b ) has a carbon number of 2 to 20. Specifically, the structure (CH2OR b ) has 2 to 20 carbon atoms, 2 to 6 oxygen atoms, and 0 to 3 heteroatoms selected from nitrogen atoms, fluorine atoms, phosphorus atoms, sulfur atoms, chlorine atoms, and bromine atoms. In one aspect of the present invention, R b It is an ester-forming group that forms an ester structure together with the adjacent CH2O. More specifically, as R b , examples include acetyl, pivaloyl and benzoyl.

[0070] In one embodiment of the present invention, X of the compound represented by Formula III is 2Selected from halogen atoms and sulfonyloxy groups. In one aspect, examples of the halogen atoms include chlorine atoms and bromine atoms. In one aspect, examples of the sulfonyloxy group include substituents having a -OS(O)2- structure having 1 to 20 carbon atoms, 3 to 5 oxygen atoms, 1 to 2 sulfur atoms, and 0 to 3 heteroatoms selected from nitrogen atoms, fluorine atoms, phosphorus atoms, chlorine atoms, and bromine atoms.

[0071] In one embodiment of the present invention, the sulfonyloxy group is a group represented by -OS(O)2-Q, wherein Q is a C substituted with one or more halogen atoms, for example, one or more fluorine atoms. 1－6 Alkyl; and may be 1 to 3 selected from C 1－3 The phenyl group is substituted with a substituent on an alkyl group or a halogen atom. Specific examples thereof include a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a benzenesulfonyloxy group, and a toluenesulfonyloxy group. In one aspect of the present invention, X 2 It is a bromine atom.

[0072] In one aspect of the present invention, R a It is C 1－3 Alkyl, such as methyl or ethyl. In one embodiment, R a It is ethyl.

[0073] In one aspect of the present invention, X 1 is a halogen atom, such as a chlorine atom or a bromine atom. In one embodiment, X 1 It is a bromine atom.

[0074] In one aspect of the present invention, the reaction (coupling reaction) of the compound shown in formula II and the compound shown in formula III can be implemented in the presence of a metal catalyst. In one aspect of the present invention, the metal catalyst is not particularly limited as long as it is a metal catalyst that can obtain the compound shown in formula I by coupling reaction. For example, it can be mentioned: copper catalyst, nickel catalyst, palladium catalyst, iron catalyst. In one embodiment of the present invention, the metal catalyst is a copper catalyst.

[0075] As a copper catalyst, there is no particular limitation as long as it is a catalyst containing copper atoms in the catalyst. For example, it can be: lithium tetrachlorocuprate (Li2CuCl4), cuprous (I) iodide (CuI), cuprous (I) bromide (CuBr), cuprous (I) chloride (CuCl), copper (II) bromide (CuBr2), copper (II) chloride (CuCl2), cuprous (I) cyanide (CuCN), a combination of copper (II) chloride and lithium chloride in a molar ratio of 1:2 (CuCl2·2LiCl), a combination of copper (I) cyanide and lithium chloride in a molar ratio of 1:2 (CuCN·2LiCl), cuprous (I) bromide-dimethyl sulfide complex (CuBr / CH3SCH3), copper (II) acetylacetonate (Cu(acac)2), copper (II) acetate (Cu(OAc)2). The combination of lithium chloride and copper (II) chloride and the combination of lithium chloride and copper (I) cyanide can be added to the reaction system after mixing the two, or they can be added to the reaction system separately. In one embodiment of the present invention, the copper catalyst is lithium tetrachlorocuprate. Lithium tetrachlorocuprate is a complex salt of lithium chloride-copper (II) chloride (Li2CuCl4). In one embodiment, lithium tetrachlorocuprate can be purchased in the form of a THF solution or the like.

[0076] The nickel catalyst is not particularly limited as long as it contains nickel atoms, and examples thereof include nickel (II) chloride (NiCl 2 ) and nickel (II) acetylacetonate (Ni(acac) 2 ).

[0077] The palladium catalyst is not particularly limited as long as it contains a palladium atom in the catalyst. Examples thereof include palladium(II) acetate (Pd(OAc)2), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4), palladium(II) acetylacetonate (Pd(acac)2), and palladium(II) chloride (PdCl2).

[0078] The iron catalyst is not particularly limited as long as it contains an iron atom, and examples thereof include iron (III) acetylacetonate (Fe(acac) 3 ) and iron (III) chloride (FeCl 3 ).

[0079] The amount of the metal catalyst is not particularly limited as long as it is a catalytic amount relative to the compound represented by Formula III, and is, for example, 0.1 to 20 mol%, 0.1 to 10 mol%, 0.5 to 20 mol%, 0.5 to 10 mol%, 0.5 to 7 mol%, 1 to 10 mol%, 1 to 7 mol% or 3 to 6 mol%.

[0080] In one aspect of the present invention, the reaction (coupling reaction) of the compound shown in Formula II with the compound shown in Formula III can be implemented in the presence of an additive. In one embodiment of the present invention, as an additive, as long as it is an additive that has no adverse effect on the coupling reaction compared to the case where it is not added and increases the yield of the compound shown in Formula I and / or shortens the reaction time, it is not particularly limited. For example, it can be cited: nitrogen additives, unsaturated hydrocarbon additives, silane additives, or combinations thereof. In one aspect, the additive is a nitrogen additive.

[0081] As a nitrogen-based additive, there is no particular limitation as long as it is a compound having a nitrogen atom in the compound. Specifically, there can be cited compounds having 4 to 20 carbon atoms, 1 to 5 nitrogen atoms, and 0 to 5 heteroatoms selected from oxygen atoms, fluorine atoms, silicon atoms, phosphorus atoms, sulfur atoms, chlorine atoms, and bromine atoms. More specifically, as a nitrogen-based additive, for example, there can be cited: lactam-based additives such as N-methylpyrrolidone (NMP); urea-based additives such as N,N'-dimethylpropyleneurea (DMPU); phosphoric acid amide-based additives such as hexamethylphosphoric triamide (HMPA); amine-based additives such as hexamethylenetetramine (HMTA) and tetramethylethylenediamine (TMEDA). In one embodiment of the present invention, the nitrogen-containing additive is a lactam-based additive, such as N-methylpyrrolidone (NMP).

[0082] As unsaturated hydrocarbon additives, there are no particular limitations as long as they are hydrocarbon compounds having carbon-carbon unsaturated bonds (double bonds, triple bonds) in the compound. Specifically, there are compounds having 4 to 20 carbon atoms, 1 to 6 carbon-carbon unsaturated bonds, and 0 to 5 heteroatoms selected from nitrogen atoms, oxygen atoms, fluorine atoms, silicon atoms, phosphorus atoms, sulfur atoms, chlorine atoms, and bromine atoms. More specifically, as unsaturated bond additives, for example, 1,3-diene additives such as 1,3-butadiene and isoprene; and aromatic additives such as 1-phenylpropyne.

[0083] The silyl-based additive is not particularly limited as long as it is a compound having a silicon atom in the compound. Specifically, there can be mentioned compounds having 2 to 20 carbon atoms, 1 to 2 silicon atoms, and 0 to 5 heteroatoms selected from nitrogen atoms, oxygen atoms, fluorine atoms, phosphorus atoms, sulfur atoms, chlorine atoms, and bromine atoms. More specifically, as a silyl-based additive, for example, trimethylchlorosilane (TMS-Cl) can be mentioned.

[0084] In one embodiment of the present invention, examples of additives include: N-methylpyrrolidone (NMP), N,N'-dimethylpropylene urea (DMPU), hexamethylphosphoric triamide (HMPA), hexamethylenetetramine (HMTA), tetramethylethylenediamine (TMEDA), 1,3-butadiene, isoprene, 1-phenylpropyne, trimethylsilyl chloride (TMS-Cl). In one embodiment of the present invention, the additive is N-methylpyrrolidone (NMP). N-methylpyrrolidone can be purchased, and a purchased high-purity reagent can be used directly, or it can be purified by distillation before use.

[0085] In one embodiment of the present invention, the amount of the additive is 0.1 to 10 equivalents, 0.1 to 5 equivalents, 1 to 10 equivalents, or 1 to 5 equivalents relative to the compound represented by Formula III.

[0086] In one aspect of the present invention, the reaction (coupling reaction) of the compound shown in Formula II with the compound shown in Formula III can be carried out in a solvent. As a solvent that can be used, as long as it has no adverse effect on the reaction, for example, it can be cited: aliphatic hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, and cyclopentyl methyl ether; nitriles such as acetonitrile. In one embodiment of the present invention, the reaction is carried out in a solvent selected from ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, and cyclopentyl methyl ether, or a mixed solvent of two or more solvents.

[0087] In one embodiment of the present invention, the order of mixing the compounds in the coupling reaction is not particularly limited. In one embodiment of the present invention, a mixture comprising a compound shown in formula II can be added to the compound shown in formula III in a solvent (in the presence of a metal catalyst and / or an additive as required). X 2 -(CH2) m -X(III) R 1 -MgX 1 (II) As a mixture comprising a compound of formula II, for example, a mixture comprising a compound of formula II and a solvent can be mentioned. As a solvent, a solvent that can be used in a coupling reaction can be mentioned. In one embodiment, the solvent is the same as the solvent of the coupling reaction.

[0088] In one embodiment of the present invention, X in the compound represented by formula III is CO2R a or CH2OR bIn the case of, the amount of the compound represented by Formula II used in the reaction is 1 to 5 equivalents, 1 to 3 equivalents, 1.5 to 5 equivalents, or 1.5 to 3 equivalents relative to the compound represented by Formula III.

[0089] In one embodiment of the present invention, when X of the compound represented by formula III is CO2H, the amount of the compound represented by formula II used in the reaction is 1 to 5 equivalents, 2 to 5 equivalents, 1 to 3 equivalents, 2 to 3 equivalents, or 2.5 to 3 equivalents relative to the compound represented by formula III.

[0090] In one embodiment of the present invention, the time for adding the mixture comprising the compound of Formula II is 5 minutes to 80 minutes, 5 minutes to 30 minutes, or 5 minutes to 10 minutes. In one approach, the rate of adding the mixture comprising the compound of Formula II is 0.1 mL / min to 1000 mL / min, 0.1 mL / min to 200 mL / min, 0.1 mL / min to 100 mL / min, or 0.3 mL / min to 20 mL / min.

[0091] In one embodiment of the present invention, the reaction of the compound of formula II with the compound of formula III can be carried out at a reaction temperature of -20 to 35°C, -20 to 25°C, -10 to 35°C, -10 to 25°C, -10 to 10°C, 0°C to 25°C or 0 to 10°C.

[0092] In one embodiment of the present invention, the reaction of the compound of formula II and the compound of formula III can be carried out under an inert gas atmosphere, for example, a nitrogen atmosphere or an argon atmosphere.

[0093] In one aspect of the present invention, the compound represented by formula II can be obtained, for example, by converting the compound represented by formula IIc in a solvent. R 1 -MgX 1 (II) R 1 -X 1 (IIc)

[0094] Specifically, the compound represented by Formula II can be obtained by, for example, reacting a compound represented by Formula IIc with magnesium in a solvent. R 1 -X 1 (IIc) In one embodiment of the present invention, the reaction can be carried out in the presence of an activator selected from iodine and 1,2-dibromoethane. Specifically, in a solvent, in the presence of magnesium (an activator selected from iodine and 1,2-dibromoethane as needed), a compound shown in formula IIc or a mixture containing the compound is added, thereby converting the compound shown in formula IIc into a compound shown in formula II. Among them, as a mixture containing a compound of formula IIc, for example, a mixture containing a compound of formula IIc and a solvent can be cited. As a solvent, a solvent that can be used for a reaction that converts a compound of formula IIc into a compound of formula II can be cited. In one embodiment, the solvent is the same as the solvent of the reaction.

[0095] In one embodiment, the compound represented by Formula II can be obtained by reacting the compound represented by Formula IIc with the compound represented by Formula IId or a lithium chloride complex thereof. R 1 -X 1 (IIc) R 3 -MgX 4 (IId) [Where R 3 is selected from isopropyl and sec-butyl, X 4 selected from bromine atoms and chlorine atoms] Specifically, the compound represented by Formula IIc and the compound represented by Formula IId can be mixed in a solvent to convert the compound represented by Formula II.

[0096] In the reaction of converting the compound of formula IIc to the compound of formula II, any solvent that does not adversely affect the reaction may be used, for example, aliphatic hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, and cyclopentyl methyl ether, etc. In one embodiment of the present invention, the reaction is carried out in a solvent selected from ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, and cyclopentyl methyl ether, or a mixed solvent of two or more solvents.

[0097] In one embodiment of the present invention, the amount of magnesium is 1 to 10 equivalents, 2 to 10 equivalents, 1 to 6 equivalents, or 2 to 6 equivalents relative to the compound represented by Formula IIc. The amount of iodine and 1,2-dibromoethane is 0.01 to 0.1 equivalents, 0.01 to 0.05 equivalents, 0.03 to 0.1 equivalents, or 0.03 to 0.05 equivalents relative to magnesium. The amount of the compound represented by Formula IId or its lithium chloride complex is 1 to 3 equivalents, 1 to 2 equivalents, 1.1 to 3 equivalents, or 1.1 to 2 equivalents relative to the compound represented by Formula IIc. The amount of lithium chloride is 0.5 to 2 equivalents, 0.5 to 1.5 equivalents, 1 to 1.5 equivalents, or 1 to 1.2 equivalents relative to magnesium.

[0098] In one embodiment of the present invention, the time for adding the compound of Formula IIc or the mixture comprising the compound is 5 minutes to 60 minutes, 5 minutes to 30 minutes, or 10 minutes to 30 minutes. In one embodiment, the rate of adding the compound of Formula IIc or a mixture comprising the same is 0.1 mL / min to 1000 mL / min, 0.1 mL / min to 200 mL / min, 0.1 mL / min to 100 mL / min, or 0.5 mL / min to 20 mL / min.

[0099] In one aspect of the present invention, the conversion can be performed at a reaction temperature of -40 to 80° C., -40 to 60° C., -20 to 80° C., -20 to 60° C., 0 to 60° C., or 20 to 60° C. In one aspect, the conversion can be performed under an inert gas atmosphere, such as a nitrogen atmosphere or an argon atmosphere.

[0100] The compound represented by formula II may be generated in the reaction system of the coupling reaction, or may be generated separately and added to the reaction system.

[0101] In one embodiment of the present invention, the compound represented by Formula IIc can be produced from the compound represented by Formula IV by the following method, for example. R 4 -CH2-X 1 (IIc) [Where R 4 It is a C containing 3 to 7 double bonds 17－29 Hydrocarbon, X 1 is a halogen atom]

[0102] (1) converting the compound represented by formula IV into the compound represented by formula IIa; (2) converting the compound represented by formula IIa into the compound represented by formula IIb; and (3) converting the compound represented by formula IIb into the compound represented by formula IIc. R 4 -CO2R 2 (IV) [Where R 2 is a hydrogen atom or C 1－6 Alkyl and other ester-forming groups] R 4 -CH2-OH(IIa) R4 -CH2-OX 3 (IIb) [Wherein, X 3 is sulfonyl] R 4 -CH2-X 1 (IIc) [Wherein, X 1 is a halogen atom]

[0103] In one embodiment of the present invention, the compound represented by Formula IIc can be produced from the compound represented by Formula IIa by the following method, for example. R 1 -X 1 (IIc)

[0104] (2) converting the compound represented by formula IIa into the compound represented by formula IIb; (3) converting the compound represented by formula IIb into the compound represented by formula IIc. R 1 -OH(IIa) R 1 -OX 3 (IIb) [Wherein, X 3 is sulfonyl] R 1 -X 1 (IIc)

[0105] (1) In one embodiment of the present invention, the conversion of the compound of formula IV into the compound of formula IIa can be performed by reacting the compound of formula IV with a reducing agent in a solvent. As the reducing agent, a reducing agent commonly used by those skilled in the art for converting carboxylic acids and / or esters into alcohols can be used, for example: Red-Al (registered trademark) (sodium dihydrobis(2-methoxyethoxy)aluminate), lithium aluminum hydride, diisobutylaluminum hydride, lithium borohydride. More preferably, Red-Al (registered trademark) which is not pyrophoric can be cited. As the solvent that can be used, as long as it has no adverse effect on the reaction, for example: aliphatic hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, and cyclopentyl methyl ether, etc. In one embodiment of the present invention, the reaction is carried out in a solvent selected from ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, and cyclopentyl methyl ether, or a mixed solvent of two or more solvents.

[0106] In one embodiment of the present invention, the amount of the reducing agent is 0.1 to 4 equivalents, 0.5 to 4 equivalents, 0.1 to 2 equivalents, or 0.5 to 2 equivalents relative to the compound represented by Formula IV. In one aspect, the conversion can be performed at a reaction temperature of -20 to 60° C., -20 to 40° C., 0 to 60° C., 0 to 40° C., or 0 to 25° C. In one aspect, the conversion can be performed under an inert gas atmosphere, such as a nitrogen atmosphere or an argon atmosphere.

[0107] (2) In one embodiment of the present invention, the conversion of the compound of Formula IIa into the compound of Formula IIb can be carried out by reacting the compound of Formula IIa with a sulfonylating agent in the presence of a base in a solvent.

[0108] X 3 The sulfonyl group shown is not particularly limited as long as it is a substituent that forms an oxysulfonyl structure (-OSO2- structure) together with an adjacent oxygen atom. Examples of the sulfonyl group include a substituent having a -SO2- structure having 1 to 20 carbon atoms, 2 to 4 oxygen atoms, 1 to 2 sulfur atoms, and 0 to 3 heteroatoms selected from nitrogen atoms, fluorine atoms, phosphorus atoms, chlorine atoms, and bromine atoms. Specifically, examples include: methanesulfonyl, trifluoromethanesulfonyl, benzenesulfonyl, toluenesulfonyl. In one aspect of the present invention, the sulfonyl group is toluenesulfonyl (p-toluenesulfonyl, etc.).

[0109] In one embodiment of the present invention, the sulfonyl group is a group represented by -S(O)2-Q, wherein Q is C which may be substituted with one or more halogen atoms such as fluorine atoms. 1－6 Alkyl; and may be 1 to 3 selected from C 1－3 The phenyl group is substituted with a substituent on an alkyl group or a halogen atom. Specific examples thereof include a methanesulfonyl group, a trifluoromethanesulfonyl group, a benzenesulfonyl group, and a toluenesulfonyl group.

[0110] As the sulfonylating agent, any of the following can be used: 3The sulfonylating agent corresponding to the sulfonyl group shown. For example, methanesulfonyl chloride (MsCl), trifluoromethanesulfonic anhydride (Tf2O), benzenesulfonyl chloride (BScL), toluenesulfonyl chloride (TsCl) (p-toluenesulfonyl chloride (p-TsCl) etc.), methanesulfonic anhydride (Ms2O), toluenesulfonic anhydride (Ts2O). More preferably, trifluoromethanesulfonic anhydride, toluenesulfonyl chloride (p-toluenesulfonyl chloride etc.), methanesulfonic anhydride, toluenesulfonic anhydride which are not designated as poisons can be mentioned. More preferably, toluenesulfonyl chloride (TsCl) (p-toluenesulfonyl chloride (p-TsCl) etc. can be mentioned. As a base, known compounds can be used, for example, amines can be mentioned. As amines, tertiary amines, heterocyclic aromatic amines, and combinations thereof can be mentioned. As tertiary amines, trialkylamines such as triethylamine, trimethylamine, and diisopropylethylamine (for example, tri(C 1－6 alkyl) amines), and dialkyl monoarylamines such as dimethylaniline and diethylaniline (for example, di(C 1－6 Alkyl) single C 6－10 Arylamine). Examples of heterocyclic aromatic amines include heterocyclic aromatic amines having nitrogen atoms as ring constituent atoms, such as pyridine, 4-dimethylaminopyridine, and imidazole (for example, monocyclic heterocyclic aromatic amines having 1 to 2 nitrogen atoms as ring constituent atoms). In one embodiment, the base is a trialkylamine, specifically a combination of triethylamine and trimethylamine. As solvents that can be used, any solvent that does not adversely affect the reaction may be used, and examples thereof include aliphatic hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, and cyclopentyl methyl ether; nitriles such as acetonitrile; halogenated alkanes such as dichloromethane, and the like. In one embodiment of the present invention, the reaction is carried out in a solvent selected from ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, and cyclopentyl methyl ether, or a mixed solvent of two or more solvents.

[0111] In one embodiment of the present invention, the amount of the sulfonylating agent is 1 to 4 equivalents, 1 to 2.5 equivalents, 1.2 to 4 equivalents, or 1.2 to 2.5 equivalents relative to the compound represented by formula IIa. In one embodiment of the present invention, the amount of the base is 0.1 to 5 equivalents, 0.1 to 3 equivalents, 1 to 5 equivalents, or 1 to 3 equivalents relative to the compound represented by formula IIa.

[0112] In one aspect of the present invention, the conversion can be carried out at a reaction temperature of 0-60° C., 0-40° C., 20-60° C., 20-40° C., or 20-30° C. In one aspect, the conversion can be carried out under an inert gas atmosphere, such as a nitrogen atmosphere or an argon atmosphere.

[0113] (3) In one aspect of the present invention, conversion of the compound of formula IIb to the compound of formula IIc can be performed by reacting the compound of formula IIb with a halogenating agent in a solvent. As the halogenating agent, any of the following can be used: 1 The halogen atoms shown correspond to the halide salts. 1 When X is a chlorine atom, examples of the halogenating agent (chlorinating agent) include lithium chloride (LiCl), sodium chloride (NaCl), and tetrabutylammonium chloride (TBACl). In one embodiment, the halogenating agent (chlorinating agent) is lithium chloride (LiCl). 1 When X is a bromine atom, examples of the halogenating agent (brominating agent) include lithium bromide (LiBr), sodium bromide (NaBr), and tetrabutylammonium bromide (TBABr). In one embodiment, the halogenating agent (brominating agent) is lithium bromide (LiBr). 1 In the case of iodine atoms, sodium iodide (NaI) can be cited as a halogenating agent (iodinating agent). As the solvent that can be used, as long as it has no adverse effect on the reaction, for example, aliphatic hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, and cyclopentyl methyl ether; nitriles such as acetonitrile, ketones such as acetone, etc. In one embodiment of the present invention, the reaction is carried out in a solvent selected from ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, and cyclopentyl methyl ether or ketones such as acetone, or a mixed solvent of two or more solvents.

[0114] In one embodiment of the present invention, the amount of the halogenating agent is 1 to 10 equivalents, 1 to 5 equivalents, 2 to 10 equivalents, or 2 to 5 equivalents relative to the compound represented by Formula IIb. In one aspect of the present invention, the conversion can be performed at a reaction temperature of 20-80° C., 20-60° C., 40-80° C., or 40-60° C. In one aspect, the conversion can be performed under an inert gas atmosphere, such as a nitrogen atmosphere or an argon atmosphere.

[0115] In one aspect of the invention, two or more conversions can be performed in a one-pot synthesis using the same reaction vessel. In one aspect of the invention, (2) conversion of a compound of Formula IIa to a compound of Formula IIb and (3) conversion of a compound of Formula IIb to a compound of Formula IIc can be performed in a one-pot synthesis.

[0116] In this specification, one-pot synthesis is a method in which the same reaction vessel is used, the intermediate product generated in the previous conversion is not separated or purified, and the subsequent conversion is performed continuously. The number of consecutive conversions is not particularly limited as long as it is 2 or more.

[0117] In one embodiment of the present invention, as a one-pot synthesis for preparing the compound represented by formula IIc, a one-pot synthesis comprising the following steps can be specifically mentioned: (2) reacting the compound represented by Formula IIa with TsCl in a solvent in the presence of one or more trialkylamines to convert it into the compound represented by Formula IIb; and (3) reacting the compound represented by Formula IIb with LiBr without isolating it to prepare the compound represented by Formula IIc. R 4 -CH2-OX 3 (IIb) [Wherein, X 3 is tosyl] R 4 -CH2-X 1 (IIc) [Wherein, X 1 is a bromine atom]

[0118] In one embodiment of the present invention, as the compound of IV, C 18－22 Polyunsaturated fatty acids, such as C22:6n-3 (DHA), C20:5n-3 (EPA), C20:4n-6 (arachidonic acid), C20:3n-6 (dihomo-γ-linolenic acid (DGLA)) or their esters, specifically their C 1－6 Alkyl esters, such as ethyl esters.

[0119] In one aspect of the invention, X is CH2OR b The compound of formula I can be converted into an alcohol by methods commonly used by those skilled in the art. b In the case of an ether structure that forms an acetal structure, it can be converted into an alcohol by using, for example, a Bronsted acid such as trifluoroacetic acid or hydrochloric acid. b In the case of a silyl ether structure, it can be converted into an alcohol compound by using a fluoride ion supply source such as potassium fluoride or tetrabutylammonium fluoride. The obtained alcohol is a compound represented by Formula V. R 1 -(CH2) m -CH2OH(V)

[0120] In one aspect of the present invention, in order to convert the alcohol into a carboxylic acid, the oxidation of the compound of formula V can be carried out by an oxidation reaction commonly performed by a person skilled in the art. As an oxidizing agent, for example, Jones reagent; a combination of 2,2,6,6-tetramethylpiperidinyl 1-oxyl (TEMPO), sodium hypochlorite and sodium chlorite and the like can be used. The obtained ultra-long chain polyunsaturated fatty acid is a compound shown in formula Ib. R 1 -(CH2) m -CO2H(Ib)

[0121] In one aspect of the invention, the fatty acid of formula Ib can be converted to give C 1－6 Alkyl ester, for example ethyl ester. The esterification reaction can be carried out under conditions commonly performed by those skilled in the art.

[0122] In one aspect of the present invention, the compound represented by formula IIc {for example, (3E, 6E, 9E, 12E, 15E)-20-bromo-3, 6, 9, 12, 15-eicosapentaene (CAS Registry Number: 181213-47-8), (3E, 6E, 9E, 12E, 15E)-20-chloro-3, 6, 9, 12, 15-eicosapentaene (CAS Registry Number: 2519469-69-1)} and synthetic intermediates such as the compound represented by formula III can be prepared by known methods or obtained by purchase. R 4 -CH2-X 1 (IIc) X 2 -(CH2) m -X(III)

[0123] In one embodiment of the present invention, the following production method can be mentioned, wherein a long-chain polyunsaturated fatty acid (LC-PUFA) having 18 to 30 carbon atoms and containing 3 to 7 double bonds or its C 1-6 The alkyl ester is converted to obtain a very long chain polyunsaturated fatty acid (VLC-PUFA) having 20 to 50 carbon atoms and 3 to 7 double bonds or its C 1-6 Alkyl esters, wherein In the conversion process, the long-chain polyunsaturated fatty acids or their C 1－6 Alkyl ester-derived Grignard reagents and ω-halogenated C 2－20 Aliphatic acid or its C 1－6 Alkyl ester reaction to obtain ultra-long chain polyunsaturated fatty acids or their C 1－6The conversion process does not include the following steps: (a) a protection step of converting a compound having a hydroxyl group into a compound having a protected hydroxyl group; (b) a deprotection step of converting a compound having a protected hydroxyl group into a compound having a hydroxyl group; (c) an oxidation step of converting an alcohol into an aldehyde or a carboxylic acid; (d) an oxidation step of converting an aldehyde into a carboxylic acid; or (e) a step of converting a compound having a hydroxyl group into an aldehyde or a carboxylic acid; 1－6 The process of producing a compound derived from an alkyl ester is carried out in the presence of a stoichiometric amount of a phosphorus compound.

[0124] In one aspect of the present invention, the following method can be mentioned, wherein the conversion step does not include the following steps: (a) converting a compound having a hydroxyl group into a compound having a C 1－20 Ether protecting group, C 3－20 Silyl ether protecting group or C 1－20 ester protecting group of the compound protection process; (b) having C 1－20 Ether protecting group, C 3－20 Silyl ether protecting group or C 1－20 (c) an oxidation step of a compound having a hydroxymethyl group to a compound having a formyl group or a carboxyl group; (d) an oxidation step of a compound having a formyl group to a compound having a carboxyl group; or (e) a step of reacting a compound having a hydroxymethyl group with a hydroxymethyl group to a compound having a hydroxymethyl group. 1－6 The process of producing a compound derived from an alkyl ester is carried out in the presence of a stoichiometric amount of triphenylphosphine or a triphenylphosphonium salt.

[0125] The production method that does not include step (a), (b), (c), (d) and / or step (e) in the conversion step means that in one or more conversion steps of converting LC-PUFA or its alkyl ester to produce VLC-PUFA or its alkyl ester, step (a) etc. are not included. On the other hand, in the steps other than the conversion step, step (a) etc. may be included.

[0126] For example, when a compound represented by formula Ia is produced and then the compound of formula Ia is deprotected and oxidized to produce VLC-PUFA, the conversion step includes (b) a deprotection step to convert the compound to a hydroxyl group and (c) an oxidation step to convert the alcohol to a carboxylic acid. R 1 -(CH2) m -CH2OR b (Ia) On the other hand, for example, when a compound represented by Formula IIIa is deprotected and oxidized to be converted into a compound represented by Formula IIIb, and the compound represented by Formula IIIb is used in a coupling reaction with a compound represented by Formula II, it does not mean that the conversion step includes (b) deprotection to convert to a hydroxyl group and (c) oxidation of an alcohol to a carboxylic acid. 2 -(CH2) m -CH2OR b (IIIa) X 2 -(CH2) m -CO2H(IIIb) That is, the conversion step of converting the compound of formula IIIa to the compound of formula IIIb is not included in one or more conversion steps of converting LC-PUFA or its alkyl ester to produce VLC-PUFA or its alkyl ester.

[0127] In one aspect of the present invention, a long-chain polyunsaturated fatty acid having 18 to 30 carbon atoms and containing 3 to 7 double bonds or a C 1－6 Examples of the alkyl ester include the compound represented by formula IV, or the long-chain polyunsaturated fatty acid or its alkyl ester described in the present specification. R 4 -CO2R 2 (IV) [Where R 4 It is a C containing 3 to 7 double bonds 17－29 Hydrocarbon, R 2 is a hydrogen atom or C 1－6 alkyl]

[0128] In one embodiment of the present invention, the very long chain polyunsaturated fatty acid having 20 to 50 carbon atoms and containing 3 to 7 double bonds or its C 1－6 The alkyl esters include compounds represented by formula I, or very long chain polyunsaturated fatty acids or alkyl esters thereof described in the present specification. R 1 -(CH2) m -X(I) [Where R 1 It is a C containing 3 to 7 double bonds 18－30 Hydrocarbon, m is an integer selected from 1 to 19, X is CO2H or CO2R a ; R a It is C 1－6 alkyl]

[0129] In one aspect of the present invention, as a long-chain polyunsaturated fatty acid or its C 1－6Alkyl ester derived Grignard reagents and ω-halogenated C 2－20 Fatty acids or their C 1－6 The reaction of alkyl esters is carried out by long-chain polyunsaturated fatty acids or their C 1－6 Examples of the Grignard reagent derived from the alkyl ester include the compound represented by formula II or the Grignard reagent described in the present specification. R 1 -MgX 1 (II) [Where R 1 It is a C containing 3 to 7 double bonds 18－30 Hydrocarbon, X 1 is a halogen atom]

[0130] In one embodiment of the present invention, as ω halogenated C 2－20 Fatty acids or their C 1－6 Examples of the alkyl ester include the compound represented by formula III, or the ω halogenated fatty acid or its alkyl ester described in the present specification. X 2 -(CH2) m -X(III) [Wherein, X 2 is a halogen atom, m is an integer selected from 1 to 19, X is CO2H or CO2R a ; R a It is C 1－6 alkyl]

[0131] In one embodiment of the present invention, the reaction can be carried out in the presence of a metal catalyst. Examples of the metal catalyst include the metal catalysts described in this specification. In one aspect of the present invention, the reaction can be carried out in the presence of an additive. Examples of the additive include those described in the present specification.

[0132] In one aspect of the present invention, the protected hydroxyl group may be a hydroxyl group protected by a protecting group commonly used by those skilled in the art for protecting a hydroxyl group. C The group shown in the formula includes, for example: -O-R C The formation of an ether structure with a -O-C (sp3) structure protects the hydroxyl group, -O-R C The protective hydroxyl group, -O-R C A protected hydroxyl group is formed with an ester structure having a -O-C(=O) structure.

[0133] In one aspect of the present invention, examples of the protected hydroxyl group forming an ether structure, the protected hydroxyl group forming a silyl ether structure, the protected hydroxyl group forming an ester structure, the ether protecting group, the silyl ether protecting group, and the ester protecting group in the protection step (a) and the deprotection step (b) include, respectively, 1－20 The ether structure protects the hydroxyl group and forms C 3－20 The protected hydroxyl groups of the silyl ether structure form C 1－20 The protected hydroxyl group of the ester structure, C 1－20 Ether protecting group, C 3－20 Silyl ether protecting group, C 1－20 Ester protecting group. The number of carbon atoms in these substituents is the number of carbon atoms of the part that replaces the hydrogen atom of the hydroxyl group. For example, the number of carbon atoms in tert-butyl ether is 4.

[0134] As C 1－20 Examples of ether protecting groups include tert-butyl, benzyl, p-methoxyphenylbenzyl, trityl, methoxymethyl, methoxyethoxymethyl, and tetrahydropyranyl. Protected hydroxyl groups formed from these protecting groups include tert-butyloxy, benzyloxy, p-methoxyphenylbenzyloxy, trityloxy, methoxymethyloxy, methoxyethoxymethyloxy, and tetrahydropyranyloxy. Tert-butyl ether, benzyl ether, p-methoxyphenylbenzyl ether, trityl ether, methoxymethyl ether, methoxyethoxymethyl ether, and tetrahydropyranyl ether are formed from these groups.

[0135] As C 3－20 Examples of silyl ether protecting groups include trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, and tert-butyldiphenylsilyl. Protected hydroxyl groups formed by these protecting groups are trimethylsilyloxy, triethylsilyloxy, tert-butyldimethylsilyloxy, and tert-butyldiphenylsilyloxy. These groups form trimethylsilyl ether, triethylsilyl ether, tert-butyldimethylsilyl ether, and tert-butyldiphenylsilyl ether.

[0136] As C 1－20 Examples of ester protecting groups include acetyl, pivaloyl, and benzoyl. Protected hydroxyl groups formed by these protecting groups are acetoxy, pivaloyloxy, and benzoyloxy. Acetate, pivaloyl ester, and benzoate are formed by these groups.

[0137] In one aspect of the present invention, the oxidation conditions in the (c) alcohol (hydroxymethyl) oxidation step or the (d) aldehyde (formyl) oxidation step are not particularly limited as long as they are conditions for converting to aldehyde (formyl) or carboxylic acid (carboxyl), or converting to carboxylic acid (carboxyl), respectively. For example, oxidation using Jones reagent can be mentioned.

[0138] In one embodiment of the present invention, examples of the phosphorus compound in the step (e) carried out in the presence of a stoichiometric amount of a phosphorus compound include triphenylphosphine and triphenylphosphonium salts {(tribromomethyl)triphenylphosphonium bromide, (trichloromethyl)triphenylphosphonium chloride, etc.}.

[0139] Here, the stoichiometric amount of the phosphorus compound (triphenylphosphine or the like) means that the amount of the phosphorus compound used in the step is an equimolar amount or more relative to the amount of the long-chain polyunsaturated fatty acid or its alkyl ester used.

[0140] A production method that does not include these steps (a), (b), (c), (d) and / or step (e) is a production method suitable for industrial-scale production from the perspective of atom economy, separation from by-products in post-treatment of the reaction, and / or the perspective of waste disposal issues.

[0141] As a manufacturing method suitable for industrial-scale manufacturing, for example, a method with a short number of steps and rapid synthesis, and / or a method with high yield and large-scale synthesis can be cited. On the other hand, as a manufacturing method suitable for industrial-scale, for example, a method without protection and / or deprotection steps (from the perspective of atom economy), a method without complicated removal operations of by-products in post-reaction treatment (from the perspective of separation from by-products in post-reaction treatment), and / or a method without by-products of highly harmful substances (from the perspective of waste disposal problems) can be cited.

[0142] Examples of the present invention are described below, but the present invention is not limited to these examples.

[0143] [Chemical formula 4]

[0144] In Examples 1 to 6 described below, the following reagents and solvents were purchased and used. Lithium tetrachlorocuprate (Li2CuCl4 solution) Supplier: Sigma-Aldrich. Super dehydrated N-methylpyrrolidone Supplier: Wako, Product No.: 131-17615. Super dehydrated tetrahydrofuran supplier: Wako, product number: 207-17905 (contains stabilizer BHT).

[0145] [Example 1] Preparation of (all-Z)-19,22,25,28,31-triacontaenoic acid ethyl ester (4) Step 1: Preparation of (all-Z)-5,8,11,14,17-eicosapentaenoic acid-1-ol (1)

[0146] Under nitrogen atmosphere, super dehydrated tetrahydrofuran (300 mL) was added to (all-Z)-5,8,11,14,17-eicosapentaenoic acid ethyl ester (EPA-EE) (36.0 g, 108.9 mmol). Red-Al (registered trademark) (63 mL, 217.8 mmol, 2.0 eq, 70 wt% toluene solution) was slowly added dropwise under ice cooling. After reacting for 2 hours under ice cooling, a mixture of ethanol: hexane = 2:3 (110 mL) and 15% sodium hydroxide aqueous solution (55 mL) were added to stop the reaction. Extraction was performed with hexane, and the organic phase was washed with saturated brine until the pH of the aqueous phase was below 9. The solvent was removed by distillation to obtain compound 1 (32.87 g, yield: quantitative) as a tea-colored transparent oil. Compound 1 was used directly in the next step without purification.

[0147] 1 H-NMR (500MHz, CDCl3) δ0.97 (3H, t, J=7.5), 1.21 (1H, brs), 1.40-1.49 (2H, m), 1.55-1.6 4 (2H, m), 2.03-2.16 (4H, m), 2.74-2.92 (8H, m), 3.65 (2H, t, J = 6.5), 5.26-5.47 (10H, m).

[0148] Step 2: Preparation of (all-Z)-1-(4-methylbenzenesulfonyloxy)-5,8,11,14,17-eicosapentaene (2): Under nitrogen atmosphere, super dehydrated tetrahydrofuran (63 mL) was added to compound 1 (32.0 g, 110.9 mmol), and a tetrahydrofuran solution (2 mol / L) of triethylamine (46.4 mL, 332.8 mmol, 3.0 eq) and trimethylamine (5.5 mL, 11.1 mmol) was added. p-Toluenesulfonyl chloride (42.3 g, 221.9 mmol, 2.0 eq) was dissolved in super dehydrated tetrahydrofuran (200 mL), and the solution was slowly added dropwise under ice cooling. Then, the reaction mixture was stirred at room temperature overnight. Water (100 mL) was added to stop the reaction. The reaction mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine. The solvent was removed by distillation to obtain a tea-colored transparent oily compound 2 (48.97 g, yield: quantitative). The crude product was used directly in the next step without purification.

[0149] 1H-NMR (500MHz, CDCl3) δ0.96 (3H, t, J=7.5), 1.35-1.43 (2H, m), 1.61-1.70 (2H, m), 1.96-2.14 (4H, m), 2.45 (3H, s), 2. 76 (2H, t, J = 6.6), 2.79-2.90 (6H, m), 4.03 (2H, t, J = 6.5), 5.22-5.45 (10H, m), 7.34 (2H, d, J = 8.0), 7.79 (2H, d, J = 8.3). In the post-treatment of this step, the by-products are removed only by a simple liquid separation operation, and a complicated removal operation of the by-products is unnecessary.

[0150] Step 3: (all-Z)-20-bromo-3,6,9,12,15-eicosapentaene (3): Under nitrogen atmosphere, super dehydrated tetrahydrofuran (300mL) was added to a mixture of compound 2 (40.0g, 90.36mmol) and LiBr (15.7g, 180.73mmol, 2.0eq), and the mixture was heated to reflux at 60°C. After 2.5 hours of reaction, the reaction mixture was placed and cooled to room temperature, and water (100mL) was added. The reaction mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine. The solvent was distilled off to obtain a brown transparent oily crude product. By purifying with silica gel column chromatography (hexane), a colorless transparent oily compound 3 (25.98g, yield: 82%) was obtained.

[0151] 1 H-NMR (500MHz, CDCl3) δ0.97 (3H, t, J=7.5), 1.47-1.58 (2H, m), 1.81-1.93 (2H, m ), 2.02-2.17 (4H, m), 2.74-2.92 (8H, m), 3.40 (2H, t, J = 6.8), 5.26-5.49 (10H, m). In the post-treatment of this step, by-products are removed only by a simple liquid separation operation and silica gel column chromatography, and a complicated removal operation of by-products is unnecessary.

[0152] Step 4: (all-Z)-19,22,25,28,31-tetradecanoic acid ethyl ester (4): Under nitrogen atmosphere, super dehydrated tetrahydrofuran (13.3 mL) was added to a mixture of magnesium flakes (0.45 g, 18.63 mmol, 5.7 eq) and iodine (0.15 g, 0.58 mmol, 0.03 eqv.s. Mg), and the mixture was heated to reflux at 60°C for 30 minutes. Super dehydrated tetrahydrofuran (7.4 mL) was added to compound 3 (1.73 g, 4.92 mmol, 1.5 eq), and the solution was added dropwise to the solution refluxed at 60°C at a flow rate of 0.9 mL / min over 10 minutes. After reacting for 30 minutes, the mixture was cooled to 0°C and the reaction solution was used as a Grignard reagent.

[0153] Under nitrogen atmosphere, super dehydrated tetrahydrofuran (14.9 mL), super dehydrated N-methylpyrrolidone (1.33 mL, 13.78 mmol, 4.2 eq) and Li2CuCl4 solution (1 mL, 0.10 mmol, 0.03 eq (relative to 14-bromotetradecanoic acid ethyl ester), 0.1 mol / L tetrahydrofuran solution) were added to 14-bromotetradecanoic acid ethyl ester (1.11 g, 3.28 mmol). Under ice cooling, Grignard reagent (1.5 eq) was added dropwise at a flow rate of 4.3 mL / min over 5 minutes. After stirring for 30 minutes under ice cooling, saturated NH4Cl aqueous solution (20 mL) was added to stop the reaction. Extraction was performed with ethyl acetate, and the organic phase was washed with saturated saline, and the solvent was removed by distillation to obtain a crude product in the form of a brown transparent oil. The residue was purified by silica gel column chromatography (hexane and hexane:diethyl ether=20:1) to obtain Compound 4 (1.41 g, yield: 81%) as a colorless transparent oil.

[0154] 1 H-NMR (500MHz, CDCl3) δ0.98 (3H, t, J=7.5), 1.17-1.45 (31H, m), 1.56-1.68 (2H, m), 1.99-2 .13 (4H, m), 2.28 (2H, t, J = 7.6), 2.73-2.92 (8H, m), 4.12 (2H, q, J = 7.1), 5.25-5.47 (10H, m).

[0155] [Example 2] One-pot synthesis of compound 3: Under nitrogen atmosphere, super dehydrated tetrahydrofuran (0.4 mL) was added to compound 1 (169.5 mg, 0.59 mol), and a tetrahydrofuran solution (2 mol / L) of triethylamine (0.25 mL, 1.82 mmol, 3.1 eq) and trimethylamine liquid (0.025 mL, 0.05 mmol, 0.1 eq) was added. p-Toluenesulfonyl chloride (221.2 mg, 1.16 mmol, 2.0 eq) was dissolved in super dehydrated tetrahydrofuran (1.4 mL), and the solution was slowly added dropwise under ice cooling. Then, the reaction mixture was stirred at room temperature for 5 hours. Under nitrogen atmosphere, a super dehydrated tetrahydrofuran (1.5 mL) solution of LiBr (206.9 mg, 2.38 mmol, 4.0 eq) was added to the above reaction solution, and heated to reflux at 60°C. After reacting for 3 hours, the reaction mixture was cooled to room temperature and water (10 mL) was added. The reaction mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine. The solvent was distilled off to obtain a brown transparent oily crude product. Purification by silica gel column chromatography (hexane) gave a colorless transparent oily compound 3 (177.5 mg, yield: 86%). The compound 3 obtained by this method contained 8 wt% of (all-Z)-20-chloro-3,6,9,12,15-eicosapentaene.

[0156] In this example, compound 3 can be easily produced from compound 1 with high yield by one-pot synthesis without isolating and purifying compound 2. In addition, in the post-treatment of this example, by-products are removed only by simple liquid separation operation and silica gel column chromatography, and complicated removal operation of by-products is not required.

[0157] [Example 3] Preparation of (all-Z)-19,22,25,28,31-triacontaenoic acid (5): Under nitrogen atmosphere, super dehydrated tetrahydrofuran (1 mL), super dehydrated N-methylpyrrolidone (0.09 mL, 0.93 mmol, 4.2 eq) and Li2CuCl4 solution (0.07 mL, 0.007 mmol, 0.03 eq (relative to 14-bromotetradecanoic acid), 0.1 mol / L tetrahydrofuran solution) were added to 14-bromotetradecanoic acid (68.8 mg, 0.22 mmol). Under ice cooling, the Grignard reagent (3.0 eq) prepared by the same method as in Example 1 (Step 4) was added dropwise at a flow rate of 0.6 mL / min over 5 minutes. After stirring for 30 minutes, saturated NH4Cl aqueous solution (5 mL) was added to the reaction mixture to stop the reaction. Extraction was performed with ethyl acetate, and the organic phase was washed with saturated saline. The solvent was removed by distillation to obtain a crude product as a yellow transparent oil. The residue was purified by silica gel column chromatography (hexane and hexane:diethyl ether:acetic acid=40:20:1) to obtain Compound 5 (78.3 mg, yield: 70%) as a white solid.

[0158] 1 H-NMR (500MHz, CDCl3) δ0.98 (3H, t, J=7.5), 1.18-1.42 (28H, m), 1.60-1.69 (2H, m), 2.00 -2.13(4H,m), 2.35(2H,t,J=7.5), 2.75-2.91(8H,m), 5.25-5.47(10H,m), 8.80(1H,brs).

[0159] [Example 4] (all-Z)-13,16,19,22,25-octadecapentaenoic acid ethyl ester (6): Under nitrogen atmosphere, super dehydrated tetrahydrofuran (1 mL), super dehydrated N-methylpyrrolidone (0.09 mL, 0.93 mmol, 4.2 eq) and Li2CuCl4 solution (0.06 mL, 0.006 mmol, 0.03 eq (relative to 8-bromooctanoic acid ethyl ester), 0.1 mol / L tetrahydrofuran solution) were added to 8-bromooctanoic acid ethyl ester (55.5 mg, 0.22 mmol). Under ice cooling, the Grignard reagent (3.0 eq) prepared by the same method as Example 1 (Step 4) was added dropwise at a flow rate of 0.3 mL / min over 10 minutes. After stirring for 1 hour, saturated NH4Cl aqueous solution (5 mL) was added to the reaction mixture to stop the reaction. The reaction mixture was extracted with ethyl acetate, and the organic phase was washed with saturated saline. The solvent was distilled off to obtain a crude product in the form of a brown transparent oil. The residue was purified by silica gel column chromatography (hexane and hexane:diethyl ether=20:1) to obtain Compound 6 (82.5 mg, yield: 84%) as a colorless transparent oil.

[0160] 1 H-NMR (500MHz, CDCl3) δ0.98 (3H, t, J=7.5), 1.18-1.42 (19H, m), 1.57-1.67 (2H, m), 1.99-2 .13 (4H, m), 2.28 (2H, t, J = 7.6), 2.74-2.91 (8H, m), 4.12 (2H, q, J = 7.1), 5.27-5.47 (10H, m).

[0161] [Example 5] Preparation of (all-Z)-13,16,19,22,25-octadecapentaenoic acid (7): Under nitrogen atmosphere, super dehydrated tetrahydrofuran (1 mL) and Li2CuCl4 solution (0.07 mL, 0.007 mmol, 0.03 eq (relative to 8-bromooctanoic acid), 0.1 mol / L tetrahydrofuran solution) were added to 8-bromooctanoic acid (50.3 mg, 0.23 mmol). The above solution was added dropwise at a flow rate of 0.5 mL / min to a Grignard reagent (2.5 eq) prepared by the same method as Example 1 (Step 4) under ice cooling under nitrogen atmosphere for 5 minutes. After stirring for 3 hours, saturated NH4Cl aqueous solution (5 mL) was added to the reaction mixture to stop the reaction. The reaction mixture was extracted with ethyl acetate, and the organic phase was washed with saturated saline. The solvent was removed by distillation to obtain a crude product as a yellow transparent oil. The residue was purified by silica gel column chromatography (hexane and hexane:diethyl ether:acetic acid=40:20:1) to obtain Compound 7 (40.2 mg, yield: 43%) as a white solid.

[0162] 1H-NMR (500MHz, CDCl3) δ0.98 (3H, t, J=7.5), 1.20-1.41 (16H, m), 1.58-1.68 (2H, m), 1.95- 2.15 (4H, m), 2.35 (2H, t, J=7.5), 2.72-2.91 (8H, m), 5.24-5.48 (10H, m), 10.15 (1H, brs).

[0163] [Example 6] 2-[(all-Z)-15,18,21,24,27-triacontapentaen-1-yl]tetrahydro-2H-pyran (8): Under nitrogen atmosphere, super dehydrated tetrahydrofuran (1 mL) and Li2CuCl4 solution (0.07 mL, 0.007 mmol, 0.03 eq (relative to 2-[(10-bromodecyl)oxy]tetrahydro-2H-pyran), 0.1 mol / L tetrahydrofuran solution) were added to 2-[(10-bromodecyl)oxy]tetrahydro-2H-pyran (76.4 mg, 0.24 mmol) . The above solution was added dropwise at a flow rate of 0.3 mL / min to a Grignard reagent (1.7 eq) prepared by the same method as Example 1 (Step 4) under ice cooling under nitrogen atmosphere for 5 minutes. After stirring overnight, saturated NH4Cl aqueous solution (5 mL) was added to the reaction mixture to stop the reaction. The reaction mixture was extracted with ethyl acetate, and the organic phase was washed with saturated saline, and the solvent was removed by distillation to obtain a crude product in the form of a brown transparent oil. The residue was purified by silica gel column chromatography (hexane and toluene: hexane: diethyl ether = 90:10:1) to obtain Compound 8 (81.6 mg, yield: 67%) as a colorless transparent oil.

[0164] 1 H-NMR (500MHz, CDCl3) δ0.98 (3H, t, J=7.5), 1.19-1.41 (22H, m), 1.47-1.63 (6H, m), 1.68-1.76 (1H, m), 1.77-1.90 (1H, m), 2.00-2.12 (4H, m), 2.71-2.9 6 (8H, m), 3.38 (1H, dt, J1=6.7, J2=9.5), 3.46-3.54 (1H, m), 3.73 (1H, dt, J1 =7.0, J2=9.5), 3.82-3.92 (1H, m), 4.58 (1H, t, J=3.6), 5.25-5.48 (10H, m). Industrial Applicability

[0165] According to the present invention, there is provided a method for producing a very long chain polyunsaturated fatty acid, which is suitable for efficient production on an industrial scale. According to the present invention, there is provided a method for producing a synthetic intermediate, which is useful in the production of very long chain polyunsaturated fatty acids suitable for efficient production on an industrial scale.

Claims

1. A method for producing a compound represented by formula I or a salt thereof, characterized in that: R 1 -(CH2) m -X(I) In Formula I, R 1 It is a C containing 3 to 7 double bonds 18－30 Hydrocarbon, m is an integer selected from 1 to 19, X is CO2H, CO2R a , or CH2OR b ; R a It is C 1－6 alkyl; R b It is an ether-forming group, a silyl ether-forming group, or an ester-forming group.

2. The method according to claim 1, wherein: The method comprises: The compound represented by formula II and the compound represented by formula III are reacted in a solvent to obtain the compound represented by formula I, R 1 -MgX 1 (I I) In Formula II, X 1 is a halogen atom, X 2 -(CH2) m -X(III) In Formula III, X 2 is selected from a halogen atom and a sulfonyloxy group.

3. The method according to claim 2, wherein: The reaction is carried out in the presence of a metal catalyst.

4. The method according to claim 2 or 3, wherein: The reaction is carried out in the presence of an additive.

5. The method according to any one of claims 1 to 4, wherein: R 1 It is a C containing 3 to 6 double bonds 18 , C 20 or C 22 Hydrocarbon.

6. The method according to any one of claims 1 to 5, wherein: R 1 is a group represented by formula XI or a group represented by formula XII, CH3-(CH2-CH=CH) a -(CH2) b -(XI) In formula XI, a is 5 and b is an integer selected from 2 to 14, or a is 6 and b is an integer selected from 1 to 11, CH3-(CH2)3-(CH2-CH=CH) c -(CH2) d -(XI I) In Formula XII, c is 3 and d is an integer selected from 5-17, or c is 4 and d is an integer selected from 2-14.

7. The method according to claim 6, wherein: R 1 is a group represented by formula XI, a is 5 and b is 4, or a is 6 and b is 3, or R 1 is a group represented by formula XII, c is 3 and d is 7, or c is 4 and d is 4.

8. The method according to any one of claims 1 to 7, wherein: R 1 All the double bonds contained are cis.

9. The method according to any one of claims 1 to 8, wherein: m is 7, 9, 11, or 13.

10. The method according to any one of claims 3 to 9, wherein: The metal catalyst is selected from a copper catalyst, a nickel catalyst, a palladium catalyst and an iron catalyst.

11. The method according to any one of claims 3 to 10, wherein: The metal catalyst is selected from Li2CuCl4, CuI, CuBr, CuCl, CuBr2, CuCl2, CuCN, CuCl2·2LiCl, CuCN·2LiCl, CuBr / CH3SCH3, Cu(acac)2, Cu(OAc)2, NiCl2, Ni(acac)2, Pd(OAc)2, Pd(PPh3)4, Pd(acac)2, PdCl2, Fe(acac)3 and FeCl3.

12. The method according to any one of claims 3 to 11, wherein: The metal catalyst is Li2CuCl4.

13. The method according to any one of claims 4 to 12, wherein: The additive is selected from nitrogen-based additives, unsaturated hydrocarbon-based additives, silyl-based additives, or a combination thereof.

14. The method according to any one of claims 4 to 13, wherein: The additive is selected from NMP, DMPU, HMPA, HMTA, TMEDA, 1,3-butadiene, isoprene, 1-phenylpropyne and TMS-Cl, or a combination thereof.

15. The method according to any one of claims 3 to 14, wherein: The amount of the metal catalyst is 0.1 to 20 mol % relative to the compound represented by formula III.

16. The method according to any one of claims 2 to 15, wherein: The amount of the compound represented by formula II is 1 to 5 equivalents relative to the compound represented by formula III.

17. The method according to any one of claims 4 to 16, wherein: The amount of the additive is 0.1 to 10 equivalents relative to the compound represented by formula III.

18. The method according to any one of claims 2 to 17, wherein: X 1 It is a bromine atom.

19. The method according to any one of claims 1 to 18, wherein: CH2OR b It represents an ether structure having 2 to 20 carbon atoms, a silyl ether structure having 4 to 20 carbon atoms, or an ester structure having 2 to 20 carbon atoms.

20. The method according to any one of claims 1 to 19, wherein: R b Selected from tert-butyl, benzyl, p-methoxyphenylbenzyl, trityl, methoxymethyl, methoxyethoxymethyl, tetrahydropyranyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, acetyl, pivaloyl and benzoyl.

21. The method according to any one of claims 1 to 20, wherein: X is CO2H, and the compound represented by formula I is a very long chain polyunsaturated fatty acid having 20 to 50 carbon atoms and containing 3 to 7 double bonds, or X is CO2R a The compound shown in formula I is a C of a very long chain polyunsaturated fatty acid having 20 to 50 carbon atoms and containing 3 to 7 double bonds. 1－6 Alkyl esters.

22. The method according to any one of claims 1 to 21, wherein: The compound shown in formula I is C 28－36 :5n-3、C 28－36 :4n-6、C 28－36 :6n-3 or C 28－36 : 3n-6 very long chain polyunsaturated fatty acids or their C 1－6 Alkyl esters.

23. The method according to any one of claims 1 to 22, wherein: The compound represented by formula I is a very long chain polyunsaturated fatty acid of C32:4n-6, C34:4n-6, C32:5n-3, C34:5n-3, C32:6n-3 or C34:6n-3 or its C 1－6 Alkyl esters.

24. The method according to any one of claims 1 to 23, wherein: The compound shown in formula I is a C32:4n-6 or C34:5n-3 ultra-long chain polyunsaturated fatty acid or its C 1－6 Alkyl esters.

25. The method according to any one of claims 2 to 24, wherein: The reaction includes: In a solvent, a mixture containing a compound represented by formula II is added to the compound represented by formula III, X 2 -(CH2) m -X(III) R 1 -MgX 1 (I I)。 26. The method according to any one of claims 4 to 25, wherein: The reaction is carried out in a solvent in the presence of a metal catalyst and an additive at a temperature of -20°C to 35°C.

27. The method according to any one of claims 4 to 26, wherein: The reaction includes: In a solvent, in the presence of a metal catalyst and an additive, a mixture containing a compound represented by formula II is added to the compound represented by formula III over a period of 5 to 80 minutes, X 2 -(CH2) m -X(III) R 1 -MgX 1 (I I)。 28. The method according to any one of claims 4 to 27, wherein: The reaction comprises: adding a mixture containing a compound represented by formula II to a compound represented by formula III at a rate of 0.1 to 1000 mL / min in a solvent in the presence of a metal catalyst and an additive, X 2 -(CH2) m -X(III) R 1 -MgX 1 (I I)。 29. The method according to any one of claims 2 to 28, wherein: The method further comprises: In a solvent, the compound represented by formula IIc is converted into the compound represented by formula II, R 1 -X 1 (IIc) R 1 -MgX 1 (I I)。 30. The method of claim 29, wherein: The conversion includes: In a solvent, in the presence of magnesium, adding a compound represented by formula IIc or a mixture comprising the compound to obtain a compound represented by formula II, R 1 -X 1 (IIc) R 1 -MgX 1 (I I)。 31. The method according to claim 30, wherein: The conversion includes: It takes 5 to 60 minutes to add the compound represented by formula IIc or a mixture containing the compound, R 1 -X 1 (IIc).

32. The method according to claim 30 or 31, wherein: The conversion includes: The compound represented by formula IIc or a mixture containing the compound is added at a rate of 0.1 to 1000 mL / min, R 1 -X 1 (IIc).

33. The method according to any one of claims 2 to 32, wherein: The method further comprises: Converting the compound represented by formula IIa into the compound represented by formula IIb; Converting the compound represented by formula IIb into the compound represented by formula IIc; and Converting the compound represented by formula IIc into the compound represented by formula II; R 1 -OH(IIa) R 1 -OX 3 (IIb) In Formula IIb, X 3 is a sulfonyl group, R 1 -X 1 (IIc) R 1 -MgX 1 (I I)。 34. The method according to any one of claims 1 to 19 and 21 to 32, wherein: X is CH2OR b , the method further comprises: Converting the compound represented by Formula Ia into the compound represented by Formula V; and The compound represented by formula V is converted into the compound represented by formula Ib, R 1 -(CH2) m -CH2OR b (Ia) R 1 -(CH2) m -CH2OH(V) R 1 -(CH2) m -CO2H(Ib), The compound represented by formula Ib is a very long chain polyunsaturated fatty acid having 20 to 50 carbon atoms and 3 to 7 double bonds.

35. The method according to any one of claims 1 to 34, wherein: The method further comprises: converting the ultra-long chain polyunsaturated fatty acids into C 1－6 Alkyl esters.

36. The compound of formula II is used to prepare very long chain polyunsaturated fatty acids or C 1－6 Uses of alkyl esters, R 1 -MgX 1 (II) In Formula II, R 1 It is a C containing 3 to 7 double bonds 18－30 Hydrocarbon, X 1 It is a halogen atom.

37. The compound of formula III is used to prepare very long chain polyunsaturated fatty acids or C 1－6 Uses of alkyl esters, X 2 -(CH2) m -X(III) In Formula III, X 2 is selected from halogen atoms and sulfonyloxy groups, X is CO2H, CO2R a or CH2OR b ; R a It is C 1－6 alkyl; R b It is an ether-forming group, a silyl ether-forming group or an ester-forming group.

38. A method for producing a compound represented by formula I or a salt thereof, characterized in that: include: (1) converting the compound represented by formula IV into the compound represented by formula IIa; (2) converting the compound represented by formula IIa into the compound represented by formula IIb; (3) converting the compound represented by formula IIb into the compound represented by formula IIc; (4) converting the compound represented by formula IIc into the compound represented by formula II; as well as (5) reacting the compound represented by formula II with the compound represented by formula III to convert the compound represented by formula I; R 1 -(CH2) m -X(I) In Formula I, R 1 It is a C containing 3 to 7 double bonds 18－30 Hydrocarbon, m is an integer selected from 1 to 19, X is CO2H, CO2R a or CH2OR b ; R a It is C 1－6 alkyl; R b is an ether-forming group, a silyl ether-forming group or an ester-forming group, R 4 -CO2R 2 (IV) In Formula IV, R 4 It is a C containing 3 to 7 double bonds 17－29 Hydrocarbon, R 2 is a hydrogen atom or an ester-forming group, R 4 -CH2-OH(IIa) R 4 -CH2-OX 3 (IIb) In Formula IIb, X 3 is a sulfonyl group, R 4 -CH2-X 1 (IIc) In Formula IIc, X 1 is a halogen atom, R 4 -CH2-MgX 1 (II) X 2 -(CH2) m -X(III) In Formula III, X 2 is selected from a halogen atom and a sulfonyloxy group.

39. The method of claim 38, wherein: The reaction of the compound represented by formula (5) II with the compound represented by formula (III) is carried out in a solvent in the presence of a metal catalyst.

40. The method of claim 38, wherein: The conversion of the compound represented by formula IV (1) comprises: reacting the compound represented by formula IV with a reducing agent in a solvent; The conversion of the compound represented by formula IIa (2) comprises: reacting the compound represented by formula IIa with a sulfonylating agent in a solvent in the presence of a base; The conversion of the compound represented by formula IIb (3) comprises: reacting the compound represented by formula IIb with a halogenating agent in a solvent; The conversion of the compound represented by formula IIc (4) comprises: reacting the compound represented by formula IIc with magnesium in a solvent; and The reaction of the compound represented by formula II with the compound represented by formula III (5) comprises: reacting the compound represented by formula II with the compound represented by formula III in a solvent in the presence of a metal catalyst.

41. The method according to any one of claims 38 to 40, wherein: The conversion of the compound represented by formula (2) IIa and the conversion of the compound represented by formula (3) IIb are performed by a one-pot synthesis.

42. The method according to any one of claims 38 to 41, wherein: The method comprises: the one-pot synthesis of the compound represented by formula IIc in (3), wherein the one-pot synthesis comprises: (2) reacting the compound represented by Formula IIa with TsCl in a solvent in the presence of one or more amines to prepare the compound represented by Formula IIb; and (3) without isolating the compound represented by formula IIb, reacting it with LiBr to prepare the compound represented by formula IIc, R 4 -CH2-OX 3 (IIb) In Formula IIb, X 3 is tosyl, R 4 -CH2-X 1 (IIc) In Formula IIc, X 1 It is a bromine atom.

43. The method according to any one of claims 38 to 42, wherein: The conversion of the compound represented by formula IV (1) is carried out by reacting the compound represented by formula IV with sodium dihydrobis(2-methoxyethoxy)aluminate in a solvent.

44. A method for treating a long-chain polyunsaturated fatty acid or its C 1－6 The alkyl esters are converted to obtain very long chain polyunsaturated fatty acids or their C 1－6 A method for producing an alkyl ester, characterized in that: The long-chain polyunsaturated fatty acid has 18 to 30 carbon atoms and contains 3 to 7 double bonds. The ultra-long-chain polyunsaturated fatty acid has 20 to 50 carbon atoms and contains 3 to 7 double bonds. The conversion step includes: making the long-chain polyunsaturated fatty acid or its C 1－6 Alkyl ester-derived Grignard reagents and ω-halogenated C 2－20 Aliphatic acid or its C 1－6 Alkyl ester reaction to obtain the ultra-long chain polyunsaturated fatty acid or its C 1－6 Alkyl esters, The conversion step does not include one or more steps selected from the following steps: (a) a protection step of converting a compound having a hydroxyl group into a compound having a protected hydroxyl group; (b) a deprotection step of converting a compound having a protected hydroxyl group into a compound having a hydroxyl group; (c) an oxidation step of converting an alcohol into an aldehyde or a carboxylic acid; (d) an oxidation step of converting an aldehyde into a carboxylic acid; and (e) a step of converting an aldehyde into a carboxylic acid relative to the long-chain polyunsaturated fatty acid or its C 1－6 The step of producing a compound derived from an alkyl ester is carried out in the presence of a stoichiometric amount of a phosphorus compound.

45. A method for treating a long-chain polyunsaturated fatty acid or its C 1－6 The alkyl esters are converted to obtain very long chain polyunsaturated fatty acids or their C 1－6 A method for producing an alkyl ester, characterized in that: The long-chain polyunsaturated fatty acid has 18 to 30 carbon atoms and contains 3 to 7 double bonds. The ultra-long-chain polyunsaturated fatty acid has 20 to 50 carbon atoms and contains 3 to 7 double bonds. The conversion step includes: making the long-chain polyunsaturated fatty acid or its C 1－6 Alkyl ester-derived Grignard reagents and ω-halogenated C 2－20 Aliphatic acid or its C 1－6 The alkyl ester reacts in the presence of a metal catalyst to obtain the ultra-long chain polyunsaturated fatty acid or its C 1－6 Alkyl esters, The conversion process does not include one or more steps selected from the following steps: (a) converting a compound having a hydroxyl group into a compound having a C-forming 1－20 The ether structure protects the hydroxyl group and forms C 3－20 The protected hydroxyl groups of the silyl ether structure or the C 1－20 A step of protecting a compound having a protected hydroxyl group of an ester structure; (b) having a C 1－20 The ether structure protects the hydroxyl group and forms C 3－20 The protected hydroxyl groups of the silyl ether structure or the C 1－20 (c) an oxidation step of a compound having a hydroxymethyl group to a compound having a formyl group or a carboxyl group; (d) an oxidation step of a compound having a formyl group to a compound having a carboxyl group; and (e) a step of reacting a compound having a formyl group to a compound having a carboxyl group relative to the long-chain polyunsaturated fatty acid or its C 1－6 The process of producing a compound derived from an alkyl ester is carried out in the presence of a stoichiometric amount of triphenylphosphine or a triphenylphosphonium salt.

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