Method for producing cyclohexenone compound

Abstract

A method for producing a cyclohexenone compound that includes an isomerization step that brings a reaction raw material including a compound represented by formula (4) into contact with an isomerization catalyst in a solvent to obtain a compound represented by formula (3). Preferably, the following steps are carried out in order: an addition step for reacting a compound (1) with methyl vinyl ketone in a solvent in the presence of a base to obtain a compound (2); a cyclization step for reacting the compound (2) in a solvent in the presence of a strong acid to obtain a compound (3); and an isomerization step for bringing a compound (4) included as an impurity in the reaction product obtained by the cyclization step into contact with an isomerization catalyst in a solvent.

Description

Method for producing cyclohexenone compounds

[0001] The present invention relates to a method for producing a cyclohexenone compound.

[0002] Cyclohexenone compounds are useful as synthetic intermediates for various pharmaceutical active ingredients, for example, as synthetic intermediates for nervous system agents described in Patent Document 1.

[0003] Known methods for producing cyclohexenone compounds and intermediates thereof are described in Non-Patent Document 1. Non-Patent Document 1 discloses a method in which 2-cyclohexenone is used as a starting material, and 3-hydroxy-3-trifluoromethylcyclohexan-1-one is reacted with (trimethylsilyl)trifluoromethane to produce 3-hydroxy-3-trifluoromethylcyclohexan-1-one, which is then reacted with pyridinium chlorochromate (PCC) to produce 3-trifluoromethyl-2-cyclohexen-1-one, as shown in the following reaction formula:

[0004]

[0005] However, this method only provides an unsatisfactory yield of 28%, and also produces a considerable amount of the isomer represented by the formula (4) below as a by-product. Furthermore, the pyridinium chlorochromate used here is highly toxic and carcinogenic, and its waste products are also hazardous, raising concerns about the environmental impact.

[0006] Non-Patent Document 2 describes a method for producing an enone ester compound, as shown in the following reaction scheme.

[0007]

[0008] It is also conceivable to produce a cyclohexenone compound by deesterifying and decarboxylating the enone ester compound obtained here according to the following reaction scheme described in Non-Patent Document 3.

[0009]

[0010] Specifically, this method involves producing 3-carboxy-1,1,1-trifluoroheptane-2,6-dione from ethyl trifluoroacetoacetate and methyl vinyl ketone, then producing an enone ester compound, which is then deesterified under basic conditions, and then subjected to a decarboxylation reaction under acidic conditions.

[0011] However, when the method of Non-Patent Document 3 is applied to the compound represented by formula (3) shown below, which is the target compound of the present invention, the reaction does not proceed efficiently, and there are problems in that a large amount of high-boiling-point impurities is produced, and a large amount of isomers is produced as by-products.

[0012] In view of the above circumstances, the present inventors have investigated various methods for isomerizing the isomer represented by formula (4), which is a by-product during the synthesis of the compound represented by formula (3), to the target compound represented by formula (3). As a result, they have found that by carrying out the isomerization reaction using a specific metal catalyst, the isomer represented by formula (4) can be reduced and the target compound represented by formula (3) can be efficiently recovered.

[0013] Non-Patent Document 4 describes a method using rhodium(III) chloride as a catalyst for the isomerization reaction of the following aromatic compound: However, as shown in Comparative Example 3 below, the compound represented by formula (4) that is the target of the present invention does not undergo a good isomerization reaction even when a rhodium-based catalyst is used.

[0014]

[0015] International Publication No. 2018 / 038265

[0016] J.Fluorine.Chem., 2000, 101, 199-202Synthetic Commun, 22(4), 573-579(1992)Angew. Chem. Int. Ed. 2014, 53, 2628-2632J. Chem. Soc., Perkin Trans. 1, 1977, 359-363

[0017] An object of the present invention is to provide a method for producing a cyclohexenone compound in high yield, at low cost, with high productivity, while reducing the burden of purification and the environmental load.

[0018] The present inventors have found that by employing specific production and purification methods, cyclohexenone compounds can be produced in high yields and at low cost with high productivity, while minimizing the purification burden and environmental impact.

[0019] The gist of the present invention is as follows.

[0020] [1] A method for producing a cyclohexenone compound, comprising an isomerization step of contacting a reaction raw material containing a compound represented by the following formula (4) with an isomerization catalyst in a solvent to obtain a compound represented by the following formula (3):

[0021]

[0022]

[0023] [2] The method for producing a cyclohexenone compound according to [1], wherein the reaction raw material further contains the compound represented by (3).

[0024] [3] The method for producing a cyclohexenone compound according to [2], which comprises, before the isomerization step, a cyclization step of reacting a compound represented by the following formula (2) in a solvent in the presence of a strong acid to obtain a compound represented by the formula (3):

[0025]

[0026] [4] The method for producing a cyclohexenone compound according to [3], which comprises, before the cyclization step, an addition step of reacting a compound represented by the following formula (1) with methyl vinyl ketone in a solvent in the presence of a base to obtain a compound represented by the formula (2):

[0027]

[0028] [5] The method for producing a cyclohexenone compound according to any one of [1] to [4], wherein the isomerization catalyst is a ruthenium-containing catalyst.

[0029] [6] The method for producing a cyclohexenone compound according to any one of [1] to [5], wherein the solvent is at least one selected from the group consisting of organic solvents and water.

[0030] [7] The method for producing a cyclohexenone compound according to any one of [1] to [6], wherein the temperature at which the reaction raw material containing the compound represented by formula (4) is brought into contact with the isomerization catalyst in a solvent is 10°C or higher and 100°C or lower.

[0031] According to the method for producing a cyclohexenone compound of the present invention, a cyclohexenone compound can be produced in high yield, at low cost, with reduced purification burden and environmental load, and with high productivity.

[0032] Hereinafter, embodiments of the method for producing a cyclohexenone compound of the present invention will be described in detail.

[0033] The method for producing a cyclohexenone compound of the present invention includes an isomerization step of contacting a reaction raw material containing a compound represented by the following formula (4) with an isomerization catalyst in a solvent to obtain a compound represented by the following formula (3):

[0034]

[0035]

[0036] The method for producing a cyclohexenone compound of the present invention preferably includes, before the isomerization step, a cyclization step in which a compound represented by the following formula (2) is reacted in a solvent in the presence of a strong acid to obtain a compound represented by the formula (3). The method for producing a cyclohexenone compound of the present invention preferably includes, before the cyclization step, an addition step in which a compound represented by the following formula (1) is reacted with methyl vinyl ketone in a solvent in the presence of a base to obtain a compound represented by the following formula (2).

[0037]

[0038]

[0039] In the method for producing a cyclohexenone compound of the present invention, it is preferable to produce 3-trifluoromethyl-2-cyclohexen-1-one represented by formula (3) by sequentially carrying out the following addition step, cyclization step, and isomerization step.

[0040]

[0041] In the present invention, it is preferable to carry out the following steps in sequence: an addition step in which a compound represented by formula (1) (hereinafter sometimes referred to as "compound (1)") is reacted with methyl vinyl ketone in a solvent in the presence of a base to obtain a compound represented by formula (2) (hereinafter sometimes referred to as "compound (2)"); a cyclization step in which compound (2) is reacted in a solvent in the presence of a strong acid to obtain a compound represented by formula (3) (hereinafter sometimes referred to as "compound (3)"); and an isomerization step in which a compound represented by formula (4) (hereinafter sometimes referred to as "compound (4)") contained as an impurity in the reaction product obtained in the cyclization step is contacted with an isomerization catalyst in a solvent;

[0042] The method for producing a cyclohexenone compound of the present invention will be described below in order of each step.

[0043] [Addition Step] The addition step is a step in which compound (1) is reacted with methyl vinyl ketone in a solvent in the presence of a base to obtain compound (2).

[0044]

[0045] <Reaction Substrate> As the compound (1), ethyl 4,4,4-trifluoroacetoacetate, a commercially available product may be used, or one produced by a known method may be used. The same applies to methyl vinyl ketone.

[0046] The amount of methyl vinyl ketone used may be at least a reaction equivalent, and is usually 1 mol to 2 mol, preferably 1 mol to 1.5 mol, per mol of compound (1).

[0047] <Base> As the base, either an organic base or an inorganic base can be used.

[0048] Examples of the organic base include aliphatic amines such as triethylamine; aromatic amines such as aniline; and heterocyclic amines such as pyridine, lutidine, 1,8-diazabicyclo[5.4.0]-7-undecene, 1,5-diazabicyclo[4.3.0]-5-nonene, and 1,5,7-triazabicyclo[4.4.0]dec-5-ene.

[0049] Examples of inorganic bases include metal hydrides, metal hydroxides, and metal carbonates. Examples of metal hydrides include lithium hydride, sodium hydride, and potassium hydride. Examples of metal hydroxides include lithium hydroxide, sodium hydroxide, potassium hydroxide, and calcium hydroxide. Examples of metal carbonates include lithium carbonate, sodium carbonate, potassium carbonate, lithium hydrogen carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate.

[0050] These bases may be used alone or in combination of two or more.

[0051] Among these bases, inorganic bases are preferred, metal hydrides are more preferred, and sodium hydride is particularly preferred, from the viewpoint of reactivity. By using a metal hydride, the amount of base used can be reduced.

[0052] The amount of base used is, relative to 1 mol of compound (1), typically 0.001 mol or more, preferably 0.005 mol or more, more preferably 0.01 mol or more, and typically 2 mol or less, preferably 1 mol or less, more preferably 0.5 mol or less. When the amount of base used is the above-mentioned lower limit or more, the reaction can be carried out efficiently. When the amount of base used is the above-mentioned upper limit or less, the formation of by-products can be suppressed.

[0053] <Solvent> As the solvent, at least one selected from the group consisting of organic solvents and water is used.

[0054] Examples of the organic solvent include aliphatic hydrocarbon solvents such as hexane, cyclohexane, heptane, and cycloheptane; aromatic hydrocarbon solvents such as toluene and xylene; aliphatic alcohol solvents having 1 to 8 carbon atoms such as methanol, ethanol, normal propanol, isopropanol, butanol, pentanol, hexanol, heptanol, and octanol; ketone solvents such as methyl ethyl ketone and methyl isobutyl ketone; and ether solvents such as diethyl ether, di-n-butyl ether, diisopropyl ether, di-n-butyl ether, methyl tert-butyl ether, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, and dioxane.

[0055] From the viewpoint of reactivity, the solvent is preferably an organic solvent, more preferably an aromatic hydrocarbon solvent, and particularly preferably toluene.

[0056] The amount of solvent used, relative to 1 kg of compound (1), is usually 1 L or more, preferably 2 L or more, more preferably 3 L or more, and usually 20 L or less, preferably 15 L or less, more preferably 10 L or less. When the amount of solvent used is the above-mentioned lower limit or more, the reaction can be carried out efficiently. When the amount of solvent used is the above-mentioned upper limit or less, the target product can be obtained with high productivity.

[0057] <Reaction conditions> The lower limit of the reaction temperature in the addition step is usually 0°C or higher, preferably 10°C or higher, more preferably 20°C or higher, and particularly preferably 30°C or higher, and the upper limit is usually 80°C or lower, preferably 70°C or lower, more preferably 60°C or lower, and particularly preferably 50°C or lower. If the reaction temperature is at least the above lower limit, the reaction substrates can be reacted efficiently. If the reaction temperature is at most the above upper limit, the production of by-products can be suppressed.

[0058] The reaction time is usually 0.1 to 24 hours, preferably 0.5 to 12 hours. If the reaction time is equal to or greater than the lower limit, the reaction can be carried out efficiently. If the reaction time is equal to or less than the upper limit, the target product can be obtained with high productivity.

[0059] The reaction pressure is usually atmospheric pressure, but may be increased.

[0060] <Reaction Method> When compound (1) and methyl vinyl ketone are reacted in a solvent in the presence of a base, the order in which they are supplied can be selected as appropriate. They may be supplied to the reaction system all at once or in multiple batches. For example, a base, a solvent, and liquid compound (1) are supplied to a reactor to form a uniform bed, and liquid methyl vinyl ketone is supplied under reaction conditions to form a uniform solution, thereby carrying out the reaction and obtaining compound (2).

[0061] <Post-treatment> The reaction solution containing compound (2) may be directly subjected to the next step, or the remaining base may be neutralized with an acid, and the resulting organic layer may be separated and then subjected to a treatment such as filtration before being subjected to the next step. Alternatively, the resulting organic layer may be concentrated to obtain a concentrate, which may be subjected to the next step, or the product may be further purified by a purification means such as column chromatography before being subjected to the next step.

[0062] [Cyclization Step] The cyclization step is a step in which the compound (2) obtained in the addition step is reacted in a solvent in the presence of a strong acid to obtain a compound (3).

[0063]

[0064] <Reaction Substrate> The compound (2), 3-ethoxycarbonyl-1,1,1-trifluoroheptane-2,6-dione, may be one obtained by the above-mentioned addition step or one produced by a known method.

[0065] <Strong Acid> A strong acid is an acid whose acid dissociation constant in water at 25°C is less than 0. Examples of strong acids that can be used include inorganic strong acids such as sulfuric acid, hydrochloric acid, and nitric acid, and organic strong acids such as methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, and trifluoroacetic acid. These strong acids may be used alone or in combination of two or more, but from the viewpoint of productivity, it is preferable to use only one. Of these, from the viewpoints of cost and reactivity, inorganic strong acids are preferably used, and sulfuric acid is particularly preferred. Sulfuric acid having a concentration of 30% by mass or more but less than 90% by mass is usually used.

[0066] The amount of the strong acid used is, relative to 1 mol of compound (2), usually 0.1 mol or more, preferably 0.2 mol or more, more preferably 0.3 mol or more, and usually 20 mol or less, preferably 10 mol or less, more preferably 5 mol or less. When the amount of the strong acid used is the above-mentioned lower limit or more, the reaction can be carried out efficiently. When the amount of the strong acid used is the above-mentioned upper limit or less, the generation of by-products can be suppressed.

[0067] <Solvent> Examples of the solvent used in the cyclization step include the same solvents as those used in the addition step described above. From the viewpoint of reactivity, organic solvents are preferred, alcohol solvents are more preferred, and ether solvents are particularly preferred, with isopropanol and methyl tert-butyl ether being particularly preferred. The solvent may be used alone or in combination of two or more types, but from the viewpoint of productivity, it is preferable to use only one type.

[0068] The amount of solvent used per kg of compound (2) is usually 1 L or more, preferably 2 L or more, more preferably 3 L or more, and usually 20 L or less, preferably 15 L or less, more preferably 10 L or less. When the amount of solvent used is the above-mentioned lower limit or more, the reaction can be carried out efficiently. When the amount of solvent used is the above-mentioned upper limit or less, the target product can be obtained with high productivity.

[0069] <Reaction conditions> The lower limit of the reaction temperature in the cyclization step is usually 50°C or higher, preferably 60°C or higher, and more preferably 70°C or higher, and the upper limit is usually 120°C or lower, preferably 110°C or lower, and more preferably 100°C or lower. If the reaction temperature is equal to or higher than the lower limit, the reaction can be carried out efficiently. If the reaction temperature is equal to or lower than the upper limit, the generation of by-products can be suppressed.

[0070] The reaction time is usually 0.1 to 72 hours, preferably 12 to 36 hours. If the reaction time is equal to or greater than the lower limit, the reaction can be carried out efficiently. If the reaction time is equal to or less than the upper limit, the target product can be obtained with high productivity.

[0071] The reaction pressure is usually atmospheric pressure, but may be increased.

[0072] <Reaction Method> When reacting compound (2) with a strong acid, the order in which these compounds are supplied can be selected as appropriate. These compounds may be supplied to the reaction system all at once, or may be supplied in multiple batches. For example, the reaction can be carried out by supplying compound (2) together with a solvent into a reactor to form a bed solution, and then supplying a strong acid under reaction conditions. Conversely, a solution of compound (2) may be added dropwise to a bed solution containing a strong acid.

[0073] <Post-treatment> In the cyclization step, an isomer compound (4) represented by the following formula (4) is produced as a by-product.

[0074]

[0075] The reaction solution containing compound (3) and compound (4) is usually subjected to treatments such as neutralization of the strong acid with a base, separation, filtration, etc., followed by distillation of the solvent from the organic layer containing compound (3) and compound (4). The isolated compound (3) and compound (4) may be subjected to the subsequent isomerization step, or the distillate obtained by distilling off compound (3) and compound (4) from the organic layer containing compound (3) and compound (4) may be subjected to the subsequent isomerization step. Alternatively, these may be further purified by a purification means such as column chromatography and then subjected to the subsequent isomerization step.

[0076] [Isomerization Step] The isomerization step is a step of isomerizing compound (4) in a solvent in the presence of an isomerization catalyst.

[0077]

[0078] <Reaction Substrate> As the starting material compound (4) in the isomerization step, a highly purified product of 3-trifluoromethyl-3-cyclohexen-1-one can be used. However, it is preferable for an industrial process to use a mixture containing compound (3) and compound (4) obtained in the above cyclization step.

[0079] The mixture containing compound (3) and compound (4) obtained in the cyclization step typically contains 5 mol % to 50 mol % of compound (4) relative to compound (3). By contacting this mixture with an isomerization catalyst, compound (4) is isomerized to convert it to compound (3), thereby increasing the content of compound (3) and decreasing the content of compound (4). The content of compound (4) in the reaction product liquid obtained after the isomerization reaction is thereby reduced to typically less than 5 mol %, preferably 4 mol % or less, and particularly preferably 3 mol % or less relative to compound (3), allowing for the production of higher purity compound (3) in high yield.

[0080] <Isomerization catalyst> The isomerization catalyst is not particularly limited as long as it can isomerize compound (4) to compound (3). As the isomerization catalyst, a ruthenium-containing catalyst is preferred, and a ruthenium-based catalyst or a ruthenium-containing composite metal catalyst is particularly preferred. From the viewpoints of reactivity and cost, a ruthenium-based catalyst is particularly preferred. These isomerization catalysts may be used alone or in combination of two or more, but from the viewpoint of productivity, it is preferable to use only one.

[0081] Examples of ruthenium catalysts include ruthenium-supported carbon catalysts (hereinafter sometimes referred to as "Ru / C"), ruthenium(III) chloride, tris(acetylacetonato)ruthenium(III), tris(2,2'-bipyridyl)ruthenium(II) chloride, dichloro(p-cymene)ruthenium(II) (dimer), etc. The ruthenium-containing composite metal catalyst may be any catalyst that contains ruthenium and allows the reaction to proceed, such as a platinum-ruthenium composite metal catalyst.

[0082] Among these, ruthenium(III) chloride and ruthenium-supported carbon catalysts are preferred from the viewpoints of reactivity and cost. In the case of ruthenium-supported carbon catalysts, the amount of ruthenium supported is preferably about 5 to 10 mass % relative to the carbon from the viewpoints of availability and cost.

[0083] The amount of the isomerization catalyst used, in terms of the metal in the catalyst, is generally 0.001 mol or more, preferably 0.005 mol or more, more preferably 0.01 mol or more, relative to 1 mol of compound (4), and generally 2 mol or less, preferably 1 mol or less, more preferably 0.5 mol, relative to 1 mol of compound (4). When the amount of the isomerization catalyst used is equal to or greater than the lower limit, the reaction can be carried out efficiently. When the amount of the isomerization catalyst used is equal to or less than the upper limit, the generation of by-products can be suppressed.

[0084] <Solvent> Examples of the solvent used in the isomerization step include the same solvents as those used in the addition step described above. From the viewpoints of reactivity and productivity, ether solvents are preferred, and methyl tert-butyl ether is particularly preferred. These solvents allow the reaction to be carried out efficiently without inhibiting the isomerization reaction. The solvent may be used alone or in combination of two or more types, but from the viewpoint of productivity, it is preferable to use only one type.

[0085] The amount of solvent used is usually 1 L or more, preferably 2 L or more, more preferably 3 L or more, and usually 20 L or less, preferably 15 L or less, more preferably 10 L or less, per kg of compound (4) or a mixture containing compound (3) and compound (4). When the amount of solvent used is equal to or greater than the lower limit, the reaction can be carried out efficiently. When the amount of solvent used is equal to or less than the upper limit, the target product can be obtained with high productivity.

[0086] <Reaction Conditions> The reaction temperature in the isomerization step (the temperature at which the reaction raw material containing the compound represented by formula (4) is brought into contact with the isomerization catalyst) has a lower limit of usually 10°C or higher, preferably 20°C or higher, and more preferably 30°C or higher, and an upper limit of usually 100°C or lower, preferably 80°C or lower, and more preferably 60°C or lower. When the reaction temperature is equal to or higher than the lower limit, the reaction can be carried out efficiently. When the reaction temperature is equal to or lower than the upper limit, the production of by-products can be suppressed.

[0087] The reaction time is usually 0.1 to 72 hours, preferably 1 to 24 hours. If the reaction time is equal to or greater than the lower limit, the reaction can be carried out efficiently. If the reaction time is equal to or less than the upper limit, the target product can be obtained with high productivity.

[0088] The reaction pressure is usually atmospheric pressure, but may be increased.

[0089] <Reaction Method> When reacting compound (4) or a mixture containing compound (3) and compound (4) with an isomerization catalyst, the order in which these compounds are supplied can be selected as appropriate. These compounds may be supplied to the reaction system all at once, or may be supplied in multiple batches. For example, the reaction can be carried out by supplying a mixture containing compound (3) and compound (4) together with a solvent into a reactor to serve as a bed, and then supplying the isomerization catalyst under reaction conditions.

[0090] <Post-treatment> After the isomerization reaction, the reaction mixture is usually subjected to treatments such as separation and filtration, and then the target product may be isolated from the organic layer by an isolation means such as concentration or distillation. After isolation, the target product may be further purified by a purification means such as column chromatography.

[0091] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0092] [Abbreviations] The abbreviations used in the following examples and comparative examples are as follows: Compound (1): ethyl 4,4,4-trifluoroacetoacetate Compound (2): 3-ethoxycarbonyl-1,1,1-trifluoroheptane-2,6-dione Compound (3): 3-trifluoromethyl-2-cyclohexen-1-one Compound (4): 3-trifluoromethyl-3-cyclohexen-1-one MTBE: methyl tert-butyl ether

[0093] [Analytical Method] In the following examples and comparative examples, the chemical purity of the obtained compounds (contents (area %) of compound (3) and compound (4)) was measured by gas chromatography (GC) under the following analytical conditions.

[0094] <GC analysis conditions> Analytical equipment: Agilent Agilent 6850 Column: Agilent DB-35 (0.32 mm x 30 m, 0.5 μm) Injection volume: 1 μL Injection method: Split (10:1) Injection port temperature: 200°C Oven: 40°C (2 min) → (10°C / min) → 220°C (3 min) Carrier gas: Helium Linear velocity: 33 cm / sec Detector: FID: H ２ 30 mL / min, Air 400 mL / min Make-up: He 30 mL / min Detector temperature: 250°C

[0095] [Production Example 1]

[0096] [1] Production of compound (2)

[0097] In a separable flask, under a nitrogen atmosphere, 0.8 g (20.4 mmol) of 60% by mass sodium hydride and 650.2 g (750 mL) of toluene were stirred at 20° C., and 150 g (814.7 mmol) of compound (1) was added dropwise thereto, followed by stirring, and the reaction solution was heated to 40° C. After heating, 62.8 g (896.2 mmol) of methyl vinyl ketone was added dropwise thereto, and the mixture was allowed to react for 5 hours.

[0098] After the reaction, the reaction mixture was cooled to 20°C, and 53.8 g (896.2 mmol) of acetic acid was added dropwise. The mixture was then concentrated under reduced pressure until the volume was approximately 300 mL. After concentration, 592.5 g (750 mL) of isopropanol was added, and the mixture was again concentrated under reduced pressure until the volume was approximately 300 mL. This gave 238.4 g (90.3 area%, 94% yield) of an isopropanol solution of compound (2).

[0099] [2] Production of compound (3)

[0100] In a separable flask, under a nitrogen atmosphere, 276 g of 98% by mass sulfuric acid and 300 g of water were stirred at 25°C, and 355.5 g of isopropanol and 238.4 g of the solution of compound (2) obtained in the above addition step were added dropwise. After stirring, the reaction solution was heated to 87°C and reacted for 22 hours. This reaction yielded an isopropanol solution of a mixture of compound (3) and compound (4) as the reaction solution. Here, the amount of sulfuric acid used was 3.4 mol per 1 mol of compound (2).

[0101] The isopropanol solution of compound (3) and compound (4) obtained in the above cyclization step was cooled to 25°C, and 900 g of water and 335.7 g of MTBE were added, followed by stirring and standing to obtain organic layer 1. 335.7 g of MTBE was added to the remaining aqueous layer, followed by stirring and standing to remove the aqueous layer, obtaining organic layer 2. The obtained organic layer 2 was mixed with organic layer 1, and 450 g of water was added, followed by stirring and standing to remove the aqueous layer. 450 g of 5% by mass sodium bicarbonate water was added to the obtained organic layer, followed by stirring and standing to remove the aqueous layer. 450 g of 1% by mass saline solution was added to the obtained organic layer, followed by stirring and standing to remove the aqueous layer. 78.3 g (814.9 mmol) of methanesulfonic acid was added dropwise to the obtained organic layer, and the reaction solution was heated to 55°C and reacted for 3 hours.

[0102] After the reaction, the reaction solution was cooled to 25°C and concentrated to a liquid volume of about 450 ml at a reduced pressure of 100 hPa, thereby obtaining a mixture (3-1) (yield: 47%, compound (3): 61.8 area %, compound (4): 21.6 area %) as a concentrated residue.

[0103] The obtained concentrated residue mixture (3-1) was concentrated under a reduced pressure of 30 hPa while gradually heating from 25°C to 60°C until no more distillate was produced, thereby obtaining a mixture (3-2) as a distillate (yield: 39%, compound (3): 77.6 area %, compound (4): 15.2 area %).

[0104] The obtained distillate mixture (3-2) was heated from 25°C to 100°C under the conditions of 10 plates, a reflux ratio of 4, and a reduced pressure of 10 hPa, and subjected to batch rectification to obtain a mixture (3-3) (compound (3): 83.5 area %, compound (4): 14.2 area %) as an oily compound.

[0105] The obtained mixture (3-3) was heated from 25°C to 100°C under the conditions of 10 plates, a reflux ratio of 4, and a reduced pressure of 10 hPa, and subjected to batch rectification to obtain 22.39 g of compound (3) (integrated yield from compound (1): 18%, chemical purity: 98.8 area%, content: 98.2 mass%, compound (4): 1.2 area%).

[0106] The analytical results of this compound (3) are as follows: <Compound (3)> GC-MS (Cl:Isobutene gas): m / z=164 (M ＋ , 35), 136 (100), 67 (50) １ H-NMR (CDCl ３ , 400MHz): δ2.13(2H,m), 2.49(4H,m),6.37(1H,s)

[0107] Example 1: Isomerization catalyst: RuCl ３ Isomerization of compound (4) using

[0108] To 350 mg of the mixture (3-3) obtained in Production Example 1 (a mixture of compound (3) and compound (4), compound (4): 14.2 area %, compound (3): 83.5 area %), 2 ml of MTBE and 6 mg of ruthenium (III) chloride (0.01 mol equivalent relative to the substrate) were added, and the solution was heated to 40°C and reacted for 26 hours. The resulting reaction solution was analyzed by GC under the aforementioned analytical conditions, and the results showed that the compound (3) was 92.4 area % and the compound (4) was 2.0 area %.

[0109] [Example 2: Isomerization of compound (4) using isomerization catalyst: 5 mass% Ru / C]

[0110] Isomerization was carried out in the same manner as in Example 1, except that 6 mg of ruthenium (III) chloride (0.01 mol equivalent relative to the substrate) was changed to 86 mg of 5 mass% ruthenium / carbon (0.01 mol equivalent relative to the substrate). GC analysis of the resulting reaction solution under the aforementioned analytical conditions revealed that the compound (3) accounted for 94.0 area % and the compound (4) accounted for 2.3 area %.

[0111] Example 3: Isomerization of Compound (4) Using Isomerization Catalyst: Tris(acetylacetonato)ruthenium(III)

[0112] Isomerization was carried out in the same manner as in Example 1, except that 6 mg of ruthenium (III) chloride (0.01 mol equivalent relative to the substrate) was replaced with 9 mg of tris(acetylacetonato)ruthenium (III) (0.01 mol equivalent relative to the substrate). The resulting reaction solution was analyzed under the above-mentioned GC analysis conditions, and the concentration was 93.0 area % of compound (3) and 3.1 area % of compound (4).

[0113] Comparative Example 1: Isomerization of Compound (4) Using Palladium (II) Chloride as Isomerization Catalyst Isomerization was carried out in the same manner as in Example 1, except that 6 mg of ruthenium (III) chloride (0.01 mol equivalent relative to the substrate) was replaced with 1.6 mg of palladium (II) chloride (0.01 mol equivalent relative to the substrate). The resulting reaction solution was analyzed under the above-mentioned GC analysis conditions, and the results showed that compound (3) accounted for 89.4 area % and compound (4) for 6.5 area %. In this Comparative Example 1, the isomerization efficiency of compound (4) was lower than in Example 1, which used ruthenium (III) chloride.

[0114] Comparative Example 2 Isomerization of Compound (4) Using Nickel (II) Chloride as Isomerization Catalyst Isomerization was carried out in the same manner as in Example 1, except that 6 mg of ruthenium (III) chloride (0.01 mol equivalent relative to the substrate) was replaced with 1.2 mg of nickel (II) chloride (0.01 mol equivalent relative to the substrate). The resulting reaction solution was analyzed under the above-mentioned GC analysis conditions, and the concentration of Compound (3) was 86.1 area % and the concentration of Compound (4) was 7.9 area %.

[0115] Comparative Example 3: Isomerization of Mixture (4) Using Rhodium (III) Chloride as Isomerization Catalyst The mixture (3-3) obtained in Example 1 was left at room temperature for two weeks and analyzed under the aforementioned GC analysis conditions. As a result, the resulting mixture (3-3A) contained 87.2 area % of compound (3), 9.4 area % of compound (4), and 3.4 area % of other impurities. Isomerization was carried out in the same manner as in Example 1, except that mixture (3-3) was replaced with mixture (3-3A) and 6 mg of ruthenium (III) chloride (0.01 mol equivalent relative to the substrate) was replaced with 9 mg of rhodium (III) chloride (0.01 mol equivalent relative to the substrate). The resulting reaction solution was analyzed under the aforementioned GC analysis conditions. As a result, the resulting mixture contained 87.6 area % of compound (3) and 8.6 area % of impurity (4).

[0116] The results of Examples 1 to 3 and Comparative Examples 1 to 3 are summarized in Table 1 below.

[0117]

[0118] From Examples 1 to 3 and Comparative Examples 1 to 3 in Table 1, it was found that when a ruthenium-containing catalyst was used, compound (4) was efficiently isomerized, the content of compound (3) was increased, and the content of compound (4) was reduced. On the other hand, when a catalyst not containing ruthenium was used, compound (4) was not efficiently isomerized, and the content of compound (4) could not be reduced.

[0119] Although the present invention has been described in detail using specific embodiments, it will be apparent to those skilled in the art that various modifications can be made without departing from the spirit and scope of the present invention. This application is based on Japanese Patent Application No. 2021-25335 filed on February 19, 2021, and is incorporated by reference in its entirety.

Claims

1. A method for producing a cyclohexenone compound, comprising an isomerization step of contacting a reaction raw material containing a compound represented by the following formula (4) with an isomerization catalyst in a solvent to obtain a compound represented by the following formula (3): 【Chemistry 1】 【Chemistry 2】

2. The method for producing a cyclohexenone compound according to claim 1, wherein the reaction raw material further contains a compound represented by formula (3).

3. The method for producing a cyclohexenone compound according to claim 2, further comprising, prior to the isomerization step, a cyclization step of reacting a compound represented by the following formula (2) in a solvent in the presence of a strong acid to obtain a compound represented by the formula (3): 【Chemistry 3】

4. The method for producing a cyclohexenone compound according to claim 3, further comprising, prior to the cyclization step, an addition step of reacting a compound represented by the following formula (1) with methyl vinyl ketone in a solvent in the presence of a base to obtain a compound represented by the formula (2): 【Chemistry 4】

5. The method for producing a cyclohexenone compound according to claim 1, wherein the isomerization catalyst is a ruthenium-containing catalyst.

6. The method for producing a cyclohexenone compound according to claim 1, wherein the solvent is at least one selected from the group consisting of organic solvents and water.

7. A reaction raw material containing the compound represented by formula (4) is contacted with an isomerization catalyst in a solvent at a high temperature. The cyclohexene according to any one of claims 1 to 6, having a temperature of 10°C or higher and 100°C or lower. Methods for producing non-compounds.

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