How Rotundone is Made

Abstract

To provide a production method of rotundone.SOLUTION: A production method includes: (step 1) a step of preparing a rotundone-containing composition; (step 2) a step of making the rotundone in the composition react with a specific crystallized compound having an amino group so as to obtain a solid of a crystalline rotundone derivative; (step 3) a step of recrystallizing the crystalline rotundone derivative, and (step 4) a step of hydrolyzing an imino group of the crystalline rotundone derivative in the crystal obtained in the step 3 so as to release rotundone from the crystalline rotundone derivative. Preferably the crystallized compound is a semicarbazone hydrochloride or a 2,4-dinitrophenyl hydrazine when selected from a crystallized compound group I, or a t-butylamine, phenylamine, benzyl amine or hydroxylamine hydrochloride when selected from a crystallized compound group II.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for producing rotundone. [Background technology]

[0002] Rotundone ((3S,5R,8S)-3,8-dimethyl-5-(prop-1-en-2-yl)-3,4,5,6,7,8-hexahydroazulen-1(2H)-one) is found in Syrah grapes, black pepper, white pepper, and the like, and is a compound that has attracted attention as an active ingredient for imparting flavors such as citrus flavors (Patent Document 1), fruity flavors (Patent Document 2), enhancing saltiness (Patent Document 3), enhancing richness (Patent Document 4), and enhancing astringency (Patent Document 5), as well as for masking unpleasant flavors (Patent Document 6).

[0003] Therefore, various organic chemical methods for producing rotundone have been investigated. For example, Patent Document 7 describes a method for producing hydroxyl adducts (e.g., rotundol, in which the carbonyl group at the 1-position of rotundone is converted to alcohol) by reacting laccase with a material containing α-guaiene and / or α-bulnesene, specifically patchouli oil, in the presence of an oxygen source. Furthermore, Patent Document 8 describes the production of a mixture of numerous α-guaiene oxides, including rotundone, as a by-product (see Examples 3, 4, and 5 in the document), and the possession of a floral, woody odor. Patent Document 9 also describes the production of numerous guaiene oxides, including rotundone, through distillation, heating, refluxing, and re-distillation of guaiene-rich raw oils, specifically guaiac wood oil. Patent Document 10 describes the production of rotundone by allylic oxidation of α-guaiene using a noble metal catalyst (Au, Pd / TiO). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Patent No. 6262170 [Patent Document 2] Patent No. 6262171 [Patent Document 3] Patent Publication No. 2021-171024 [Patent Document 4] Patent Publication No. 2021-171025 [Patent Document 5] Patent Publication No. 2021-171026 [Patent Document 6] Patent Publication No. 2021-171023 [Patent Document 7] Japanese Patent Application Laid-Open No. 2017-216974 [Patent Document 8] Special Publication No. 2013-534927 [Patent Document 9] Special Publication No. 2020-511128 [Patent Document 10] International Publication No. 2011 / 106166 Summary of the Invention [Problem to be solved by the invention]

[0005] However, the above-mentioned conventional method for producing rotundone by oxidation of α-guaiene merely yields a mixture of rotundone and a wide variety of by-products, including isomers with boiling points very close to that of rotundone, and therefore the development of a new method for producing rotundone has been desired. Therefore, an object of the present invention is to provide a method for producing rotundone with few impurities. [Means for solving the problem]

[0006] The present inventors have conducted extensive research in light of the above-mentioned problems and have found that the above-mentioned problems can be solved by employing a crystallization process using a primary amine or a specific nitrogen-containing compound that behaves similarly thereto.

[0007] Thus, a brief summary of representative inventions among those disclosed in this application is as follows. [1] A method for producing rotundone, comprising the steps of: (Step 1) Preparing a Rotundone-Containing Composition (Step 2) A step of reacting the rotundone in the rotundone-containing composition with a crystallizing compound having an amino group to produce a crystalline rotundone derivative, which comprises carrying out the following step 2A or 2B: (Step 2A) A step of reacting the rotundone in the rotundone-containing composition with a crystallizing compound selected from the following crystallizing compound group I to produce a crystalline rotundone derivative. (Crystallized compound group I)

[0008] [ka] [In the formula (a), R1 to R3 each independently represent hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms, X represents a halogen atom, and in the formula (b), R4 to R8 each independently represent hydrogen or a nitro group.] (Step 2B) A step of reacting the rotundone in the rotundone-containing composition with a crystallizing compound selected from the crystallizing compound group II below to generate a crystalline rotundone derivative precursor, and then reacting the precursor with an acid to generate a salt of the precursor as a crystalline rotundone derivative. (Crystallized compound group II)

[0009] [ka] [In the formula (c), n represents an integer of 0 to 4.] (Step 3) Recrystallizing the crystalline rotundone derivative (Step 4) A step of hydrolyzing the imino group of the crystalline rotundone derivative in the crystals obtained in Step 3 to liberate rotundone from the crystalline rotundone derivative. [2] The method according to [1], wherein the crystallization compound is semicarbazone hydrochloride or 2,4-dinitrophenylhydrazine when selected from crystallization compound group I, or t-butylamine, phenylamine, benzylamine, or hydroxylamine hydrochloride when selected from crystallization compound group II. [3] The method according to [1] or [2], wherein the acid in step 2B is hydrochloric acid. [4] The production method according to [1] or [2], wherein the step 3 comprises mixing a recrystallization solvent with the crystalline rotundone derivative. [5] The method according to [4], wherein the recrystallization solvent is ethyl acetate, methanol, ethanol, water, acetone, cyclohexane, toluene, hexane, or a mixture of two or more thereof. [6] The method according to [1] or [2], wherein the hydrolysis in step 4 is hydrolysis using copper(II) chloride. [7] The method according to [1] or [2], wherein step 1 is a step of oxidizing all or part of the α-guaiene contained in the α-guaiene-containing composition to convert it into rotundone, thereby preparing a rotundone-containing composition. [8] The method according to [7], wherein the α-guaiene-containing composition to be oxidized is any one of patchouli oil, patchouli oil obtained by simple distillation and / or precision distillation, guaiacwood oil, and guaiacwood oil obtained by simple distillation and / or precision distillation. [9] The method according to [7], wherein the oxidation of α-guaiene is one selected from the group consisting of air oxidation, oxidation using t-butyl hydroperoxide and a chromium oxide catalyst, oxidation using laccase, oxidation using sodium chlorite·N-hydroxyphthalimide, and electrolytic oxidation.

[10] The production method according to [9], wherein the air oxidation is carried out without a catalyst or using a catalyst selected from the group consisting of cobalt (II) acetate tetrahydrate, cobalt 2-ethylhexanoate, cobalt naphthenate, cobalt acetylacetonate, and chromium (VI) oxide.

[11] The method of producing according to [1] or [2], wherein the rotundone concentration of the rotundone-containing composition is within the range of 20 to 80 mass %.

[12] The method according to [7], wherein the α-guaiene concentration of the α-guaiene-containing composition is within the range of 20 to 60 mass%.

[13] The manufacturing method according to [1] or [2], further comprising a step of washing the crystals of the crystalline rotundone derivative with a washing solvent between the steps 3 and 4, wherein the washing solvent is a hydrocarbon solvent, water, a 70 to 99% aqueous ethanol solution, or an ether.

[14] The method according to

[13] , wherein the washing solvent is heptane.

[15] The method of manufacturing according to [1] or [2], wherein step 3 is carried out two or more times.

[16] A method for producing rotundone, comprising the steps of: (Step 1) Preparing a Rotundone-Containing Composition (Step 2) A step of reacting the rotundone in the rotundone-containing composition with a crystallizing compound selected from the following crystallizing compound group I to obtain a crystalline rotundone derivative, and then reacting the crystalline rotundone derivative with an acid to produce a salt of the crystalline rotundone derivative. (Crystallized compound group I)

[0010] [ka] [In the formula (a), R1 to R3 each independently represent hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms, X represents a halogen atom, and in the formula (b), R4 to R8 each independently represent hydrogen or a nitro group.] (Step 3) Recrystallizing the salt of the crystalline rotundone derivative (Step 4) A step of hydrolyzing the imino group of the salt of the crystalline rotundone derivative in the crystals obtained in Step 3 to liberate rotundone from the salt of the crystalline rotundone derivative.

[16] A compound represented by formula A or a salt thereof.

[0011] [ka] [In the formula, R is any one of Ra, Rb, Rc, Rd, and Re, in Ra, R1 to R3 each independently represent hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms, in Rb, R4 to R8 each independently represent hydrogen or a nitro group, and in Rc, n represents an integer of 0 to 4.]

[18] The salt according to

[17] , wherein the compound or the salt thereof is a hydrochloride salt of the compound.

[19] The compound or a salt thereof is a compound represented by the following formula Aa1 or Ab1:

[0012] [ka]

[0013] Alternatively, the compound or salt thereof according to

[17] , which is a hydrochloride salt of a compound represented by the following formula Ac1, Ac2, Ad1, or Ae:

[0014] [ka]

[0015]

[20] The compound or salt thereof according to

[17] , wherein the compound or salt thereof is a hydrochloride salt of a compound represented by the following formula Aa1 or Ab1:

[0016] [ka] [Effects of the Invention]

[0017] The present invention makes it possible to provide a method for producing rotundone with higher purity than conventional methods. DETAILED DESCRIPTION OF THE INVENTION

[0018] The present invention will be described in more detail below with reference to specific examples. In this specification, the symbol "to" indicates a range including a lower limit and an upper limit, and concentrations (ppt, ppb, ppm, etc.) and % indicate mass concentrations and mass %, respectively, unless otherwise specified. Concentrations are final concentrations unless otherwise specified.

[0019] The present invention is a method for producing rotundone that can obtain rotundone with a higher purity than conventional methods. However, the following reasons have existed that have prevented the purity of rotundone from increasing.

[0020] Although the known methods for producing rotundone include the oxidation of α-guaiene (air oxidation or oxidation with peroxides, etc.), the oxidation reaction conditions that can selectively oxidize α-guaiene to produce rotundone have not yet been discovered, and only a mixture of rotundone and a variety of by-products, including isomers with similar boiling points, is obtained. Therefore, even if high-purity α-guaiene could be prepared, rotundone would ultimately be obtained as one component of a complex mixture.

[0021] In addition, isomers can generally be removed by precision distillation if there is a certain degree of difference in boiling point; however, simply oxidizing α-guaiene as in the past has resulted in the production of many isomers with boiling points very close to that of rotundone, as mentioned above, making it impossible to obtain high-purity rotundone.

[0022] Furthermore, in the field of organic chemical synthesis, many methods for improving the purity of a target compound are known, and one example is improving the purity by recrystallization of the target compound. However, when the target compound (rotundone in this case) is not a crystalline compound, obtaining the target compound requires at least three steps: crystalline derivatization of the target compound, recrystallization purification of the derivative, and returning it to the target compound. This method is not necessarily easy to adopt. Furthermore, depending on the target compound, there are problems such as (1) difficulty in finding a derivative that can be crystallized, (2) inability to increase purity even by recrystallization, and (3) inability to obtain crystals without solidification. However, the present inventors have discovered a crystallization compound suitable for rotundone and found that by using this compound, rotundone can be produced with a higher purity than conventional methods, as will be described in the Examples below, thereby completing the present invention.

[0023] [Rotandon manufacturing method] <Manufacturing method 1> A method for producing rotundone according to one embodiment of the present invention is characterized by comprising the following steps. Hereinafter, this method may be referred to as "Production Method 1" or "the present Production Method 1." Production Method 1 and Production Method 2, which will be described later, may be collectively or individually referred to as "the present Production Method." (Step 1) Preparing a Rotundone-Containing Composition (Step 2) A step of reacting the rotundone in the rotundone-containing composition with a crystallizing compound having an amino group to obtain a crystalline rotundone derivative, which comprises carrying out the following step 2A or 2B: (Step 2A) A step of reacting the rotundone in the rotundone-containing composition with a crystallizable compound selected from the following crystallizable compound group I to produce a crystalline rotundone derivative. (Crystallized compound group I)

[0024] [ka] [In the formula (a), R1 to R3 each independently represent hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms, X represents a halogen atom, and in the formula (b), R4 to R8 each independently represent hydrogen or a nitro group.] or (Step 2B) a step of reacting the rotundone in the rotundone-containing composition with a crystallizing compound selected from the crystallizing compound group II below to generate a crystalline rotundone derivative precursor, and then reacting the precursor with an acid to generate a salt of the precursor as a crystalline rotundone derivative. (Crystallized compound group II)

[0025] [ka] [In the formula (c), n represents an integer of 0 to 4.] (Step 3) Recrystallizing the crystalline rotundone derivative (Step 4) A step of hydrolyzing the imino group of the crystalline rotundone derivative in the crystals obtained in Step 3 to liberate rotundone from the crystalline rotundone derivative.

[0026] Specific examples of each step of the present production method 1 will be described below, but the present invention is not limited to these.

[0027] (Process 1) Step 1 is a step of preparing a composition containing rotundone (sometimes referred to herein as a rotundone-containing composition). The method for obtaining the rotundone-containing composition prepared in step 1 is not particularly limited, and the rotundone concentration can be any. Examples include, but are not limited to, natural products containing rotundone (typical examples include nutsedge (also known as koboshi berry) and Shiraz grapes), compositions containing rotundone obtained by organic chemical synthesis, and compositions containing rotundone obtained by synthesis using microorganisms or enzymes. These can be appropriately distilled to achieve the desired rotundone concentration. However, from the perspective of obtaining high-purity rotundone and production costs, the rotundone concentration in the rotundone-containing composition may be somewhat low, thereby reducing the procurement cost of the rotundone-containing composition. The rotundone concentration may be, for example, 80% by mass or less, 50% by mass or less, or 40% by mass or less. However, an excessively low concentration reduces the yield of rotundone obtained by the production method, so 20% by mass or more is preferred. From the viewpoint of both the rotundone yield and the procurement cost of the rotundone-containing composition, the content is, for example, 20 to 80 mass %, preferably 20 to 50 mass %, and more preferably 25 to 35 mass %.

[0028] In one embodiment of Step 1, the rotundone-containing composition may be prepared by the following Step 1A. (Step 1A) A step of oxidizing all or part of α-guaiene contained in a composition containing α-guaiene (also referred to as an α-guaiene-containing composition in this specification) to convert it into rotundone, thereby preparing a rotundone-containing composition. The oxidation method may be any method that converts α-guaiene to rotundone by allylic oxidation. Known oxidation methods include air oxidation (e.g., J. Nat. Prod. 2015, 78, 131), oxidation using t-butyl hydroperoxide (TBHP) and a chromium oxide catalyst (e.g., J. Agric. Food Chem. 2014, 62, 10809), oxidation using laccase (e.g., JP 2017-216974 A and JP 2022-500018 A), oxidation using sodium chlorite and N-hydroxyphthalimide (e.g., WO 2019-110299 A), and electrolytic oxidation (e.g., Nature 2016, 533, 77). One of these oxidation methods may be used, but the present invention is not limited to these. From the viewpoint of the yield of the crystalline rotundone derivative in step 2, it is preferable to obtain a rotundone-containing composition containing 20 to 80 mass % of rotundone by the oxidation in step 1A.

[0029] A specific example of air oxidation, which is a typical oxidation method, will be shown below.

[0030] In air oxidation, the temperature of the reaction system is usually set to around 60-80°C, and a gas containing oxygen is blown into the system to oxidize the compounds in the system. The blowing time can be adjusted depending on the amount of the target product produced, but it is usually carried out for 10-40 hours.

[0031] After completion of the air oxidation, an operation for removing by-produced peroxides may be carried out in order to remove impurities. Examples of such an operation include, but are not limited to, an operation for decomposing peroxides by heating to about 120°C, or an operation for decomposing peroxides by reacting with nitrogen at about 120°C.

[0032] Catalysts used in air oxidation include various cobalt salts such as cobalt(II) acetate tetrahydrate (Co(OAc)2·4H2O), cobalt 2-ethylhexanoate, cobalt naphthenate, and cobalt acetylacetonate, as well as chromium(VI) oxide. A preferred example is cobalt(II) acetate tetrahydrate, but this is not limited to this. Since the conversion of α-guaiene to rotundone by air oxidation proceeds even without a catalyst, air oxidation without a catalyst is preferred from the standpoint of production cost, but the use of a catalyst is preferred from the standpoint of rotundone yield.

[0033] Preferred examples of α-guaiene-containing compositions include inexpensive and easily available essential oils, such as patchouli oil (sometimes written as patchouli, patchouli, etc.) and guaiacwood oil (sometimes written as guaiac wood, guaiacwood, guaiacwood, guaiacwood, etc.), with patchouli oil being particularly preferred from the viewpoint of inexpensive procurement.

[0034] The α-guaiene concentration in the α-guaiene-containing composition is not particularly limited, and may be a relatively low concentration, for example, 50% by mass or less or 40% by mass or less, from the viewpoint of procurement costs of the α-guaiene-containing composition. However, an excessively low concentration reduces the yield of rotundone, and therefore, examples of the α-guaiene concentration include 15 to 80% by mass, preferably 20 to 60% by mass, and more preferably 25 to 35% by mass.

[0035] When an α-guaiene-containing composition is oxidized in Step 1A to prepare a rotundone-containing composition, it is desirable to provide an additional distillation step before or after the oxidation of the α-guaiene-containing composition in order to further increase the purity of the rotundone obtained by the present production method. Examples of distillation include simple distillation and precision distillation (also called rectification), and either or both of these can be performed.

[0036] In the present invention, the α-guaiene-containing composition to be subjected to the oxidation may be a purchased product as it is, or a purchased product that has been distilled (for example, by simple distillation and / or rectification). Preferably, the α-guaiene-containing composition to be subjected to the oxidation is either a purchased product obtained by simple distillation and / or rectification of patchouli oil or a purchased product obtained by simple distillation and / or rectification of guaiacuwood oil.

[0037] Furthermore, in the present invention, a composition obtained by converting α-guaiene in the α-guaiene-containing composition prepared in Step 1 to rotundone by oxidation can be used as the rotundone-containing composition to be subjected to Step 2, regardless of the presence or type of distillation before or after the oxidation. In other words, in the present invention, any of a composition obtained by oxidizing an undistilled α-guaiene-containing composition, a composition obtained by oxidizing a distilled α-guaiene-containing composition, a composition obtained by oxidizing an undistilled α-guaiene-containing composition and subjecting it to distillation, and a composition obtained by oxidizing a distilled α-guaiene-containing composition and subjecting it to distillation can be used as the rotundone-containing composition to be subjected to Step 2.

[0038] As a specific example of the additional distillation step, any of the following additional steps can be employed. In the following steps, the α-guaiene-containing composition is an essential oil. (Step 1A-1) Oxidation of essential oil → Simple distillation and rectification of oxidized essential oil (Step 1A-2) Oxidation of essential oils → Simple distillation of oxidized essential oils (Step 1A-3) Oxidation of essential oils → Rectification of oxidized essential oils (Step 1A-4) Distillation of essential oil → Oxidation of distilled essential oil → Distillation of oxidized essential oil (Step 1A-5) Distillation of essential oil → Oxidation of distilled essential oil → Simple distillation and distillation of oxidized essential oil (Step 1A-6) Distillation of essential oil → Oxidation of distilled essential oil → Simple distillation of oxidized essential oil (Step 1A-7) Simple distillation of essential oil → Oxidation of rectified essential oil → Rectification of oxidized essential oil (Step 1A-8) Simple distillation of essential oil → oxidation of rectified essential oil → simple distillation and rectification of oxidized essential oil (Step 1A-9) Simple distillation of essential oil → oxidation of rectified essential oil → simple distillation of oxidized essential oil When any of Steps 1A-1 to 1A-3 is carried out, the amount of impurities produced by oxidation can be reduced by distillation, thereby making it possible to maintain a high rotundone concentration in the rotundone-containing composition to be subjected to Step 2.

[0039] When steps 1A-4 to 1A-9 are performed, the concentration of α-guaiene in the essential oil (i.e., the α-guaiene-containing composition) can be increased by distillation, and by reducing the production of impurities due to oxidation, the concentration of rotundone in the rotundone-containing composition to be subjected to step 2 can be kept high.

[0040] On the other hand, for example, if essential oil (i.e., an α-guaiene-containing composition) is subjected to simple distillation and / or rectification, followed by oxidation to convert α-guaiene to rotundone, and the oxidized essential oil is directly subjected to step 2 or later, the purity of rotundone obtained by the present production method may be lower than when any of steps 1A-1 to 1A-9 is performed. Without being bound by any theory, it is presumed that the oxidation of essential oil produces a wide variety of compounds (impurities), resulting in a low rotundone concentration, and that the presence of impurities makes it more difficult to produce a crystalline rotundone derivative by reaction between the crystallized compound and rotundone than when simple distillation and / or rectification is performed as in steps 1A-1 to 1A-9.

[0041] The methods for simple distillation and rectification are not limited, and any method known to those skilled in the art may be used. Note that, since rotundone has a high boiling point, it is preferable to carry out the distillation at a reduced pressure of 1 kPa or less (preferably 0.4 kPa or less).

[0042] An example of simple distillation is vacuum distillation, and any method can be used, with a preferred example being vacuum distillation using a mantle heater.

[0043] From the viewpoint of labor hours and manufacturing costs, any of steps 1A-1 to 1A-9 may not be adopted because it increases the labor hours. However, when considering the purity, yield, labor hours, and manufacturing costs of the rotundone obtained by the present manufacturing method, it is preferable to adopt step 1A-1.

[0044] (Process 2) This step involves reacting the rotundone in the rotundone-containing composition with a crystallizing compound having an amino group specified in crystallizing compound group I or II to produce a crystalline rotundone derivative, and involves either step 2A or 2B below. In this specification, a crystallizing compound is one that reacts (combines) with rotundone to produce an imine compound that can be recrystallized itself or its salt; if the imine compound itself can be recrystallized in step 3, it is considered to be a compound of crystallizing compound group I in step 2A, and if a salt of the imine compound can be recrystallized in step 3, it is considered to be a compound of crystallizing compound group II in step 2B.

[0045] (Process 2A) Step 2A is a step of reacting the rotundone in the rotundone-containing composition with a crystallizing compound selected from the following crystallizing compound group I to produce a crystalline rotundone derivative. (Crystallized compound group I)

[0046] [ka] [In the formula (a), R1 to R3 each independently represent hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms, X represents a halogen atom, and in the formula (b), R4 to R8 each independently represent hydrogen or a nitro group.]

[0047] In step 2A, the crystallizing compound belonging to crystallizing compound group I reacts with rotundone to produce a hydrazone structure, and the resulting crystalline rotundone derivative can be obtained as a solid by appropriate solvent removal. In this group I, crystallizing compound (a) is a salt of semicarbazide, of which semicarbazide hydrochloride (where X is chlorine) is particularly preferred. Crystallizing compound (b) is a phenylhydrazine, preferably in which one or two, more preferably two, of R4 to R8 are nitro groups and the others are hydrogen, and even more preferably R4 and R6 are nitro groups and the others are hydrogen. Specific examples include phenylhydrazine and 2,4-dinitrophenylhydrazine, with 2,4-dinitrophenylhydrazine being particularly preferred.

[0048] The conditions for reacting a crystallizing compound belonging to crystallizing compound group I with rotundone to obtain a crystalline rotundone derivative may be any conditions that allow the ketone group of rotundone to react with the amino group of the crystallizing compound to form an imino group, and appropriate acid catalysts, dehydrating agents, pH, temperature, etc. may be selected. Examples of acid catalysts include, but are not limited to, sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, zinc chloride, phosphoryl chloride, boron trifluoride, titanium chloride, and acetic acid. Examples of dehydration reagents or procedures selected from potassium hydroxide, molecular sieves, calcium chloride, sodium sulfate, magnesium sulfate, and azeotropic dehydration procedures include, but are not limited to, potassium hydroxide, molecular sieves, calcium chloride, sodium sulfate, magnesium sulfate, and azeotropic dehydration procedures. For example, when semicarbazide hydrochloride is used as the crystallizing compound, it is preferable not to lower the pH too much; sodium acetate is a preferred example. The amount of the crystallizing compound used may be 1 to 3 equivalents, preferably 1.5 to 1.7 equivalents, relative to rotundone, but is not limited thereto and can be adjusted appropriately to allow the reaction to proceed. The solvent may be any solvent that does not react with the compounds in the reaction system, and representative examples include, but are not limited to, methanol and toluene. The reaction temperature can also be selected under known conditions depending on the properties of the crystallized compound and acid catalyst used, but in the case of crystallized compound 1, the reaction can be carried out under ice cooling and a nitrogen atmosphere.

[0049] (Process 2B) Step 2B is a step of reacting the rotundone in the rotundone-containing composition with a crystallizing compound selected from the crystallizing compound group II below to generate a crystalline rotundone derivative precursor, and reacting the precursor with an acid to generate a salt of the precursor as a crystalline rotundone derivative. (Crystallized compound group II)

[0050] [ka] [In the formula (c), n represents an integer of 0 to 4.]

[0051] In the crystallization compound group II, the crystallization compound (c) can be referred to as a primary arylamine having 6 to 10 carbon atoms and a primary aralkylamine having an amino group bonded to a benzene ring via a linear alkyl group having 1 to 4 carbon atoms. Preferred examples thereof include phenylamine, where n = 0, i.e., the nitrogen atom is directly bonded to the benzene ring, and benzylamine, where n = 1. Preferred examples of the crystallization compound (d), a primary alkylamine having a linear or branched alkyl group having 1 to 10 carbon atoms, include pentylamine, isopentylamine, butylamine, butylamine, and propylamine, with butylamine being more preferred and t-butylamine being particularly preferred. The hydroxylamine of the crystallization compound (e) is a primary amine represented by NHOH. A particularly preferred example of a salt of hydroxylamine is hydroxylamine hydrochloride.

[0052] The conditions for reacting a crystallizing compound belonging to crystallizing compound group II with rotundone to produce a crystalline rotundone derivative precursor may be any conditions that allow the ketone group of rotundone to react with the amino group of the crystallizing compound to form an imino group, and appropriate acid catalysts, dehydrating agents, pH, temperature, etc. may be selected. Examples of acid catalysts include, but are not limited to, sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, zinc chloride, phosphoryl chloride, boron trifluoride, titanium chloride, and acetic acid. Examples of dehydration reagents or procedures selected from potassium hydroxide, molecular sieves, calcium chloride, sodium sulfate, magnesium sulfate, and azeotropic dehydration procedures include, but are not limited to, potassium hydroxide, molecular sieves, calcium chloride, sodium sulfate, magnesium sulfate, and azeotropic dehydration procedures. For example, when semicarbazide hydrochloride is used as the crystallizing compound, it is preferable not to lower the pH too much; sodium acetate is a preferred example. The amount of the crystallizing compound used may be, for example, 1 to 3 equivalents, preferably 1.5 to 1.7 equivalents, relative to rotundone, but is not limited thereto, and can be appropriately adjusted to allow the reaction to proceed. Any solvent that does not react with the compounds in the reaction system may be used, including, but not limited to, methanol and toluene. The reaction temperature can be selected according to the properties of the crystallization compound and acid catalyst used. For crystallization compounds (c) and (d), the reaction can proceed under ice cooling and a nitrogen atmosphere, while for crystallization compound (e), the reaction can proceed at room temperature. In step 2B, the crystalline rotundone derivative precursor may be obtained as an oil at room temperature. However, by converting it into a salt as described below, it can be obtained as a solid, allowing for recrystallization in step 3.

[0053] Salts of crystalline rotundone derivative precursors can generally be produced by reacting a large excess of acid (typically hydrogen chloride) with the crystalline rotundone derivative precursor at room temperature or under heated conditions (for example, heating to a temperature of about 20 to 80°C). Semicarbazide salts can be produced by reacting a large excess of acid with the crystalline rotundone derivative precursor at room temperature or under heated conditions.

[0054] (Step 3) Step 3 is a step of recrystallizing the crystalline rotundone derivative, and this step can increase the purity of the crystalline rotundone derivative.

[0055] The recrystallization method is not particularly limited, but a typical method involves mixing the crystalline rotundone derivative (which may have crystallized) obtained in step 2 with a solvent (this solvent may be referred to as a recrystallization solvent in this specification) (after completely dissolving the crystals if they have formed before mixing), adding seed crystals as appropriate, and concentrating the recrystallization solvent by an appropriate method to obtain crystals. The recrystallization solvent is usually a solvent in which the solubility of the target product (the crystalline rotundone derivative in this invention) is low at low temperatures and high at high temperatures, and can be selected from water or an organic solvent as it has a relatively high boiling point.

[0056] Specific examples of recrystallization solvents include organic solvents such as ethyl acetate, methanol, ethanol, water, acetone, cyclohexane, toluene, and hexane, or mixtures of two or more of these. A preferred example of a mixture of two or more solvents is a hexane / ethyl acetate mixed solvent. The ratio of the two solvents can be adjusted depending on the solubility of the various crystalline rotundone derivatives of the present invention, but is usually within the range of 1:50 to 50:1, preferably 1:40 to 40:1, and more preferably 1:30 to 30:1. The type of recrystallization solvent and the ratio of each solvent in the case of a mixed solvent may be selected appropriately while checking the solubility of the crystalline rotundone derivative. An example of a particularly suitable recrystallization solvent that can be used for various crystalline rotundone derivatives is ethyl acetate.

[0057] Step 3 may be carried out multiple times, and by carrying out the step two or more times, when a trace amount of epimer is present, the amount of epimer removed can be increased compared to a single step, thereby further increasing the purity of rotundone. In this case, carrying out the step two times is preferred from the viewpoints of the purity of the obtained rotundone and production costs.

[0058] (Cleaning process) Furthermore, between Step 3 and Step 4 described below, i.e., after Step 3 and before Step 4, washing of the crystalline rotundone derivative crystals with a solvent (herein, the solvent used for this washing may be referred to as a washing solvent) may be performed. This has the advantage of reducing the odor of the rotundone-containing composition and / or α-guaiene-containing composition, particularly when the rotundone-containing composition prepared in Step 1 is produced from a composition having an aroma such as an essential oil (e.g., an α-guaiene-containing composition such as patchouli oil). Washing solvents that do not excessively dissolve and cause loss of the crystalline rotundone derivative crystals can be used. Representative examples of the washing solvent include, but are not limited to, hydrocarbon solvents such as heptane, hexane, and cyclohexane; highly polar solvents such as water and aqueous ethanol (ethanol concentrations are typically 70 to 99%); and ethers. The solvent can be selected depending on the solubility of the crystalline rotundone derivative crystals and the quality of the odor of the washed crystals.

[0059] (Step 4) Step 4 is a step of hydrolyzing the imino group of the crystalline rotundone derivative contained in the crystals obtained in step 3 to liberate rotundone.

[0060] To liberate rotundone, any method can be used that can liberate a compound having a ketone group by hydrolysis of an imine compound.

[0061] A typical method involves first dissolving crystals of the crystalline rotundone derivative in a solvent at room temperature or under heating (for example, heating to about 40 to 60°C), and then allowing hydrolysis to proceed at room temperature or under heating (for example, heating to about 40 to 60°C). Note that hydrolysis at room temperature proceeds more slowly than with heating, but may result in higher purity. Therefore, from the perspective of further increasing purity, hydrolysis at room temperature is preferred. The solvent is not particularly limited, and a typical example is tetrahydrofuran (THF). The compound used for hydrolysis is not particularly limited, and can be selected from compounds that exhibit acidic or basic properties in aqueous solution. Specific examples include various salts that exhibit weak acidic or basic properties in aqueous solution (typically copper(II) chloride), as well as hydrochloric acid, sulfuric acid, nitric acid, potassium hydroxide, and sodium hydroxide. Preferred examples are copper(II) chloride, hydrochloric acid, and sodium hydroxide, and particularly preferred is copper(II) chloride. Without being bound by any theory, it is believed that epimerization (also called epimerization) of rotundone may proceed due to a large excess of hydrogen ions or hydroxide ions in strong acids or strong bases such as hydrochloric acid or sodium hydroxide, whereas epimerization due to hydrogen ions or hydroxide ions may be less likely to proceed in weak acids or weak bases such as copper(II) chloride, potentially resulting in a higher purity of the resulting rotundone. The solvent used for hydrolysis is not particularly limited and can be selected from any solvent used in the hydrolysis of imino groups. Preferred examples include aqueous acetonitrile (usually 70 to 99% by mass of acetonitrile), aqueous methanol (usually 70 to 99% by mass of methanol), and tetrahydrofuran (THF). From the viewpoint of reaction rate, aqueous acetonitrile is preferred. From the viewpoint of suppressing epimerization, aqueous methanol and tetrahydrofuran are preferred, with aqueous methanol being particularly preferred.

[0062] After liberating rotundone by hydrolysis of the imino group, an organic solvent is added to the system, and rotundone is transferred to the organic layer. The rotundone is then washed appropriately with an aqueous sodium bicarbonate solution or saturated saline solution, and the solvent is removed by vacuum distillation or the like to obtain rotundone, which may then be further purified by vacuum distillation.

[0063] The rotundone liberated in step 4 can be subjected to appropriate solvent removal or distillation to obtain highly pure rotundone. The distillation method is not particularly limited, and reduced-pressure distillation or molecular distillation can be selected, but from the viewpoint of suppressing the progression of epimerization due to heating, a method that can suppress heating under as high a vacuum as possible is preferred, and examples of such a method include Kugelrohr distillation and molecular distillation.

[0064] <Manufacturing method 2> In another aspect of the present invention, there is provided a method for producing rotundone, which comprises the following steps. In this specification, this method may be referred to as "Production Method 2" or "the present Production Method 2." (Step 1) Preparing a Rotundone-Containing Composition (Step 2) A step of reacting the rotundone in the rotundone-containing composition with a crystallizing compound selected from the following crystallizing compound group I to produce a crystalline rotundone derivative, and reacting the crystalline rotundone derivative with an acid to produce a salt of the crystalline rotundone derivative. (Crystallized compound group I)

[0065] [ka] [In the formula (a), R1 to R3 each independently represent hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms, X represents a halogen atom, and in the formula (b), R4 to R8 each independently represent hydrogen or a nitro group.] (Step 3) Recrystallizing the salt of the crystalline rotundone derivative (Step 4) A step of hydrolyzing the imino group of the salt of the crystalline rotundone derivative in the crystals obtained in Step 3 to liberate rotundone from the salt of the crystalline rotundone derivative. Step 1 of the present production method 2 can be carried out in the same manner as step 1 of the present production method 1 described above.

[0066] In step 2 of the present production method 2, the crystallized compound of crystallized compound group I is the same as crystallized compound 1 defined in step 2A of the present production method 1, and the crystalline rotundone derivative produced by reacting rotundone in the rotundone-containing composition with a crystallized compound selected from crystallized compound group I is the crystalline rotundone derivative obtained in step 2A of the present production method 1 and can be produced in the same manner as in step 2 of the present production method 1. As explained in the section on the present production method 1, this crystalline rotundone derivative can itself form crystals, but from the perspectives of the purity of the rotundone obtained and the handleability of the crystals, it can be further salted as in the present production method 2, and the salt can be subjected to step 3 to obtain crystals of the salt of the crystalline rotundone derivative. The salt can be produced by the method exemplified in step 2B of the present production method 1, and the salt is preferably hydrochloride.

[0067] Step 3 of the present production method 2 can be carried out in the same manner as step 3 of the present production method 1.

[0068] Step 4 of the present production method 2 can be carried out in the same manner as step 4 of the present production method 1.

[0069] [Application of this manufacturing method to rotundone diastereomers] This production method can also be applied to rotundone diastereomers. For example, (3R,5R,8S)-5-isopropenyl-3,8-dimethyl-3,4,5,6,7,8-hexahydro-1(2H)-azulenone, an epimer of rotundone, is known (Japanese Patent No. 6339128), and this compound can also be produced in high purity by this production method.

[0070] [Rotandon derivatives] In one embodiment of the present invention, the rotundone derivative (sometimes referred to herein as the present rotundone derivative) is a compound represented by the following formula A or a salt thereof, which itself or the salt thereof can form crystals at room temperature. The salt is preferably a hydrochloride salt.

[0071] The present rotundone derivative can be produced by step 2 of the present production method 1 or 2 described above, and can be used to produce high-purity rotundone by subjecting it or a salt thereof to the above-mentioned recrystallization (step 3 of the present production method 1 or 2) and hydrolysis of the imino group (step 4 of the present production method 1 or 2).

[0072] [ka]

[0073] In the formula, R is any one of Ra, Rb, Rc, Rd, and Re; in Ra, R1 to R3 each independently represent hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms; in Rb, R4 to R8 each independently represent hydrogen or a nitro group; and in Rc, n represents an integer of 0 to 4.

[0074] That is, the present rotundone derivative is any of the compounds represented by the following formulae Aa to Ae or a salt thereof. The salt is preferably a hydrochloride salt.

[0075] [ka]

[0076] In formula Aa, R1 to R3 each independently represent hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms. Preferably, at least one of R1 to R3 is hydrogen, and more preferably, all of R1 to R3 are hydrogen. In formula Ab, R4 to R8 each independently represent hydrogen or a nitro group. Preferably, one or two, more preferably two, of R4 to R8 are nitro groups, and even more preferably, R4 and R6 are nitro groups. In formula Ac, n represents an integer of 0 to 4, and preferably n is 0 or 1. When n=0 in formula Ac, it means that the nitrogen atom and the benzene ring are directly bonded, i.e., phenylamine. In formula Ad, R9 represents a linear or branched alkyl group having 1 to 10 carbon atoms, preferably a linear or branched alkyl group having 3 to 6 carbon atoms, more preferably a linear or branched alkyl group having 4 carbon atoms, even more preferably a branched alkyl group having 4 carbon atoms, and particularly preferably a t-butyl group.

[0077] In one embodiment of the present invention, the present rotundone derivative is preferably a compound represented by the following formula Aa1 or Ab1, and can be obtained according to step 2A of the present production method 1. Formula Aa1 is the formula Aa in which all of R1 to R3 are hydrogen. Formula Ab1 is the formula Ab in which, of R4 to R8, R4 and R6 are nitro groups and the rest are hydrogen.

[0078] [ka]

[0079] In one embodiment of the present invention, the present rotundone derivative is preferably a compound represented by the following formula Ac1, Ac2, Ad1, or Ae, and can be obtained according to the method for producing a crystalline rotundone derivative precursor described in step 2B of the present production method 1. Formula Ac1 is the formula Ac when n=0, and formula Ac2 is the formula Ac when n=1. Formula Ad1 is the formula Ad when R9 is a t-butyl group. More preferably, it is a hydrochloride salt of each of the compounds represented by the following formulas Ac1 to Ae, and can be obtained according to step 2B of the present production method 1.

[0080] [ka]

[0081] In another embodiment of the present invention, the present rotundone derivative is preferably a salt of a compound represented by the following formula Aa1 or Ab1, and can be obtained according to step 2 of the present production method 2. The salt is preferably a hydrochloride salt. More preferably, the present rotundone derivative is the hydrochloride salt of a compound represented by formula Aa1.

[0082] [ka]

[0083] [Flavoring composition containing rotundone] Rotundone itself can impart a spicy, peppery, and / or woody flavor or aroma to various articles, and the flavor or aroma that can be imparted can be changed depending on the concentration. Typically, when added in small amounts to articles, it can impart or enhance the freshness and juiciness of fruits, including citrus fruits. Thus, in one embodiment of the present invention, a composition containing rotundone obtained by the present production method can be used to impart flavor to various articles (herein, this may be referred to as a flavor-imparting composition containing rotundone or the present flavor-imparting composition). Note that, in this specification, the flavor-imparting composition containing rotundone (the present flavor-imparting composition) may consist solely of rotundone, or may contain components other than rotundone. Examples of components other than rotundone will be described later.

[0084] Furthermore, in this specification, "addition" includes at least one of simply adding to a target by spraying, dripping, etc., and mixing with a target, and "flavor" refers to one or more senses that can be changed by aroma, typically including the senses of smell and taste. When the present flavor-imparting composition contains a component other than rotundone, the content of rotundone in the present flavor-imparting composition is not particularly limited and varies depending on the other components mixed, so a general description cannot be made, but the concentration can usually be in the range of 0.5 ppt to 0.5 ppm, preferably 1 ppt to 0.2 ppm, based on the total mass of the flavor-imparting composition.

[0085] The flavor-imparting composition of the present invention can be added to various edible consumer goods such as foods and beverages, cosmetics, health and hygiene products, etc. For example, a flavor-imparting composition containing rotundone can be used to enhance citrus flavor (see, for example, JP 2016-198025 A or JP 6262170 A), fruit flavor (see, for example, JP 2016-198026 A or JP 6262171 A), salty flavor (see, for example, JP 2021-171024 A), kokumi (rich flavor) (see, for example, JP 2021-171025 A), or astringency (see, for example, JP 2021-171026 A). It can also be used to improve the lingering fragrance of the object to which it is added (see, for example, JP 2018-184507 A) or to mask unpleasant flavors (see, for example, JP 2021-171023 A).

[0086] The flavor-imparting composition containing rotundone may contain, in addition to rotundone, any other components (specific examples will be described later) such as a solvent, a dispersion medium, a flavor-imparting component other than rotundone, and auxiliary components such as antioxidant components, but may also consist essentially of rotundone. When the flavor-imparting composition of the present invention contains components other than rotundone, the concentration of rotundone in the flavor-imparting composition of the present invention can be determined as desired depending on the target to which the unpleasant flavor improving composition is added and the aroma characteristics.

[0087] Specific examples of optional other components that may be contained in the present flavoring composition in addition to rotundone include various flavor compounds, flavor compositions, oil-soluble colorants, vitamins, functional substances, fish extracts, meat extracts, animal and plant extracts, yeast extracts, animal and plant proteins, animal and plant protein hydrolysates, starch, dextrin, sugars, amino acids, nucleic acids, organic acids, solvents, etc. Examples include natural essential oils, natural flavors, and synthetic flavors described in "Patent Office Gazette, Collection of Well-Known and Commonly Used Techniques (Flavors) Part II: Food Flavors, published January 14, 2000," "Survey on the Actual Use of Food Flavoring Compounds in Japan" (2000 Ministry of Health, Labour and Welfare Research Report, Japan Flavor and Flavor Manufacturers Association, published March 2001), and "Synthetic Flavors: Chemistry and Product Knowledge" (revised and expanded edition published December 20, 2016, edited by the Synthetic Flavor Editorial Committee, Chemical Daily Co., Ltd.).

[0088] [Method of producing a flavoring composition containing rotundone] The flavor-imparting composition containing rotundone (the flavor-imparting composition of the present invention) may be a solution in which rotundone and other components are dissolved in a water-soluble or oil-soluble solvent, prepared by adding a composition containing rotundone to an appropriate solvent by a known method, or it may be further made into an emulsion preparation, a powder preparation, or other solid preparation (such as solid fat).

[0089] There are no particular limitations on the type of solvent used. Examples of water-soluble solvents include ethanol, methanol, acetone, tetrahydrofuran, acetonitrile, 2-propanol, methyl ethyl ketone, glycerin, ethylene glycol, propylene glycol, dipropylene glycol, hexyl glycol, benzyl benzoate, triethyl citrate, diethyl phthalate, triacetin, and short-chain fatty acid triglycerides such as tripropionin. Of these, ethanol or propylene glycol is particularly preferred when used in foods and beverages. Examples of oil-soluble solvents include vegetable oils and fats, animal oils and fats, refined oils and fats (e.g., processed oils and fats such as medium-chain fatty acid triglycerides), hercolin, and various essential oils.

[0090] To prepare the flavor-imparting composition into an emulsion, a composition containing rotundone can be emulsified with a water-soluble solvent and an emulsifier. The emulsification method is not particularly limited, and an emulsion with excellent stability can be obtained by emulsifying with various emulsifiers conventionally used in foods and beverages, such as fatty acid monoglycerides, fatty acid diglycerides, fatty acid triglycerides, propylene glycol fatty acid esters, sucrose fatty acid esters, polyglycerol fatty acid esters, lecithin, modified starch, sorbitan fatty acid esters, Quillaja extract, gum arabic, tragacanth gum, guar gum, karaya gum, xanthan gum, pectin, alginic acid and its salts, carrageenan, gelatin, casein, Quillaja saponin, sodium caseinate, etc., using a homomixer, colloid mill, rotating disk homogenizer, high-pressure homogenizer, etc. The amount of these emulsifiers used is not strictly limited and can vary over a wide range depending on the type of emulsifier used, but is usually within the range of about 0.01 to about 100 parts by mass, preferably about 0.1 to about 50 parts by mass, per part by mass of rotundone. Furthermore, to stabilize the emulsion, the aqueous solvent solution may contain, in addition to water, one or a mixture of two or more polyhydric alcohols such as glycerin, propylene glycol, sorbitol, maltitol, sucrose, glucose, trehalose, sugar solution, and reduced starch syrup.

[0091] The emulsion thus obtained can be dried, if desired, to form a powder formulation. During powdering, sugars such as gum arabic, trehalose, dextrin, sugar, lactose, glucose, starch syrup, and reduced starch syrup can be added as needed. The amounts of these can be selected appropriately depending on the desired properties of the powder formulation.

[0092] Addition of a flavoring composition containing rotundone to a consumer product A flavoring composition containing rotundone (the present flavoring composition) can be added to various consumer goods to impart flavor.

[0093] Specific examples of consumer goods include cosmetics and hygiene products such as perfumes such as eau de cologne, eau de toilette, eau de parfum, and parfum; hair care products such as shampoo, conditioner, and hair styling products (hair cream, pomade, etc.); cosmetics such as foundation, lipstick, lip balm, lip gloss, lotion, cosmetic emulsion, cosmetic cream, cosmetic gel, serum, and pack; deodorant products such as antiperspirant spray, deodorant sheet, deodorant cream, and deodorant stick; bath additives such as inorganic salts, refreshing products, carbon dioxide gas products, skin care products, enzyme products, and herbal products; Examples of fragrance compositions include, but are not limited to, suntan cosmetics such as suntan products and sunscreen products; face washes such as face soaps and cleansing creams, body soaps and body washes, laundry soaps, laundry detergents, disinfectants, deodorizing detergents, fabric softeners, kitchen detergents, and cleaning detergents; health and sanitary products such as toothpaste, tissue paper, and toilet paper; air fresheners for indoor and car interiors, air fresheners for various items such as daily necessities and furniture, and room fragrances; insect repellents, insect repellents, and insecticides for pest control and insecticides. Consumer goods that can be used to apply the fragrance composition to items such as fabrics, skin, and hair are particularly preferred. The items referred to here are preferably those having a fibrous structure on the surface, and suitable examples include various textile products such as towels, hand towels, dishcloths, bedding, curtains, rugs, and clothing.

[0094] Food and beverages include rice crackers such as rice crackers and mochi, sweets containing bean paste, uriwara (sweet bean paste), yokan (sweet bean jelly), castella cakes, biscuits, cookies, pies, cakes, chips, and other baked or fried sweets, puddings, creams, chocolates, gum, caramel, candies, dips, spreads, pastes, and other confectioneries; bread; noodles such as udon, soba, and ramen; rice dishes such as sushi, gomoku-han (mixed rice), fried rice, and pilaf; Chinese foods such as gyoza (dumplings), shumai (steamed dumplings), and spring rolls; flour-based foods such as okonomiyaki and takoyaki; pickles and pickle bases; processed seafood foods and beverages; processed meat foods and beverages; salt, seasoning salt, soy sauce, miso, furikake (rice seasoning), ochazuke bases, margarine, mayonnaise, dressings, vinegars, soup bases, sauces, ketchup, dressings, curry roux, stew bases, soup bases, dashi bases, and complex seasonings. condiments such as seasonings, new mirin, and mixed flour; dairy products such as cheese, yogurt, and butter; simmered dishes such as boiled vegetables, oden, and hot pot; take-out bento ingredients and side dishes; fruit juice, fruit juice drinks or soft drinks containing fruit juice, and fruit drinks containing fruit pulp or pieces; vegetable-containing beverages, such as soups; sports drinks, honey drinks, nutritional supplements, lactic acid bacteria drinks, coffee drinks, cocoa drinks, green tea, black tea, oolong tea, soft drinks, cola drinks, fruit juice drinks, dairy drinks, and beer-flavored drinks; beverages containing medicinal herbs and herbs; and alcoholic beverages such as wine, beer, chuhai, cocktail drinks, happoshu, fruit wine, condiment wine, and other brewed alcoholic beverages (sparkling) or liqueurs (sparkling), including so-called "third beer."

[0095] Other luxury items include, but are not limited to, cigarettes and electronic cigarettes.

[0096] The concentration of rotundone in various consumer goods such as food and beverages, cosmetics, and health and hygiene products can be determined arbitrarily depending on the flavor of the consumer goods and the degree of desired effect. For example, for enhancing citrus flavor, see JP 2016-198025 A or JP 6262170 A, for enhancing fruit flavor, see JP 2016-198026 A or JP 6262171 A, for enhancing saltiness, see JP 2021-171024 A, for enhancing richness, see JP 2021-171025 A, for enhancing astringency, see JP 2021-171026 A, for improving the lingering fragrance of the added object, see JP 2018-184507 A, and for masking unpleasant tastes, see JP 2021-171023 A. [Example]

[0097] The present invention will be explained in more detail below with reference to examples, although the present invention is not limited to these examples.

[0098] [Example 1] Example in which (a) semicarbazide salts of crystallizable compound group I were used as crystallizable compounds In Example 1, various examples are shown in which, in the present Production Method 1, Step 1A (any of 1A-1 to 1A-6) is performed as Step 1 to prepare patchouli oil as an α-guaiene-containing composition, which is then subjected to air oxidation to prepare a rotundone-containing composition, and Step 2A is performed as Step 2 to use semicarbazide hydrochloride as the crystallized compound (Examples 1-1 to 1-10).

[0099] (Example 1-1) (Step 1A-1: Oxidation of essential oil → Simple distillation and rectification of oxidized essential oil) Commercially available patchouli oil was prepared as an α-guaiene-containing composition, and the α-guaiene contained therein was air-oxidized to prepare a rotundone-containing composition.

[0100] [ka]

[0101] A 5-L flask equipped with a glass ball filter was charged with patchouli oil (4000 g, α-guaiene concentration 29.0%, 19.6 mol) as an α-guaiene-containing composition, and cobalt(II) acetate tetrahydrate (48.7 g, 0.196 mol), and air was continuously blown into the flask at 65°C for approximately 32 hours. During the air blowing, sampling was carried out periodically to monitor raw material consumption and the amount of rotundone produced. The air oxidation was terminated after the amount of rotundone produced reached a plateau. The mixture was then heated at 120°C for 20 minutes to decompose impurity peroxides, yielding a crude product.

[0102] MCT (1000 g) was added to the obtained crude product, and simple distillation was carried out, and distillation was continued until the internal temperature reached 240° C. Next, using a distillation column packed with Sulzer packing, precision distillation was carried out under conditions of a distillation temperature of 65 to 147° C. and a heating temperature of 145 to 196° C. at 0.4 kPa, and the obtained fractionated product was obtained as a rotundone-containing composition (rotundone yield 315.3 g, 1.44 mol, yield 7.4%, rotundone concentration 45.6%). [Rotandon concentration measurement conditions] Equipment: GC-2025 (Shimadzu Corporation) Column: TC-1 (30 mL x 0.53 mm I.D. x 1 μm df) Temperature conditions: 140℃-10℃ / min-300℃ Split ratio: 20:1 Linear speed: 60cm / s Inlet temperature: 300℃ Detector temperature: 300℃

[0103] (Process 2A) In this example, in step 2A, which is one aspect of step 2, rotundone contained in the rotundone-containing composition obtained in step 1 was reacted with semicarbazide hydrochloride, an example of crystallized compound (a) in crystallized compound group I, to produce a crystalline rotundone derivative.

[0104] [ka]

[0105] A 3 L four-neck flask equipped with a mechanical stirrer was charged with 157.7 g (45.6% concentration, 0.722 mol assuming all rotundone) of the rotundone-containing composition (the fraction obtained in step 1) and 722 mL of methanol. Semicarbazide hydrochloride (120.8 g, 1.08 mol), sodium acetate (100.7 g, 1.23 mol), and acetic acid (64.9 g, 1.08 mol) were then added sequentially at room temperature, followed by heating. The reaction was completed 5 h after reflux was achieved, and then 360 mL of methanol was recovered under atmospheric pressure to obtain the crystalline rotundone derivative (compound of formula Aa1).

[0106] (Step 3) The crystalline rotundone derivative obtained in step 2 was recrystallized using a recrystallization solvent.

[0107] The contents of the flask containing the crystalline rotundone derivative obtained in step 2 were cooled to approximately room temperature, and then 10% aqueous sodium carbonate (2.9 kg) was poured into the flask. Ethyl acetate (3.61 kg) was added and the mixture was heated to 50°C, after which the organic and aqueous layers were separated. The resulting organic layer was heated to 50°C and washed three times with approximately 50°C hot water (1.4 L). Ethyl acetate and water were recovered from the resulting organic layer under atmospheric pressure. After recovering ethyl acetate (2.2 L), seed crystals were added and the mixture was allowed to cool to room temperature with stirring, resulting in the precipitation of crystals. The crystals were filtered and smelled, revealing a rotundone-like scent with a slight patchouli oil-like scent.

[0108] (Cleaning process) The crystals were then washed several times with heptane (500 mL total heptane), and the solvent was removed under reduced pressure to yield white solid crystals (49.61 g). After washing, the white crystals no longer had the patchouli oil-like scent that was present before washing. This heptane washing is preferred because it reduces the scent derived from the patchouli essential oil used in step 1 in the final high-purity rotundone obtained.

[0109] The purity of the obtained crystals was confirmed by HPLC, and was found to be 96.0% at a detection wavelength of 254 nm (yield: 49.6 g, 0.180 mmol, 24.9%).

[0110] The physical properties of the crystalline rotundone derivative (formula Aa1, rotundone-semicarbazone derivative, (3S,5R,8S)-2-(3,8-dimethyl-5-prop-1-en-2-yl-3,4,5,6,7,8-hexahydro-1(2H)-azulenylidene)hydrazinecarboxamide) were as follows. 1 H-NMR(CDCl3, 400 MHz) δ (ppm) 1.05(3H, d, J=4.0 Hz), 1.07(3H, d, J=3.2 Hz), 1.58(1H, m), 1.76(3H, s), 1.75-1.98(5H, m), 2.21(1H, d, J=15.6 Hz), 2.43(1H, dd, J=12.8, 14.4 Hz), 2.64(1H, dd, J=7.2, 17.2 Hz), 2.75(1H, br s), 3.04(1H, br s), 4.68(1H, s), 4.72(1H, s), 7.54(1H, s). 13 C-NMR(CDCl3, 100 MHz)δ (ppm) 17.33, 19.82, 20.35, 27.70, 30.71, 32.83, 33.60, 35.48, 41.10, 46.40, 108.63, 141.35, 151.49, 157.97, 158.45, 159.62. (Step 4)

[0111] [ka]

[0112] A 1-L four-neck flask was charged with 49.6 g (0.180 mol) of the crystalline rotundone derivative (formula Aa1, rotundone-semicarbazone) obtained in step 3, 410 mL of tetrahydrofuran (THF), and 136 mL (0.272 mol) of 2 mol / L hydrochloric acid. The mixture was refluxed for 3 hours, cooled to room temperature, and then 500 g of 20% brine and 136 mL of 2N hydrochloric acid were added. After shaking, the organic and aqueous layers were separated to obtain the organic layer. The aqueous layer was extracted with ethyl acetate (250 mL), and the extract was mixed with the organic layer. The mixture was washed sequentially with 5% aqueous sodium bicarbonate (400 g) and 20% brine (400 g). The solvent was then distilled off under reduced pressure. The resulting crude product (44.4 g) was purified by vacuum distillation to obtain the desired rotundone. The yield was 34.89 g (0.160 mol), the yield was 88.7%, and the purity was 86%. [Purity measurement conditions] Equipment: Agilent 7890B Column: CHIRAMIX (registered trademark) (length 30 m, inner diameter 0.25 mm, liquid layer thickness 0.25 μm) Oven temperature: 150-180°C (+1.0°C / min), hold at 180°C for 30 minutes Carrier gas: Nitrogen (0.7 mL / min)

[0113] (Example 1-2) In Example 1-1, a rotundone-containing composition was prepared by performing step 1A-5 (rectification of patchouli oil → oxidation of rectified patchouli oil → simple distillation and rectification of oxidized patchouli oil) instead of step 1A-1.

[0114] That is, 3000 g of commercially available patchouli oil was prepared as an α-guaiene-containing composition, and this was rectified using a distillation column packed with Sulzer packing under conditions of 0.4 kPa, a distillation temperature of 95 to 99° C., and a heating temperature of 129 to 133° C. The α-guaiene concentration in the rectified α-guaiene-containing composition was about 45%.

[0115] Thereafter, the rectified patchouli oil was oxidized under the same conditions as in Example 1-1, and the oxidized patchouli oil was subjected to simple distillation and rectification to obtain a rotundone-containing composition.

[0116] Subsequently, steps 2A to 4 were carried out under the same conditions as in Example 1-1, and rotundone with a purity of 88% was obtained. The purity was measured in the same manner as in Example 1-1.

[0117] (Examples 1-3 to 1-6) Rotundone was obtained in the same manner as in Example 1-1 or 2, except that the simple distillation and rectification before and after the air oxidation of the α-guaiene-containing composition in step 1A were carried out as in the following steps 1A-2, 1A-3, 1A-4, or 1A-6. Rotundone purity was measured in the same manner as in Example 1-1. Example 1-3 (Step 1A-2: Oxidation of patchouli oil → Simple distillation of oxidized patchouli oil) Rotundone was obtained in the same manner as in Example 1-1, except that step 1A-2 was performed instead of step 1A-1 in Example 1-1, i.e., rectification was not performed after simple distillation of oxidized patchouli oil in step 1A-1. The purity of the obtained rotundone was 81%. Example 1-4 (Step 1A-3: Oxidation of patchouli oil → Rectification of oxidized patchouli oil) Rotundone was obtained in the same manner as in Example 1-1, except that step 1A-3 was performed instead of step 1A-1 in Example 1-1, i.e., oxidized patchouli oil was not subjected to simple distillation but only rectification was performed in step 1A-1. The purity of the obtained rotundone was 84%. Example 1-5 (Step 1A-4: Distillation of patchouli oil → Oxidation of distilled patchouli oil → Distillation of oxidized patchouli oil) Rotundone was obtained in the same manner as in Example 1-2, except that step 1A-4 was carried out instead of step 1A-5, i.e., oxidized patchouli oil was not subjected to simple distillation but only rectification was carried out. The purity of the obtained rotundone was 86%. Example 1-6 (Step 1A-6: Distillation of patchouli oil → Oxidation of distilled patchouli oil → Simple distillation of oxidized patchouli oil) Rotundone was obtained in the same manner as in Example 1-2, except that step 1A-6 was carried out instead of step 1A-5, i.e., simple distillation was carried out without rectification of the oxidized patchouli oil. The purity of the obtained rotundone was 87%.

[0118] (Examples 1-7) In Example 1-7, commercially available patchouli oil was oxidized in the same manner as in Example 1-1, except that the oxidation time was shortened, to obtain a rotundone-containing composition with a rotundone concentration of 24.3% as the rotundone-containing composition prepared in step 1. Steps 2A to 4 were then carried out under the same conditions as in Example 1-1, yielding a rotundone with a purity of 82%. The purity was measured in the same manner as in Example 1-1.

[0119] (Examples 1-8 to 1-9) In Example 1-8, rotundone was obtained in the same manner as in Example 1-1, except that the crystalline rotundone derivative was not washed with heptane. The purity of rotundone was measured in the same manner as in Example 1-1. The purity of the obtained rotundone was 88%, but a slight patchouli oil-like scent was detected.

[0120] Furthermore, as Example 1-9, rotundone was obtained in the same manner as in Example 1-1, except that the crystalline rotundone derivative in Example 1-1 was not washed with heptane, and 200% by mass of water was added to the rotundone obtained in step 4, followed by steam distillation under atmospheric pressure. Rotundone purity was measured in the same manner as in Example 1-1. The purity of the obtained rotundone was 81%, but a very slight patchouli oil-like scent was detected, which was weaker than that of Example 1-7.

[0121] Examples 1-10 In Example 1-10, step 1A-6 (rectification of patchouli oil → oxidation of rectified patchouli oil → simple distillation of oxidized patchouli oil), step 2A, and step 3 were carried out in the same manner as in Example 1-6, and step 4 was carried out as follows to obtain rotundone. The purity of rotundone was measured in the same manner as in Example 1-1.

[0122] In step 4, 2.22 g (8.06 mmol) of the crystalline rotundone derivative (formula Aa1, rotundone-semicarbazone) obtained in step 3, 68 g of methanol, and 3.4 g of water were placed in a 300 mL four-neck flask and heated to dissolve the crystalline rotundone derivative. Next, 2.75 g (16.1 mmol) of copper(II) chloride dihydrate was added at 50 °C and hydrolysis was carried out over 2.5 hours. The contents of the flask were then cooled to room temperature and poured into 0.5 M dilute hydrochloric acid (160 mL). Extraction was performed with 80 mL of ethyl acetate to separate the organic layer (ethyl acetate layer) and aqueous layer. The aqueous layer was also extracted twice with 40 mL of ethyl acetate. The ethyl acetate extract and the separated organic layer were combined, and the combined organic layer was washed sequentially with saturated brine, 5% aqueous sodium bicarbonate, and saturated brine, and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain a crude product, which was then subjected to Kugelrohr distillation to obtain rotundone with a purity of 92%.

[0123] Thus, the purity of rotundone can be further increased by hydrolysis using copper(II) chloride.

[0124] (Examples 1-11) In Example 1-11, rotundone was obtained in the same manner as in Example 1-10, except that the recrystallization in step 3 in Example 1-10 was performed twice in the same manner as in Example 1-6 (i.e., Example 1-1). Rotundone purity was measured in the same manner as in Example 1-1.

[0125] In step 3, the contents of the flask containing the crystalline rotundone derivative obtained in step 2 were cooled to approximately room temperature, and the solid obtained by filtering on a filter paper was washed with heptane. 9.3 g of the white solid obtained after washing was added with 140 g of ethyl acetate and 120 g of a 5% aqueous sodium carbonate solution and washed under heating. The organic layer was then washed twice with water, and the solvent was removed from the resulting organic layer under normal pressure. Seed crystals were added and the mixture was allowed to cool to room temperature while stirring, yielding crystals.

[0126] For the second recrystallization, the obtained crystals were again dissolved in 146 g of ethyl acetate at approximately 50 °C, seed crystals were added, and the mixture was allowed to cool to room temperature. After cooling, the reaction solution was filtered and washed with heptane to obtain 2.22 g of white crystals of the crystalline rotundone derivative. The purity of this product was measured by HPLC at a detection wavelength of 254 nm, and was found to be 98%.

[0127] The crystals of this crystalline rotundone derivative were subjected to step 4 in the same manner as in Examples 1-9. The purity of the obtained rotundone was 96%. Thus, by performing two recrystallizations and hydrolysis using copper(II) chloride, the purity of rotundone can be further increased.

[0128] [Example 2] Example in which (b) phenylhydrazines of crystallizable compound group I were used as crystallizable compounds In this example, (b) phenylhydrazines are used as the crystallized compound group I in step 2A of the present production method 1.

[0129] (Process 1) In the same manner as in step 1A-1 of Example 1-1, patchouli oil, which is an α-guayene-containing composition, was oxidized to obtain a rotundone-containing composition having a rotundone concentration of approximately 45%, which was then purified by silica gel column chromatography (hexane / ethyl acetate=8:1) to obtain a rotundone-containing composition having a rotundone concentration of approximately 71%. (Process 2A)

[0130] [ka]

[0131] 2,4-Dinitrophenylhydrazine (0.60 g, 1.5 mmol), methanol (6 mL), and concentrated sulfuric acid (0.11 g, 1.1 mmol) were placed in a recovery flask, and after heating to 50°C, the rotundone-containing composition (rotundone concentration 71%, 0.22 g, 1.0 mmol) was added. Water was added at the same temperature for 2 hours, and the solid was filtered off. The resulting solid was washed with aqueous sodium bicarbonate and then with water, yielding 0.40 g (1.0 mmol) of a crystalline rotundone derivative as a reddish-brown solid.

[0132] (Step 3) The crystalline rotundone derivative obtained in step 2A was dissolved in methanol, and then recrystallized by distilling off the methanol and adding seed crystals to obtain crystals of the crystalline rotundone derivative, compound of formula Ab1 (rotundone-dinitrophenylhydrazone derivative, (3S,5R,8S)-3,8-dimethyl-5-prop-1-en-2-yl-3,4,5,6,7,8-hexahydro-1(2H)-azulenone 2-(2,4-dinitrophenyl)hydrazone), with a purity of 95%. The physical properties of the compound of formula Ab1 were as follows. The purity was measured in the same manner as in Example 1-1. 1 H-NMR(CDCl3,400MHz) (ppm) : 1.13(3H, d, J=7.2 Hz), 1.14(3H, d, J=6.0 Hz), 1.65(1H, m), 1.78(3H, s), 1.78-1.92(3H, m), 2.03(1H, dd, J=11.2, 11.2 Hz), 2.22(1H, m), 2.31(1H, d, J=16.0 Hz), 2.51(1H, dd, J=12.0, 15.6 Hz), 2.89-2.94(2H, m), 3.26(1H, m), 4.71(1H, s), 4.75(1H, s), 7.97(1H, d, J=9.6 Hz), 8.28(1H, dd, J=2.0, 9.6 Hz), 9.14(1H, d, J=2.4 Hz), 10.90(1H, s). 13C-NMR(CDCl3,100MHz) (ppm) :17.4, 19.7, 20.3, 27.9, 30.7, 32.8, 34.2, 35.8, 41.4, 46.3, 108.9, 116.3, 123.8, 128.6, 129.8, 137.1, 141.9, 144.9, 151.2, 162.8, 166.5.

[0133] (Step 4) Rotundone was liberated from the crystalline rotundone derivative of formula Ab1 obtained in step 3 by hydrolysis of the imino groups with dilute hydrochloric acid in the same manner as in Example 1-1, and the purity of the resulting rotundone was approximately 84%. The purity was measured in the same manner as in Example 1-1. The purity can be further increased by using copper(II) chloride for the hydrolysis of the imino groups in step 4, as in Example 1-9, or by performing recrystallization multiple times in step 3 and using copper(II) chloride for the hydrolysis of the imino groups in step 4, as in Example 1-10. The same applies to the subsequent examples.

[0134] [Example 3] Example of production of a salt of a crystalline rotundone derivative precursor In this example, an example in which step 2B is carried out as one aspect of step 2 in the present production method 1 will be described.

[0135] (1) Examples of crystallizable compounds: (d) (alkylamines) of crystallizable compound group II (Process 1) In the same manner as in Example 2, α-guaiene in the α-guaiene-containing composition was air-oxidized to convert it to rotundone, thereby preparing a rotundone-containing composition.

[0136] (Process 2B) Step 2B was carried out as follows. (i) Synthesis of crystalline rotundone derivative precursor (rotundone-t-butylimine derivative)

[0137] [ka]

[0138] The rotundone-containing composition prepared in step 1 (rotundone concentration 71%, 2.18 g, 10.0 mmol), t-butylamine (2.93 g, 40 mmol), and toluene (100 mL) were added to a recovery flask. Titanium tetrachloride (1.0 M dichloromethane solution, 10 mL, 10 mmol) was then added under ice-cooling and a nitrogen atmosphere. The mixture was allowed to react for 1 hour under ice-cooling, then warmed to room temperature and allowed to react overnight. The reaction was quenched with saturated aqueous sodium carbonate and filtered through Celite. The resulting filtrate was separated into layers, and the aqueous layer was extracted with toluene. The combined organic layer was partitioned into an aqueous phase using hexane and 2 mol / L hydrochloric acid, made alkaline with 25% aqueous sodium hydroxide, extracted with toluene, washed three times with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed under reduced pressure, and the resulting crude product was purified by Kugelrohr distillation to obtain 0.47 g (1.72 mmol) of a crystalline rotundone derivative precursor of formula Ad1 (formula Ad1, rotundone t-butylimine, (3S,5R,8S)-(3,8-dimethyl-5-prop-1-en-2-yl-3,4,5,6,7,8-hexahydro-1(2H)-azulenylidene)-1,1-dimethylethylamine) as a brown oil. Its physical properties were as follows: 1 H-NMR(CDCl3,400MHz)(ppm) :0.95(3H, t, J=7.6 Hz), 1.00(3H, d, J=7.2 Hz), 1.25(9H, s), 1.27-1.57(3H, m), 1.75 (3H, s), 1.84(1H, m), 1.95-2.25(3H, m), 2.39(1H, m), 2.62-2.72(2H, m), 3.13(1H, m), 4.66(1H, s), 4.71(1H, s) 13C-NMR(CDCl3,100MHz)(ppm): 17.47, 20.04, 20.40, 27.43, 30.29, 31.30, 33.00, 35.49, 37.69, 40.85, 46.66, 40.17, 54.61, 108.27, 146.43, 152.12, 156.74, 170.66. MS(EI, 70 eV):273(M+, 100), 258(84), 216(52), 202(64), 176(27), 174(27), 160(50), 134(30). (ii) Synthesis of crystalline rotundone derivatives (rotundone-t-butylimine hydrochloride derivatives) Tetrahydrofuran (THF) was added to the obtained crystalline rotundone derivative precursor of formula Ad1, followed by the addition of 2 mol / L hydrogen chloride in diethyl ether under ice cooling to obtain a solid crystalline rotundone derivative, (3S,5R,8S)-(3,8-dimethyl-5-prop-1-en-2-yl-3,4,5,6,7,8-hexahydro-1(2H)-azulenylidene)-1,1-dimethylethylamine hydrochloride. The physical properties of the rotundone derivative were as follows: 1 H-NMR(CDCl3,400MHz)(ppm) :1.15(3H, d, J=7.2 Hz), 1.20(3H, d, J=7.2 Hz), 1.71(9H, s), 1.73(3H, s), 1.83-1.93 (3H, m), 2.01(1H, m), 2.44-2.50(3H, m), 2.52-2.70(2H, m), 2.96(1H, m), 3.26(1H, m), 4.72(1H, m), 4.72(2H, s). 13 C-NMR(CDCl3,100MHz)(ppm): 17.14, 18.55, 20.24, 27.59, 29.27, 30.67, 31.55, 36.53, 38.78, 42.72, 44.96, 60.69, 109.67, 143.79, 150.02, 184.02, 185.78.

[0139] (Step 3) The crystalline rotundone derivative obtained in step 2B was dissolved in acetone, and then recrystallized by distilling off the acetone and adding seed crystals to obtain crystals of the crystalline rotundone derivative.

[0140] (Step 4) Rotundone was liberated from the crystalline rotundone derivative obtained in step 3 by hydrolysis of the imino groups with dilute hydrochloric acid in the same manner as in Example 1-1, and the purity of the resulting rotundone crystals was approximately 85%. The purity was measured in the same manner as in Example 1-1.

[0141] (2) The crystallized compound is Example 1 (arylamine) of (c) of crystallized compound group II. (Process 1) In the same manner as in Example 2, α-guaiene in the α-guaiene-containing composition was air-oxidized to convert it to rotundone, thereby preparing a rotundone-containing composition.

[0142] (Process 2B) Step 2B was carried out as follows. (i) Synthesis of crystalline rotundone derivative precursor (rotundone-phenylimine derivative)

[0143] [ka]

[0144] The rotundone-containing composition prepared in step 1 (rotundone concentration 71%, 2.18 g, 10.0 mmol), phenylamine (3.73 g, 40 mmol), and toluene (100 mL) were placed in a recovery flask, and titanium tetrachloride (1.0 M dichloromethane solution, 10 mL, 10 mmol) was added under ice-cooling and a nitrogen atmosphere. The reaction was completed at the same temperature for 1 hour, quenched with saturated aqueous sodium carbonate, and then filtered through Celite. The resulting filtrate was separated, and the aqueous layer was extracted with toluene. The combined organic layer was washed twice with saturated brine and then dried over anhydrous magnesium sulfate. After filtration, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 20:1) to obtain 2.19 g (7.46 mmol) of a yellow oily crystalline rotundone derivative precursor of formula Ac1 ((3S,5R,8S)-(3,8-dimethyl-5-prop-1-en-2-yl-3,4,5,6,7,8-hexahydro-1(2H)-azulenylidene)benzenamine). Its physical properties were as follows: 1 H-NMR(CDCl3, 400 MHz) (ppm): 1.00(3H, d, J=7.6 Hz), 1.12(3H, d, J=7.6 Hz), 1.66(1H, m), 1.77(3H, s), 1.77-1.95(4H, m), 2.05(1H, dd, J=11.2, 11.2 Hz), 2.27(1H, d, J=15.6 Hz), 2.48-2.66(3H, m), 3.28(1H, dddd, J=3.6, 3.6, 10.8, 14.4 Hz), 6.81(2H, d, J=7.6 Hz), 7.01(1H, dd, J=7.2, 7.2 Hz), 7.28(2H, dd, J=7.2, 7.2 Hz). 13C-NMR(CDCl3, 100 MHz)(ppm): 17.41, 19.43, 20.26, 27.46, 30.80, 32.77, 35.75, 36.26, 40.19, 46.31, 108.60, 119.81, 122.64, 128.74, 144.43, 151.43, 153.03, 164.10, 177.47. MS(EI, 70 eV):293(M+, 100), 278(52), 252(23), 236(49), 210(35), 201(33), 77(20). (ii) Synthesis of crystalline rotundone derivatives (rotundone-phenylimine hydrochloride derivatives) Tetrahydrofuran (THF) was added to the obtained crystalline rotundone derivative precursor of formula Ac1, followed by the addition of 2 mol / L hydrogen chloride in diethyl ether under ice cooling to obtain solid rotundone phenylimine hydrochloride ((3S,5R,8S)-(3,8-dimethyl-5-prop-1-en-2-yl-3,4,5,6,7,8-hexahydro-1(2H)-azulenylidene)benzonamine hydrochloride) as a crystalline rotundone derivative. Its physical properties were as follows: 1 H-NMR(CDCl3,400MHz) (ppm) :1.18(3H, d, J=7.6 Hz), 1.27(3H, d, J=7.2 Hz), 1.72(1H, m), 1.77(3H, s), 1.90-2.01(3H, m), 2.11(1H, dd, J=10.4, 10.4 Hz), 2.42-2.58(2H, m), 2.72(1H, dd, J=12.0, 15.6 Hz), 3.03(1H, m), 3.19(1H, d, J=5.2 Hz), 4.16(1H, m), 4.75-4.76(2H, m), 5.29 (1H, br s), 7:30-7:55 (5H m). 13C-NMR(CDCl3,100MHz) (ppm): 17.20, 18.24, 20.04, 27.93, 30.41, 31.76, 37.20, 39.15, 42.52, 45.02, 109.79, 124.70, 129.61, 136.59, 142.84, 149.46, 149.74, 88.22, 188.63.

[0145] (Step 3) The crystalline rotundone derivative obtained in step 2B was dissolved in acetone, and then recrystallized by distilling off the acetone and adding seed crystals to obtain crystals of the crystalline rotundone derivative.

[0146] (Step 4) Rotundone was liberated from the crystalline rotundone derivative obtained in step 3 by hydrolysis of the imino groups with dilute hydrochloric acid in the same manner as in Example 1-1, and the purity of the resulting rotundone crystals was approximately 85%. The purity was measured in the same manner as in Example 1-1.

[0147] (3) The crystallized compound is Example 2 (aralkylamine) of (c) of crystallized compound group II. (Process 1) In the same manner as in Example 2, α-guaiene in the α-guaiene-containing composition was air-oxidized to convert it to rotundone, thereby preparing a rotundone-containing composition.

[0148] (Process 2B) Step 2B was carried out as follows. (i) Synthesis of crystalline rotundone derivative precursor (rotundone-benzylimine derivative)

[0149] [ka]

[0150] The rotundone-containing composition prepared in Example 2 (rotundone concentration 71%, 2.18 g, 10.0 mmol), benzylamine (4.29 g, 40 mmol), and toluene (100 mL) were placed in a recovery flask. Titanium tetrachloride (1.0 M dichloromethane solution, 10 mL, 10 mmol) was then added under ice-cooling and a nitrogen atmosphere. The reaction was completed after 1.5 hours at the same temperature and 1 hour at room temperature. The reaction was then quenched with saturated aqueous sodium carbonate and filtered through Celite. The resulting filtrate was separated into layers, and the aqueous layer was extracted with toluene. The combined organic layer was partitioned with 5% aqueous citric acid. The resulting aqueous layer was made alkaline with 25% aqueous sodium hydroxide, extracted again with toluene, washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed under reduced pressure to obtain 1.78 g (5.79 mmol) of a crystalline rotundone derivative precursor of formula Ac2 ((3S,5R,8S)-(3,8-dimethyl-5-prop-1-en-2-yl-3,4,5,6,7,8-hexahydro-1(2H)-azulenylidene)benzylamine) as an orange oil. Its physical properties were as follows: 1 H-NMR(CDCl3, 400 MHz) (ppm) :1.05(3H, d, J=5.2 Hz), 1.07(3H, d, J=7.2 Hz), 1.60(1H, m), 1.77(3H, s), 1.77-1.92(3H, m), 1.98-2.04(2H, m), 2.24(1H, d, J=15.6 Hz), 2.49(1H, dd, J=12.0, 15.6 Hz), 2.67-2.71(2H, m), 3.28(1H, m), 4.56(2H, s), 4.69(1H, s), 4.73(1H, s), 7.22(1H, m), 7:30-7:35 (4 hours, midnight) 13C-NMR(CDCl3, 100 MHz)(ppm): 17.51, 19.91, 20.37, 27.39, 30.91, 32.91, 35.70, 35.77, 40.34, 46.50, 56.45, 108.49, 126.24, 127.40, 128.22, 141.05, 144.59, 151.82, 161.24, 177.81. MS(EI, 70 eV): 307(M+, 72), 286(37), 250(44), 226(20), 91(100). (ii) Synthesis of crystalline rotundone derivatives (rotundone-benzylimine hydrochloride derivatives) Tetrahydrofuran (THF) was added to the obtained crystalline rotundone derivative precursor of formula Ac2, followed by the addition of 2 mol / L hydrogen chloride in diethyl ether under ice cooling to obtain a pale yellow to brown solid rotundone benzylimine hydrochloride ((3S,5R,8S)-(3,8-dimethyl-5-prop-1-en-2-yl-3,4,5,6,7,8-hexahydro-1(2H)-azulenylidene)benzylamine hydrochloride) as a crystalline rotundone derivative. Its physical properties were as follows: 1 H-NMR(CDCl3, 400 MHz) (ppm): 1.02-1.07(6H, m), 1.49(1H, m), 1.62(3H, s), 2.40-2.48(3H, m), 2.87(1H, m), 3.10(1H, d, J=18.4 Hz), 3.69(1H, s), 4.60(2H, s), 4.76(1H, s), 4.82(1H, s), 7.16-7.24(3H, m), 7.45-7.48(2H m), 13.27(1H, s). 13C-NMR(CDCl3, 100 MHz) (ppm): 16.81, 17.88, 19.59, 27.35, 29.74, 31.49, 36.61, 37.05, 42.17, 44.60, 50.18, 109.31, 127.87, 128.06, 128.50, 133.47, 141.05, 149.11, 185.81, 188.27.

[0151] (Step 3) The crystalline rotundone derivative obtained in step 2B was dissolved in acetone, and then recrystallized by distilling off the acetone and adding seed crystals to obtain crystals of the crystalline rotundone derivative.

[0152] (Step 4) Rotundone was liberated from the crystalline rotundone derivative obtained in step 3 by hydrolysis of the imino groups with dilute hydrochloric acid in the same manner as in Example 1-1, and the purity of the resulting rotundone crystals was approximately 83%. The purity was measured in the same manner as in Example 1-1.

[0153] (4) Examples of crystallizable compounds: (e) (salts of hydroxylamine) of crystallizable compound group II (Process 1) In the same manner as in Example 2, α-guaiene in the α-guaiene-containing composition was air-oxidized to convert it to rotundone, thereby preparing a rotundone-containing composition.

[0154] (Process 2B) Step 2B was carried out as follows. (i) Synthesis of crystalline rotundone derivative precursor (rotundone-oxime derivative)

[0155] [ka]

[0156] Hydroxylamine hydrochloride (1.01 g, 15 mmol) and methanol (5 mL) were placed in a recovery flask, and sodium acetate (1.20 g, 15 mmol) was added at room temperature. After stirring for 20 minutes, the rotundone-containing composition (rotundone concentration 71%, 2.18 g, 10.0 mmol) prepared in step 1 was added dropwise over 10 minutes. After reacting at room temperature for 3 days, the conversion rate reached 99%, and the reaction was terminated. Deionized water was added and the mixture was filtered through a filter paper. The resulting residue was washed with hexane, and the filtrate was concentrated to obtain a crude product. Silica gel chromatography (hexane / ethyl acetate = 8:1 to 6:1) was performed to obtain a colorless oily crystalline rotundone derivative precursor of formula Ae ((3S,5R,8S)-3,8-dimethyl-5-prop-1-en-2-yl-3,4,5,6,7,8-hexahydro-2H-azulen-1-one oxime) (yield: 2.31 g, 9.90 mmol, 99.0%). The physical properties were as follows: 1 H-NMR(CDCl3, 400 MHz) δ (ppm) 1.04(3H, d, J=6.8 Hz), 1.07(3H, d, J=6.8 Hz), 1.59-1.65(2H, m), 1.75(3H, s), 1.77-1.88(2H, m), 1.99(1H, m), 2.19-2.30(2H, m), 2.40(1H, dd, J=11.6, 15.2 Hz), 2.68(1H, dd, J=7.6, 7.6 Hz), 2.86(1H, dd, J=7.6, 18.0 Hz), 2.92(1H, m), 4.67(1H, s), 4.71(1H, s), 8.37(1H, br s). 13 C-NMR(CDCl3, 100 MHz) δ (ppm)17.34, 19.75, 20.37, 28.39, 30.70, 32.91, 33.26, 35.52, 41.29, 46.35, 108.59, 139.33, 151.59, 158.62, 167.37. MS(EI, 70 eV):233(M+, 52), 216(100), 202(35), 176(48), 160(62), 146(42), 134(37), 91(39). (ii) Synthesis of crystalline rotundone derivative precursor (rotundone-oxime hydrochloride derivative) Tetrahydrofuran (THF) was added to the obtained crystalline rotundone derivative precursor of formula Ae, followed by the addition of 2 mol / L hydrogen chloride in diethyl ether under ice cooling to obtain a white to pale yellow solid rotundone oxime hydrochloride ((3S,5R,8S)-3,8-dimethyl-5-prop-1-en-2-yl-3,4,5,6,7,8-hexahydro-2H-azulen-1-one oxime hydrochloride) as a crystalline rotundone derivative. Its physical properties were as follows: 1 H-NMR(CD3OD, 400 MHz) (ppm): 1.16(3H, dd, J=0.8, 7.2 Hz), 1.19(3H, dd, J=1.2, 7.6 Hz), 1.71(1H, m), 1.78(3H, s), 1.86-2.01(3H, m), 2.12(1H, m), 2.52-2.88(3H, m), 3.03(1H, dddd, J=6.8, 6.8, 6.8, 6.8 Hz), 3.26(1H, m), 4.74(1H, s), 4.79(1H, s). 13 C-NMR(CD3OD, 100 MHz) (ppm):17.21, 18.63, 20.34, 29.74, 31.47, 33.33, 36.87, 37.95, 43.74, 46.69, 110.04, 137.45, 151.72, 179.66, 183.42.

[0157] (Step 3) The crystalline rotundone derivative obtained in step 2B was dissolved in acetone, and then recrystallized by distilling off the acetone and adding seed crystals to obtain crystals of the crystalline rotundone derivative.

[0158] (Step 4) Rotundone was liberated from the crystalline rotundone derivative obtained in step 3 by hydrolysis of the imino groups with dilute hydrochloric acid in the same manner as in Example 1-1, and the purity of the obtained rotundone crystals was approximately 82%. The purity was measured in the same manner as in Example 1-1.

[0159] [Example 4] An example in which the crystallized compound is (a) (semicarbazide salts) in the present production method 2 (Process 1) In the same manner as in Example 2 of Production Method 1, α-guaiene in the α-guaiene-containing composition was air-oxidized to convert it to rotundone, thereby preparing a rotundone-containing composition.

[0160] (Process 2) Tetrahydrofuran (THF) was added to the crystalline rotundone derivative (rotundone-semicarbazone derivative) of formula Aa1 obtained in Example 1, and then a 2 mol / L solution of hydrogen chloride in diethyl ether was added under ice cooling to convert it into a hydrochloride salt.The solvent was then recovered under reduced pressure to obtain a white to pale yellow solid crystalline rotundone derivative salt (rotundone-semicarbazone hydrochloride derivative, (3S,5R,8S)-2-(3,8-dimethyl-5-prop-1-en-2-yl-3,4,5,6,7,8-hexahydro-1(2H)-azulenylidene)hydrazinecarboxamide hydrochloride) as a solid.

[0161] The physical properties of the obtained rotundone-semicarbazone hydrochloride derivative were as follows: 1H-NMR(CDCl3, 400 MHz) δ (ppm): 1.16(3H, d, J=6.0 Hz), 1.16(3H, d, J=6.0 Hz), 1.65(1H, m), 1.74(3H, s), 1.80-1.90(3H, m), 2.04(1H, m), 2.45-2.66(3H, m), 2.94(1H, ddd, J=6.0, 6.0, 6.0 Hz), 3.29(1H, dd, J=4.0, 20.0 Hz), 3.40(1H, m), 4.72(1H, m), 4.73(1H, s), 6.18 (1H, br), 8.77 (1H, br), 10.39(1H, br). 13 C-NMR(CDCl3, 100 MHz) δ (ppm):17.17, 18.39, 20.16, 28.21, 30.34, 32.10, 37.19, 37.50, 42.41, 45.31, 109.74, 139.67, 149.93, 156.76.

[0162] (Step 3) The crystalline rotundone derivative obtained in step 2 was dissolved in acetone, and then recrystallized by distilling off the acetone and adding seed crystals to obtain crystals of the crystalline rotundone derivative.

[0163] (Step 4) Rotundone was liberated from the crystalline rotundone derivative obtained in step 3 by hydrolysis of the imino groups with dilute hydrochloric acid in the same manner as in Example 1-1, and the purity of the obtained rotundone crystals was approximately 84%. The purity was measured in the same manner as in Example 1-1.

[0164] [Comparative Example 1] Confirmation of Rotundone Purification by Other Purification Methods The back-extraction method is known as a method for increasing the purity of compounds. We confirmed how much higher purity can be obtained by this method compared to crystallization as in the present production method.

[0165] The α-guaiene-containing composition was prepared from the rectified patchouli oil obtained in Example 1-2 (α-guaiene concentration: 40%). The α-guaiene was converted to rotundone by air oxidation at 50°C for 10 hours without solvent using cobalt 2-ethylhexanoate as an oxidation catalyst. Toluene was added to the resulting rotundone-containing composition, and azeotropic dehydration was performed according to a conventional method. Then, according to (2)(i) of Example 2, n-butylamine was reacted with rotundone in the presence of titanium tetrachloride to obtain an imine rotundone derivative. The rotundone derivative was purified by back-extraction with 5% aqueous citric acid and toluene, followed by alkalinization with 25% aqueous sodium hydroxide, and extraction with toluene, without recrystallization, as in the present production method. The concentrate after solvent recovery was added to 20% aqueous tetrahydrofuran and silica gel, and hydrolysis was performed at 50°C to liberate rotundone. The purity of the rotundone obtained by liberation was measured by GC, and was found to be only 65%. The GC chart showed that there were multiple peaks near the peak of rotundone that were thought to be isomers with the same molecular weight. [Purity measurement conditions] Column: TC-WAX (30 mL x 0.53 mm I.D. x 1 μm df) Temperature conditions: 160℃-10℃ / min-220℃ Split ratio: 20:1 Linear speed: 60cm / s Inlet temperature: 220℃ Detector temperature: 220℃

[0166] [Comparative Example 2] Examples of compounds other than the present crystallized compound The case where O-methylhydroxylamine hydrochloride was used in place of the present crystallized compound in step 2 to produce a rotundone-oxime methyl ether derivative is shown.

[0167] [ka]

[0168] Rotundone (2.18 g, 10.0 mmol) and pyridine (10 ml) were placed in a recovery flask, followed by O-methylhydroxylamine hydrochloride (1.67 g, 20.0 mmol) at room temperature. After overnight reaction at room temperature, the mixture was poured into saturated brine and extracted with toluene. The resulting organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After filtration, the solvent was removed under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 20:1) to obtain a colorless oily (3S,5R,8S)-3,8-dimethyl-5-prop-1-en-2-yl-3,4,5,6,7,8-hexahydro-2H-azulen-1-one O-methyloxime (1.91 g, 7.72 mmol, yield 77.2%). This compound did not yield a hydrochloride salt when converted to the hydrochloride salt as in Example 3(1), and therefore could not be derived into a crystalline salt.

[0169] The physical properties of the compound of formula 10 were as follows: 1 H-NMR(CDCl3, 400 MHz) (ppm) 1.02(3H, d, J=6.8 Hz), 1.07(3H, d, J=7.2 Hz), 1.74-1.89(4H, m), 1.75(3H, s), 1.97(1H, m), 2.14(1H, dd, J=2.0, 18.8 Hz), 2.19(1H, m), 2.39(1H, m), 2.60(1H, m), 2.78(1H, dd, J=7.2, 18.8 Hz), 2.98(1H, m), 3.87(3H, s), 4.67(1H, s), 4.71(1H, s). 13 C-NMR(CDCl3, 100 MHz) (ppm)17.32, 19.71, 20.37, 28.01, 29.68, 30.78, 32.84, 33.78, 35.44, 41.22, 46.38, 61.50, 108.52, 139.54, 151.68, 158.18, 166.32. MS(EI, 70 eV):247(M+, 81), 216(100), 201(20), 190(24), 160(27), 146(32), 91(23).

[0170] [Summary of Examples] As shown in the above examples and comparative examples, in the method for producing rotundone, the back-extraction method, which is a known method for improving purity, can have the problem of not being able to remove isomers of the same molecular weight when they are likely to be present, whereas the present production method has the advantageous effect of producing crystals with very few impurities by crystallization, thereby producing rotundone with high purity.

[0171] In the examples of this specification, an oxidized α-guaiene-containing composition was used as the rotundone-containing composition. However, based on the principles of the present production method, the present production method can be applied to any composition containing rotundone, even if the rotundone-containing composition is not an oxide of an α-guaiene-containing composition.

Claims

1. A method for producing rotundone, comprising the steps of: (Step 1) A step of preparing a rotundone-containing composition having a rotundone concentration in the range of 20 to 80% by mass. (Step 2) A step of reacting the rotundone in the rotundone-containing composition with a crystallizing compound having an amino group to produce a crystalline rotundone derivative, which comprises carrying out the following step 2A or 2B: (Step 2A) A step of reacting the rotundone in the rotundone-containing composition with a crystallizable compound selected from the following crystallizable compound group I to produce a crystalline rotundone derivative. (Crystallized compound group I) 【Chemical 1】 [Wherein, in (a), R １ ~R ３ each independently represents hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms, X represents a halogen atom, and in (b), R ４ ~R ８ each independently represents hydrogen or a nitro group. (Step 2B) A step of reacting the rotundone in the rotundone-containing composition with a crystallizing compound selected from the crystallizing compound group II below to generate a crystalline rotundone derivative precursor, and then reacting the precursor with an acid to generate a salt of the precursor as a crystalline rotundone derivative. (Crystallized compound group II) 【Chemistry 2】 [In the formula (c), n represents an integer of 0 to 4.] (Step 3) Recrystallizing the crystalline rotundone derivative (Step 4) A step of hydrolyzing the imino group of the crystalline rotundone derivative in the crystals obtained in Step 3 to liberate rotundone from the crystalline rotundone derivative.

2. The method according to claim 1, wherein the crystallization compound is semicarbazone hydrochloride or 2,4-dinitrophenylhydrazine when selected from crystallization compound group I, or t-butylamine, phenylamine, benzylamine, or hydroxylamine hydrochloride when selected from crystallization compound group II.

3. The method according to claim 1 or 2, wherein the acid in step 2B is hydrochloric acid.

4. The method according to claim 1 or 2, wherein the step 3 comprises mixing a recrystallization solvent with the crystalline rotundone derivative.

5. 5. The method of claim 4, wherein the recrystallization solvent is ethyl acetate, methanol, ethanol, water, acetone, cyclohexane, toluene, hexane, or a mixture of two or more thereof.

6. The method according to claim 1 or 2, wherein the hydrolysis in step 4 is carried out using copper(II) chloride.

7. 3. The production method according to claim 1, wherein the step 1 is a step of preparing a rotundone-containing composition by oxidizing all or part of α-guaiene contained in the α-guaiene-containing composition to convert it to rotundone.

8. 8. The method according to claim 7, wherein the α-guaiene-containing composition to be oxidized is any one of patchouli oil, patchouli oil obtained by simple distillation and / or precision distillation, guaiacwood oil, and guaiacwood oil obtained by simple distillation and / or precision distillation.

9. 8. The method according to claim 7, wherein the oxidation of α-guaiene is one type of oxidation selected from the group consisting of air oxidation, oxidation using t-butyl hydroperoxide and a chromium oxide catalyst, oxidation using laccase, oxidation using sodium chlorite-N-hydroxyphthalimide, and electrolytic oxidation.

10. 10. The production method according to claim 9, wherein the air oxidation is carried out without a catalyst or using a catalyst selected from the group consisting of cobalt (II) acetate tetrahydrate, cobalt 2-ethylhexanoate, cobalt naphthenate, cobalt acetylacetonate, and chromium (VI) oxide.

11. 8. The method according to claim 7, wherein the α-guaiene-containing composition has an α-guaiene concentration in the range of 20 to 60% by mass.

12. 3. The production method according to claim 1 or 2, further comprising a step between step 3 and step 4 of washing the crystals of the crystalline rotundone derivative with a washing solvent, wherein the washing solvent is a hydrocarbon solvent, water, a 70 to 99% aqueous ethanol solution, or an ether.

13. The process of claim 12, wherein the washing solvent is heptane.

14. The method according to claim 1 or 2, wherein step 3 is carried out two or more times.

15. A method for producing rotundone, comprising the steps of: (Step 1) A step of preparing a rotundone-containing composition having a rotundone concentration in the range of 20 to 80% by mass. (Step 2) A step of reacting the rotundone in the rotundone-containing composition with a crystallizing compound selected from the crystallizing compound group I below to obtain a crystalline rotundone derivative, and then reacting the crystalline rotundone derivative with an acid to produce a salt of the crystalline rotundone derivative. (Crystallized compound group I) 【Chemistry 3】 [Wherein, in (a), R １ ~R ３ each independently represents hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms, X represents a halogen atom, and in (b), R ４ ~R ８ each independently represents hydrogen or a nitro group. (Step 3) Recrystallizing the crystalline salt of the rotundone derivative (Step 4) A step of hydrolyzing the imino group of the salt of the crystalline rotundone derivative in the crystals obtained in Step 3 to liberate rotundone from the salt of the crystalline rotundone derivative.

16. A compound represented by formula A or a salt thereof. 【Chemistry 4】 [In the formula, R is any one of Ra, Rb, Rc, Rd, and Re, and in Ra, R １ ~R ３ each independently represents hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms; ４ ~R ８ each independently represents hydrogen or a nitro group, and in Rc, n represents an integer of 0 to 4.

17. 17. The compound or salt thereof according to claim 16, wherein the compound or salt thereof is the hydrochloride salt of the compound.

18. The compound or a salt thereof is a compound represented by the following formula Aa1 or Ab1: 【Chemistry 5】 Alternatively, the compound or salt thereof according to claim 16, which is a hydrochloride salt of a compound represented by the following formula Ac1, Ac2, Ad1, or Ae: 【Chemistry 6】

19. The compound or salt thereof according to claim 16, wherein the compound or salt thereof is a hydrochloride salt of a compound represented by the following formula Aa1 or Ab1: 【Chemistry 7】

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