Method for producing β-iron

Abstract

Provided is a method for industrially mass-producing β-ionone, which is useful as a perfume compound, by an inexpensive and safe method. Using 3-methylcyclohexanone as a starting material for synthesis, 6-methylaminomethylene-2,2,3-trimethylcyclohexanone is produced by introducing two methyl groups in one step into 6-methylaminomethylene-3-methylcyclohexanone. 6-Hydroxymethylene-2,2,3-trimethylcyclohexanone obtained by hydrolyzing 6-methylaminomethylene-2,2,3-trimethylcyclohexanone is used as an intermediate. After isomerizing γ-methylcyclocitral derived therefrom to β-methylcyclocitral, β-ionone is industrially mass-produced by subjecting this to an aldol condensation reaction with acetone.

Description

Technical Field

[0001] The present invention relates to a novel method for producing β - ionone useful for perfume compounds and the like and a purification method thereof.

Background Art

[0002] Iris is an essential oil with a violet - like floral fragrance extracted from the rhizomes of herbs (Iris pallida, Iris germanica, Iris florentina) of the Iridaceae family and is extremely important as a perfume. However, its production is time - consuming and labor - intensive, and the production volume is small, so it is traded at a very high price. Natural iris essential oil contains, as aroma substances, cis - γ - ionone, cis - α - ionone, trans - α - ionone, and β - ionone, which are isomers of ionone, and it is known that their aromas are slightly different from each other. If these aroma substances can be supplied at a lower cost than natural products by chemical synthesis, a large demand is expected, and many studies have been conducted for the purpose of synthesizing them. The above - mentioned formula (1) β - ionone in the present invention accounts for only about 2% or less of all ionone isomers in natural iris essential oil, so it is not regarded as the main component of iris fragrance and has not been noticed so far. Therefore, there are many literatures on the synthesis of γ - ionone (Patent Document 1, Patent Document 2, Patent Document 3, Non - Patent Document 1) and α - ionone (Patent Document 4, Non - Patent Document 2), but there are few literatures on the synthesis of β - ionone.

[0003] A method (Non - Patent Document 3) has been proposed to synthesize β - ionone by cyclizing pseudo - irone, which is synthesized through several steps starting from methyl methacrylate, in an acetic acid / sulfuric acid mixture. However, for industrial production, there are difficulties such as steps that require a reaction at high temperature for a long time in an autoclave.

[0004] A method for synthesizing β - ionone by reacting β - methylcyclocitral with an ylide reagent, acetylidenetriphenylphosphorane, under high pressure has been proposed (Non - Patent Document 4). However, there are problems such as the requirement for a reaction under high pressure (14 kbar) and a low yield.

[0005] A method for synthesizing β - ionone by subjecting β - methylcyclocitral and acetone to an aldol condensation reaction in the presence of sodium ethoxide has been proposed (Non - Patent Document 5). However, it is not a method for large - scale synthesis, and there are problems such as the complexity and multiple steps required for the synthesis of β - methylcyclocitral.

[0006] A method for synthesizing β - ionone through a multi - step reaction from synthetic ionone (trade name: Ion Alpha) mainly composed of α - ionone, which is commercially available as a fragrance, has been proposed (Non - Patent Document 6). However, there is a problem in that an expensive fragrance is used as a starting material.

[0007] Thus, a manufacturing method for synthesizing β - ionone, which is useful as a fragrance compound, inexpensively and safely in a large amount has not been proposed.

Prior Art Documents

Patent Documents

[0008]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Non - Patent Documents

[0009]

Non - Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Summary of the Invention

Problems to be Solved by the Invention

[0010] An object of the present invention is to provide a method for industrially mass-producing β-ionone, which is useful as a fragrance compound, by an inexpensive and safe method.

Means for Solving the Problems

[0011] As a result of intensive research to solve the above problems, the present inventors used 3-methylcyclohexanone of the above formula (2) as a starting material for synthesis, introduced two methyl groups into 6-methylanilinomethylene-3-methylcyclohexanone of the formula (3) in one step to produce 6-methylanilinomethylene-2,2,3-trimethylcyclohexanone of the formula (4), hydrolyzed it to obtain 6-hydroxymethylene-2,2,3-trimethylcyclohexanone of the formula (5) as an intermediate, isomerized γ-methylcyclocitral of the formula (6) derived therefrom to β-methylcyclocitral of the formula (7), and further aldol-condensed β-methylcyclocitral of the formula (7) with acetone in the presence of a base to find a method for industrially mass-producing β-ionone of the formula (1), thus completing the present invention. When this reaction is shown in a reaction process diagram, it can be represented as follows.

[0012]

Chemical formula

[0013] In the above reaction process diagram, γ-methylcyclocitral of the formula (6) can be synthesized by the methods described in the literature (Patent Document 3, Non-Patent Document 1), but the present inventors used 3-methylcyclohexanone of the formula (2) as a synthetic starting material that is inexpensive and easily available.

[0014] When synthesizing β-ionone of the formula (1) in the above reaction process diagram, about 2 to 10% of α-ionone of the formula (8) is simultaneously produced with respect to β-ionone of the formula (1). There is a difference in aroma between β-ionone of the formula (1) and α-ionone of the formula (8), and the aroma characteristics of β-ionone of the formula (1) cannot be fully exhibited in the form of a mixture. Therefore, it is necessary to separate the two. Although the two can be clearly separated by gas chromatograph analysis, it is difficult to separate and purify them by distillation or column chromatography because their physical properties are similar.

[0015] Therefore, as a result of advancing research on the method for separating the β-iron of formula (1) and the α-iron of formula (8), as shown in the following reaction formula, by preferentially converting the α-iron of formula (8) to an epoxide by an oxidation reaction, separation and purification by distillation or column chromatography becomes easy, and it was found that the β-iron of formula (1) can be purified to a high purity.

[0016]

Chemical formula

[0017] Accordingly, the present invention provides the following methods for producing β-iron, a method for producing β-methylcyclocitral which is a synthetic intermediate of β-iron, and further a method for purifying β-iron to a high purity.

[0018] [1] A method for producing a compound represented by the following formula (1)

[0019]

Chemical formula

[0020] which comprises using 3-methylcyclohexanone represented by the following formula (2)

[0021]

Chemical formula

[0022] as a starting material, and introducing two methyl groups into the carbon adjacent to the carbonyl of 6-methylanilinomethylene-3-methylcyclohexanone represented by the following formula (3)

[0023]

Chemical formula

[0024] in a one-step reaction operation to produce the following formula (4)

[0025] [Chemical formula]

[0026] 6-methylanilinomethylene-2,3,3-trimethylcyclohexanone represented by the following formula (5), obtained by hydrolyzing

[0027] [Chemical formula]

[0028] 6-hydroxymethylene-2,3,3-trimethylcyclohexanone represented by the following formula (6), via this as an intermediate, and the following formula (6) derived therefrom

[0029] [Chemical formula]

[0030] γ-methylcyclocitral represented by the following formula (7)

[0031] [Chemical formula]

[0032] After isomerizing to β-methylcyclocitral represented by the following formula (7), and then performing an aldol condensation thereof in the presence of acetone and a base. A production method comprising the step.

[0033] [2] The following formula (7) [Chemical formula]

[0034] A method for producing β-methylcyclocitral represented by the following formula (7), the following formula (6)

[0035] [Chemical formula]

[0036] A production method comprising a step of isomerizing γ-methylcyclocitral represented by the following formula in a basic solvent.

[0037] [3] The following formula (1) [Chemical formula]

[0038] A method for purifying β-ion to high purity, which comprises a step of preferentially converting α-ion in formula (1) β-ion containing α-ion as an impurity into an epoxide by an oxidation reaction according to the following formula (8).

[0039] [Chemical formula]

[0040] A purification method comprising a step of preferentially converting α-ion in formula (1) β-ion containing α-ion as an impurity into an epoxide by an oxidation reaction according to the following formula (8). [Advantages of the Invention]

[0041] According to the present invention, β-ion useful as a fragrance compound can be produced in large quantities by an industrial method at a low cost and safely as compared with the conventional production methods, and a novel synthesis method of β-methylcyclocitral which can be an intermediate for synthesizing various fragrance compounds, and a method for purifying a mixture of β-ion and α-ion into high-purity β-ion can be provided. [Modes for Carrying Out the Invention]

[0042] Hereinafter, the present invention will be described in more detail.

[0043] One aspect of the present invention is the following formula (1)

[0044] [Chemical formula]

[0045] Relates to the production of β-ionone useful as a fragrance compound, represented by

[0046] The 3-methylcyclohexanone represented by the formula (2) used as the starting material of the present invention can be obtained industrially at low cost. For example, 3-methylcyclohexanone (manufactured by Tokyo Chemical Industry), 3-methylcyclohexanone (manufactured by Sigma-Aldrich), etc. can be mentioned.

[0047] 6-Methylanilinomethylene-3-methylcyclohexanone represented by the formula (3) can be prepared by a conventionally known method. For example, as shown in the following reaction formula, 3-methylcyclohexanone of the formula (2) is reacted with ethyl formate in the presence of a base to hydroxymethylenate, and the hydroxyl group of the obtained compound is reacted with N-methylaniline to produce it.

[0048]

Chemical formula

[0049] Examples of the base used in the hydroxymethylenation of the above reaction formula include sodium methoxide, sodium ethoxide, potassium methoxide, potassium tert-butoxide, sodium hydride, etc., but sodium methoxide is particularly preferred.

[0050] The base and ethyl formate used in the hydroxymethylenation of the above reaction formula can be used in amounts of 1.2 mol to 4.0 mol, preferably 2.0 to 2.5 mol, respectively, per 1 mol of 3-methylcyclohexanone of the formula (2).

[0051] Examples of the solvent used in the hydroxymethylenation of the above reaction formula include toluene, tetrahydrofuran, tert-butyl methyl ether, cyclopentyl methyl ether, diethyl ether, etc., but toluene is particularly preferred.

[0052] When converting hydroxymethylene in the above reaction formula to methylanilinomethylene, N-methylaniline used can increase the yield of the compound of formula (3) by using 1.0 mol to 10.0 mol, preferably 3.0 to 5.0 mol, based on 1 mol of 3-methylcyclohexanone of formula (2).

[0053] Solvents used when converting hydroxymethylene in the above reaction formula to methylanilinomethylene can include, for example, methanol, benzene, etc., but methanol is particularly preferred.

[0054] 6-Methylanilinomethylene-3-methylcyclohexanone represented by formula (3) in the above reaction formula is a viscous liquid immediately after production, but gradually solidifies when left in a refrigerator for several days. By washing this with hexane, the purity of 6-methylanilinomethylene-3-methylcyclohexanone of formula (3) can be increased.

[0055] To produce 6-methylanilinomethylene-3-methylcyclohexanone represented by formula (3) from 3-methylcyclohexanone represented by formula (2), it is preferable to charge 3-methylcyclohexanone of formula (2) and a solvent into a reaction vessel, add the entire amount of a base to the reaction vessel at room temperature all at once while stirring the inside of the reaction vessel, and further add ethyl formate dropwise or add the entire amount all at once. The reaction temperature is preferably in the range of 0°C to 30°C.

[0056] To produce 6-methylanilinomethylene-3-methylcyclohexanone of formula (3) from the hydroxymethylene form of 3-methylcyclohexanone obtained in the above reaction, it is preferable to charge the hydroxymethylene form of 3-methylcyclohexanone and a solvent into a reaction vessel, add N-methylaniline, and stir at room temperature. The reaction temperature is preferably in the range of 0°C to 30°C.

[0057] After converting 3-methylcyclohexanone represented by formula (2) to 6-methylanilinomethylene-3-methylcyclohexanone represented by formula (3), two methyl groups are introduced into the carbon adjacent to the carbonyl in a one-step reaction operation, and then the protecting group is removed by acid hydrolysis to produce 6-hydroxymethylene-2,2,3-trimethylcyclohexanone represented by formula (5) which is an intermediate. This reaction can be represented as follows by a reaction formula.

[0058]

Chemical formula

[0059] Examples of the base used in the methylation of the above reaction formula include potassium tert-butoxide, sodium tert-pentoxide, potassium tert-pentoxide, sodium hydride, etc., and potassium tert-butoxide is particularly suitable.

[0060] Examples of the solvent used in the methylation of the above reaction formula include toluene, tetrahydrofuran, tert-butyl methyl ether, cyclopentyl methyl ether, tert-amyl alcohol, tert-butyl alcohol, etc., and tert-butyl methyl ether is particularly suitable.

[0061] The base and methyl iodide used in the methylation of the above reaction formula can be used in amounts of 2.0 mol to 5.0 mol, preferably 2.2 to 3.0 mol, respectively, per 1 mol of 6-methylanilinomethylene-3-methylcyclohexanone of formula (3).

[0062] To produce 6-methylanilinomethylene-2,2,3-trimethylcyclohexanone represented by formula (4) from 6-methylanilinomethylene-3-methylcyclohexanone represented by formula (3), it is preferable to charge a base and a solvent into a reaction vessel, add a solution of 6-methylanilinomethylene-3-methylcyclohexanone represented by formula (3) while stirring the inside of the reaction vessel, and further add methyl iodide dropwise. The reaction temperature is preferably in the range of 0°C to 30°C.

[0063] Examples of the acid used to produce 6-hydroxymethylene-2,2,3-trimethylcyclohexanone represented by formula (5) in the above reaction formula include hydrochloric acid, sulfuric acid, nitric acid, etc., and hydrochloric acid is particularly preferable.

[0064] The acid used to produce 6-hydroxymethylene-2,2,3-trimethylcyclohexanone represented by formula (5) in the above reaction formula can be used in an amount of 2.5 moles to 20.0 moles, preferably 6.0 to 9.0 moles, per 1 mole of 6-methylanilinomethylene-2,2,3-trimethylcyclohexanone represented by formula (4).

[0065] To produce 6-hydroxymethylene-2,2,3-trimethylcyclohexanone represented by formula (5) from 6-methylanilinomethylene-2,2,3-trimethylcyclohexanone represented by formula (4) obtained in the above reaction, it is preferable to charge 6-methylanilinomethylene-2,2,3-trimethylcyclohexanone represented by formula (4) into a reaction vessel, add water and an acid, and stir the inside of the reaction vessel. The reaction temperature is preferably in the range of 0°C to 30°C.

[0066] 6-Hydroxymethylene-2,2,3-trimethylcyclohexanone represented by formula (5) can be converted to γ-methylcyclocitral represented by formula (6) in a six-step reaction by a method described in the literature (Patent Document 3, Non-Patent Document 1) as shown in the following reaction formula.

[0067]

Chemical formula

[0068] The γ-methylcyclocitral represented by the formula (6) can be reacted in a basic solvent as shown in the following reaction formula to produce the β-methylcyclocitral represented by the formula (7).

[0069]

Chemical formula

[0070] Examples of the base used in the reaction of the above reaction formula include potassium hydroxide, sodium hydroxide, calcium hydroxide, sodium methoxide, etc., but potassium hydroxide is particularly preferred. Also, this alkali can be used in an amount of 0.1 mol to 5.0 mol, preferably 2.0 to 2.5 mol, per 1 mol of the γ-methylcyclocitral of the formula (6).

[0071] The solvent used in the reaction of the above reaction formula needs to dissolve the base used. Examples thereof include alcohol solvents such as methanol, ethanol, isopropyl alcohol, ethylene glycol, and propylene glycol, but methanol is particularly preferred.

[0072] To produce the β-methylcyclocitral represented by the formula (7) from the γ-methylcyclocitral represented by the formula (6), it is preferable to charge the γ-methylcyclocitral of the formula (6) into a reaction vessel, add a solvent in which the base is dissolved, and stir the inside of the reaction vessel. The reaction time at that time can be 30 minutes to 4 hours, preferably 1 hour to 2 hours, and the reaction temperature can be 10°C to 50°C, preferably 15°C to 30°C.

[0073] The β-methylcyclocitral represented by the formula (7) can be reacted with acetone in the presence of a base by aldol condensation as shown in the following reaction formula to produce the β-ionone represented by the formula (1).

[0074]

Chemical formula

[0075] Examples of the base used in the aldol condensation reaction of the above reaction formula include sodium hexamethyldisilazide, potassium hexamethyldisilazide, lithium hexamethyldisilazide, sodium methoxide, sodium ethoxide, sodium hydride, etc. More preferably, the use of sodium hexamethyldisilazide can be exemplified.

[0076] For the base used in the aldol condensation reaction of the above reaction formula, 0.2 mol to 1.0 mol, preferably 0.5 to 0.7 mol, can be used per 1 mol of formula (7) β-methylcyclocitral.

[0077] For the acetone used in the aldol condensation reaction of the above reaction formula, 5 mol to 50 mol, preferably 15 to 20 mol, can be used per 1 mol of formula (7) β-methylcyclocitral.

[0078] Examples of the solvent used in the aldol condensation reaction of the above reaction formula include methanol, ethanol, tetrahydrofuran, tert-butyl methyl ether, cyclopentyl methyl ether, etc. Particularly, tert-butyl methyl ether is preferable.

[0079] To produce β-ionone represented by formula (1) from β-methylcyclocitral represented by formula (7), it is preferable to previously charge a solution of the base into the reaction vessel, dropwise add a solution of formula (7) β-methylcyclocitral under a dry air atmosphere, and then dropwise add acetone. Also, the temperature at that time desirably does not raise the temperature inside the reaction system, and 0°C to 15°C can be exemplified.

[0080] When synthesizing β-iron of formula (1) in the above reaction, α-iron represented by the following formula (8) is simultaneously generated at about 2 to 10%. Although they can be clearly separated by gas chromatographic analysis, they are difficult to separate by distillation or column chromatography because of their similar physical properties.

[0081]

Chemical formula

[0082] Therefore, as a result of researching the separation method of β-iron represented by formula (1) and α-iron represented by formula (8), as shown in the following reaction formula, by preferentially converting α-iron of formula (8) to an epoxide by an oxidation reaction, it becomes easy to separate by distillation or column chromatography, and it was found that β-iron of formula (1) can be produced with high purity.

[0083]

Chemical formula

[0084] As methods for preferentially converting α-iron represented by formula (8) to an epoxide by an oxidation reaction, a method of generating dimethyldioxirane from acetone under basic conditions using oxone (potassium peroxymonosulfate) as an oxidizing agent for epoxidation, and a method of using hydrogen peroxide as an oxidizing agent and methyltrioxorhenium as a catalyst for epoxidation were found, but a method using oxone as an oxidizing agent, which can be carried out at a lower cost, is preferred.

[0085] The oxone used to preferentially convert α-iron represented by formula (8) to an epoxide by an oxidation reaction can be used in an amount of 1 to 10 moles, preferably 2 to 5 moles, per mole of α-iron of formula (8).

[0086] Sodium hydrogen carbonate, which is used as a base to preferentially convert α-iron represented by formula (8) into an epoxide by an oxidation reaction, can be used in an amount of 1 to 8 moles, preferably 2 to 4 moles, per mole of oxone.

[0087] Acetone, which is used to preferentially convert α-iron represented by formula (8) into an epoxide by an oxidation reaction, can be used in an amount of 20 to 200 milliliters, preferably 50 to 100 milliliters, per 10 grams of the mixture of formula (1) β-iron and formula (8) α-iron.

[0088] To preferentially epoxidize α-iron of formula (8) in the mixture of formula (1) β-iron and formula (8) α-iron, it is preferable to previously charge the reaction vessel with a mixture of β-iron and α-iron, acetone, and sodium hydrogen carbonate, and then dropwise add an aqueous solution of oxone at room temperature. Also, it is desirable that the temperature at that time does not raise the temperature inside the reaction system too much, and 15°C to 30°C can be exemplified.

[0089] The β-iron of formula (1) obtained in the above reaction can be purified by ordinary purification methods, such as operations like distillation or silica gel column chromatography.

[0090] By the steps shown above, high-quality β-iron represented by the above formula (1) with a chemical purity of 96% or more can be produced.

[0091] The β-iron represented by the above formula (1) thus obtained can be provided as a liquid, solid, or powder fragrance or food flavor.

[0092] Also, for example, it can be provided as a fragrance or food flavor for perfumes, cosmetics, hair cosmetics, daily necessities (laundry detergents, dishwashing detergents, toilet paper, tissue paper, sanitary products, dental care products), etc.

[0093] In addition, for example, it can be provided as a perfume, food flavor such as confectionery, chocolate, ice cream, jam, soft drink, alcoholic beverage (whiskey, wine, beer, sake, cocktail), and vitamin agent.

[0094] Hereinafter, the present invention will be described more specifically with reference to examples. Note that the present invention is not limited thereto.

[0095] Example 1: Synthesis of 6-hydroxymethylene-3-methylcyclohexanone A 1 L eggplant-shaped flask was charged with 3-methylcyclohexanone (30.0 g, 0.267 mol) represented by the above formula (2) and dry toluene (300 mL). While stirring the inside of the flask, the entire amount of sodium methoxide (28.9 g, 0.535 mol, 2.0 eq.) was added at once, and then the entire amount of ethyl formate (43.1 mL, 0.535 mol, 2.0 eq.) was added at once. A drying tube was attached and stirred at room temperature. Immediately, the liquid color turned yellow and then the whole liquid solidified, making stirring difficult, so the stirring was stopped and left standing at room temperature overnight. 400 mL of water was added to dissolve the reaction mixture, which was transferred to a separatory funnel to separate the toluene layer and the aqueous layer. The toluene layer was extracted with 150 mL of a 5% aqueous sodium hydroxide solution, and the previously separated aqueous layer and the sodium hydroxide extract were combined and washed twice with 60 mL of dichloromethane. The aqueous layer was transferred to a beaker, and 36% hydrochloric acid was added dropwise with stirring until the liquid became acidic (universal test paper - red). The acidic aqueous layer was extracted twice with 120 mL and 60 mL of hexane. The hexane extract was dried over sodium sulfate and then concentrated to obtain 34.8 g of a crude product of 6-hydroxymethylene-3-methylcyclohexanone (crude product yield 92.8%). The crude product was used directly in the next reaction without purification.

[0096] In addition, as a result of gas chromatographic analysis of the crude product obtained in Example 1 above, it contained approximately 10% of 2-hydroxymethylene-3-methylcyclohexanone, and the chemical purity of 6-hydroxymethylene-3-methylcyclohexanone was 82.1% (analysis conditions, column: GL Sciences InertCap1 (30 m × 0.25 mm × 0.25 μm), temperature rising conditions: 50°C to 270°C, held at 50°C for 2 minutes, then heated at 10°C / min, held at 270°C for 6 minutes, carrier gas: helium, constant pressure mode, linear velocity: 31.8 cm / sec at 50°C, retention time: 9.9 minutes).

[0097] Example 2: Synthesis of 6-methylanilinomethylene-3-methylcyclohexanone (the compound of the above formula (3)) A 500 mL eggplant-shaped flask was charged with the crude product of 6-hydroxymethylene-3-methylcyclohexanone (34.8 g, 0.249 mol) obtained in Example 1 above and methanol (80 mL). While stirring the inside of the flask, the entire amount of N-methylaniline (80.7 mL, 0.746 mol, 3.0 eq.) was added at once. After stirring at room temperature for 1 hour, it was allowed to stand at room temperature overnight. After distilling off the methanol with an evaporator and then distilling off N-methylaniline under reduced pressure, a dark red viscous oil was obtained. When this was stored in a refrigerator, the oil gradually solidified within a few days. After the whole solidified, hexane was added for washing, and the solid was filtered to obtain 41.6 g of the crude product of 6-methylanilinomethylene-3-methylcyclohexanone represented by the formula (3) (crude product yield 72.9%). The crude product was used directly in the next reaction without purification.

[0098] Furthermore, as a result of gas chromatographic analysis of the crude product obtained in Example 2 above, it contained about 1% of 2-methylanilinomethylene-3-methylcyclohexanone, and the chemical purity of 6-methylanilinomethylene-3-methylcyclohexanone was 97.3% (analysis conditions, column: GL Sciences InertCap1 (30 m × 0.25 mm × 0.25 μm), temperature rising conditions: 50°C to 270°C, held at 50°C for 2 minutes, then heated at 10°C / min, held at 270°C for 6 minutes, carrier gas: helium, constant pressure mode, linear velocity: 31.8 cm / second at 50°C, retention time: 22.2 minutes).

[0099] Physical property data of 6-methylanilinomethylene-3-methylcyclohexanone of formula (3) 1H-NMR (400 MHz, CDCl3): δ ppm 0.97 (d, J = 6.4 Hz, 3H), 1.11 - 1.23 (m, 1H), 1.66 - 1.74 (m, 1H), 1.79 - 1.92 (m, 1H), 1.93 - 2.17 (m, 3H), 2.51 (dq, J = 17.4 Hz, 2.3 Hz, 1H), 3.43 (s, 3H), 7.01 - 7.13 (m, 3H), 7.28 - 7.36 (m, 2H), 7.58 (s, 1H) 13C-NMR (100 MHz, CDCl3): δ ppm 21.8, 26.4, 29.4, 31.7, 42.4, 47.3, 111.0, 121.4, 124.0, 128.8, 145.2, 145.9, 199.4 MS (m / z): 77, 91, 104, 106, 130, 144 (100), 146, 158, 172, 186, 212, 214, 229 (M+)

[0100] Example 3: Synthesis of 6-hydroxymethylene-2,2,3-trimethylcyclohexanone (compound of formula (5) above) A 1 L eggplant-shaped flask was charged with potassium tert-butoxide (29.4 g, 0.262 mol, 2.4 eq.) and dry tert-butyl methyl ether (320 mL). To this, a solution of 6-methylanilinomethylene-3-methylcyclohexanone (25.0 g, 0.109 mol) represented by the above formula (3), obtained in Example 2 above, dissolved in dry tert-butyl methyl ether (35 mL) was added dropwise over 60 minutes while stirring the inside of the flask at room temperature under a dry air atmosphere. After completion of the dropwise addition, the mixture was stirred at room temperature for 30 minutes, and then methyl iodide (16.3 mL, 0.262 mol, 2.4 eq.) was added dropwise over 90 minutes. After completion of the dropwise addition, the reaction mixture was stirred at room temperature overnight. Water (350 mL) was added to the reaction mixture, and after the precipitate was dissolved, it was transferred to a separatory funnel and the organic layer was separated. The remaining aqueous layer was extracted twice with tert-butyl methyl ether (50 mL). The previously separated organic layer and the tert-butyl methyl ether extract were combined, dried over sodium sulfate, and the solvent was distilled off using an evaporator to obtain a dark red oil. To this dark red oil, water (220 mL) and 36% hydrochloric acid (65 mL) were added, and the mixture was vigorously stirred at room temperature for 2 hours. The reaction mixture was transferred to a separatory funnel and extracted three times with dichloromethane (60 mL, 30 mL, 10 mL). The dichloromethane layer was extracted twice with 200 mL and 100 mL of a 4% aqueous sodium hydroxide solution, and the extract was washed once with 50 mL of hexane. 35 mL of 36% hydrochloric acid was added to the sodium hydroxide extract with stirring to make the solution acidic (universal test paper - red), and the aqueous layer was extracted twice with dichloromethane (50 mL, 20 mL). The dichloromethane extract was dried over sodium sulfate, and dichloromethane was distilled off using an evaporator to obtain 15.6 g of a dark red oil. (Crude product yield: 85%) This was purified by silica gel column chromatography (Wako Gel 60N, 63 - 212 μm) to obtain 14.6 g of an orange oil of 6-hydroxymethylene-2,2,3-trimethylcyclohexanone of formula (5). (Yield: 79%)

[0101] In addition, as a result of gas chromatographic analysis of the purified product obtained in Example 3 above, the chemical purity of 6-hydroxymethylene-2,2,3-trimethylcyclohexanone (4) was 95.7% (analysis conditions, column: GL Sciences InertCap1 (30 m × 0.25 mm × 0.25 μm), temperature rising conditions: 50°C to 270°C, held at 50°C for 2 minutes, then heated at 10°C / min, held at 270°C for 6 minutes, carrier gas: helium, constant pressure mode, linear velocity: 31.8 cm / sec at 50°C, retention time: 12.1 minutes).

[0102] Physical property data of 6-hydroxymethylene-2,2,3-trimethylcyclohexanone of formula (5) 1H-NMR (400 MHz, CDCl3): δ ppm 0.94 (d, J = 6.6 Hz, 3H), 1.07 (s, 3H), 1.21 (s, 3H), 1.37 - 1.50 (m, 1H), 1.54 - 1.70 (m, 2H), 2.27 - 2.41 (m, 2H), 8.74 (d, J = 2.8 Hz, 1H), 14.76 (d, J = 2.8 Hz, 1H) 13C-NMR (100 MHz, CDCl3): δ ppm 15.8, 20.7, 22.6, 24.8, 26.9, 37.9, 40.7, 106.6, 189.4, 189.9 MS (m / z): 55, 69, 70, 83, 97, 107, 111, 121, 125 (100), 135, 140, 150, 168 (M+)

[0103] Example 4: Synthesis of β-methylcyclocitral (the compound of formula (7) above) Into a 500 mL eggplant-shaped flask, L-(+)-tartaric acid (20.4 g, 0.136 mol, 2.0 eq.) and water (70 mL) were charged, and a solution prepared by dissolving 2-(dimethylamino)-2-(2,2,3-trimethyl-6-methylenecyclohexyl)acetonitrile (15.0 g, 0.068 mol) obtained in the above reaction step formula (Chemical Formula 9) in methanol (140 mL) was added thereto. The flask was heated to a temperature at which methanol refluxed slowly, and heating was continued for 3 hours with stirring. After the flask was cooled to room temperature, the reaction mixture was poured into water (200 mL) and extracted twice with hexane (100 mL, 30 mL). After the hexane layer was dried over sodium sulfate, hexane was distilled off using an evaporator to obtain a red oil containing γ-methylcyclocitral. To this oil, a methanol solution of potassium hydroxide (8.0 g potassium hydroxide / 100 mL methanol) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into water (200 mL) and extracted twice with hexane (100 mL, 30 mL). After the hexane layer was washed with brine, dried over sodium sulfate, and hexane was distilled off using an evaporator, 9.95 g (yield: 88%) of a crude product of β-methylcyclocitral represented by formula (7) was obtained. The crude product was used directly in the next reaction without purification.

[0104] In addition, as a result of gas chromatographic analysis of the crude product obtained in Example 4 above, the chemical purity of β-cyclocitral (7) was 70.5% (analysis conditions, column: GL Sciences InertCap1 (30 m × 0.25 mm × 0.25 μm), temperature rising conditions: 50 °C to 270 °C, held at 50 °C for 2 minutes, then heated at 10 °C / min, held at 270 °C for 6 minutes, carrier gas: helium, constant pressure mode, linear velocity: 31.8 cm / sec at 50 °C, retention time: 12.8 minutes).

[0105] Physical property data of β-methylcyclocitral of formula (6) 1H-NMR (400 MHz, CDCl3): δ ppm 0.90 (d, J = 6.4 Hz, 3H), 1.06 (s, 3H), 1.22 (s, 3H), 1.35 - 1.49 (m, 2H), 1.53 - 1.60 (m, 1H), 2.09 (s, 3H), 2.17 - 2.30 (m, 2H), 10.12 (s, 1H) 13C-NMR (100 MHz, CDCl3): δ ppm 15.6, 19.4, 20.7, 26.2, 26.2, 34.7, 36.0, 39.8, 140.8, 155.6, 192.9 MS (m / z): 67, 77, 79, 81 (100), 91, 95, 109, 123, 133, 137, 148, 151, 166 (M+)

[0106] Example 5: Synthesis of β-Irone (the compound of formula (1)) A 300 mL eggplant-shaped flask was charged with a 1.9 M tetrahydrofuran solution of sodium hexamethyldisilazane (15 mL, 28.5 mmol, 0.53 eq.), cooled to 10 °C, and thereto was added dropwise a solution of the β-methylcyclocitral of formula (7) (8.94 g, 53.8 mmol) obtained in Example 4 above dissolved in dry tert-butyl methyl ether (55 mL). Subsequently, acetone (63 mL, 16 eq.) was added dropwise. After stirring at 10 °C for 1 hour, the solvent was distilled off using an evaporator. To the flask residue was added brine (300 mL), and the mixture was extracted twice with hexane (100 mL, 50 mL). The hexane layer was washed twice with 1% hydrochloric acid (300 mL), dried over sodium sulfate, and then hexane was distilled off using an evaporator. Vacuum drying of the residual oil gave 9.96 g of an orange oil containing β-irone represented by formula (1).

[0107] Furthermore, as a result of gas chromatographic analysis of the crude product obtained in Example 5 above, the ratio of formula (1) β-ionone to formula (8) α-ionone was 95:5, and the chemical purity of formula (1) β-ionone was 58% (analysis conditions, column: GL Sciences InertCap1 (30 m × 0.25 mm × 0.25 μm), temperature rising conditions: 50°C to 270°C, held at 50°C for 2 minutes, then heated at 10°C / min, held at 270°C for 6 minutes, carrier gas: helium, constant pressure mode, linear velocity: 31.8 cm / sec at 50°C, retention time: 16.4 minutes).

[0108] Example 6: Preferential Epoxidation Reaction of α-Ionone in a Mixture of α-Ionone and β-Ionone Epoxidation with Dimethyldioxolane Using Oxone as the Oxidizing Agent Into a 300 mL eggplant-shaped flask, charged were a mixture of formula (1) β-ionone and formula (8) α-ionone (9.96 g, β:α = 95:5), which was the crude product obtained in Example 5 above, acetone (80 mL), and sodium hydrogen carbonate (3.04 g, 36.2 mmol, 2.5 eq. relative to Oxone). While stirring at room temperature, an aqueous solution (60 mL) of Oxone (8.90 g, 14.5 mmol, 0.30 eq. relative to the iron mixture) was added dropwise over 10 minutes. After completion of the dropwise addition, stirring was continued at room temperature for 1 hour. The reaction mixture was poured into water (250 mL) and extracted twice with hexane (50 mL, 20 mL). The hexane layer was washed with brine (80 mL), dried over sodium sulfate, and the hexane was distilled off using an evaporator to obtain 9.55 g of an orange oil as the crude product.

[0109] Furthermore, as a result of gas chromatographic analysis of the crude product obtained in Example 6 above, the ratio of α-ion of formula (8) to β-ion of formula (1) was 1% or less, and the chemical purity of β-ion of formula (1) was 54% (analysis conditions, column: GL Sciences InertCap1 (30 m × 0.25 mm × 0.25 μm), temperature rising conditions: 50°C to 270°C, held at 50°C for 2 minutes, then heated at 10°C / second, held at 270°C for 6 minutes, carrier gas: helium, constant pressure mode, linear velocity: 31.8 cm / second at 50°C, retention time: β-ion 16.4 minutes, α-ion 15.6 minutes).

[0110] Example 7: Purification of β-ion (compound of formula (1)) The crude product obtained in Example 6 above was purified by flash chromatography and then further purified by vacuum distillation to obtain 2.02 g of β-ion represented by formula (1) (yield 20.3% calculated from the weight of the iron isomer mixture used in Example 6).

[0111] Furthermore, as a result of gas chromatographic analysis of the β-ion represented by formula (1) obtained in Example 7 above, the chemical purity was 96.8% (analysis conditions, column: GL Sciences InertCap1 (30 m × 0.25 mm × 0.25 μm), temperature rising conditions: 50°C to 270°C, held at 50°C for 2 minutes, then heated at 10°C / minute, held at 270°C for 6 minutes, carrier gas: helium, constant pressure mode, linear velocity: 31.8 cm / second at 50°C, retention time: 16.4 minutes).

[0112] Physical property data of β-ion of formula (1) 1H-NMR (400 MHz, CDCl3): δ ppm 0.91 (s, 3H), 0.91 (d, J = 7 Hz, 3H), 1.06 (s, 3H), 1.37 - 1.52 (m, 2H), 1.55 - 1.62 (m, 1H), 1.73 (s, 3H), 2.06 (m, 2H), 2.30 (s, 3H), 6.07 (d, J = 16 Hz, 1H), 7.26 (d, J = 16 Hz, 1H) 13C-NMR (100 MHz, CDCl3): δ ppm 16.2, 21.9, 22.1, 26.6, 27.1, 27.6, 32.2, 37.2, 39.0, 132.5, 134.2, 136.2, 144.2, 198.8 MS (m / z): 77, 79, 91, 93, 105, 107, 109, 121, 122, 133, 135, 149, 191 (100), 192, 206 (M+)

Claims

1. A method for producing β-ionone represented by the following formula (1), which uses 3-methylcyclohexanone represented by the following formula (2) as a starting material for synthesis, via 6-methylanilinomethylene-3-methylcyclohexanone represented by the following formula (3), and introduces two methyl groups in one step to produce 6-methylanilinomethylene-2,2,3-trimethylcyclohexanone represented by the following formula (4), hydrolyzes 6-methylanilinomethylene-2,2,3-trimethylcyclohexanone to obtain 6-hydroxymethylene-2,2,3-trimethylcyclohexanone represented by the following formula (5), and is derived therefrom to obtain γ-methylcyclocitral represented by the following formula (6), isomerizes it to β-methylcyclocitral represented by the following formula (7) in a basic solvent, and then includes a step of subjecting this to an aldol condensation in the presence of acetone and a base. 【Chemical 1】

2. A method for producing β-methylcyclocitral represented by the following formula (7), characterized by reacting γ-methylcyclocitral represented by the following formula (6) in a basic solvent. 【Chemical 2】 【Chemical Formula 3】

3. As a method for separating and removing α-ionone represented by the following formula (8) from a mixture of β-ionone represented by the following formula (1) and its isomer α-ionone represented by the following formula (8), a method for purifying β-ionone represented by the formula (1) to high purity, which includes a step of preferentially converting α-ionone represented by the formula (8) to an epoxide by an oxidation reaction. 【Chemical Formula 4】 ​ 【Chemical Formula 5】 ​ 【Chemical Formula 6】 ​ 【Chemical Formula 7】 ​ ​ [Chemical Formula 8] ​ 【Chemical Formula 9】 ​ ​ 【Chemical Formula 10】 ​ 【Chemical Formula 11】 ​

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