Preparation methods of α-corpse alcohol-based compounds and γ-corpse alcohol-based compounds

Abstract

The present invention provides a method for preparing an α-cadaverine-based compound of the following general formula (3): wherein R 2 represents a monovalent hydrocarbon group having 1 to 9 carbon atoms, the method comprising: making a 3,5,5-trimethyl-3-cyclopentene compound of the following general formula (1): wherein R 2 As defined above, and X represents a leaving group, and the methylating agent of the following general formula (2): wherein M represents Li, Mg, Z 1 、ZnZ 1 、Cu、CuZ 1 or CuLiZ 1 , and Z 1 represents a halogen atom or a methyl group, undergoing a nucleophilic substitution reaction to form an α-cadaverine-based compound (3). The present invention also provides a method for preparing a γ-cadaverine-based compound of the following general formula (4): wherein R 2 represents a monovalent hydrocarbon group having 1 to 9 carbon atoms, and the method comprises: subjecting the thus obtained α-cadaverine-based compound (3) to positional isomerization reaction at the double bond to form a γ-cadaverine-based compound (4). #imgabs0#

Description

Technical Field

[0001] The present invention relates to a process for preparing α-necrodyl compounds and a process for preparing γ-necrodyl compounds. The present invention also relates to a process for preparing α-necrodyl compounds and a process for preparing γ-necrodyl compounds, both starting from the novel compound (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol. The present invention also relates to the novel compound, (2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol. Background Art

[0002] α-Corporal compounds, or a group of compounds containing a (3,4,5,5-tetramethyl-2-cyclopentenyl)methyl group, and γ-Corporal compounds, or a group of compounds containing a (2,2,3,4-tetramethyl-3-cyclopentenyl)methyl group, are commonly found in natural products such as pheromones (bioactive substances). For example, α-Corporal, an α-corporal compound, is known to act as a defensive agent against the red-striped carrion beetle (Necrodes surinamensis) (Non-Patent Document 1 below). α-Corporal isobutyrate, another α-corporal compound, has been identified as a sex pheromone against the grape mealybug (Pseudococcus maritimus) (Non-Patent Documents 2 and 3 below). A γ-cadaverine-based compound, γ-cadaverine isobutyrate, has also been identified as a sex pheromone of the spherical mealybug (scientific name: Nipaecoccus viridis) (Non-Patent Document 4 below).

[0003] Insect sex pheromones are biologically active substances that generally have the function of attracting males to females. Even small amounts of these substances show high attraction activity. Many applications of using sex pheromones to manage pests have been designed and put into practice. For example, sex pheromones are widely used as a means of predicting pest outbreaks and confirming geographical distribution (invasion of specific areas) as well as a means of controlling pests. Widely used pest control methods are: mass trapping, lure and kill or attract and kill methods, lure and infect or attract and infect methods, and mating disruption methods. Trapping with sex pheromones has high trapping ability and species specificity and is therefore very useful for detecting and monitoring the pests of interest.

[0004] Mealybugs are small insects that suck plant juices. Some species severely damage grain and fruit trees, making them a major agricultural pest. Mealybugs live on plant tissues, such as nodes or stumps of flowers, making them difficult to find. Consequently, their removal during plant quarantine on crops is challenging. Therefore, sex pheromone-based traps are an effective means of controlling mealybugs.

[0005] Adult female mealybugs lack wings and have degenerated legs, so they can only move slightly. Adult male mealybugs have wings, which are extremely small and fragile. After emerging from their wings, they do not eat and can survive for a few days at most (the following non-patent documents 5 and 6). The sex pheromones released by these less mobile females (which are crucial for attracting this short-lived male) play a key role in finding a mating partner. Sex pheromones are believed to be under high selection pressure in the evolutionary process (the following non-patent documents 7 and 8). In fact, the pheromone of mealybugs has a variety of highly species-specific structures (the following non-patent documents 9 and 10). Therefore, mealybug sex pheromones are an effective means for pest control and pest quarantine, and are also an important model for studying the changes in the chemical communication mechanism of insects.

[0006] Catalogue of existing technologies

[0007] [Non-patent document 1] J. Meinwald et al., J. Org. Chem., 1990, 55, 4051-4062.

[0008] [Non-patent document 2] JG Millar et al., Tetrahedron Lett., 2007, 48, 8434-8437.

[0009] [Non-patent document 3] JG Millar et al., J. Agric. Food Chem., 2010, 58, 4977-4982.

[0010] [Non-patent document 4] A. Levi-Zada et al., J. Chem. Ecol., 2019, 45, 455-463.

[0011] [Non-patent document 5] JC Franco et al., Biorational Control of Arthropod Pests; I. Ishaaya, AR Horowitz, Eds., Springer, Dordrecht, 2009, 233-278.

[0012] [Non-patent document 6] L. Ross et al., Curr. Biol., 2009, 19, R184-R186.

[0013] [Non-patent document 7] J. Tabata et al., JRSoc. Interface, 2017, 14, 20170027.

[0014] [Non-patent document 8] J. Tabata et al., Biol. Lett., 2018, 14, 20190262.

[0015] [Non-patent document 9] JG Millar et al., Semiochemicals in Pest and Weed Control, 2005, Chapter 2, 11-27.

[0016] [Non-patent document 10] JG Millar et al., Nat. Prod. Rep., 2015, 32, 1067. Summary of the Invention

[0017] Methods for synthesizing α-cadaverine-based compounds are known, as described in Non-Patent Document 1 by Meinwald et al. and Non-Patent Document 3 by Millar et al. Methods for synthesizing γ-cadaverine-based compounds are known, as described in Non-Patent Document 4 by Levi-Zada.

[0018] However, the method described in Non-Patent Document 1 is not suitable for industrial-scale production because it requires expensive reagents (such as ruthenium oxide, tert-butyldimethylsilyl chloride, phenylselenium chloride, and sulfur trioxide-pyridine complex) and explosive reagents (such as diazomethane), requires a reaction using liquid ammonia (which is difficult to carry out in conventional reaction equipment), and purification of the intermediate (by preparative HPLC). This production method is inefficient because it includes as many as 13 steps from the starting material camphoric anhydride to obtain α-cadaverine.

[0019] The method described in Non-Patent Document 3 is unsuitable for industrial-scale production due to the use of sodium hydride in the intramolecular Knoevenagel reaction. Dimethylzinc, which easily ignites in air, is used in the step of introducing a methyl group into the α,β-unsaturated ketone via a conjugate addition reaction; and hexamethylphosphoric triamide, a highly toxic substance, is used for the methylation. Metallic lithium in ethylenediamine is used in the step of isomerizing the exo-olefin to the trisubstituted olefin. This reaction is difficult to stop at the appropriate time. If the reaction continues for too long, unwanted tetrasubstituted olefins will form, potentially reducing the yield. Furthermore, these compounds are difficult to isolate. This serial synthesis, starting from methyl acetoacetate, involves eight steps and yields a 7% yield. Therefore, this method is inefficient.

[0020] In the method described in Non-Patent Document 4, α-cadaverine acetate is obtained by distilling purified cadaverine lavender (Lavandula luisieri) essential oil. The ester is subjected to a solvation reaction, followed by double bond isomerization using a boron trifluoride-ether complex, and the alcohol is acylated to obtain γ-cadaverine isobutyrate. In methods of obtaining starting materials from natural essential oils, it is difficult to separate compounds with similar properties, and the final product may be contaminated with impurities. Therefore, this method is not suitable for synthesizing bioactive substances that exhibit activity even in trace amounts.

[0021] The present invention has been accomplished under these circumstances, and aims to provide a method for efficiently preparing an α-cadaverine-based compound and a method for preparing a γ-cadaverine-based compound.

[0022] After intensive research, the present inventors discovered that α-cadaverine compounds can be prepared by a nucleophilic substitution reaction of 3,5,5-trimethyl-3-cyclopentene compounds, thereby completing the present invention. The present inventors also discovered that γ-cadaverine compounds can be prepared by positional isomerization at the double bond of α-cadaverine compounds, thereby completing the present invention.

[0023] According to one aspect of the present invention, the present invention provides a method for preparing an α-cadaverine-based compound of the following general formula (3):

[0024]

[0025] where R 2 represents a monovalent hydrocarbon group having 1 to 9 carbon atoms, and the bold non-wedge bond and the cut non-wedge bond represent the relative configuration.

[0026] The method comprises:

[0027] The following 3,5,5-trimethyl-3-cyclopentene compound is prepared:

[0028]

[0029] where R 2 As defined above, X represents a leaving group, and cleavage of a non-wedge bond represents a relative configuration,

[0030] A nucleophilic substitution reaction is carried out with a methylating agent of the following general formula (2):

[0031] CH3-M (2)

[0033] Where M represents Li, Mg, Z 1 、ZnZ 1 、Cu、CuZ 1 or CuLiZ 1 , Z 1 represents a halogen atom or a methyl group,

[0034] to form α-cadaverine-based compound (3).

[0035] According to another aspect of the present invention, there is provided a method for preparing a γ-cadaverine-based compound of the following general formula (4):

[0036]

[0037] where R 2represents a monovalent hydrocarbon group having 1 to 9 carbon atoms,

[0038] The method comprises:

[0039] The aforementioned method for preparing the α-cadaverine-based compound (3), and

[0040] The α-cadaverine-based compound (3) thus obtained is subjected to positional isomerization reaction at the double bond to form a γ-cadaverine-based compound (4).

[0041] According to another aspect of the present invention, the present invention provides a method for preparing an α-cadaverine-based compound (3), the method comprising:

[0042] (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol of the following formula (5C):

[0043]

[0044] The cut non-wedge bond represents the relative configuration,

[0045] performing an esterification reaction, a combination of an esterification reaction and a halogenation reaction, or a combination of an esterification reaction and a sulfonylation reaction to form the 3,5,5-trimethyl-3-cyclopentene compound (1);

[0046] The aforementioned process for preparing an α-cadaverine-based compound (3) from the thus obtained 3,5,5-trimethyl-3-cyclopentene compound (1).

[0047] According to another aspect of the present invention, there is provided a method for preparing an α-cadaverine-based compound (3),

[0048] The method comprises:

[0049] The following 3,5,5-trimethyl-2-oxo-3-cyclopentene-1-carboxylate compound of general formula (6) is prepared:

[0050]

[0051] where R 1 represents a monovalent hydrocarbon group having 1 to 10 carbon atoms,

[0052] Reduction reaction is performed to form (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C), and;

[0053] The aforementioned process for preparing an α-cadaverine-based compound (3) from the thus obtained (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C).

[0054] According to another aspect of the present invention, there is provided a method for preparing an α-cadaverine-based compound (3),

[0055] The method comprises:

[0056] The following 3,5,5-trimethyl-2-oxo-3-cyclopentene-1-carboxylate compound of general formula (6) is prepared:

[0057]

[0058] where R 1 represents a monovalent hydrocarbon group having 1 to 10 carbon atoms,

[0059] converted to the corresponding carboxylic acid, and

[0060] The carboxylic acid thus obtained is subjected to a reduction reaction to form (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C), and

[0061] The aforementioned process for preparing an α-cadaverine-based compound (3) from the thus obtained (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C).

[0062] According to another aspect of the present invention, the present invention provides (2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol of the following formula (5):

[0063]

[0064] According to the present invention, α-cadaverine compounds and γ-cadaverine compounds can be prepared in high yield without special equipment. According to the present invention, (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol is also provided, which is a useful intermediate for preparing α-cadaverine compounds and γ-cadaverine compounds. DETAILED DESCRIPTION

[0065] The embodiments of the present invention will be described in detail below. It should be noted that the present invention is not limited to or by these embodiments. The intermediates, reagents, and target compounds represented by chemical formulae in this specification may contain some stereoisomers, such as enantiomers or diastereomers. Unless otherwise indicated, chemical formulae should be interpreted as representing all such isomers. Isomers may be only a single isomer or a combination thereof.

[0066] A. The α-cadaverine-based compound and the γ-cadaverine-based compound prepared according to the method of the present invention will be described below.

[0067] (a) α-cadaverine-based compounds

[0068] The term "α-cadaverine compounds" refers to a group of compounds having a (3,4,5,5-tetramethyl-2-cyclopentenyl)methyl group.

[0069] The target compound of the present invention is an α-cadaverine carboxylate compound of the following general formula (3) among α-cadaverine-based compounds:

[0070]

[0071] The bold non-tapered bonds and cleaved non-tapered bonds in the general formula (3) represent relative configurations.

[0072] R in the general formula (3) 2 represents a monovalent hydrocarbon group having 1 to 9, preferably 1 to 5 carbon atoms.

[0073] Monovalent hydrocarbon group R 2 Examples of the hydrocarbon group include straight-chain saturated hydrocarbon groups such as methyl groups, ethyl groups, n-propyl groups, n-butyl groups, n-pentyl groups, n-hexyl groups, n-heptyl groups, n-octyl groups and n-nonyl groups; branched-chain saturated hydrocarbon groups such as isopropyl groups, 2-methylbutyl groups and tert-butyl groups; cyclic saturated hydrocarbon groups such as cyclopropyl groups, cyclobutyl groups, cyclopentyl groups, cyclohexyl groups and cyclopentylmethyl groups; straight-chain unsaturated hydrocarbon groups such as vinyl groups, allyl groups and ethynyl groups; branched-chain unsaturated hydrocarbon groups such as isopropenyl groups and 2-methyl-2-propenyl groups; cyclic unsaturated hydrocarbon groups such as phenyl groups, tolyl groups, dimethylphenyl groups, benzyl groups and phenethyl groups; and isomers thereof. A portion of the hydrogen atoms in the hydrocarbon group may be substituted by a monovalent hydrocarbon group having 1 to 8 carbon atoms.

[0074] Specifically, the general formula (3) represents a (1R,4R)-α-cadaverine-based compound of the following general formula (3-1), a (1S,4S)-α-cadaverine-based compound of the following general formula (3-2), or both.

[0075]

[0076] The boldface wedge bonds and cut wedge bonds in the general formulae (3-1) and (3-2) represent the absolute configuration.

[0077] Specific examples of the α-cadaverine-based compound (3) include the following formula (3A; or R in the general formula (3): 2 =isopropyl group) (1RS, 4RS)-(3,4,5,5-tetramethyl-2-cyclopentenyl) isobutyric acid methyl ester (ie, R in the general formula (3-1), (3-2) or a combination thereof) 2is an isopropyl group), (1RS, 4RS)-(3,4,5,5-tetramethyl-2-cyclopentenyl) methyl acetate (ie, R in the general formula (3-1), (3-2) or a combination thereof 2 is a methyl group) and (1RS, 4RS)-(3,4,5,5-tetramethyl-2-cyclopentenyl) benzoic acid methyl ester (i.e., R in the general formula (3-1), (3-2) or a combination thereof 2 Among them, considering the preparation of sex pheromones of grape mealybugs and spherical mealybugs, (1RS,4RS)-(3,4,5,5-tetramethyl-2-cyclopentenyl)isobutyric acid methyl ester (3A) is preferred.

[0078]

[0079] The bold non-tapered bonds and cleaved non-tapered bonds in the general formula (3A) represent relative configurations.

[0080] (b) γ-cadaverine-based compounds

[0081] The term "γ-cadaverine compounds" refers to a group of compounds having a (2,2,3,4-tetramethyl-3-cyclopentenyl)methyl group.

[0082] The target compound of the present invention is a γ-cadaverine carboxylate compound of the following general formula (4) among the γ-cadaverine-based compounds:

[0083]

[0084] R in general formula (4) 2 As defined by general formula (3).

[0085] Specifically, the general formula (4) represents a (1R)-γ-cadaverine-based compound of the following general formula (4-1), a (1S)-γ-cadaverine-based compound of the following general formula (4-2), or both.

[0086]

[0087] The bold wedge bonds in the general formula (4-1) and the cut wedge bonds in the general formula (4-2) represent the absolute configurations.

[0088] Specific examples of the γ-cadaverine-based compound (4) include (1RS)-(2,2,3,4-tetramethyl-3-cyclopentenyl)isobutyric acid methyl ester of the following formula (4A) (i.e., R in the general formula (4-1) or (4-2) or a combination thereof) 2 isopropyl group), (1RS)-(2,2,3,4-tetramethyl-3-cyclopentenyl)acetic acid methyl ester (ie, R in the general formula (4-1) or (4-2) or a combination thereof 2is a methyl group) and (1RS)-(2,2,3,4-tetramethyl-3-cyclopentenyl)benzoic acid methyl ester (i.e., R in the general formula (4-1) or (4-2) or a combination thereof 2 Among them, considering the preparation of sex pheromones of grape mealybugs and spherical mealybugs, (1RS)-(2,2,3,4-tetramethyl-3-cyclopentenyl)isobutyric acid methyl ester (4A) is preferred.

[0089]

[0090] B. Next, a method for preparing an α-cadaverine-based compound (3) and a method for preparing a γ-cadaverine-based compound (4) according to the present invention will be described below.

[0091] The present inventors conceived a plan for synthesizing the α-cadaverine-based compound (3) and the γ-cadaverine-based compound (4), as described below.

[0092] Retrosynthetic analysis is represented by the following reaction formula of (1RS)-(2,2,3,4-tetramethyl-3-cyclopentenyl)isobutyric acid methyl ester (4A) as an example of the target compound γ-cadaverine-based compound (4).

[0093]

[0094] In the retrosynthetic reaction schemes shown above, open arrows represent transformations in the retrosynthetic analysis. i Pr represents an isopropyl group, M represents a cationic moiety, and Et represents an ethyl group. The bold non-wedge bonds in formula (3A) and the cleaved non-wedge bonds in formulas (3A), (1A), and (5C) represent relative configurations.

[0095] The target compound (1RS)-(2,2,3,4-tetramethyl-3-cyclopentenyl)isobutyric acid methyl ester (4A) of step D' is believed to be synthesized by positional isomerization of the double bond in (1RS,4RS)-(3,4,5,5-tetramethyl-2-cyclopentenyl)isobutyric acid methyl ester (3A) in the α-cadaverine-based compound (3). This is because the tetrasubstituted double bond in (1RS)-(2,2,3,4-tetramethyl-3-cyclopentenyl)isobutyric acid methyl ester (4A) is likely more stable than the trisubstituted double bond in (1RS,4RS)-(3,4,5,5-tetramethyl-2-cyclopentenyl)isobutyric acid methyl ester (3A).

[0096] The target compound of step C', (1RS,4RS)-(3,4,5,5-tetramethyl-2-cyclopentenyl)isobutyric acid methyl ester (3A), is believed to be synthesized through a regioselective and stereoselective nucleophilic substitution reaction between (1RS,2SR)-(3,5,5-trimethyl-2-isobutyryloxy-3-cyclopentenyl)isobutyric acid methyl ester of formula (1A) in the reaction formula and a methylating agent of formula (2) in the reaction formula.

[0097] Step B' The target compound (1RS,2SR)-(3,5,5-trimethyl-2-isobutyryloxy-3-cyclopentenyl)isobutyric acid methyl ester (1A) is believed to be synthesized by esterification of (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol of formula (5C).

[0098] The target compound (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C) of step A' is believed to be synthesized by stereoselectively reducing ethyl 2-oxo-3-cyclopentene-1-carboxylate of formula (6A) in the reaction scheme.

[0099] The reaction formula obtained by the above retrosynthetic analysis is as follows according to an embodiment of the present invention:

[0100]

[0101] In step A, the 3,5,5-trimethyl-2-oxo-3-cyclopentene-1-carboxylate compound of formula (6) is stereoselectively reduced to form (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C).

[0102] Step B: (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C) formed according to step A or other methods is subjected to one or more reactions selected from esterification reaction, esterification reaction and halogenation reaction, and esterification reaction and sulfonylation reaction to form a 3,5,5-trimethyl-3-cyclopentene compound of formula (1).

[0103] Step C: The 3,5,5-trimethyl-3-cyclopentene compound (1) formed according to step B or other methods undergoes a nucleophilic substitution reaction with a methylating agent (2) to introduce a methyl group regioselectively and stereoselectively to form an α-cadaverine compound (3).

[0104] Step D: The α-cadaverine compound (3) formed in Step C is subjected to positional isomerization of its double bond to form a γ-cadaverine compound (4).

[0105] Steps A to D, which are embodiments of the present invention, will be described in detail below. Step C (in which the target compound of the present invention, α-cadaverine compound (3)), step D (in which another target compound of the present invention, γ-cadaverine compound (4)), step B (in which the starting material of step C is synthesized), and step A (in which the starting material of step B is synthesized) will be described in order. In the description of step A, a method for synthesizing (2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol of the following formula (5) without stereoselectively reducing the 3,5,5-trimethyl-2-oxo-3-cyclopentene-1-carboxylate compound (6) will also be described.

[0106]

[0107] [1] Step C

[0108] Next, Step C (in which an α-cadaverine-based compound (3) is synthesized) will be described. The α-cadaverine-based compound (3) is synthesized by subjecting a 3,5,5-trimethyl-3-cyclopentene compound (1) to a nucleophilic substitution reaction with a methylating agent (2), as shown in the following chemical reaction formula:

[0109]

[0110] The cleaved non-tapered bonds in the general formulae (1) and (3) and the bold non-tapered bonds in the general formula (3) represent relative configurations.

[0111] In the general formula (1), R 2 represents a monovalent hydrocarbon group having 1 to 9, preferably 1 to 5 carbon atoms.

[0112] Examples of the monovalent hydrocarbon group include straight-chain saturated hydrocarbon groups such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and n-nonyl groups; branched-chain saturated hydrocarbon groups such as isopropyl, 2-methylbutyl, and tert-butyl groups; cyclic saturated hydrocarbon groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclopentylmethyl groups; straight-chain unsaturated hydrocarbon groups such as vinyl, allyl, and ethynyl groups; branched-chain unsaturated hydrocarbon groups such as isopropenyl and 2-methyl-2-propenyl groups; cyclic unsaturated hydrocarbon groups such as phenyl, tolyl, dimethylphenyl, benzyl, and phenethyl groups; and isomers thereof. A portion of the hydrogen atoms in the hydrocarbon group may be substituted by a monovalent hydrocarbon group having 1 to 8 carbon atoms.

[0113] To prepare sex pheromones of grape mealybugs and spherical mealybugs, R 2 Isopropyl is preferred because R 2The target compound having an isopropyl group can be directly formed without changing the acyl group.

[0114] The leaving group X in the general formula (1) represents an acyloxy group having 1 to 10 carbon atoms including the carbon atom of the carbonyl group; an alkanesulfonyloxy group having 1 to 10 carbon atoms; an arylsulfonyloxy group having 6 to 20 carbon atoms; or a halogen atom.

[0115] Examples of acyloxy groups having 1 to 10 carbon atoms, including the carbon atom of the carbonyl group, include straight-chain acyloxy groups such as formyloxy groups, acetyloxy groups, propionyloxy groups, butyryloxy groups, valeryloxy groups, hexanoyloxy groups, heptanoyloxy groups, octanoyloxy groups, nonanoyloxy groups, decanoyloxy groups, and crotonyloxy groups; branched acyloxy groups such as isobutyryloxy groups, pivaloyloxy groups, 2-methylbutyryloxy groups, 3-methyl-2-butenoyloxy groups, and 3-methyl-3-butenoyloxy groups; cyclic acyloxy groups such as cyclohexylcarbonyloxy groups and benzoyloxy groups; halogenated acyloxy groups such as trichloroacetoxy groups and trifluoroacetoxy groups; and isomers thereof. A portion of the hydrogen atoms of the acyloxy group may be substituted by a monovalent hydrocarbon group having 1 to 8 carbon atoms or a halogen atom. Examples of halogen atoms include chlorine atoms, bromine atoms, and iodine atoms.

[0116] Among the acyloxy groups, a formyloxy group, an acetoxy group, a propionyloxy group, a pivaloyloxy group, an isobutyryloxy group and a benzoyloxy group are preferred in view of availability.

[0117] The example of the alkanesulfonyloxy group with 1 to 10 carbon atoms includes a methanesulfonyloxy group, an ethylsulfonyloxy group, a 1-butylsulfonyloxy group, a 1-pentanesulfonyloxy group, a 1-hexanesulfonyloxy group, a 1-heptanesulfonyloxy group, a 1-octanesulfonyloxy group, a 1-nonanesulfonyloxy group, a 1-decanesulfonyloxy group, an allylsulfonyloxy group, a 10-camphorsulfonyloxy group, a trifluoromethanesulfonyloxy group, an α-benzylsulfonyloxy group and an isomer thereof. A part of the hydrogen atoms in the alkanesulfonyloxy group can be substituted by a methyl group, an ethyl group or a halogen atom. The example of a halogen atom includes a chlorine atom, a bromine atom and an iodine atom. In the alkanesulfonyloxy group, considering availability, a methanesulfonyloxy group and an ethylsulfonyloxy group are preferred.

[0118] Examples of arylsulfonyloxy groups having 6 to 20 carbon atoms include benzenesulfonyloxy, 4-chlorobenzenesulfonyloxy, 4-methoxybenzenesulfonyloxy, 2-nitrobenzenesulfonyloxy, 2,4,6-trimethylbenzenesulfonyloxy, p-toluenesulfonyloxy, 1-naphthalenesulfonyloxy, 2-naphthalenesulfonyloxy, and isomers thereof. Some of the hydrogen atoms in the arylsulfonyloxy group may be substituted with a methyl group, an ethyl group, or a halogen atom. Examples of halogen atoms include fluorine, chlorine, bromine, and iodine atoms.

[0119] Among the arylsulfonyloxy groups, a benzenesulfonyloxy group and a p-toluenesulfonyloxy group are preferred in view of availability.

[0120] Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Among the halogen atoms, a chlorine atom and a bromine atom are preferred in view of availability.

[0121] The leaving group X is preferably an acyloxy group or a halogen atom. For the preparation of sex pheromones of grape mealybugs and spherical mealybugs, the leaving group X is more preferably an acyloxy group, and even more preferably an isobutyryloxy group, because R 2 is an isopropyl group, and the primary and secondary alcohols of (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C) can be esterified simultaneously.

[0122] Specifically, general formula (1) represents a (1R,2S)-3,5,5-trimethyl-3-cyclopentene compound of the following general formula (1-1), a (1S,2R)-3,5,5-trimethyl-3-cyclopentene compound of the following general formula (1-2), or both.

[0123]

[0124] The cut wedge bond in the general formula (1-1) and the bold wedge bond in the general formula (1-2) represent the absolute configuration.

[0125] Specific examples of the 3,5,5-trimethyl-3-cyclopentene compound (1) include (1RS,2SR)-(3,5,5-trimethyl-2-acyloxy-3-cyclopentenyl)carboxylic acid methyl ester, such as the following general formula (1A; or R in the general formula (1): 2=isopropyl group, X =isobutyryloxy group); (1RS,2SR)-(3,5,5-trimethyl-2-alkylsulfonyloxy-3-cyclopentenyl)carboxylic acid methyl esters, such as (1RS,2SR)-(3,5,5-trimethyl-2-methanesulfonyloxy-3-cyclopentenyl)acetic acid methyl ester; and (1RS,2SR)-(3,5,5-trimethyl-2-halo-3-cyclopentenyl)carboxylic acid methyl esters, such as (1RS,2SR)-(3,5,5-trimethyl-2-halo-3-cyclopentenyl)carboxylic acid methyl esters, such as (1RS,2SR)-(3,5,5-trimethyl-2-bromo-3-cyclopentenyl)isobutyrate. In consideration of the preparation of sex pheromones of grape mealybugs and spherical mealybugs, (1RS,2SR)-(3,5,5-trimethyl-2-isobutyryloxy-3-cyclopentenyl)isobutyric acid methyl ester (1A) is preferred.

[0126]

[0127] The cleaved non-tapered bond in the general formula (1A) represents a relative configuration.

[0128] Specifically, formula (1A) represents (1R,2S)-(3,5,5-trimethyl-2-isobutyryloxy-3-cyclopentenyl)isobutyric acid methyl ester of the following formula (1A-1), (1S,2R)-(3,5,5-trimethyl-2-isobutyryloxy-3-cyclopentenyl)isobutyric acid methyl ester of the following formula (1A-2), or both.

[0129]

[0130] The cut wedge bond in the general formula (1A-1) and the bold wedge bond in the general formula (1A-2) represent the absolute configuration.

[0131] 3,5,5-Trimethyl-3-cyclopentene compound (1) and (1RS,2SR)-(3,5,5-trimethyl-2-isobutyryloxy-3-cyclopentenyl)isobutyric acid methyl ester (1A) can be synthesized according to Step B described in detail below or other methods.

[0132] Methylating agents (2) are used for nucleophilic substitution reactions. Organometallic reagents containing Group I or Group II metal elements or transition metal elements are generally used for nucleophilic substitution reactions.

[0133] M in the methylating agent (2) represents Li, Mg, Z 1 、ZnZ 1 、Cu、CuZ 1 or CuLiZ 1 , and Z 1 Represents a halogen atom or a methyl group. Halogen atom Z 1 Examples of include a chlorine atom, a bromine atom, and an iodine atom.

[0134] The methylating agent (2) is preferably an organolithium reagent such as methyllithium; and an organomagnesium reagent such as Grignard reagent and methylmagnesium halide, particularly a Grignard reagent in view of selectivity and / or ease of preparation.

[0135] The methylating agent (2) can be prepared by a metal exchange reaction between an organolithium or organomagnesium reagent and a stoichiometric amount (1 mol or more) of a transition metal compound, or by an in situ reaction between an organolithium or Grignard reagent and a catalytic amount of a transition metal compound.

[0136] Examples of the transition metal compound include transition metal compounds containing copper, iron, nickel, palladium, zinc or silver; cuprous halides such as cuprous chloride (I), cuprous bromide (I) and cuprous iodide (I); copper halides such as cuprous chloride (II), cuprous bromide (II) and cuprous iodide (II); copper cyanides such as cuprous cyanide (I) and cuprous cyanide (II); copper oxides such as cuprous oxide (I) and cuprous oxide (II); and copper compounds such as dilithium tetrachlorocuprate (Li2CuCl4). In view of reactivity, copper halides and cuprous halides are preferred.

[0137] The amount of the transition metal compound to be used is preferably 0.01 mol to 10 mol, more preferably 0.1 mol to 5 mol, per mol of the 3,5,5-trimethyl-3-cyclopentene compound (1), in view of reactivity and selectivity.

[0138] When the transition metal compound is used for nucleophilic substitution reaction, the co-catalyst may be preferably used in an amount of 0.01 to 1000 parts by weight relative to 100 parts by weight of the transition metal compound to improve the solubility of the transition metal compound in the solvent.

[0139] Specific examples of the co-catalyst include phosphorus compounds such as trialkylphosphites, for example, triethylphosphite, and triarylphosphines, for example, triphenylphosphine.

[0140] In the nucleophilic substitution reaction, a lithium salt (such as lithium chloride, lithium bromide or lithium iodide) may be present as a reaction catalyst in an amount of 0.001 mol to 1,000 mol per mol of the 3,5,5-trimethyl-3-cyclopentene compound (1). In view of reactivity and selectivity, a combination of copper halide and cuprous halide and lithium salt is preferred.

[0141] The amount of the methylating agent (2) to be used may be optionally determined while taking into consideration reagents, reaction conditions, reaction yield, cost efficiency including prices of intermediates, and / or easiness of separation and purification of the target compound from the reaction mixture, and is preferably 0.2 mol to 100 mol, more preferably 0.5 mol to 20 mol, and even more preferably 0.8 mol to 5 mol per mol of the 3,5,5-trimethyl-3-cyclopentene compound (1).

[0142] Examples of the solvent used in the nucleophilic substitution reaction include ether solvents such as tetrahydrofuran, 4-methyltetrahydropyran, diethyl ether, tert-butyl methyl ether, and 1,4-dioxane; hydrocarbon solvents such as toluene, xylene, and hexane; and polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, dichloromethane, and chloroform. In view of reactivity and solubility, tetrahydrofuran is preferred.

[0143] If necessary, the solvents may be used alone or in combination. The solvents may be commercially available products.

[0144] The amount of the solvent used varies depending on the production scale, and is preferably 200 g to 4,000 g per mol of the 3,5,5-trimethyl-3-cyclopentene compound (1) in consideration of the reaction rate.

[0145] The reaction temperature for preparing the α-cadaverine-based compound (3) is preferably -78°C to 150°C, more preferably -78°C to 80°C, in view of reactivity and suppression of by-product formation.

[0146] The reaction time for preparing the α-cadaverine-based compound (3) varies depending on the solvent and / or reaction scale, and is preferably 0.1 hour to 120 hours.

[0147] (1RS,4RS)-(3,4,5,5-tetramethyl-2-cyclopentenyl)isobutyric acid methyl ester (3A) in the α-cadaveric alcohol-based compound (3) can be synthesized through a nucleophilic substitution reaction between (1RS,2SR)-(3,5,5-trimethyl-2-isobutyryloxy-3-cyclopentenyl)isobutyric acid methyl ester (1A) and a methylating agent (2), as shown in the following chemical reaction formula (see also Example 1 below).

[0148]

[0149] [2] Step D

[0150] Next, step D for synthesizing the γ-cadaverine compound (4) will be described. The γ-cadaverine compound (4) is synthesized by subjecting the α-cadaverine compound (3) synthesized in step C to positional isomerization of its double bond, as shown in the following chemical reaction formula.

[0151]

[0152] The isomerization of the double bond takes place in the presence of the reagents in a solvent, with cooling or heating if necessary.

[0153] Examples of reagents for double bond isomerization reactions include alkali metal-ethylenediamine in ethylenediamine, such as lithium-ethylenediamine in ethylenediamine; Lewis acids such as boron trifluoride-diethyl ether complex; inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, and sulfuric acid; and p-toluenesulfonic acid, trifluoroacetic acid, acetic acid, formic acid, and oxalic acid. In view of reactivity and ease of handling, p-toluenesulfonic acid is preferred.

[0154] In view of reactivity, the amount of the reagent used for the isomerization reaction of the double bond is preferably 0.0001 mol to 100 mol, more preferably 0.001 mol to 10 mol, even more preferably 0.01 mol to 1 mol, per mol of the α-cadaverine group compound (3).

[0155] Examples of reagents used in the double bond isomerization reaction include ether solvents such as tetrahydrofuran, 4-methyltetrahydropyran, diethyl ether, tert-butyl methyl ether, and 1,4-dioxane; hydrocarbon solvents such as toluene, xylene, and hexane; and polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, dichloromethane, and chloroform. In view of the reaction rate, hydrocarbon solvents such as toluene are preferred.

[0156] If necessary, the solvent may be used alone or in combination. The solvent may be a commercially available product.

[0157] The amount of the solvent used varies depending on the production scale, and is preferably 200 g to 8,000 g per mol of the α-cadaverine-based compound (3) in consideration of the reaction rate.

[0158] The reaction temperature for double bond isomerization is preferably -78°C to the boiling point of the solvent, more preferably 0°C to 150°C, in view of reactivity and suppression of by-product formation.

[0159] The reaction time for double bond isomerization varies depending on the solvent to be used and / or the reaction scale, and is preferably 0.1 hour to 120 hours.

[0160] Methyl (1RS)-(2,2,3,4-tetramethyl-3-cyclopentenyl)isobutyrate (4A) in the γ-cadaverine-based compound (4) can be synthesized by positional isomerization of the double bond of methyl (1RS,4RS)-(3,4,5,5-tetramethyl-2-cyclopentenyl)isobutyrate (3A), as shown in the following chemical reaction formula (see also Example 2 below).

[0161]

[0162] Specifically, formula (3A) represents (1R,4R)-(3,4,5,5-tetramethyl-2-cyclopentenyl)isobutyric acid methyl ester of the following formula (3A-1), (1S,4S)-(3,4,5,5-tetramethyl-2-cyclopentenyl)isobutyric acid methyl ester of the following formula (3A-2), or both.

[0163]

[0164] The boldface wedge bonds and cut wedge bonds in the general formulae (3A-1) and (3A-2) represent the absolute configuration.

[0165] [3] Step B

[0166] Step B for synthesizing a 3,5,5-trimethyl-3-cyclopentene compound (1) will be described below. As shown in the following chemical reaction formula, a 3,5,5-trimethyl-3-cyclopentene compound (1) is synthesized by subjecting (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C) to (i) an esterification reaction, (ii) a combination of an esterification reaction and a halogenation reaction, or (iii) a combination of an esterification reaction and a sulfonylation reaction. One or more reactions are selected based on reactivity, reaction selectivity, availability, ease of synthesis, storage stability, toxicity, and / or price.

[0167]

[0168] The 3,5,5-trimethyl-3-cyclopentene compound (1) is as described above.

[0169] The esterification reactions in (i), (ii) and (iii) above can be carried out in any known method for preparing esters, such as reaction with an acylating agent, reaction with a carboxylic acid or transesterification.

[0170] For the reaction with the acylating agent, (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C) is contacted sequentially or simultaneously with the acylating agent in a solvent in the presence of a base.

[0171] Examples of the acylating agent include acyl halides such as acetyl chloride, isobutyryl chloride and benzoyl chloride; carboxylic anhydrides such as acetic anhydride and isobutyric anhydride; carboxylic acid mixed anhydrides such as carboxylic acid / trifluoroacetic acid mixed anhydride, carboxylic acid / methanesulfonic acid mixed anhydride, carboxylic acid / trifluoromethanesulfonic acid mixed anhydride, carboxylic acid / benzenesulfonic acid mixed anhydride, carboxylic acid / p-toluenesulfonic acid mixed anhydride; and p-nitrophenyl carboxylate.

[0172] The amount of the acylating agent used is preferably 1 mol to 500 mol, more preferably 1 mol to 50 mol, even more preferably 1 mol to 5 mol, per mol of (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C).

[0173] Examples of the base used in the reaction with the acylating agent include diisopropylethylamine, N,N-dimethylaniline, N,N-diethylaniline, pyridine, 2-ethylpyridine and 4-dimethylaminopyridine.

[0174] The amount of the base to be used is preferably 1 mol to 500 mol per mol of (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C).

[0175] The solvent used in the reaction with the acylating agent may be the above-mentioned base itself, or an ether solvent such as tetrahydrofuran, 4-methyltetrahydropyran, diethyl ether, methyl tert-butyl ether and 1,4-dioxane; a hydrocarbon solvent such as toluene, xylene and hexane; and a polar solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, dichloromethane and chloroform.

[0176] If necessary, the solvents may be used alone or in combination. The solvents may be commercially available products.

[0177] The amount of the solvent used is preferably 0 g to 100,000 g, more preferably 0 g to 10,000 g, per mol of (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C). When a base is used as the solvent, any additional solvent other than the base may not be required.

[0178] When carboxylic acid anhydride, carboxylic acid mixed anhydride or p-nitrophenylcarboxylate is particularly used as the acylating agent in the reaction, an acid catalyst may be used instead of the base.

[0179] Examples of the acid catalyst include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and nitric acid; organic acids such as oxalic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; and Lewis acids such as aluminum trichloride, aluminum ethoxide, aluminum isopropoxide, aluminum oxide, boron trifluoride, boron trichloride, boron tribromide, magnesium chloride, magnesium bromide, magnesium iodide, zinc chloride, zinc bromide, zinc iodide, tin tetrachloride, tin tetrabromide, dibutyltin dichloride, dibutyltin dimethanolate, dibutyltin oxide, titanium tetrachloride, titanium tetrabromide, titanium (IV) methoxide, titanium (IV) ethoxide, titanium (IV) isopropoxide and titanium (IV) oxide.

[0180] If necessary, the acylating agent may be used alone or in combination. The acylating agent may be a commercially available product.

[0181] The amount of the acid catalyst used in the reaction with a specific acylating agent (such as carboxylic acid anhydride, carboxylic acid mixed anhydride or p-nitrophenylcarboxylate) is preferably 0.0001 mol to 100 mol per mol of (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C).

[0182] The reaction temperature for the reaction with the acylating agent is preferably -50°C to 150°C, more preferably -20°C to 50°C, in view of the reaction rate and suppression of formation of by-products.

[0183] The reaction time for the reaction with the acylating agent varies depending on the solvent to be used and / or the reaction scale, and is preferably 0.1 hour to 120 hours.

[0184] The reaction with the carboxylic acid is a dehydration reaction between (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C) and the carboxylic acid, and is usually carried out in the presence of an acid catalyst.

[0185] Specific examples of the carboxylic acid used in the reaction between (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C) and the carboxylic acid include linear saturated carboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, valeric acid and hexanoic acid; branched saturated carboxylic acids such as isobutyric acid, isovaleric acid, 4-methylvaleric acid, 2-methylbutyric acid and pivalic acid; linear unsaturated carboxylic acids such as acrylic acid, crotonic acid and 3-butenoic acid; branched unsaturated carboxylic acids such as methacrylic acid, senecioic acid, tiglic acid, angelic acid, 3-methyl-4-pentenoic acid and 4-methyl-4-pentenoic acid; and aromatic carboxylic acids such as benzoic acid.

[0186] The amount of the carboxylic acid used is preferably 1 mol to 500 mol, more preferably 1 mol to 50 mol, even more preferably 1 mol to 5 mol, per mol of (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C).

[0187] An acid catalyst can be used in the reaction between (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C) and a carboxylic acid. The acid catalyst can be those used in the reaction with an acylating agent.

[0188] The amount of the acid catalyst used is preferably 0.0001 to 100 mol, more preferably 0.001 to 1 mol, even more preferably 0.01 to 0.05 mol, per mol of (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C).

[0189] The solvent and its amount used in the reaction between (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C) and carboxylic acid may be those described above for the reaction with the acylating agent.

[0190] The reaction temperature of the reaction of (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C) with carboxylic acid is preferably -50 to 150°C, more preferably 0 to 150°C, in consideration of reaction rate and suppression of by-product formation.

[0191] The reaction can be carried out in a solvent, for example a hydrocarbon solvent, such as hexane, heptane, benzene, toluene, xylene or cumene, while the resulting water is removed from the system by azeotropic distillation. Alternatively, the water can be removed by reflux distillation at the boiling point of the solvent under normal pressure, or by distillation at a temperature below the boiling point of water under reduced pressure.

[0192] The reaction time of the reaction between (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C) and carboxylic acid varies depending on the solvent to be used and / or the reaction scale, and is preferably 0.1 to 120 hours.

[0193] The transesterification reaction is carried out by reacting (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C) with an alkyl carboxylate in the presence of an acid catalyst and removing the resulting alcohol.

[0194] The alkyl carboxylate is preferably a primary alkyl carboxylate. In consideration of price and / or ease of reaction, methyl carboxylate, ethyl carboxylate and n-propyl carboxylate are preferred.

[0195] Examples of the carboxylic acid include those used in the above-mentioned reaction with the carboxylic acid.

[0196] The amount of the alkyl carboxylate used is preferably 1 mol to 500 mol, more preferably 1 mol to 50 mol, even more preferably 1 mol to 5 mol, per mol of (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C).

[0197] Examples of the acid catalyst used in the transesterification reaction include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and nitric acid; organic acids such as oxalic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; and Lewis acids such as aluminum trichloride, aluminum ethoxide, aluminum isopropoxide, aluminum oxide, boron trifluoride, boron trichloride, boron tribromide, magnesium chloride, magnesium bromide, magnesium iodide, zinc chloride, zinc bromide, zinc iodide, tin tetrachloride, tin tetrabromide, dibutyltin dichloride, dibutyltin dimethanolate, dibutyltin oxide, titanium tetrachloride, titanium tetrabromide, titanium (IV) methoxide, titanium (IV) ethoxide, titanium (IV) isopropoxide and titanium (IV) oxide.

[0198] If necessary, an acid catalyst may be used alone or in combination. The acid catalyst may be a commercially available product.

[0199] The amount of the acid catalyst used is preferably 0.0001 to 100 mol, more preferably 0.001 to 1 mol, even more preferably 0.01 to 0.05 mol, per mol of (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C).

[0200] The transesterification reaction can be carried out using the reactant alkyl carboxylate as solvent (without any additional solvent) or using an auxiliary solvent. The former embodiment without any additional solvent is preferred because it does not require additional operations such as concentration or solvent recovery.

[0201] Examples of the solvent used in the transesterification reaction include ether solvents such as tetrahydrofuran, 4-methyltetrahydropyran, diethyl ether, tert-butyl methyl ether, and 1,4-dioxane; and hydrocarbon solvents such as toluene, xylene, and hexane.

[0202] If necessary, the solvent may be used alone or in combination. The solvent may be a commercially available product.

[0203] The amount of the solvent used is preferably 10 g to 10,000 g per mol of (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C).

[0204] Taking the reaction rate into consideration, the transesterification reaction can be preferably carried out at a temperature close to the boiling point of the lower alcohol (such as C1-C3 alcohol, for example methanol, ethanol and 1-propanol) formed in the transesterification, while the alcohol is distilled off. The alcohol can be distilled off at a temperature lower than its boiling point under reduced pressure.

[0205] The reaction time of the transesterification reaction varies depending on the solvent to be used and / or the reaction scale, and is preferably 0.1 hour to 120 hours.

[0206] Next, the halogenation reaction combined with the esterification reaction in scheme (ii) will be described. Any known halogenation method can be applied. Examples of known halogenation reaction methods include reactions with a halogenating agent or with a sulfonyl halide.

[0207] Examples of the halogenating agent include thionyl halides such as thionyl chloride and thionyl bromide; phosphorus halides such as phosphorus trichloride, phosphorus pentachloride and phosphorus pentabromide; phosphorus oxyhalides such as phosphorus oxychloride and phosphorus oxybromide; and aromatic phosphorus halides such as triphenylphosphine dichloride and triphenylphosphine dibromide.

[0208] Examples of the sulfonyl halide include methanesulfonyl chloride, ethanesulfonyl chloride and trifluoromethanesulfonyl chloride. When the sulfonyl halide is used, the secondary hydroxyl group is sulfonated and then the resulting sulfonyloxy group can be substituted with a halogen atom by heating if necessary.

[0209] The halogenation reaction is preferably carried out under alkaline or weakly acidic conditions. A preferred example of the halogenation reaction is carried out using a sulfonyl halide in the presence of a base. For example, alkaline or weakly acidic conditions can be selected by adjusting the amount of the sulfonyl halide and the base.

[0210] Examples of the base used in the halogenation reaction include amines such as diethylamine, triethylamine, diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]-7-undecene, 1,5-diazabicyclo[4.3.0]-5-nonene, N-methylmorpholine, and N,N-dimethylaniline; organic bases such as imidazole and pyrazole; inorganic bases such as alkali metal or alkaline earth metal hydroxides, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, and barium hydroxide; alkali metal or alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, and barium carbonate; metal alkoxides such as sodium ethoxide; alkali metal amides such as sodium amide and lithium amide; and alkali metal hydrides such as sodium hydride and lithium hydride. Specific preferred examples include pyridine and triethylamine.

[0211] Examples of the solvent used in the halogenation reaction include ether solvents such as tetrahydrofuran, 4-methyltetrahydropyran, diethyl ether, tert-butyl methyl ether, and 1,4-dioxane; hydrocarbon solvents such as toluene, xylene, and hexane; and polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, dichloromethane, and chloroform. In view of the reaction rate, hydrocarbon solvents such as toluene are preferred.

[0212] If necessary, the solvents may be used alone or in combination. The solvents may be commercially available products.

[0213] The amount of the solvent used is preferably 10 g to 10,000 g per mol of the (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)carboxylic acid methyl ester compound.

[0214] The reaction temperature of the halogenation reaction is preferably -78°C to 150°C, more preferably -10°C to 100°C, in consideration of the reaction rate.

[0215] The reaction time of the halogenation reaction varies depending on the solvent to be used and / or the reaction scale, and is preferably 0.1 hour to 120 hours.

[0216] Finally, the combination of the sulfonylation reaction and the esterification reaction in scheme (iii) will be described. Any sulfonylation reaction method can be applied. Examples of known sulfonylation reactions include reactions with alkanesulfonating agents or with aromatic sulfonating agents.

[0217] Examples of the alkanesulfonating agent include alkanesulfonic anhydrides which may be substituted, such as methanesulfonic anhydride, ethanesulfonic anhydride and trifluoromethanesulfonic anhydride; and alkanesulfonyl chlorides which may be substituted, such as methanesulfonyl chloride, ethanesulfonyl chloride and trifluoromethanesulfonyl chloride.

[0218] Examples of the aromatic sulfonating agent include aromatic sulfonic anhydrides such as benzenesulfonic anhydride and p-toluenesulfonic anhydride; and aromatic sulfonyl chlorides such as benzenesulfonyl chloride and p-toluenesulfonyl chloride.

[0219] The sulfonylation reaction is preferably carried out under alkaline or weakly acidic conditions, and preferred examples of the sulfonylation reaction include reactions with sulfonyl halide and base. For example, alkaline or weakly acidic conditions can be selected by adjusting the amounts of sulfonyl halide and base.

[0220] Examples of the base used in the sulfonylation reaction include amines such as diethylamine, triethylamine, diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]-7-undecene, 1,5-diazabicyclo[4.3.0]-5-nonene, N-methylmorpholine and N,N-dimethylaniline; pyridines such as pyridine, methylethylpyridine, lutidine and N,N-dimethyl-4-aminopyridine; organic bases such as imidazole and pyrazole; inorganic bases such as alkali metal or alkaline earth metal hydroxides, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide and barium hydroxide; alkali metal or alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate and barium carbonate; metal alkoxides such as sodium ethoxide; alkali metal amides such as sodium amide and lithium amide; and alkali metal hydrides such as sodium hydride and lithium hydride. Specific limited examples include pyridine and triethylamine.

[0221] Examples of the solvent used in the sulfonylation reaction include ether solvents such as tetrahydrofuran, 4-methyltetrahydropyran, diethyl ether, tert-butyl methyl ether, and 1,4-dioxane; hydrocarbon solvents such as toluene, xylene, and hexane; and polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, dichloromethane, and chloroform. In view of the reaction rate, hydrocarbon solvents such as toluene are preferred.

[0222] If necessary, the solvent may be used alone or in combination. The solvent may be a commercially available product.

[0223] The amount of the solvent used is preferably 10 g to 10,000 g per mol of the (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)carboxylic acid methyl ester compound.

[0224] The reaction temperature of the sulfonylation reaction is preferably -78°C to 150°C, more preferably -10°C to 100°C, in consideration of the reaction rate.

[0225] The reaction time of the sulfonylation reaction varies depending on the solvent to be used and / or the reaction scale, and is preferably 0.1 hour to 120 hours.

[0226] Selection among (i) esterification; (ii) a combination of esterification and halogenation; and (iii) a combination of esterification and sulfonylation is performed based on, for example, the leaving group X, as described below.

[0227] When the leaving group X is an acyloxy group, an esterification reaction is selected to convert the secondary hydroxyl group of the compound having a 3,5,5-trimethyl-3-cyclopentene group.

[0228] When the leaving group X is a halogen atom, the primary hydroxyl group of (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C) is esterified, and then the secondary hydroxyl group is converted with a halogenating agent.

[0229] When the leaving group X is an alkanesulfonyloxy group, the primary hydroxyl group of (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C) is esterified, and then the secondary hydroxyl group is converted with an alkanesulfonating agent.

[0230] When the leaving group X is an arylsulfonyloxy group, the primary hydroxyl group of (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C) is esterified, and then the secondary hydroxyl group is converted with an arylsulfonating agent.

[0231] [4] Step A

[0232] The following describes a method for producing (2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5). (2-Hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5) is synthesized by subjecting a 3,5,5-trimethyl-2-oxo-3-cyclopentene-1-carboxylate compound (6) (hereinafter also referred to as the starting material (6)) to a reduction reaction.

[0233] The preparation method may be any of the following schemes: (i) a method of directly reducing the starting material (6), and (ii) a method of converting the starting material (6) into its corresponding carboxylic acid and subjecting the carboxylic acid to a reduction reaction.

[0234] First, (i) a method of directly reducing the starting material (6) will be described.

[0235] As shown in the following chemical reaction formula, (2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5) is synthesized by subjecting a 3,5,5-trimethyl-2-oxo-3-cyclopentene-1-carboxylate compound (6) to a reduction reaction.

[0236]

[0237] R in general formula (6) 1 represents a monovalent hydrocarbon group having 1 to 10, preferably 1 to 6, carbon atoms.

[0238] Monovalent hydrocarbon group R 1 Examples of the hydrocarbon radical include straight-chain saturated hydrocarbon radicals such as a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, an n-heptyl group, an n-octyl group, and an n-nonyl group; branched-chain saturated hydrocarbon radicals such as an isopropyl group, a 2-methylbutyl group, and a tert-butyl group; cyclic saturated hydrocarbon radicals such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cyclopentylmethyl group; straight-chain unsaturated hydrocarbon radicals such as a vinyl group, an allyl group, and an ethynyl group; branched-chain unsaturated hydrocarbon radicals such as an isopropenyl group and a 2-methyl-2-propenyl group; cyclic unsaturated hydrocarbon radicals such as a phenyl group, a tolyl group, a dimethylphenyl group, a benzyl group, and a phenethyl group; and isomers thereof. A portion of the hydrogen atoms in the hydrocarbon radical may be substituted by a monovalent hydrocarbon radical having 1 to 9 carbon atoms.

[0239] Specific examples of the 3,5,5-trimethyl-2-oxo-3-cyclopentene-1-carboxylate compound (6) include ethyl 3,5,5-trimethyl-2-oxo-3-cyclopentene-1-carboxylate (6A), tert-butyl 3,5,5-trimethyl-2-oxo-3-cyclopentene-1-carboxylate, and phenyl 3,5,5-trimethyl-2-oxo-3-cyclopentene-1-carboxylate.

[0240] (2-Hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5) has four stereoisomers. That is, (2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5) includes (1R,2R)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol of the following formula (5-1), (1R,2S)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol of the following formula (5-2), (1S,2R)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol of the following formula (5-3), and (1S,2S)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol of the following formula (5-4), as well as racemic forms, scalemic mixtures, and diastereomeric mixtures thereof.

[0241]

[0242] The cut wedge bonds and bold wedge bonds in the general formulae (5-1), (5-2), (5-3) and (5-4) represent absolute configurations.

[0243] Among the four isomers (5-1) to (5-4) of (2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol, the aforementioned (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C) is (1R,2S)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5-2) and / or (1S,2R)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5-3).

[0244] The reduction reaction can be carried out as any known reduction reaction of carboxylic acid esters. In the reduction reaction, the reaction substrate is reacted with a reducing agent in a solvent, if necessary, with cooling or heating.

[0245] The reduction substrate depends on the reducing agent to be used and / or the reaction conditions. For example, when R 1 In the case of a primary or secondary alkyl group, the 3,5,5-trimethyl-2-oxo-3-cyclopentene-1-carboxylate compound (6) itself can be used as a reduction substrate.

[0246] Examples of reducing agents used in the reduction reaction include hydrogen; boron compounds such as borane, alkylborane, dialkylborane and bis(3-methyl-2-butyl)borane; metal hydrides such as dialkylsilane, trialkylsilane, monoalkylaluminum hydride and dialkylaluminum hydride; complex hydrides such as sodium borohydride, lithium borohydride, potassium borohydride, calcium borohydride, sodium aluminum hydride, lithium aluminum hydride, sodium trimethoxyborohydride, zinc borohydride, lithium trimethoxyaluminum hydride, lithium diethoxyaluminum hydride, lithium tri-tert-butoxyaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, lithium triethylborohydride and diisobutylaluminum hydride; and alkoxy derivatives or alkyl derivatives thereof. In view of the ease of reaction conditions and / or post-processing, complex hydrides are preferred.

[0247] The amount of the reducing agent used in the reduction reaction varies depending on the reducing agent to be used and / or the reducing conditions, and is preferably 0.5 mol to 500 mol, more preferably 0.9 mol to 8 mol, per mol of the substrate, i.e., 3,5,5-trimethyl-2-oxo-3-cyclopentene-1-carboxylate compound (6).

[0248] Examples of the solvent used in the reduction reaction include water; alcohol solvents such as methanol, ethanol, isopropanol, tert-butanol, benzyl alcohol, methoxyethanol and ethoxyethanol; ether solvents such as ethylene glycol monomethyl ether, triethylene glycol monomethyl ether, tetrahydrofuran, 4-methyltetrahydropyran, diethyl ether, tert-butyl methyl ether and 1,4-dioxane; hydrocarbon solvents such as toluene, xylene and hexane; and polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, dichloromethane and chloroform.

[0249] If necessary, the solvent may be used alone or in combination. The solvent may be a commercially available product.

[0250] The solvent used in the reduction reaction is appropriately selected according to the reducing agent to be used. Examples of preferred combinations of the reducing agent and the solvent include a combination of the reducing agent lithium borohydride with an ether solvent, a mixed solvent of an ether solvent and an alcohol solvent, or a mixed solvent of an ether solvent and a hydrocarbon solvent; and a combination of the reducing agent lithium aluminum hydride with an ether solvent or a mixed solvent of an ether solvent and a hydrocarbon solvent.

[0251] The amount of the solvent used in the reduction reaction varies depending on the production scale, and is preferably 0.01 g to 100,000 g, more preferably 0.1 g to 10,000 g, even more preferably 1 g to 1,000 g per mol of the substrate (6) in consideration of the reaction rate.

[0252] The reaction temperature of the reduction reaction is preferably -78°C to 100°C, more preferably -20°C to 80°C, in view of the reaction rate and suppression of formation of by-products.

[0253] The reaction time of the reduction reaction varies depending on the solvent used and / or production scale, and is preferably 0.1 to 120 hours.

[0254] Specific examples of the method for producing (2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5) include a method of reacting ethyl 3,5,5-trimethyl-2-oxo-3-cyclopentene-1-carboxylate (6A) with lithium aluminum hydride as shown in the following chemical reaction formula.

[0255]

[0256] (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C) in (2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5) is synthesized by directly subjecting 3,5,5-trimethyl-2-oxo-3-cyclopentene-1-carboxylate compound (6) to a reduction reaction, similar to the case of (2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5).

[0257] Next, step A for obtaining (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C) will be described.

[0258] Depending on the solvent and / or reducing agent to be used, and the ratio of the amount of stereoisomers of (2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5), (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C) can be selectively prepared. The solvent and reducing agent can be those mentioned for the reduction reaction. A person skilled in the art can select a solvent suitable for the stereoselective reaction from the above-mentioned solvents. The stereoselective reaction can be carried out using, for example, a Lewis acidic reducing agent (e.g., diisobutylaluminum hydride).

[0259] An example of a method for producing (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C) is a method of reacting ethyl 3,5,5-trimethyl-2-oxo-3-cyclopentene-1-carboxylate (6A) with diisobutylaluminum hydride as shown in the following chemical reaction formula.

[0260]

[0261] Next, method (ii) will be described, in which the starting material (6) is converted into its corresponding carboxylic acid (and then reduced).

[0262] (2-Hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5) is synthesized by converting a 3,5,5-trimethyl-2-oxo-3-cyclopentene-1-carboxylate compound (6) into its corresponding carboxylic acid, 3,5,5-trimethyl-2-oxo-3-cyclopentene-1-carboxylic acid, followed by a reduction reaction.

[0263] First, the conversion of the 3,5,5-trimethyl-2-oxo-3-cyclopentene-1-carboxylate compound (6) to 3,5,5-trimethyl-2-oxo-3-cyclopentene-1-carboxylic acid will be described.

[0264] The conversion of 3,5,5-trimethyl-2-oxo-3-cyclopentene-1-carboxylic acid ester compound (6) to 3,5,5-trimethyl-2-oxo-3-cyclopentene-1-carboxylic acid can be carried out in any known conversion reaction from ester to carboxylic acid, such as a hydrolysis reaction under alkaline or neutral conditions, or an elimination reaction under acidic conditions. 11 In the case of a primary or secondary hydrocarbon group, hydrolysis is preferred. 1 In the case of a tertiary hydrocarbon group, an elimination reaction is preferred.

[0265] In hydrolysis reactions, the substrate reacts with water in the solvent or added water, usually in the presence of a base or salt. In elimination reactions, an acid in the solvent promotes the reaction. In both reactions, cooling or heating may be performed if necessary.

[0266] Examples of the base used in the hydrolysis reaction include hydroxides such as sodium hydroxide, lithium hydroxide, potassium hydroxide and barium hydroxide; carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate; and metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, sodium tert-butoxide, sodium tert-amylate, lithium methoxide, lithium ethoxide, lithium tert-butoxide, lithium tert-amylate, potassium methoxide, potassium ethoxide, potassium tert-butoxide and potassium tert-amylate.

[0267] If necessary, the base may be used alone or in combination. The base may be a commercially available product.

[0268] In view of reactivity, the amount of the base used is preferably 1 mol to 1,000 mol, more preferably 1 mol to 100 mol, even more preferably 1 mol to 10 mol, per mol of the 3,5,5-trimethyl-2-oxo-3-cyclopentene-1-carboxylate compound (6).

[0269] Examples of the acid or salt used in the hydrolysis include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid and phosphoric acid, or salts thereof; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and naphthalenesulfonic acid, or salts thereof; Lewis acids such as aluminum trichloride, aluminum ethoxide, aluminum isopropoxide, aluminum oxide, boron trifluoride, boron trichloride, boron tribromide, tin tetrachloride, tin tetrabromide, dibutyltin dichloride, dibutyltin dimethanolate, dibutyltin oxide, titanium tetrachloride, titanium tetrabromide, titanium (IV) methoxide, titanium (IV) ethoxide, titanium (IV) isopropoxide and titanium (IV) oxide; and oxides such as alumina, silica gel and titanium dioxide.

[0270] If necessary, the salts may be used alone or in combination. The salts may be commercially available products.

[0271] The amount of the salt used is preferably 1 mol to 1,000 mol, more preferably 1 mol to 100 mol, even more preferably 1 mol to 10 mol, per mol of the 3,5,5-trimethyl-2-oxo-3-cyclopentene-1-carboxylate compound (6) in view of reactivity.

[0272] Examples of the solvent used in the hydrolysis reaction or the elimination reaction include water; alcohol solvents such as methanol, ethanol, isopropanol, tert-butanol, benzyl alcohol, methoxyethanol and ethoxyethanol; ether solvents such as ethylene glycol monomethyl ether, triethylene glycol monomethyl ether, tetrahydrofuran, 4-methyltetrahydropyran, diethyl ether, tert-butyl methyl ether and 1,4-dioxane; hydrocarbon solvents such as toluene, xylene and hexane; and polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, dichloromethane and chloroform.

[0273] If necessary, the solvent may be used alone or in combination. The solvent may be a commercially available product.

[0274] The amount of the solvent used varies depending on the production scale, and is preferably 0.01 g to 200,000 g, more preferably 0.1 g to 20,000 g, and even more preferably 1 g to 2,000 g per mol of the 3,5,5-trimethyl-2-oxo-3-cyclopentene-1-carboxylate compound (6) in consideration of the reaction rate.

[0275] The reaction temperature of the hydrolysis reaction or elimination reaction is preferably -78°C to the boiling point of the solvent, more preferably -10°C to 100°C, in consideration of the reaction rate and suppression of formation of by-products.

[0276] The reaction time of the hydrolysis reaction or elimination reaction varies depending on the solvent to be used and / or the reaction scale, and is preferably 0.1 hour to 120 hours.

[0277] Next, the reduction reaction of 3,5,5-trimethyl-2-oxo-3-cyclopentene-1-carboxylic acid will be explained.

[0278] The reduction reaction can be carried out in any known reduction reaction such as from a carboxylic acid to an alcohol. The reduction reaction is usually carried out by reacting a reaction substrate with a reducing agent usually in a solvent, if necessary, with cooling or heating.

[0279] For example, when R 1 When the ternary group causes severe steric hindrance, the reduction reaction may proceed slowly, although it depends on the reducing agent to be used and / or the reaction conditions. Therefore, it is preferable to convert the 3,5,5-trimethyl-2-oxo-3-cyclopentene-1-carboxylate compound (6) into 3,5,5-trimethyl-2-oxo-3-cyclopentene-1-carboxylic acid, which is used as a reaction substrate for the reduction reaction.

[0280] The reducing agent, the amount of the reducing agent, the solvent, the amount of the solvent, the reaction temperature and the reaction time in the reduction reaction are as described above.

[0281] Another specific example of the method for producing (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C) includes converting a 3,5,5-trimethyl-2-oxo-3-cyclopentene-1-carboxylate compound (6) into its corresponding 3,5,5-trimethyl-2-oxo-3-cyclopentene-1-carboxylic acid, and then subjecting the carboxylic acid to a reduction reaction. This reduction method also uses, for example, diisobutylaluminum hydride, which can be used as a reducing agent in the reduction reaction.

[0282] Example

[0283] The present invention will be described with reference to the following examples. It should be understood that the present invention is not limited to or by these examples.

[0284] Unless otherwise specified, the term "purity" used herein refers to the area percentage determined by gas chromatography (hereinafter also referred to as "GC"). The term "yield ratio" refers to the relative ratio of the area percentages determined by GC.

[0285] Yields were calculated from area percentages determined by GC.

[0286] Taking into account the purity (% GC) of the starting material and the product, the yield was calculated according to the following equation.

[0287] Yield (%) = {[(mass of the product obtained by the reaction × %GC) / molecular weight of the product] ÷ [(mass of the starting material × %GC) / molecular weight of the starting material]} × 100

[0288] The term "crude yield" refers to the yield of crude product obtained without purification.

[0289] In the examples, reaction monitoring and yield calculation were performed under the following GC conditions.

[0290] GC conditions: capillary gas chromatograph GC-2014 (Shimadzu Corporation); column: DB-5, 0.25 mm × 0.25 mm φ × 30 m; carrier gas: He (1.55 mL / min), detector: FID; column temperature: 100°C, increasing at a rate of 10°C / min to a maximum of 230°C.

[0291] Example 1: Preparation of (1RS,4RS)-(3,4,5,5-tetramethyl-2-cyclopentenyl)isobutyric acid methyl ester (3A)

[0292]

[0293] in i Pr represents an isopropyl group.

[0294] Copper (I) iodide (85.7 g, 0.450 mol) and tetrahydrofuran (THF) (801 g) are placed in a reactor and cooled to a temperature of 0 to 4° C. Lithium iodide (121 g, 0.904 mol) is then added at or below 10° C. Subsequently, a 0.00258 mol / g solution of methylmagnesium chloride in THF (348 g, 0.898 mol) is added dropwise at or below 10° C. After the addition is complete, the resulting reaction mixture is stirred at 0 to 4° C. for 30 minutes to prepare a solution of the methylating agent in THF.

[0295] Next, (1RS, 2SR) - (3,5,5-trimethyl-2-isobutyryloxy-3-cyclopentenyl) isobutyric acid methyl ester (1A) (88.9 g, 0.300 mol) and THF (91.2 g) were placed in another reaction vessel and stirred at 37 ° C to 42 ° C for 30 minutes. Then, a solution of the aforementioned methylating agent in THF was added dropwise at 35 ° C to 45 ° C. After the addition was completed, the reaction mixture was stirred at 37 ° C to 42 ° C for 3.5 hours. After the stirring was completed, the reaction mixture was cooled to 4 ° C to 10 ° C, and an aqueous solution of ammonium chloride (354 g: prepared from ammonium chloride (32 g) and water (322 g)) was added to quench the reaction. In addition, 20 wt % hydrochloric acid (64.4 g) and hexane (1,200 g) were added to the resulting reaction mixture, and the reaction mixture was phase separated. The organic layer was washed four times with aqueous ammonia (1,781 g: prepared from ammonium chloride (58 g), a 25 wt% aqueous sodium hydroxide solution (193 g), and water (1,530 g). The washed organic layer was further washed with brine (1,589 g: prepared from sodium chloride (59 g) and water (1,530 g). The resulting organic layer was concentrated under reduced pressure, and the concentrate was distilled under reduced pressure to obtain the target compound, methyl (1RS,4RS)-(3,4,5,5-tetramethyl-2-cyclopentenyl)isobutyrate (3A) (65.5 g, 0.292 mol), in a yield of 97.3%.

[0296] The following is the spectral data obtained for methyl (1RS,4RS)-(3,4,5,5-tetramethyl-2-cyclopentenyl)isobutyrate (3A).

[0297] NMR spectroscopy: 1 H-NMR (500MHz, CDCl3): δ = 0.88 (d, J = 7.3Hz, 3H), 0.95 (s, 3H), 0.96 (s, 3H), 1.16 (d, J = 6.9Hz, 6H), 1.65 (q, J = 1.9Hz, 3H), 2.10-2 .15(m,1H),2.45-2.49(m,1H),2.49-2.56(m,1H),3.93(dd,J=11.1,6.9Hz,1H),4.10(dd,J=11.1,6.5Hz,1H),5.14-5.15(m,1H); 13 C-NMR (75.6MHz, CDCl3): δ=12.36,15.17,18.97,19.00,23.95,24.59,34.13,43.01,52.52,52.61,64.59,123.03,145.27,177.21.

[0298] GC-MS (EI, 70eV): m / z 224 (M+ ),136,121,105,93,81,67,55,43,27.

[0299] Infrared absorption spectrum (NaCl): νmax 3040, 2966, 2873, 1737, 1470, 1387, 1258, 1191, 1157, 1074, 982, 919, 826, 755.

[0300] Example 2: Preparation of (1RS)-(2,2,3,4-tetramethyl-3-cyclopentenyl)isobutyric acid methyl ester (4A)

[0301]

[0302] The (1RS, 4RS)-(3,4,5,5-tetramethyl-2-cyclopentenyl) methyl isobutyrate (3A) (0.61 g, 2.7 mmol) obtained in Example 1, p-toluenesulfonic acid monohydrate (p-TsOH HO) (0.08 g, 0.4 mmol) and toluene (20 mL) were placed in a reactor and stirred at 100° C. to 110° C. for 9 hours. The reaction mixture was then cooled to 4° C. to 10° C., and an aqueous solution of sodium bicarbonate (10.1 g: prepared from sodium bicarbonate (0.10 g) and water (10 g)) was added to quench the reaction. The resulting reaction mixture was phase separated, and the organic layer was washed with saturated brine (30 mL). The obtained organic layer was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate gradient = 100:1 to 80:1) to obtain the target compound, (1RS)-(2,2,3,4-tetramethyl-3-cyclopentenyl)isobutyric acid methyl ester (4A) (0.55 g, 2.4 mmol) in a yield of 89%.

[0303] The following is the spectral data of methyl (1RS)-(2,2,3,4-tetramethyl-3-cyclopentenyl)isobutyrate (4A) prepared in this way.

[0304] NMR spectroscopy: 1 H-NMR (500MHz, CDCl3): δ = 0.82 (s, 3H), 1.05 (s, 3H), 1.168 (d, J = 6.9Hz, 3H), 1.169 (d, J = 6.9Hz, 3H), 1.47-1.48 (m, 3H), 1.58 (brd, J = 1.2Hz, 3H),1.95-2.01(m,1H),2.09-2.15(m,1H),2.21-2.26(m,1H),2.50-2.58(m,1H),4.09(dd,J=11.1,7.7Hz,1H),4.15(dd,J=11.1,6.9Hz,1H);13 C-NMR (75.6MHz, CDCl3): δ=9.20,14.09,18.99,19.02,19.92,27.01,34.12,39.06,46.74,47.67,65.62,127.85,138.52,177.27.

[0305] GC-MS (EI, 70eV): m / z 224 (M + ),136,121,105,93,79,67,55,43,27.

[0306] Infrared absorption spectrum (NaCl): νmax 2967, 2929, 1737, 1470, 1386, 1360, 1261, 1193, 1157, 1073, 979, 919.

[0307] Example 3: Preparation of (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C)

[0308]

[0309] wherein Et represents an ethyl group.

[0310] 3,5,5-trimethyl-2-oxo-3-cyclopentene-1-carboxylic acid ethyl ester (6A) (84.1g, 0.429mol) and THF (1,029g) are placed in a reactor and stirred at -5°C to 5°C for 30 minutes. Then a 1.0mol / L solution of diisobutylaluminum hydride (i-Bu2AlH) in toluene (1,500mL, 1.50mol) is added dropwise to the mixture at -5°C to 5°C. After the addition is complete, the reaction mixture is stirred at room temperature for 30 minutes and further stirred at 55°C for 2 hours. After the stirring is complete, the reaction mixture is cooled to 4°C to 10°C, and ethanol (108g, 2.34mol) is added to quench the reaction. In addition, a saturated aqueous solution of potassium sodium tartrate (1,500mL) is added dropwise. After the addition is complete, the mixture is stirred at room temperature for 15 hours and further stirred at 50°C for 2 hours. After the stirring is complete, the obtained reaction mixture is phase separated. The organic layer was washed with saturated brine (1,000 mL) and concentrated under reduced pressure to obtain crude crystals. The crude crystals were recrystallized from n-hexane (500 mL) and ethyl acetate (78.5 mL) to obtain the target compound, (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C) (24.6 g, 0.158 mol), in a yield of 36.8%.

[0311] The following is the spectrum data of (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C) prepared in this way.

[0312] NMR spectroscopy: 1 H-NMR (500MHz, CDCl3): δ = 0.97 (s, 3H), 1.06 (s, 3H), 1.77-1.78 (m, 3H), 2.05 (ddd, J = 10.0, 6.5, 5.4Hz, 1H) ,3.79(dd,J=10.7,5.4Hz,1H),3.95(dd,J=10.7,10.0Hz,1H),4.58(d,J=6.5Hz,1H),5.39(q,J=1.5Hz,1H); 13 C-NMR (75.6MHz, CDCl3): δ=13.96, 25.45, 28.92, 44.67, 54.14, 59.86, 80.37, 137.91, 140.81.

[0313] GC-MS (EI, 70eV): m / z 156 (M + ),141,125,109,95,77,67,55,43,29.

[0314] Infrared absorption spectrum (NaCl): νmax 3312,3021,2971,2946,2862,1443,1404,1215,1112,1091,1030,971,952,902,873,772,718,644,594.

[0315] Example 4: Preparation of (2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5)

[0316]

[0317] wherein Et represents an ethyl group.

[0318] Lithium aluminum hydride (0.57g, 15mmol) and THF (18.7g) are placed in a reactor and stirred at room temperature for 1.5 hours. The reaction mixture is then cooled to 4°C to 10°C, 3,5,5-trimethyl-2-oxo-3-cyclopentene-1-carboxylic acid ethyl ester (6A) (1.43g, 7.27mmol) and THF (1.00g) are added dropwise at 4°C to 12°C. After completion of the addition, the reaction mixture is stirred at 20°C to 25°C for 2 hours. Subsequently, the reaction mixture is cooled to 4°C to 0°C, and water (1.13g), 25% by weight of sodium hydroxide solution (0.66g) and water (3.89g) are added successively to quench the reaction. Next, the reaction mixture is filtered through diatomaceous earth, and the resulting filtrate is concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: gradient of n-hexane: ethyl acetate = 20:1 to 2:3) to obtain the target compound, (2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5) (0.41 g, 2.6 mmol), which was a 45:55 mixture of (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C) and (1RS,2RS)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol in a yield of 36%.

[0319] The spectral data of (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C) thus prepared were the same as those determined in Example 3.

[0320] The following is the spectrum data of (1RS,2RS)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol prepared in this way.

[0321] NMR spectroscopy: 1 H-NMR (500MHz, CDCl3): δ=0.84(s,3H),1.12(s,3H),1.70-1.71(m,3H),1.88(ddd,J=10..0,7.6,5.4Hz,1H) ,3.83(dd,J=10.0,10.0Hz,1H),3.90(dd,J=10.0,5.4Hz,1H),4.50(d,J=7.6Hz,1H),5.28(q,J=1.5Hz,1H); 13 C-NMR (75.6MHz, CDCl3): δ=13.04, 23.47, 29.20, 43.04, 60.13, 60.21, 83.39, 137.47, 138.45.

[0322] GC-MS (EI, 70eV): m / z 156 (M +),141,125,109,95,77,67,55,43,29.

[0323] Infrared absorption spectrum (NaCl): νmax 3335,3022,2954,2866,1463,1448,1361,1254,1152,1090,1043,999,947,883,830,627.

[0324] Example 5: Preparation of (1RS,2SR)-(3,5,5-trimethyl-2-isobutyryloxy-3-cyclopentenyl)isobutyric acid methyl ester (1A)

[0325]

[0326] in i Pr represents an isopropyl group.

[0327] (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C) (137 g, 0.876 mol), THF (435 g) and pyridine (249 g, 3.15 mol) prepared according to the procedure described in Example 3 were placed in a reactor and stirred at 4°C to 10°C for 1 hour. Isobutyryl chloride (215 g, 2.01 mol) was then added dropwise to the mixture at or below 15°C. After the addition was complete, the reaction mixture was stirred at 4°C to 10°C for 3 hours, and brine (2,882 g: sodium chloride (262 g) and water (2,620 g)) was added to quench the reaction. Subsequently, hexane (545 g) was added to the reaction mixture, and the resulting mixture was phase separated. The organic layer was washed with hydrochloric acid (2,804 g: prepared from 20% by weight hydrochloric acid (117 g), sodium chloride (65 g), and water (2,622 g). Furthermore, the organic layer was washed sequentially with brine (2,687 g: prepared from sodium chloride (65 g) and water (2,622 g)), an aqueous sodium carbonate solution (2,753 g: prepared from sodium carbonate (131 g) and water (2,622 g), and brine (2,882 g: prepared from sodium chloride (262 g) and water (2,620 g)). The resulting organic layer was concentrated under reduced pressure, and the concentrate was distilled under reduced pressure to obtain the target compound, methyl (1RS,2SR)-(3,5,5-trimethyl-2-isobutyryloxy-3-cyclopentenyl)isobutyrate (1A) (255 g, 0.860 mol), in a yield of 98.2%.

[0328] The following is the spectral data of methyl (1RS,2SR)-(3,5,5-trimethyl-2-isobutyryloxy-3-cyclopentenyl)isobutyrate (1A) prepared in this way.

[0329] NMR spectroscopy:1 H-NMR (500MHz, CDCl3): δ1.00(s,3H),1.12(s,3H),1.12-1.15(m,12H),1.65(d,J=1.5Hz,3H),2.28(ddd,J=9.2,6.5,6.5Hz,1H ),2.48-2.54(m,2H),4.11(dd,J=11.1,6.5Hz,1H),4.17(dd,J=11.1,9.2Hz,1H),5.49(q,J=1.5Hz,1H),5.70(d,J=6.5Hz,1H); 13 C-NMR (75.6MHz, CDCl3): δ14.30,18.89,18.94,19.04(2C),24.48,27.84,3 3.98,34.28,45.21,50.19,60.69,79.97,135.32,143.10,176.51,177.07.

[0330] LC-MS (ESI, positive): m / z 314 (M + +18).

[0331] Infrared absorption spectrum (NaCl): νmax 2972, 2874, 1734, 1471, 1386, 1256, 1192, 1157, 1115, 1087, 983, 961, 900, 850, 756.

Claims

1. A method for preparing an α-cadaverine-based compound (3) of the following general formula (3): where R 2 represents a monovalent hydrocarbon group having 1 to 9 carbon atoms, and bold non-wedge bonds and cut non-wedge bonds represent relative configurations, The method comprises: The following 3,5,5-trimethyl-3-cyclopentene compound is prepared: where R 2 As defined above, X represents an acyloxy group having 1 to 10 carbon atoms including the carbon atom of the carbonyl group, and cleavage of the non-wedge bond represents a relative configuration, A nucleophilic substitution reaction is carried out with a methylating agent of the following general formula (2): CH3-M (2) Where M represents MgZ 1 or Cu, and Z 1 represents a halogen atom or a methyl group, to form α-cadaverine-based compound (3).

2. The method for preparing an α-cadaverine-based compound (3) according to claim 1, wherein the 3,5,5-trimethyl-3-cyclopentene compound (1) is (1RS,2SR)-(3,5,5-trimethyl-2-isobutyryloxy-3-cyclopentenyl)isobutyric acid methyl ester of the following formula (1A): in i Pr represents an isopropyl group, and cleavage of the non-wedge bond represents relative configuration, and The α-cadaverine-based compound (3) is (1RS,4RS)-(3,4,5,5-tetramethyl-2-cyclopentenyl)isobutyric acid methyl ester of the following formula (3A): The bold non-taped bonds and the cut non-taped bonds represent relative configurations.

3. A method for preparing a γ-cadaverine-based compound (4) of the following general formula (4): where R 2 represents a monovalent hydrocarbon group having 1 to 9 carbon atoms, The method comprises: The method for preparing an α-cadaverine-based compound (3) according to claim 1, and The α-cadaverine-based compound (3) thus obtained is subjected to positional isomerization reaction at the double bond in the presence of p-toluenesulfonic acid to form a γ-cadaverine-based compound (4).

4. The method for preparing a γ-cadaverine-based compound (4) according to claim 3, The γ-cadaverine-based compound (4) is (1RS)-(2,2,3,4-tetramethyl-3-cyclopentenyl)isobutyric acid methyl ester of the following formula (4A):

5. The method for preparing an α-cadaverine-based compound (3) according to claim 1, further comprising: (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol of the following formula (5C): The cut non-wedge bond represents the relative configuration, An esterification reaction is carried out to form the 3,5,5-trimethyl-3-cyclopentene compound (1).

6. The method for preparing an α-cadaverine-based compound (3) according to claim 5, further comprising: The following 3,5,5-trimethyl-2-oxo-3-cyclopentene-1-carboxylate compound of general formula (6) is prepared: where R 1 represents a monovalent hydrocarbon group having 1 to 10 carbon atoms, Reduction reaction is performed to form (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C).

7. The method for preparing an α-cadaverine-based compound (3) according to claim 5, further comprising: The following 3,5,5-trimethyl-2-oxo-3-cyclopentene-1-carboxylate compound of general formula (6) is prepared: where R 1 represents a monovalent hydrocarbon group having 1 to 10 carbon atoms, converted to the corresponding carboxylic acid, and The carboxylic acid thus obtained is subjected to a reduction reaction to form (1RS,2SR)-(2-hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol (5C).

8. A method for preparing a γ-cadaverine-based compound (4) of the following general formula (4): where R 2 represents a monovalent hydrocarbon group having 1 to 9 carbon atoms, The method comprises: The method for preparing an α-cadaverine-based compound (3) according to any one of claims 5 to 7, and The α-cadaverine-based compound (3) thus obtained is subjected to positional isomerization reaction at the double bond in the presence of p-toluenesulfonic acid to form a γ-cadaverine-based compound (4).

9. (2-Hydroxy-3,5,5-trimethyl-3-cyclopentenyl)methanol of the following formula (5):

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