(Z)-7-Tetradecen-2-one production method

Abstract

To provide an efficient process for producing (Z)-7-tetradecen-2-one.SOLUTION: The present invention relates to a production process, comprising the steps of: converting a compound of the formula (1) into a compound of the formula (2); subjecting the compound to an addition reaction with a compound of the formula (3) to obtain a compound of the formula (4); and oxidizing the compound to obtain (Z)-7-tetradecen-2-one (5). (X1 is a halogen atom, M1 is Li or MgZ1, and Z1 is a halogen atom or (4Z)-4-undecenyl group).SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a method for producing (Z)-7-tetradecen-2-one, which is a sex pheromone of the Oriental beetle (scientific name: Anomala orientalis , English name: Oriental beetle).

Background Art

[0002] The Oriental beetle is an important pest of blueberry trees in the United States. The feeding damage to the roots of blueberry trees by the larvae of the Oriental beetle reduces the vitality of the blueberry trees, and as a result, the fruit yield also decreases. In addition, when the density of the Oriental beetle is high and the feeding damage is severe, the blueberry trees may die. So far, in order to control the Oriental beetle, control using insecticides such as imidacloprid has been carried out. However, since the Oriental beetle burrows into the ground except during the adult period, it is not only difficult to grasp the spraying timing of the insecticide, but imidacloprid also has an adverse effect on honeybees, so it is not desirable. Therefore, attempts have been made to grasp the pest occurrence situation with a sex pheromone lure and spray the insecticide only at the necessary time, and biological control methods that minimize the use of insecticides have been studied. Among the biological control methods, control by disrupting communication using sex pheromones is expected as one of the control methods (Non-Patent Documents 1 and 2 below).

[0003] It has been reported that the sex pheromone substance of the Oriental beetle is a 7:1 mixture of (Z)-7-tetradecen-2-one and (E)-7-tetradecen-2-one (Non-Patent Document 3 below).

[0004] As a method for synthesizing (Z)-7-tetradecen-2-one, for example, in a mixed solvent of tetrahydrofuran and hexamethylphosphoric triamide (HMPA), 1-octynyllithium and 1,4-dibromobutane are reacted to synthesize 1-bromo-5-decyne. Subsequently, 1-bromo-5-decyne is subjected to a reduction reaction in a methanol solvent in the presence of a palladium-barium sulfate catalyst to synthesize 1-bromo-5-decene. Next, the obtained 1-bromo-5-decene is converted into a Grignard reagent, and subsequently, the Grignard reagent is subjected to an addition reaction with acetic anhydride to produce (Z)-7-tetradecen-2-one (Non-Patent Document 3 below).

[0005] Further, as another method for synthesizing (Z)-7-tetradecen-2-one, for example, in a mixed solvent of tetrahydrofuran and hexamethylphosphoric triamide (HMPA), 1-octynyllithium and 1,3-dibromopropane are reacted to synthesize 1-bromo-4-undecyne. Subsequently, in dimethyl sulfoxide (DMSO) in the presence of sodium hydride as a base, an acetoacetic ester synthesis reaction is carried out between ethyl acetoacetate (ethyl 3-oxobutanoate) and the above 1-bromo-4-undecyne to synthesize 3-ethoxycarbonyl-7-tetradecen-2-one. Next, the obtained 3-ethoxycarbonyl-7-tetradecen-2-one is subjected to alkali hydrolysis in a mixed solvent of potassium hydroxide, methanol and water, and subsequently, a decarboxylation reaction is carried out to synthesize 7-tetradecen-2-one. Subsequently, the obtained 7-tetradecen-2-one is subjected to a catalytic hydrogenation reaction using hydrogen in a methanol solvent in the presence of palladium-barium sulfate as a catalyst and quinoline as a catalyst poison to produce (Z)-7-tetradecen-2-one (Patent Document 1 below). In Patent Document 1, the yield of (Z)-7-tetradecen-2-one, based on the description of "In the first step, it is purified by distillation, and from the second step to the fourth step, (Z)-7-tetradecen-2-one can be produced with a purity of 95% or more without purification." in the examples of Patent Document 1, is 46.53% as estimated for 4 steps.

Prior Art Documents

Non-Patent Documents

[0006]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Patent Documents

[0007]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0008] However, the synthetic methods of (Z)-7-tetradecen-2-one in Non-Patent Document 3 and Patent Document 1 are not safe because they use a large amount of hexamethylphosphoric triamide, which is a carcinogenic substance, as a solvent, and they are not industrial because they use an expensive palladium catalyst. Furthermore, the production method of Patent Document 1 is not industrial because it uses pyrophoric sodium hydride, and as described by the inventors of Patent Document 1, impurities that cannot be detected by gas chromatography may be mixed in because purification is not performed in the second to fourth steps, which is undesirable from the perspective of quality control.

[0009] The present invention has been made in view of the above circumstances, and an object thereof is to provide a method capable of industrially producing (Z)-7-tetradecen-2-one in a short process and efficiently. [Means for Solving the Problems]

[0010] As a result of intensive studies to solve the above problems, the present inventors have found that a (Z)-1-halo-4-undecene compound is a useful intermediate in the production of (Z)-7-tetradecen-2-one (5), which is the sex pheromone of the beetle. And, by using the (Z)-1-halo-4-undecene compound, it has been found that the above (Z)-7-tetradecen-2-one can be industrially produced in a short process and efficiently, leading to the present invention.

[0011] According to a first aspect of the present invention, the following general formula (1): [Chemical formula] (wherein X 1 represents a halogen atom.) The (Z)-1-halo-4-undecene compound (1) represented by the following general formula (2): [Chemical formula] (wherein M 1 represents Li or MgZ 1 , and Z 1 represents a halogen atom or a (4Z)-4-undecenyl group.) is converted to a (Z)-4-undecenyl nucleophile represented by the following step, and the (Z)-4-undecenyl nucleophile (2) is subjected to an addition reaction with propylene oxide represented by the following formula (3): [Chemical formula] to give the following formula (4): [Chemical formula] The step of obtaining (Z)-7-tetradecen-2-ol represented by oxidizing the (Z)-7-tetradecen-2-ol (4) to obtain the following formula (5):

Chemical formula

[0012] According to a second aspect of the present invention, there is provided a method for producing (Z)-7-tetradecen-2-one (5), wherein the oxidation method described in the first aspect is carried out by Oppenauer oxidation.

[0013] According to a third aspect of the present invention, after the step of obtaining (Z)-7-tetradecen-2-one (5) described in the first or second aspect, there is further provided a method for producing (Z)-7-tetradecen-2-one (5) comprising a step of esterifying the remaining (Z)-7-tetradecen-2-ol (4). The esterification enables purification of the target (Z)-7-tetradecen-2-one (5) from the reaction mixture after the esterification.

[0014] According to a fourth aspect of the present invention, after the step of esterification, there is further provided a method for producing (Z)-7-tetradecen-2-one (5) comprising a step of purifying (Z)-7-tetradecen-2-one (5) from a mixture of the esterified product of (Z)-7-tetradecen-2-ol (4) and (Z)-7-tetradecen-2-one (5).

[0015] According to a fifth aspect of the present invention, The following general formula (6):

Chemical formula

[0016] According to the sixth aspect of the present invention, The following general formula (7):

Chemical formula

Chemical formula

Advantages of the Invention

[0017] According to the present invention, (Z)-7-tetradecen-2-one can be industrially produced in a short process, efficiently, and with good yield without using dangerous compounds such as carcinogenic substances and dangerous reactions using flammable sodium hydride. Further, according to the present invention, a useful synthetic intermediate for producing (Z)-7-tetradecen-2-one can be provided.

Modes for Carrying Out the Invention

[0018] A. Regarding the (Z)-1-halo-4-undecene compound represented by the following general formula (1) [Chemical formula]

[0019] In general formula (1), X 1 represents a halogen atom. Specifically, examples of the halogen atom X 1 include a chlorine atom, a bromine atom, and an iodine atom. From the perspective of versatility, a chlorine atom and a bromine atom are preferred, and a chlorine atom is particularly preferred.

[0020] Specific examples of the (Z)-1-halo-4-undecene compound (1) include (Z)-1-chloro-4-undecene, (Z)-1-bromo-4-undecene, and (Z)-1-iodo-4-undecene.

[0021] The (Z)-1-halo-4-undecene compound (1) can be produced, for example, according to the following chemical reaction formula. [Chemical formula]

[0022] First, a 1-halo-4-undecene compound represented by general formula (6) is produced by a coupling reaction between a hexyl nucleophile represented by general formula (7) and a 1,5-dihalo-1-pentyne compound represented by general formula (8). Subsequently, the above (Z)-1-halo-4-undecene compound (1) can be produced by subjecting the 1-halo-4-undecene compound (6) to a reduction reaction.

[0023] Next, in Sections B and C below, a specific production method of the (Z)-1-halo-4-undecene compound (1) will be described.

[0024] B. Method for producing a 1-halo-4-undecene compound (6) by a coupling reaction between a hexyl nucleophile (7) and a 1,5-dihalo-1-pentyne compound (8) [Chemical formula]

[0025] Regarding the B-1.1-halo-4-undecyne compound (6)

Chemical formula

[0026] In the general formula (6), X 1 represents a halogen atom. Specifically, examples of the halogen atom X 1 include a chlorine atom, a bromine atom, and an iodine atom. From the perspective of versatility, a chlorine atom and a bromine atom are preferred, and a chlorine atom is particularly preferred.

[0027] Specific examples of the 1-halo-4-undecyne compound (6) include 1-chloro-4-undecyne, 1-bromo-4-undecyne, and 1-iodo-4-undecyne, etc.

[0028] Regarding the coupling reaction of the hexyl nucleophile (7) and the 1,5-dihalo-1-pentyne compound (8)

[0029] B-2-1. Regarding the 1,5-dihalo-1-pentyne compound (8)

Chemical formula

[0030] In the general formula (8), X 1 and X 2 each represent a halogen atom which may be the same as or different from each other. Specifically, examples of the halogen atoms X 1 and X 2 include a chlorine atom, a bromine atom, and an iodine atom. From the perspective of reactivity, X 1 is preferably a chlorine atom and a bromine atom, and more preferably a chlorine atom. Also, from the perspective of reactivity, X 2 is preferably a bromine atom and an iodine atom, and more preferably a bromine atom. X 1 and X 2As a preferred combination, X 1 When X is a chlorine atom, X 2 is preferably a chlorine atom, a bromine atom or an iodine atom, and when X 1 is a bromine atom, X 2 is preferably a bromine atom or an iodine atom.

[0031] Specific examples of the 1,5-dihalo-1-pentyne compound (8) include 1,5-dichloro-1-pentyne, 1,5-dibromo-1-pentyne, 1,5-diiodo-1-pentyne, 5-bromo-1-chloro-1-pentyne, 1-chloro-5-iodo-1-pentyne, 1-bromo-5-chloro-1-pentyne, 1-bromo-5-iodo-1-pentyne, 5-chloro-1-iodo-1-pentyne, 5-bromo-1-iodo-1-pentyne and the like. From the viewpoint of reactivity, 1,5-dichloro-1-pentyne, 1,5-dibromo-1-pentyne, 1-bromo-5-chloro-1-pentyne, 5-chloro-1-iodo-1-pentyne and 5-bromo-1-iodo-1-pentyne are preferred, and 1,5-dibromo-1-pentyne, 1-bromo-5-chloro-1-pentyne and 5-chloro-1-iodo-1-pentyne are particularly preferred.

[0032] The 1,5-dihalo-1-pentyne compound (8) may be used alone or, if necessary, two or more thereof may be used. The 1,5-dihalo-1-pentyne compound (8) may be commercially available or may be synthesized independently.

[0033] B-2-2. Regarding the hexyl nucleophile (7) [Chemical formula]

[0034] In the general formula (7), M 2 represents Li or MgZ 2 and Z 2 represents a halogen atom or a hexyl group. Specifically, examples of the halogen atom include a chlorine atom, a bromine atom, and an iodine atom. From the perspective of versatility, a chlorine atom and a bromine atom are preferred, and a chlorine atom is particularly preferred.

[0035] Specific examples of the hexyl nucleophilic reagent (7) include hexyl lithium; and hexyl magnesium halide compounds such as hexyl magnesium chloride, hexyl magnesium bromide, and hexyl magnesium iodide.

[0036] From the perspective of reactivity, the usage amount of the hexyl nucleophilic reagent (7) in the coupling reaction is preferably 0.6 to 2.0 moles, more preferably 0.8 to 1.4 moles, relative to 1 mole (mol) of the 1,5-dihalo-1-pentyne compound (8).

[0037] One type of the hexyl nucleophilic reagent (7) may be used, or two or more types may be used as necessary. The hexyl nucleophilic reagent (7) may be commercially available or may be synthesized independently.

[0038] A solvent may be used in the coupling reaction as necessary. Examples of the solvent include general solvents such as ether solvents such as tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), diethyl ether, dibutyl ether, 4-methyltetrahydropyran (MTHP), cyclopentyl methyl ether, and 1,4-dioxane; hydrocarbon solvents such as hexane, heptane, benzene, toluene, xylene, and cumene; N , N N,N-dimethylformamide (DMF), N , N N,N-dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), γ-butyrolactone (GBL), acetonitrile, N , N’Examples of polar solvents include N,N-dimethylpropyleneurea (DMPU), hexamethylphosphoric triamide (HMPA), dichloromethane, and chloroform. From the perspective of reactivity, hydrocarbon solvents such as toluene and xylene; ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, and diethyl ether are preferred, and tetrahydrofuran, 2-methyltetrahydrofuran, toluene, and xylene are more preferred. One type of the solvent or two or more types thereof may be used as necessary. Also, commercially available solvents can be used. From the perspective of reactivity, the amount of the solvent used is preferably 30 to 8000 g, more preferably 50 to 5000 g, per 1 mol of the 1,5-dihalo-1-pentyne compound (8).

[0039] In order to cause the hexyl nucleophile (7) to undergo a coupling reaction with the 1,5-dihalo-1-pentyne compound (8), a catalyst may be used as necessary. Examples of the catalyst include copper compounds such as monovalent copper halides like cuprous chloride, cuprous bromide, and cuprous iodide, and divalent copper halides like cupric chloride, cupric bromide, and cupric iodide; iron compounds such as iron(II) chloride, iron(III) chloride, iron(II) bromide, iron(III) bromide, iron(II) iodide, iron(III) iodide, and iron(III) acetylacetonate; silver compounds such as silver chloride, silver nitrate, and silver acetate; titanium compounds such as titanium tetrachloride, titanium tetrabromide, titanium(IV) methoxide, titanium(IV) ethoxide, titanium(IV) isopropoxide, and titanium(IV) oxide; palladium(II) compounds such as dichlorobis(triphenylphosphine)palladium and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium; and nickel compounds such as nickel chloride, dichloro[1,2-bis(diphenylphosphino)ethane]nickel(II), and dichlorobis(triphenylphosphine)nickel(II). From the perspective of reactivity and / or economy, copper compounds are preferred, and copper halides such as cupric chloride, cupric bromide, and cupric iodide are more preferred. The catalyst may be used singly or, if necessary, two or more catalysts may be used in combination. Also, commercially available catalysts can be used. From the viewpoints of reaction rate and post-treatment, the amount of the catalyst used is preferably 0.0001 to 1.00 mol, more preferably 0.001 to 0.300 mol, per 1 mol of the 1,5-dihalo-1-pentyne compound (8).

[0040] When a catalyst is used in the coupling reaction, a cocatalyst may be used if necessary. Examples of the cocatalyst include trialkyl phosphites having 3 to 9 carbon atoms such as triethyl phosphite; and aryl phosphine compounds having 18 to 44 carbon atoms such as triphenylphosphine, tritolylphosphine, and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP). From the viewpoint of reactivity, trialkyl phosphites are preferred, and triethyl phosphite is particularly preferred. The cocatalyst may be used singly or, if necessary, two or more cocatalysts may be used in combination. Also, commercially available cocatalysts can be used. From the viewpoints of reactivity, the amount of the cocatalyst used is preferably 0.0001 to 1.00 mol, more preferably 0.001 to 0.300 mol, per 1 mol of the 1,5-dihalo-1-pentyne compound (8).

[0041] When a catalyst is used in the coupling reaction, a lithium salt may be added if necessary. Examples of the lithium salt include lithium halides such as lithium chloride, lithium bromide, and lithium iodide, lithium nitrate, and lithium carbonate. From the viewpoint of reactivity, lithium chloride, lithium bromide, lithium iodide, and lithium nitrate are preferred, and lithium chloride is particularly preferred. The lithium salt may be used singly or, if necessary, two or more lithium salts may be used in combination. Also, commercially available lithium salts can be used. From the viewpoint of reactivity, the amount of the lithium salt used in the coupling reaction is preferably 0.0001 to 1.00 mol, more preferably 0.001 to 0.300 mol, per 1 mol of the 1,5-dihalo-1-pentyne compound (8).

[0042] The reaction temperature in this coupling reaction varies depending on the hexyl nucleophile (7) used. From the perspective of reactivity, it is preferably -78 to 100 °C, more preferably -25 to 60 °C. The reaction time in this coupling reaction varies depending on the solvent used and / or the reaction scale. From the perspective of reactivity, it is preferably 0.5 to 100 hours.

[0043] C. A method for producing a (Z)-1-halo-4-undecene compound (1) by subjecting a 1-halo-4-undecyne compound (6) to a reduction reaction

Chemical formula

[0044] <Regarding the reduction reaction> As the reduction reaction for reducing the carbon-carbon triple bond of the 1-halo-4-undecyne compound (6) to produce the (Z)-1-halo-4-undecene compound (1), there are (i) a catalytic hydrogenation reaction, (ii) a reduction reaction using a zinc compound in an alcohol solvent, (iii) a reduction reaction by hydroboration using a dialkylborane followed by protonation, (iv) a reduction reaction using potassium hydroxide and N,N-dimethylformamide (DMF) in the presence of a palladium catalyst such as palladium acetate, and (v) a reduction reaction in which hydrosilylation is performed to obtain a vinylsilane and then desilylation is carried out. From the perspectives of selectivity and productivity, the above-mentioned (i) catalytic hydrogenation reaction, the above-mentioned (ii) reduction reaction using a zinc compound, and the above-mentioned (iii) reduction reaction by hydroboration followed by protonation are preferred, and the (i) catalytic hydrogenation reaction is more preferred.

[0045] (i) Contact reduction reaction This catalytic hydrogenation reaction is carried out by adding hydrogen gas in the presence of a metal catalyst. Examples of the metal catalyst used in the contact reduction reaction include nickel boride catalysts, nickel(0) nanoparticles (Fransisco Alonso et al, Tetrahedron, 2007, 63, 93-102), and nickel catalysts such as Uchibara nickel (e.g., U-Ni-A and U-Ni-B); and Lindlar catalysts, palladium on carbon, Pd / CaCO3, Pd / BaSO4, Pd / Al2O3, Pd / SiO2 doped with Hg, Pd / McM-41, Pd nanoparticles in hydrotalcite, Pd / Zn alloy, and Pd-PEI (wherein palladium on carbon poisoned with polyethyleneimine polymer (PEI)), etc. However, the metal catalyst is not limited thereto. Examples of the nickel boride catalyst include P-1 nickel boride catalyst and P-2 nickel boride catalyst (Thomas J. Caggiano et al. Encyclopedia of Reagents for Organic Synthesis: 3694-3699.) (hereinafter also referred to as "P-2Ni catalyst"); and nickel dispersed on graphite (e.g., Ni-Gr1 and Ni-Gr2), Caubere catalyst (Nic), and nickel in hydrogenated boron exchange resin (Ni2B-BER) (Laurence Balas, HAL, 2021; <https: / / hal.archives-ouvertes.fr / hal-00801666>), etc. However, the nickel boride catalyst is not limited thereto. From the perspective of economy, Lindlar catalyst and nickel catalyst are preferred. The amount of the metal catalyst used varies depending on the catalyst used. From the perspective of reactivity, when the catalyst is solid such as Lindlar catalyst, 0.01 to 50 g is preferably used per 1 mol of the 1-halo-4-undecene compound (6). When the catalyst is liquid such as P-2Ni catalyst, it is preferably used in such an amount that the equivalent amount as a nickel compound is 0.0001 to 2.0 mol per 1 mol of the 1-halo-4-undecene compound (6). In addition, the solid catalyst may be used after being dispersed in a solvent.

[0046] When the activity of the metal catalyst is high, a catalyst poison may be used as necessary. Examples of the catalyst poison include amine compounds such as pyridine, quinoline, and ethylenediamine; phosphine compounds such as triphenylphosphine, tritolylphosphine, and triethyl phosphite; and sulfur compounds such as benzenethiol, diphenyl sulfide, dimethyl sulfide, and dimethyl sulfoxide. The amount of the catalyst poison used varies greatly depending on the catalyst poison used. From the viewpoints of reaction rate and geometric selectivity, it is preferably 0.0001 to 20.0 mol, more preferably 0.001 to 2.0 mol, per 1 mol of the 1-halo-4-undecene compound (6).

[0047] Examples of the solvent used in the catalytic reduction reaction include hydrocarbon solvents such as hexane, heptane, benzene, toluene, xylene, and cumene; nitriles such as acetonitrile and propionitrile; esters such as methyl acetate, ethyl acetate, n-propyl acetate, and n-butyl acetate; and alcohols such as methanol, ethanol, propanol, butanol, pentanol, hexanol, 2-propanol, 2-butanol, and cyclohexanol. The solvent may be used alone or, if necessary, two or more solvents may be used. Also, commercially available solvents can be used.

[0048] When using a Lindlar catalyst, from the viewpoint of reactivity, hydrocarbon solvents such as hexane, heptane, toluene, and xylene are preferred as the solvent. When using a nickel catalyst, from the viewpoint of reactivity, alcohols such as methanol, ethanol, propanol, butanol, and 2-propanol are preferred as the solvent. When using a palladium catalyst such as palladium on carbon, from the viewpoint of reactivity, esters such as methyl acetate and ethyl acetate are preferred as the solvent. The amount of the solvent used varies depending on the catalyst and / or solvent used. From the viewpoint of reactivity, it is preferably 0 to 1000 g per 1 mol of the 1-halo-4-undecene compound (6).

[0049] The reaction temperature of the catalytic reduction reaction varies depending on the type of catalyst and / or solvent used. From the perspective of geometric selectivity, it is preferably 0 to 160 °C, more preferably 20 to 100 °C. The reaction time of the catalytic reduction reaction is preferably 0.5 to 100 hours from the perspective of yield.

[0050] (ii) Reduction reaction using a zinc compound in an alcohol solvent The reduction reaction is carried out using a zinc compound in an alcohol solvent. The number of carbon atoms of the alcohol used as the solvent is preferably 1 to 10, more preferably 1 to 5. Examples of the alcohol used as the solvent include linear alcohol compounds such as methanol, ethanol, propanol, butanol, pentanol, hexanol, heptanol, octanol, nonanol, and decanol; secondary alcohols such as 2-propanol and 2-butanol; branched alcohol compounds such as isobutyl alcohol; and cyclic alcohol compounds such as cyclohexanol. From the perspective of reactivity, alcohol compounds with 1 to 5 carbon atoms such as methanol, ethanol, propanol, butanol, pentanol, and 2-propanol are preferred. From the perspective of reactivity, the amount of the alcohol used is preferably 46 to 1000 g per 1 mol of the 1-halo-4-undecyne compound (6). From the perspective of reactivity, the amount of the zinc compound used is preferably 1.0 to 1000 mol, more preferably 1.0 to 200 mol per 1 mol of the 1-halo-4-undecyne compound (6).

[0051] Due to the low reactivity of the zinc compound, the reaction time of the reduction reaction may be prolonged. Therefore, an activator for activating the zinc compound may be added as necessary, or a pre-prepared activated zinc compound may be used. Examples of the activator include 1,2-dibromoethane, cuprous chloride, cuprous bromide, cuprous iodide, lithium bromide, iodine, and chlorotrimethylsilane. The activator may be used alone or, if necessary, two or more types may be used. From the perspective of reactivity, the amount of the activator used is preferably 0.01 to 10.0 moles per mole of the 1-halo-4-undecyne compound (6). The activated zinc compound can be prepared, for example, by treating metallic zinc with an acid such as hydrochloric acid, or by reducing zinc chloride with metallic lithium in tetrahydrofuran or 2-methyltetrahydrofuran, or by reacting metallic zinc with 1,2-dibromoethane and lithium dibromocuprate in tetrahydrofuran or 2-methyltetrahydrofuran.

[0052] The reaction temperature of the reduction reaction varies depending on the solvent used, but from the perspective of reactivity, it is preferably 20 to 180 °C. From the perspective of the completion of the reaction, the reaction time of the reduction reaction is preferably 0.5 to 150 hours.

[0053] (iii) Reduction reaction by hydroboration using a dialkylborane followed by protonation In the reduction reaction, first hydroboration is carried out using a dialkylborane in a solvent. The number of carbon atoms of the dialkylborane used for hydroboration is preferably 4 to 18, more preferably 6 to 12. Examples of the dialkylborane include dicyclohexylborane, diisopentylborane, dicyamylborane, 9-borabicyclo[3.3.1]nonane (9-BBN), diisopinocampheylborane, catecholborane, and pinacolborane. From the perspective of reactivity, dicyclohexylborane and diisopentylborane are preferred. From the perspective of reactivity, the amount of the dialkylborane used is preferably 1.0 to 4.0 moles per mole of the 1-halo-4-undecyne compound (6).

[0054] Examples of the solvent used for the hydroboration include ether solvents such as tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), diethyl ether, dibutyl ether, 4-methyltetrahydropyran, cyclopentyl methyl ether, 1,4-dioxane, and diethylene glycol dimethyl ether; and hydrocarbon solvents such as hexane, heptane, benzene, toluene, xylene, and cumene. From the perspective of reactivity, ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, and diethylene glycol dimethyl ether are more preferable. One type of the solvent or two or more types thereof may be used as necessary. In addition, commercially available solvents can be used. From the perspective of reactivity, the amount of the solvent used is preferably 100 to 3000 g per 1 mol of the 1-halo-4-undecyne compound (6).

[0055] From the perspective of geometric selectivity, the reaction temperature of the hydroboration is preferably -20°C to 50°C. The reaction time of the hydroboration varies depending on the reaction temperature and / or the scale of the reaction. From the perspective of reactivity, it is preferably 0.5 to 100 hours.

[0056] In the above reduction reaction, protonation is carried out using an acid in a solvent following the hydroboration. Examples of the acid used for protonation following the hydroboration include carboxylic acids such as acetic acid, propionic acid, butyric acid, pentanoic acid, pivalic acid, heptanoic acid, trifluoroacetic acid, chloroacetic acid, formic acid, and oxalic acid; p sulfonic acids such as p-toluenesulfonic acid; and mineral acids such as sulfuric acid, hydrochloric acid, nitric acid, and phosphoric acid. From the perspective of reactivity, carboxylic acids such as acetic acid and propionic acid are preferable. From the perspective of reactivity, the amount of the acid used is preferably 2.0 to 20.0 mol per 1 mol of the 1-halo-4-undecyne compound (6). Since the solvent used for the protonation and its amount used are such that the protonation is carried out in the same reaction system following the hydroboration, they are the same as the solvent used for the hydroboration and its amount used.

[0057] The reaction temperature for the protonation varies depending on the reagent used, but from the viewpoint of the reaction rate, it is preferably 0°C to 150°C. The reaction time for the protonation varies depending on the reaction temperature and / or the scale of the reaction, but from the viewpoint of reactivity, it is preferably 0.5 to 70 hours.

[0058] (iv) Reduction reaction using potassium hydroxide and N,N-dimethylformamide (DMF) in the presence of a palladium catalyst such as palladium acetate The reduction reaction is carried out in the presence of a palladium catalyst such as palladium acetate, potassium hydroxide, and N , N -dimethylformamide (DMF), preferably at 100 to 180°C for 0.5 to 100 hours.

[0059] (v) Reduction reaction in which hydrosilylation is carried out to obtain vinylsilane and then desilylation is performed The hydrosilylation is carried out using a metal catalyst such as Wilkinson catalyst and Trost catalyst, and a trialkylsilane. The amount of the metal catalyst used is, from the viewpoint of reactivity, preferably 0.0001 to 4.0 moles, more preferably 0.001 to 1.0 mole, per 1 mole of the 1-halo-4-undecene compound (6). The hydrosilylation is preferably carried out at 5 to 100°C for 0.5 to 100 hours. The desilylation after the hydrosilylation is preferably carried out using at least one of an acid such as sulfuric acid and hydrochloric acid, hydrogen iodide, acetyl chloride, titanium tetrachloride, and iodine, at 5°C to 80°C for 0.5 to 100 hours.

[0060] In the above manner, the (Z)-1-halo-4-undecene compound (1) can be produced.

[0061] Next, in the following Sections D and E, a method for producing (Z)-7-tetradecen-2-one represented by the following formula (5) from the above (Z)-1-halo-4-undecene compound (1) will be described. (Z)-7-Tetradecen-2-one (5) can be produced, for example, according to the following chemical reaction formula.

[0062]

Chemical formula

[0063] First, the (Z)-1-halo-4-undecene compound (1) is converted into a (Z)-4-undecenyl nucleophile (2), and subsequently, the (Z)-4-undecenyl nucleophile (2) is subjected to an addition reaction with propylene oxide (3) to produce (Z)-7-tetradecen-2-ol (4). Subsequently, (Z)-7-tetradecen-2-one (5) can be produced by subjecting the (Z)-7-tetradecen-2-ol represented by the general formula (4) to an oxidation reaction.

[0064] Next, in the following Section D, a method for producing (Z)-7-tetradecen-2-ol (4) will be described.

[0065] D. A method for producing (Z)-7-tetradecen-2-ol (4) by converting the (Z)-1-halo-4-undecene compound (1) into a (Z)-4-undecenyl nucleophile (2) and subsequently subjecting the (Z)-4-undecenyl nucleophile (2) to an addition reaction with propylene oxide (3)

Chemical formula

[0066] D-1. Regarding the (Z)-4-undecenyl nucleophile (2) In the general formula (2), M 1 represents Li or MgZ 1 and Z 1 represents a halogen atom or a hexyl group. Specifically, examples of the halogen atom include a chlorine atom, a bromine atom, and an iodine atom. From the viewpoint of versatility, a chlorine atom and a bromine atom are preferable, and a chlorine atom is particularly preferable. (Z)-4-undecenyl nucleophilic reagent (2) can be prepared according to a conventional method or according to the method described below.

[0067] As an example, among the (Z)-4-undecenyl nucleophilic reagents (2), the production method for the case of (Z)-4-undecenylmagnesium = halide reagent (2:M 1 =MgZ 1 ) will be described below. The (Z)-4-undecenylmagnesium = halide reagent (2:M 1 =MgZ 1 ) can be prepared, for example, by reacting the above (Z)-1-halo-4-undecene compound (1) with magnesium in a solvent as shown in the following chemical reaction formula.

[0068]

Chemical formula

[0069] (Z)-4-undecenylmagnesium = halide reagent (2:M 1 =MgZ 1 ) is a Grignard reagent. Here, Z 1 represents a halogen atom or a hexyl group, and when Z 1 is a halogen atom, it is the same as X 1 , and the type of halogen atom does not change before and after the reaction.

[0070] (Z)-1-Halo-4-undecene compound (1) may be used alone or in combination of two or more. Further, the (Z)-1-halo-4-undecene compound (1) may be commercially available or may be synthesized independently as in the above-described production method.

[0071] The amount of magnesium used is preferably 1.0 to 2.0 gram atoms per mole of the (Z)-1-halo-4-undecene compound (1) from the viewpoint of complete reaction. Examples of the solvent include ether solvents such as tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), diethyl ether, dibutyl ether, 4-methyltetrahydropyran (MTHP), cyclopentyl methyl ether, and 1,4-dioxane; hydrocarbon solvents such as hexane, heptane, benzene, toluene, xylene, and cumene; and N , N -dimethylformamide (DMF), N , N -dimethylacetamide (DMAC), N -methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), γ-butyrolactone (GBL), acetonitrile, N , N’ -dimethylpropyleneurea (DMPU), hexamethylphosphoric triamide (HMPA), polar solvents such as dichloromethane and chloroform, etc. However, from the viewpoint of the reaction rate of the Grignard reagent formation, ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, and 4-methyltetrahydropyran are preferred, and tetrahydrofuran and 2-methyltetrahydrofuran are more preferred. The solvent may be used alone or, if necessary, two or more solvents may be used. Also, commercially available solvents can be used. The amount of the solvent used is preferably 30 to 5000 g, more preferably 50 to 3000 g, per mole of the (Z)-1-halo-4-undecene compound (1) from the viewpoint of reactivity.

[0072] The reaction temperature in the reaction with the above magnesium varies depending on the solvent used, but is preferably 30 to 120 °C from the viewpoint of reactivity. The reaction time in the reaction with the above magnesium varies depending on the solvent used and / or the reaction scale, but is preferably 0.5 to 100 hours from the viewpoint of reactivity.

[0073] D-2. (Z)-4-Undecenylmagnesium = halide reagent (2:M 1 =MgZ 1 ) is subjected to an addition reaction with propylene = oxide (3) to produce (Z)-7-tetradecen-2-ol (4). The amount of propylene = oxide (3) used is preferably 1.0 to 10.0 moles, more preferably 1.0 to 5.0 moles, per 1 mole of the (Z)-1-halo-4-undecene compound (1) from the viewpoint of reactivity.

[0074] For the above addition reaction, a catalyst may be used as necessary. Examples of the catalyst include copper compounds such as monovalent copper halides such as cuprous chloride, cuprous bromide, and cuprous iodide, and divalent copper halides such as cupric chloride, cupric bromide, and cupric iodide; iron compounds such as iron(II) chloride, iron(III) chloride, iron(II) bromide, iron(III) bromide, iron(II) iodide, iron(III) iodide, and iron(III) acetylacetonate; silver compounds such as silver chloride, silver nitrate, and silver acetate; titanium compounds such as titanium tetrachloride, titanium tetrabromide, titanium(IV)-methoxide, titanium(IV)-ethoxide, titanium(IV)-isopropoxide, and titanium(IV) oxide; palladium(II) compounds such as dichlorobis(triphenylphosphine)palladium and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium; and nickel compounds such as nickel chloride, dichloro[1,2-bis(diphenylphosphino)ethane]nickel(II), and dichlorobis(triphenylphosphine)nickel(II). From the viewpoints of reactivity and / or economy, copper compounds are preferred, and cuprous halides such as cuprous chloride, cuprous bromide, and cuprous iodide are more preferred. One type of the catalyst or, if necessary, two or more types may be used. Also, commercially available catalysts can be used. The amount of the catalyst used is preferably 0.00001 to 1.00 moles, more preferably 0.0001 to 0.300 moles, per 1 mole of the (Z)-1-halo-4-undecene compound (1) from the viewpoints of reaction rate and post-treatment.

[0075] For the above addition reaction, a solvent may be used if necessary. Examples of the solvent include general solvents such as ether solvents like tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), diethyl ether, dibutyl ether, 4-methyltetrahydropyran (MTHP), cyclopentyl methyl ether, and 1,4-dioxane; hydrocarbon solvents such as hexane, heptane, benzene, toluene, xylene, and cumene; and N , N -dimethylformamide (DMF), N , N -dimethylacetamide (DMAC), N -methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), γ-butyrolactone (GBL), acetonitrile, N , N’ -dimethylpropyleneurea (DMPU), hexamethylphosphoric triamide (HMPA), polar solvents such as dichloromethane and chloroform, etc. However, from the perspective of reactivity, ether solvents such as diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, and 4-methyltetrahydropyran; and hydrocarbon solvents such as toluene and xylene are preferred. The solvent may be used alone or, if necessary, two or more solvents may be used. Also, commercially available solvents can be used. From the perspective of reactivity, the amount of the solvent used is preferably 20 to 7000 g, more preferably 50 to 3000 g, per 1 mol of the (Z)-1-halo-4-undecene compound (1).

[0076] The reaction temperature in the addition reaction varies depending on the (Z)-4-undecenylmagnesium halide reagent (2:M 1 =MgZ 1 ) and / or the solvent used. However, from the perspective of reactivity, it is preferably -40 to 180 °C, more preferably -25 to 100 °C, and even more preferably -10 to 70 °C. The reaction time in the addition reaction varies depending on the nucleophile, solvent and / or reaction scale used, but from the perspective of reactivity, it is preferably 0.5 to 100 hours.

[0077] Next, in Section E below, the method for producing (Z)-7-tetradecen-2-one (5) will be described.

[0078] E. A method for producing (Z)-7-tetradecen-2-one (5) by subjecting (Z)-7-tetradecen-2-ol (4) to an oxidation reaction

Chemical formula

[0079] <Regarding the oxidation reaction> The oxidation reaction is, for example, N - Corey-Kim oxidation using N-chlorosuccinimide, dimethyl sulfide, and triethylamine, Swern oxidation using dimethyl sulfoxide, oxalyl chloride, and then triethylamine in a solvent, TEMPO oxidation using 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), 2-hydroxy-2-azabicyclo[2.2.1]heptane, etc. as catalysts and sodium hypochlorite, Jones oxidation using chromium trioxide and sulfuric acid, chromic acid oxidation using chromic acid, Dess-Martin oxidation using Dess-Martin periodinane as an oxidizing agent, tetrapropylammonium perruthenate as an oxidation catalyst, 4-methylmorpholine = NLey-Griffith oxidation (TPAP oxidation) using an -oxide as a ruthenium re-oxidizing agent, Oppenauer oxidation using a hydrogen acceptor with an aluminum compound or a magnesium compound as a catalyst, or a modified method thereof can be carried out. Among these oxidation reactions, Oppenauer oxidation or a modified method thereof, which has low environmental toxicity and a low risk of explosion, is particularly preferred. Oppenauer oxidation refers to a reaction using an aluminum compound, particularly aluminum triisopropoxide. A modified method of Oppenauer oxidation refers to a reaction using a compound other than an aluminum compound, such as a magnesium compound. Further, as a further modified method of Oppenauer oxidation, a mixture of an aluminum compound and the above compound other than the aluminum compound may be used.

[0080] As an example, among the oxidation reactions, the production methods in the case of Oppenauer oxidation reaction and its modified methods will be described below. The Oppenauer oxidation reaction and its modified methods can be carried out, for example, as shown by the following chemical reaction formula, by oxidizing the above (Z)-7-tetradecen-2-ol (4) in a solvent, if necessary, using an aluminum compound and a magnesium compound as catalysts respectively, in the presence of a hydrogen acceptor.

[0081] [Chemical formula]

[0082] Examples of the aluminum compound include trialkylaluminum compounds such as trimethylaluminum and triethylaluminum; and aluminum trialkoxide compounds such as aluminum triisopropoxide and aluminum tri-tert-butoxide. Examples of the magnesium compound include magnesium halide compounds such as magnesium chloride and magnesium bromide; magnesium hydroxide; and magnesium alkoxide compounds such as magnesium methoxide, magnesium ethoxide, and magnesium tert-butoxide. The catalyst may be used singly or, if necessary, in combination of two or more. Also, commercially available catalysts can be used. From the viewpoint of reactivity, the amount of the catalyst used is preferably 0.1 to 5.0 mol, more preferably 0.5 to 3.0 mol, per 1 mol of (Z)-7-tetradecen-2-ol (4).

[0083] Examples of the hydrogen acceptor include ketone compounds such as acetone, ethyl methyl ketone, diethyl ketone, ethyl propyl ketone, isobutyl methyl ketone, diisobutyl ketone, and cyclohexanone; and aldehyde compounds such as pivaldehyde, benzaldehyde, and cyclohexanecarboxaldehyde. The hydrogen acceptor may be used singly or, if necessary, in combination of two or more. Also, commercially available hydrogen acceptors can be used. From the viewpoint of reactivity, the amount of the hydrogen acceptor used is preferably 1.0 to 10,000 mol, more preferably 1.0 to 500 mol, per 1 mol of (Z)-7-tetradecen-2-ol (4).

[0084] For the Oppenauer oxidation reaction, a solvent may be used if necessary. Examples of the solvent include ether solvents such as tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), diethyl ether, dibutyl ether, 4-methyltetrahydropyran (MTHP), cyclopentyl methyl ether, and 1,4-dioxane; hydrocarbon solvents such as hexane, heptane, benzene, toluene, xylene, and cumene; N , N -dimethylformamide (DMF), N , N -dimethylacetamide (DMAC), N -methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), γ-butyrolactone (GBL), acetonitrile, acetone, N , NPolar solvents such as N,N'-dimethylpropyleneurea (DMPU), hexamethylphosphoric triamide (HMPA), dichloromethane, chloroform, and acetone; and ester solvents such as methyl acetate, ethyl acetate, n-propyl acetate, and n-butyl acetate. From the perspective of reactivity, ether solvents such as 4-methyltetrahydropyran and hydrocarbon solvents such as toluene and xylene are preferred. One type of the solvent or, if necessary, two or more types may be used. Also, commercially available solvents can be used. The amount of the solvent used in the Oppenauer oxidation reaction is preferably 0 to 9000 g, more preferably 100 to 5000 g, per 1 mol of (Z)-7-tetradecen-2-ol (4).

[0085] The reaction temperature in the Oppenauer oxidation reaction varies depending on the catalyst and / or solvent used, but from the perspective of reactivity, it is preferably 5 to 180 °C, more preferably 50 to 140 °C. The reaction time in the halogenation reaction varies depending on the reaction scale, but from the perspective of reactivity, it is preferably 0.5 to 100 hours.

[0086] In the Oppenauer oxidation reaction, by distilling off the by-produced alcohol compound and adding the above-mentioned hydrogen acceptor, it is possible to improve the reaction rate, shorten the reaction time, and / or improve the productivity by increasing the charge amount. For example, when using aluminum triisopropoxide as the catalyst and acetone as the hydrogen acceptor, after charging (Z)-7-tetradecen-2-ol (4), aluminum triisopropoxide, acetone, and the solvent and heating, distilling off the by-produced isopropyl alcohol, and adding a certain amount of acetone repeatedly, the Oppenauer oxidation reaction can be efficiently carried out.

[0087] When producing (Z)-7-tetradecen-2-one (5) by oxidizing the hydroxyl group of (Z)-7-tetradecen-2-ol (4) through an Oppenauer oxidation reaction, the reaction may not go to completion due to the equilibrium reaction. In such cases, for example, methods such as using a large excess of acetone to shift the equilibrium and / or separating unreacted (Z)-7-tetradecen-2-ol (4) can be applied. However, using a large excess of acetone significantly reduces the charged amount, thus greatly decreasing productivity. Therefore, the method of separating the unreacted (Z)-7-tetradecen-2-ol (4) is preferred.

[0088] As a method for separating unreacted (Z)-7-tetradecen-2-ol (4), since the boiling points of (Z)-7-tetradecen-2-ol (4) and (Z)-7-tetradecen-2-one (5) are close, making separation by distillation difficult, for example, a method of purification and separation by silica gel column chromatography, and / or esterifying unreacted (Z)-7-tetradecen-2-ol (4) to form an esterification compound of (Z)-7-tetradecen-2-ol (4), and then, after making the boiling point of the esterification compound higher than that of (Z)-7-tetradecen-2-ol (4), using this boiling point difference to distillatively purify and separate (Z)-7-tetradecen-2-one (5) and the esterification compound of (Z)-7-tetradecen-2-ol (4) can be mentioned.

[0089] The separation of (Z)-7-tetradecen-2-ol (4) and (Z)-7-tetradecen-2-one (5) by silica gel column chromatography is carried out by taking advantage of the different polarities of the two compounds. Silica gel column chromatography can be performed by conventional methods, but when the scale becomes large, it is difficult to apply, for example, in terms of cost and / or production efficiency.

[0090] The unreacted (Z)-7-tetradecen-2-ol (4) is esterified to produce an esterified compound of (Z)-7-tetradecen-2-ol (4), and after making the boiling point higher than that of (Z)-7-tetradecen-2-ol (4), the method of distillation purification and separation of (Z)-7-tetradecen-2-one (5) and the esterified compound of (Z)-7-tetradecen-2-ol (4) can be applied even when the scale is large. Therefore, it is preferable compared to the above-mentioned method of purification and separation by silica gel column chromatography. The esterification can be carried out, for example, by adding an esterifying agent to the reaction solution after the Oppenauer oxidation reaction or the concentrated solution after distilling off the solvent from the reaction solution.

[0091] Examples of the esterifying agent used in the esterification reaction include acid anhydrides such as acetic anhydride, propionic anhydride, butanoic anhydride, pivaloyl anhydride, and benzoic anhydride; and acid chlorides such as acetyl chloride, propionyl chloride, butyryl chloride, pivaloyl chloride, and benzoyl chloride. From the perspective of the boiling point difference, acid anhydrides such as butanoic anhydride, pivaloyl anhydride, and benzoic anhydride; and acid chlorides such as butyryl chloride, pivaloyl chloride, and benzoyl chloride are preferable. The amount of the esterifying agent used is preferably 1.0 to 10.0 mol, more preferably 1.0 to 5.0 mol, from the perspectives of reactivity and economy, per 1 mol of the remaining unreacted (Z)-7-tetradecen-2-ol (4). The amount of the unreacted (Z)-7-tetradecen-2-ol (4) can be measured, for example, by GC analysis. Specifically, for example, after Oppenauer oxidation, post-treatment and concentration operations are carried out to obtain a reaction mixture of (Z)-7-tetradecen-2-one (5) and (Z)-7-tetradecen-2-ol (4), and then the weight of the reaction mixture can be measured. Then, by multiplying the GC% obtained by subjecting the reaction mixture to GC analysis by the weight of the reaction mixture, the amounts of (Z)-7-tetradecen-2-one (5) and (Z)-7-tetradecen-2-ol (4) can be calculated.

[0092] For this esterification, an acid or a base may be used if necessary. Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid, and nitric acid; aromatic sulfonic acids such as 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 dimethoxide, dibutyltin oxide, magnesium chloride, magnesium bromide, titanium tetrachloride, titanium tetrabromide, titanium(IV) methoxide, titanium(IV) ethoxide, titanium(IV) isopropoxide, and titanium(IV) oxide. One type of the acid or, if necessary, two or more types may be used. From the viewpoints of reactivity and economy, the amount of the acid used is preferably 0.001 to 3.00 mol, more preferably 0.01 to 1.50 mol, per 1 mol of the remaining unreacted (Z)-7-tetradecen-2-ol (4).

[0093] Examples of the base include trialkylamine compounds such as trimethylamine, triethylamine, and N , N -diisopropylethylamine; cyclic amine compounds such as piperidine, pyrrolidine, and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU); aromatic amine compounds such as pyridine, lutidine, N , N -dimethylaniline, N , N -diethylaniline, N , N -dibutylaniline, and 4-dimethylaminopyridine; and sodium methoxide, sodium ethoxide, sodium tert -butoxide, sodium tert -amyloxide, lithium methoxide, lithium ethoxide, lithium tert -butoxide, lithium tert- Amyl oxide, potassium methoxide, potassium ethoxide, potassium - tert - butoxide and potassium - tert - Metal alkoxides such as amyl oxide can be mentioned. One kind of this base or, if necessary, two or more kinds may be used. The usage amount of this base is preferably 0.010 to 10.0 mol, more preferably 0.001 to 5.0 mol, from the viewpoints of reactivity and economy, relative to 1 mol of residual (Z) - 7 - tetradecen - 2 - ol (4).

[0094] For this esterification, a solvent may be used if necessary. As this solvent, general solvents such as ether solvents such as tetrahydrofuran (THF), 2 - methyltetrahydrofuran (2 - MeTHF), diethyl ether, dibutyl ether, 4 - methyltetrahydropyran (MTHP), cyclopentyl methyl ether and 1,4 - dioxane; hydrocarbon solvents such as hexane, heptane, benzene, toluene, xylene and cumene; and N , N - Dimethylformamide (DMF), N , N - Dimethylacetamide (DMAC), N - Methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), γ - butyrolactone (GBL), acetonitrile, N , N’ - Polar solvents such as dimethylpropyleneurea (DMPU), hexamethylphosphoric triamide (HMPA), dichloromethane and chloroform can be mentioned, but from the viewpoint of reactivity, ether solvents such as diethyl ether, tetrahydrofuran, 2 - methyltetrahydrofuran and 4 - methyltetrahydropyran; and hydrocarbon solvents such as toluene and xylene are preferable. One kind of this solvent or, if necessary, two or more kinds may be used. Also, commercially available solvents can be used. This esterification may use a solvent if necessary, but the reaction may also be carried out without a solvent. The amount of the solvent used for the acetylation is preferably 0 to 8000 g, more preferably 0 to 5000 g, per 1 mol of the above-mentioned residual (Z)-7-tetradecen-2-ol (4).

[0095] The reaction temperature in the esterification varies depending on the esterifying agent and / or solvent used, but from the viewpoint of reactivity, it is preferably -40 to 140 °C, more preferably 0 to 100 °C, and still more preferably 20 to 80 °C. The reaction time in the esterification is preferably 0.5 to 100 hours from the viewpoint of reactivity.

[0096] As described above, by esterifying the remaining unreacted (Z)-7-tetradecen-2-ol (4), a boiling point difference can be created between the esterification compound of (Z)-7-tetradecen-2-ol (4) obtained as a result of the esterification and (Z)-7-tetradecen-2-one (5), enabling separation by distillation from (Z)-7-tetradecen-2-one (5). The separated esterification compound can be reused as a reaction raw material for the next batch by converting it back to (Z)-7-tetradecen-2-ol (4) through a hydrolysis reaction or the like.

[0097] As described above, (Z)-7-tetradecen-2-one (5), which is the sex pheromone of Semadaracogane, can be efficiently produced in a short process from the (Z)-1-halo-4-undecene compound (1) which is a synthetic intermediate. Further, this production method is suitable for industrial-scale production.

Examples

[0098] Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited to the following examples. In the following, unless otherwise specified, "purity" indicates the area percentage obtained by gas chromatography (GC) analysis, "formation ratio" indicates the relative ratio of the area percentages obtained by GC analysis, and "yield" is calculated based on the area percentage obtained by GC analysis. In each example, the reaction was monitored and the yield was calculated according to the following GC conditions. GC conditions: GC: Shimadzu Corporation Capillary Gas Chromatograph GC-2014, Column: DB-5 or DB-WAX, 0.25μm x 0.25mmφ x 30m, Carrier gas: He (1.55 mL / min), Detector: FID, Column temperature: 150°C rising at 5°C / min to 230°C. The yield was calculated according to the following formula, taking into account the purity (%GC) of the raw materials and products. Yield (%) = {[(weight of product obtained by reaction × %GC) / molecular weight of product] ÷ [(weight of starting material in reaction × %GC) / molecular weight of starting material]} × 100 Note that THF is tetrahydrofuran, EDA is ethylenediamine, Et represents an ethyl group and i Pr represents an isopropyl group.

[0099] Example 1 <1-Chloro-4-undecyne (6:X 1 =Cl) production>

[0100]

Chemical formula

[0101] At room temperature, cupric chloride (CuCl2) (19.20 g, 0.144 mole (mol)), triethyl phosphite (P(OEt)3) (95.52 g, 0.56 mol), lithium chloride (LiCl) (12.12 g, 0.28 mol), tetrahydrofuran (1635.68 g) and a xylene solution of 1-bromo-5-chloro-1-pentyne (8:X 1 =Cl, X 2 =Br) (5341.08 g, purity 37.1%, 10.92 mol as 1-bromo-5-chloro-1-pentyne) were added to the reactor, and at 20 - 35°C, hexylmagnesium chloride (7:M 2A tetrahydrofuran solution of [[MgCl]] (5365.64 g, 12.00 mol as hexylmagnesium chloride) was added dropwise. After completion of the dropwise addition, the mixture was stirred at 25 - 35 °C for 3 hours. Next, an aqueous acetic acid solution (acetic acid (1174.04 g) and water (3522.16 g)) was added to the reaction solution and separated by liquid separation, and the aqueous layer was removed to obtain an organic layer. The obtained organic layer was concentrated under reduced pressure, and the residue was distilled under reduced pressure to obtain 1-chloro-4-undecene (6:X 1 =Cl) (1668.32 g, 8.67 mol, purity 97.08%, b.p. = 99.0 - 101.3 °C / 0.4 kPa (3.0 mmHg)) in a yield of 72.28%.

[0102] The spectral data of the 1-chloro-4-undecene (6:X 1 =Cl) obtained above are shown below. 〔Nuclear magnetic resonance spectrum〕 1 1H-NMR (500 MHz, CDCl3): δ = 0.88 (3H, t, J = 7.3 Hz), 1.22 - 1.40 (6H, m), 1.47 (2H, q-like, J = 7.3 Hz), 1.92 (2H, tt, J = 6.9 Hz, 6.9 Hz), 2.13 (2H, tt, J = 7.3 Hz, 2.3 Hz), 2.33 (2H, tt, J = 6.9 Hz, 2.3 Hz), 3.65 (2H, t, J = 6.5 Hz); 13 13C-NMR (500 MHz, CDCl3): δ = 14.02, 16.19, 18.68, 22.55, 28.52, 28.98, 31.33, 31.79, 43.78, 77.96, 81.44 〔Mass spectrum〕EI - mass spectrum (70 eV): m / z 185 (M + -1), 123, 109, 95, 81, 67, 53 〔Infrared absorption spectrum〕(D - ATR): νmax = 2957, 2931, 2858, 1456, 1435, 1290, 727, 654 cm -1

[0103] Example 2 <Production of (Z)-1-halo-4-undecene (1:X 1 =Cl)>

[0104] [Chemical formula]

[0105] At room temperature, 1-chloro-4-undecene (6:X 1 =Cl) (1414.25 g, 7.35 mol, purity 97.08%) obtained in Example 1, P-2Ni catalyst (460.60 g, 0.12 mol as Ni), and ethylenediamine (EDA) (10.04 g) were added to a reactor, and hydrogen was added while stirring at 45 - 55 °C for 9.5 hours. The reaction rate was confirmed to be 100% by GC. Then, water (321.49 g) was added to the reaction solution, and liquid separation was performed. The aqueous layer was removed to obtain an organic layer. The obtained organic layer was concentrated under reduced pressure, and the residue was subjected to vacuum distillation to obtain (Z)-1-halo-4-undecene (1:X 1 =Cl) (1385.23 g, 6.96 mol, purity 94.79%, b.p. = 92.1 - 95.0 °C / 0.40 kPa (3.0 mmHg)) in a yield of 94.62%.

[0106] The spectral data of the (Z)-1-halo-4-undecene (1:X 1 =Cl) obtained above are shown below. [Nuclear magnetic resonance spectrum] 1 1H-NMR (500 MHz, CDCl3): δ = 0.89 (3H, t, J = 7.3 Hz), 1.23 - 1.38 (8H, m), 1.82 (2H, tt, J = 6.9 Hz, 6.9 Hz), 2.04 (2H, q-like, J = 6.5 Hz), 2.20 (2H, q-like, J = 7.3 Hz), 3.54 (2H, t, J = 6.5 Hz), 5.27 - 5.34 (1H, m), 5.40 - 5.47 (1H, m); 13 13C-NMR (500 MHz, CDCl3): δ = 14.09, 22.64, 24.37, 27.23, 28.97, 29.65, 31.75, 32.49, 44.50, 127.49, 131.71 [Mass spectrum] EI - mass spectrum (70 eV): m / z 188 (M + ), 123, 109, 97, 81, 69, 55, 41 〔Infrared Absorption Spectrum〕(D-ATR): νmax = 2956, 2926, 2855, 1457, 727, 655 cm -1

[0107] Example 3 <Production of (Z)-7-Tetradecen-2-ol (4)>

[0108]

Chemical Formula

[0109] At room temperature, magnesium (51.26 g, 2.11 mol) and tetrahydrofuran (602.70 g) were added to the reactor and stirred at 60 - 65 °C for 19 minutes. After completion of stirring, (Z)-1-Halo-4-undecene (1:X 1 =Cl) (400.00 g, 2.009 mol, purity 94.79%) prepared in Example 2 was added dropwise to the reactor at 60 - 75 °C. After completion of the dropwise addition, the mixture was stirred at 75 - 80 °C for 4 hours to prepare (Z)-4-Undecenylmagnesium = chloride (2:M 1 =MgCl).

[0110] Subsequently, cuprous chloride (CuCl) (0.42 g, purity 95%, 0.004 mol) was added to the above reactor at 0 - 10 °C, and propylene = oxide (3) (134.19 g, 2.31 mol) was added dropwise at 0 - 30 °C. After completion of the dropwise addition, the reaction mixture was stirred at 20 - 30 °C for 2 hours. Then, an aqueous acetic acid solution (acetic acid (251.10 g) and water (753.35 g)) and hexane (178.58 g) were added to the reaction solution and separated by liquid separation, and the aqueous layer was removed to obtain an organic layer. Then, the obtained organic layer was concentrated under reduced pressure, and the residue was distilled under reduced pressure to obtain (Z)-7-Tetradecen-2-ol (4) (371.58 g, 1.67 mol, purity 95.16%, b.p. = 120.8 - 124.2 °C / 0.4 kPa (3.0 mmHg)) in a yield of 82.87%.

[0111] The spectral data of (Z)-7-Tetradecen-2-ol (4) obtained above are shown below. 〔Nuclear Magnetic Resonance Spectrum〕 1 1H-NMR(500 MHz, CDCl3): δ = 0.88 (3H, t, J = 6.9 Hz), 1.18 (3H, d, J = 6.2 Hz), 1.22 - 1.50 (14H, m), 1.46 (1H, br.s), 1.97 - 2.07 (4H, m), 3.78 (1H, sext-like, J = 6.1 Hz), 5.30 - 5.39 (2H, m); 13 13C-NMR(500 MHz, CDCl3): δ = 14.06, 22.62, 23.44, 25.39, 27.12, 27.21, 28.96, 29.69, 29.72, 31.75, 39.23, 68.09, 129.50, 130.14 〔Mass Spectrum〕EI - Mass Spectrum (70 eV): m / z 212 (M + ), 194, 165, 152, 138, 123, 109, 95, 82, 67, 55, 41 〔Infrared Absorption Spectrum〕(D - ATR): νmax = 3344, 2959, 2926, 2856, 1462, 1376, 1123, 724 cm -1

[0112] Example 4 <Production of (Z)-7 - tetradecen - 2 - one (5)>

[0113]

Chemical Structure

[0114] At room temperature, (Z)-7 - tetradecen - 2 - ol (4) (33.48 g, 0.15 mol, purity 95.16%) produced in Example 3, acetone (100.00 g, 1.72 mol), and toluene (169.37 g) were added to the reactor and stirred at 75 - 85 °C for 10 minutes. After stirring, aluminum triisopropoxide (Al(O i(Pr)3) (52.08 g, 0.25 mol) was dissolved in toluene (254.06 g), and the toluene solution of aluminum triisopropoxide was added dropwise to the above reactor at 75 - 80 °C. After the addition was completed, it was refluxed for 0.5 h, and a mixed solution of isopropyl alcohol and acetone was distilled off. When the internal temperature reached 87 °C, the distillation was stopped, and acetone (100.00 g, 1.72 mol) was added. After adding acetone, it was refluxed for 0.5 h, and after the reflux was completed, a mixed solution of isopropyl alcohol and acetone was distilled off. When the internal temperature reached 87 °C, the distillation was stopped, and acetone (100.00 g, 1.72 mol) was added again. After adding acetone, it was refluxed for 0.5 h, and after the reflux was completed, a mixed solution of isopropyl alcohol and acetone was distilled off. When the internal temperature reached 87 °C, the distillation was stopped, and acetone (100.00 g, 1.72 mol) was further added. After adding acetone, it was refluxed for 0.5 h, and after the reflux was completed, a mixed solution of isopropyl alcohol and acetone was distilled off. When the internal temperature reached 91 °C, the distillation was stopped, and it was cooled to 30 °C. After cooling, 20% by mass hydrochloric acid (300.00 g, 1.65 mol as hydrogen chloride), water (200.00 g) were added and separated by liquid separation, and the aqueous layer was removed. Subsequently, it was washed with an aqueous sodium hydrogen carbonate solution (sodium hydrogen carbonate (4.0 g), water (300 g)), and the aqueous layer was removed to obtain an organic layer. The obtained organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 40:1 - 2:1) to obtain (Z)-7-tetradecen-2-one (5) (26.30 g, 0.12 mol, purity 93.73%) in a yield of 78.15%, and the starting material (Z)-7-tetradecen-2-ol (4) (13.87 g, 0.024 mol, purity 36.18%) was recovered at a recovery rate of 15.76%.

[0115] The spectral data of (Z)-7-tetradecen-2-one (5) obtained above are shown below. [Nuclear magnetic resonance spectrum] 1H-NMR (500 MHz, CDCl3): δ = 0.87 (3H, t, J = 7.3 Hz), 1.20 - 1.38 (10H, m), 1.58 (2H, tt, J = 7.6 Hz, 7.6 Hz), 1.97 - 2.05 (4H, m), 2.12 (3H, s), 2.41 (2H, t, J = 7.3 Hz), 5.28 - 5.39 (2H, m); 13 C-NMR (500 MHz, CDCl3): δ = 14.06, 22.61, 23.47, 26.91, 27.21, 28.96, 29.22, 29.66, 29.80, 31.74, 43.63, 129.08, 130.40, 209.07 〔Mass Spectrum〕EI - Mass Spectrum (70 eV): m / z 210 (M + ), 192, 167, 152, 139, 125, 111, 97, 84, 71, 55, 43 〔Infrared Absorption Spectrum〕(D - ATR): νmax = 2927, 2856, 1718, 1458, 1358, 1159, 724 cm -1

[0116] Example 5 <Production of (Z)-7-tetradecen-2-one (5)>

[0117]

Chem.

[0118] Into the reactor, (Z)-7-tetradecen-2-ol (4) (44.63 g, 0.20 mol, purity 95.16%) produced in Example 3, acetone (100.00 g, 1.72 mol), and toluene (100.00 g) were added, and the mixture was stirred at 75 - 85 °C for 10 minutes. After completion of stirring, aluminum triisopropoxide (65.36 g, 0.32 mol) was dissolved in toluene (300.00 g), and the solution was added dropwise to the above reactor at 75 - 80 °C. Subsequently, reflux was carried out for 0.5 hours, and a mixed solution of isopropyl alcohol and acetone was distilled off. When the internal temperature reached 87°C, the distillation was stopped, and acetone (100.00 g, 1.72 mol) was added. After adding acetone, reflux was carried out for 0.5 hours. After the reflux was completed, a mixed solution of isopropyl alcohol and acetone was distilled off. When the internal temperature reached 87°C, the distillation was stopped, and acetone (100.00 g, 1.72 mol) was added again. After adding acetone, reflux was carried out for 0.5 hours. After the reflux was completed, a mixed solution of isopropyl alcohol and acetone was distilled off. When the internal temperature reached 87°C, the distillation was stopped, and acetone (100.00 g, 1.72 mol) was further added. After adding acetone, reflux was carried out for 0.5 hours. After the reflux was completed, a mixed solution of isopropyl alcohol and acetone was distilled off. When the internal temperature reached 87°C, the distillation was stopped, and acetone (100.00 g, 1.72 mol) was added again. After adding acetone, reflux was carried out for 0.5 hours. After the reflux was completed, a mixed solution of isopropyl alcohol and acetone was distilled off. When the internal temperature reached 91°C, the distillation was stopped, and it was cooled to 30°C. After cooling, 20% by mass hydrochloric acid (376.00 g, 2.06 mol as hydrogen chloride), water (251.00 g) were added and separated by liquid separation. After removing the aqueous layer, it was washed with an aqueous sodium hydrogen carbonate solution (sodium hydrogen carbonate (4.0 g), water (300 g)), and the aqueous layer was removed to obtain an organic layer. The obtained organic layer was concentrated under reduced pressure, and the residue was charged into a new reactor. Subsequently, pyridine (12.54 g, 0.16 mol), toluene (100 g) were added, and benzoyl chloride (17.82 g, 0.13 mol) was added dropwise at 20 - 30°C.

[0119] After the dropping was completed, the mixture was stirred at 45 to 55 °C for 2.5 hours. As a result, the remaining unreacted (Z)-7-tetradecen-2-ol (4) was benzoylated to form (Z)-7-tetradecen-2-yl benzoate, which was confirmed by GC. Water (100.00 g) was added to the reaction solution containing the (Z)-7-tetradecen-2-yl benzoate, and the mixture was separated by liquid separation. Then, the aqueous layer was removed to obtain an organic layer. The obtained organic layer was concentrated under reduced pressure, and the residue was distilled under reduced pressure to obtain (Z)-7-tetradecen-2-one (5) (37.61 g, 0.15 mol, purity 86.30%, b.p. = 101.1 to 120.2 °C / 0.4 kPa (3.0 mmHg)) in a yield of 77.13% and (Z)-7-tetradecen-2-yl benzoate (21.54 g, 0.040 mol, purity 59.11%) in a yield of 20.12% respectively. Thus, by benzoylating the remaining unreacted raw material, a difference was created between the boiling point of (Z)-7-tetradecen-2-one (5) and the boiling point of (Z)-7-tetradecen-2-yl benzoate. Utilizing this boiling point difference, (Z)-7-tetradecen-2-one (5) and (Z)-7-tetradecen-2-yl benzoate could be separated by distillation.

[0120] The spectral data of the (Z)-7-tetradecen-2-one (5) obtained above were the same as those obtained in Example 4.

[0121] Example 6 <Production of (Z)-7-tetradecen-2-one (5)>

[0122]

Chemical formula

[0123] At room temperature, (Z)-7-tetradecen-2-ol (4) (22.32 g, 0.10 mol, purity 95.16%) produced in Example 3, acetone (227.38 g, 3.91 mol), and toluene (338.75 g) were added to a reactor, and after stirring at 75 to 85°C for 10 minutes, aluminum triisopropoxide (25.74 g, 0.13 mol) was dissolved in toluene (169.37 g) and added dropwise at 75 to 80°C. After completion of the dropwise addition, the reaction was carried out at 75 to 85°C for 24.5 hours, and then cooled to an internal temperature of 30°C. After cooling, 20% by mass hydrochloric acid (300.00 g, 1.65 mol as hydrogen chloride), water (400.00 g) were added, separated, and the aqueous layer was removed. Subsequently, it was washed with an aqueous sodium hydrogen carbonate solution (sodium hydrogen carbonate (4.0 g), water (300 g)), and the aqueous layer was removed to obtain an organic layer. The obtained organic layer was concentrated under reduced pressure, and the residue was distilled under reduced pressure to obtain 21.85 g of a mixture of (Z)-7-tetradecen-2-one (5) and (Z)-7-tetradecen-2-ol (4). That is, (Z)-7-tetradecen-2-one (5) (21.85 g, 0.15 mol, purity 59.18%, b.p. = 101.1 to 120.2°C / 0.4 kPa (3.0 mmHg)) was obtained in a yield of 61.46% and (Z)-7-tetradecen-2-ol (4) (21.85 g, 0.030 mol, purity 29.39%) was obtained in a yield of 30.24% as the above mixture. The obtained (Z)-7-tetradecen-2-ol (4) and (Z)-7-tetradecen-2-one (5) had close boiling points to each other, and thus could not be separated by distillation.

Claims

1. The following general formula (1): 【Chemical 1】 (wherein X １ represents a halogen atom.) The step of converting the (Z)-1-halo-4-undecene compound (1) represented by the following general formula (2): 【Chemical 2】 (wherein, M １ represents Li or MgZ １ and Z １ represents a halogen atom or a (4Z)-4-undecenyl group.) into a (Z)-4-undecenyl nucleophile represented by the following general formula (3): and subjecting the (Z)-4-undecenyl nucleophile (2) to an addition reaction with propylene oxide represented by the following formula (3): [Chemical Formula 3] to obtain (Z)-7-tetradecen-2-ol represented by the following formula (4): 【Chemical Formula 4】 and oxidizing the (Z)-7-tetradecen-2-ol (4) to obtain (Z)-7-tetradecen-2-one represented by the following formula (5): A method for producing (Z)-7-tetradecen-2-one (5), comprising at least the following steps: 【Chemical Formula 5】

2. The method for producing (Z)-7-tetradecen-2-one (5) according to claim 1, wherein the oxidation is carried out by Oppenauer oxidation.

3. The method for producing (Z)-7-tetradecen-2-one (5) according to claim 1 or 2, further comprising a step of esterifying the remaining (Z)-7-tetradecen-2-ol (4) after the step of obtaining (Z)-7-tetradecen-2-one (5).

4. The method for producing (Z)-7-tetradecen-2-one (5) according to claim 3, further comprising a step of purifying (Z)-7-tetradecen-2-one (5) from a reaction mixture containing the esterified product of (Z)-7-tetradecen-2-ol (4) and (Z)-7-tetradecen-2-one (5) after the step of esterification.

5. The method for producing (Z)-7-tetradecen-2-one (5) according to claim 1 or 2, further comprising a step of subjecting a 1-halo-4-undecyne compound represented by the following general formula (6): to a reduction reaction to obtain the (Z)-1-halo-4-undecene compound (1).

6. [Chemical Formula 6] (wherein X １ represents a halogen atom.) The method for producing (Z)-7-tetradecen-2-one (5) according to claim 5, further comprising a step of obtaining the 1-halo-4-undecyne (6) by a coupling reaction between a hexyl nucleophile represented by the following general formula (7): and a 1,5-dihalo-1-pentyne compound represented by the following general formula (8): ​ ​ [Chemical Formula 7] (wherein, M ２ represents Li or MgZ ２ , and Z ２ represents a halogen atom or a hexyl group.) ​ [Chemical Formula 8] (wherein X １ and X ２ each represent a halogen atom which may be the same as or different from each other.) ​ ​

Images