Method for producing azulene and related compounds

Abstract

Disclosed is a method for producing azulene and related compounds, the method comprising a step in which a mixture that contains a compound having a hydrogenated azulene skeleton or a composition containing the compound, and at least one disulfide selected from the group consisting of an aromatic disulfide having a substituent and a long-chain alkyl disulfide is heated so as to subject the compound to a dehydrogenation reaction.

Description

Method for producing azulenes

[0001] The present invention relates to a method for producing azulenes. This application claims priority based on Japanese Patent Application No. 2023-099278, filed on June 16, 2023, the contents of which are incorporated herein by reference.

[0002] Azulene is a structural isomer of naphthalene and is a deep blue, non-benzene-based aromatic compound with a 10-carbon atom skeleton. Guaiazulene, one of the compounds with an azulene skeleton, has anti-inflammatory properties and is used as an anti-inflammatory drug for stomatitis and dermatitis. Furthermore, azulene exhibits unique optical properties and redox behavior due to its structure, which is a fused five-membered and seven-membered ring structure. Therefore, azulene is also attracting attention as an electronic material for semiconductors and other applications.

[0003] In the following description, the "compound having an azulene skeleton" may be referred to as an "azulene compound."

[0004] As a method for producing azulenes, a method has long been known in which hydrogenated azulenes are dehydrogenated using sulfur, selenium, or diphenyl disulfide at high temperatures to produce azulenes. Also known is a method in which hydrogenated azulenes are dehydrogenated using a transition metal catalyst to produce azulenes (see, for example, Patent Document 1).

[0005] Japanese Patent Application Laid-Open No. 2023-22829

[0006] However, production methods in which compounds having a hydrogenated azulene skeleton (hydrogenated azulenes) are dehydrogenated using sulfur or selenium produce toxic and foul-smelling compounds such as hydrogen sulfide as by-products. Furthermore, production methods in which hydrogenated azulenes are dehydrogenated using diphenyl disulfide also produce thiophenol, a toxic and foul-smelling by-product. Therefore, when these reactions are used industrially, adequate odor control measures are required, and improvements have been sought.

[0007] On the other hand, the dehydrogenation reaction of hydrogenated azulenes using a transition metal catalyst does not produce any foul-smelling compounds, so no odor control measures are necessary. However, this reaction has a low yield, making it difficult to adopt industrially.

[0008] Therefore, there has been a demand for a novel method for producing azulenes that is simple in operation, produces few malodorous by-products, and allows for efficient production with high yields.

[0009] The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a simple and efficient method for producing azulenes.

[0010] In order to solve the above problems, one aspect of the present invention includes the following aspects.

[0011] [1] A method for producing azulenes, comprising a step of heating a mixture containing a compound having a hydrogenated azulene skeleton or a composition containing the compound, and at least one disulfide selected from the group consisting of substituted aromatic disulfides and substituted long-chain alkyl disulfides, to dehydrogenate the compound.

[0012] [2] The method for producing azulenes according to [1], wherein the compound having a hydrogenated azulene skeleton is at least one selected from the group consisting of compounds having a hexahydroazulene skeleton, compounds having an octahydroazulene skeleton, compounds having a decahydro-1H-cyclopropa[e]azulene skeleton, and compounds having an octahydro-1H-cyclopropa[e]azulene skeleton.

[0013] [3] The method for producing azulenes according to [1] or [2], wherein the composition is a plant-derived component.

[0014] [4] The method for producing azulenes according to any one of [1] to [3], wherein the disulfide is at least one selected from the group consisting of 2,2'-dithiobis(methyl benzoate), di-p-isopropylphenyl disulfide, di-2-naphthyl disulfide, 2,2'-dithiodianiline, bis(2-benzamidophenyl) disulfide, bis(4-methoxyphenyl) disulfide, and didodecyl disulfide.

[0015] [5] The method for producing azulenes according to any one of [1] to [4], wherein the dehydrogenation reaction step is carried out in a batch reactor.

[0016] [6] The method for producing azulenes according to any one of [1] to [4], wherein the dehydrogenation reaction step is carried out in a flow reactor.

[0017] [7] The method for producing azulenes according to [6], wherein in the dehydrogenation reaction step, the preheated disulfide and the composition are mixed to obtain the mixture, and then the mixture is heated.

[0018] [8] The method for producing azulenes according to [7], wherein the disulfide and the composition are mixed in a flow channel of the flow reactor to obtain the mixture.

[0019] [9] The method for producing azulenes according to [8], wherein the disulfide is heated in the flow channel before mixing the disulfide with the composition.

[0020] According to the present invention, a simple and efficient method for producing azulenes can be provided.

[0021] Fig. 1 is an explanatory diagram of a flow-type reactor used in a method for producing azulenes. Fig. 2 is an explanatory diagram of a flow-type reactor used in a method for producing azulenes. Fig. 3 is an explanatory diagram of a flow-type reactor used in a method for producing azulenes.

[0022] The method for producing azulenes in this embodiment includes a step of heating a mixture containing a compound having a hydrogenated azulene skeleton or a composition containing the compound and at least one disulfide selected from the group consisting of substituted aromatic disulfides and long-chain alkyl disulfides to dehydrogenate the compound. In the following description, the substituted aromatic disulfide and the long-chain alkyl disulfide may be collectively referred to simply as "disulfide."

[0023] <Compound Having a Hydrogenated Azulene Skeleton> A "compound having a hydrogenated azulene skeleton" refers to a compound in which the double bond in the azulene ring of an azulene is replaced with a single bond (hydrogenated). A skeleton in which the double bond in the azulene ring is replaced with a single bond is called a "hydrogenated azulene skeleton."

[0024] In this embodiment, the compound having a hydrogenated azulene skeleton can be at least one selected from the group consisting of a compound having a hexahydroazulene skeleton, a compound having an octahydroazulene skeleton, a compound having a decahydro-1H-cyclopropa[e]azulene skeleton, and a compound having an octahydro-1H-cyclopropa[e]azulene skeleton.

[0025] These compounds may have one or more substituents on the hydrogenated azulene skeleton. Examples of the substituents include a hydroxy group and an aliphatic hydrocarbon group. The aliphatic hydrocarbon group may be substituted with one or more hydroxy groups. Furthermore, the aliphatic hydrocarbon group may form a condensed ring with the hydrogenated azulene skeleton.

[0026] Examples of "compounds having a hexahydroazulene skeleton" include: 3,8-dimethyl-5-propan-2-yl-1,2,6,7,8,8a-hexahydroazulene (common name: isogurujunene) 3,8-dimethyl-5-prop-1-en-2-yl-1,2,3,4,5,6,7,8-octahydroazulen-1-ol 3,8-dimethyl-5-prop-1-en-2-yl-1,2,3,3α,4,5,6,7-octahydroazulene (common name: δ-guaiene) 1,4-dimethyl-7-propan-2-yl-1,2,3,4,5,6-hexahydroazulene Examples include: 1-methyl-4-methylidene-7-propan-2-yl-2,3,3a,5,6,8a-hexahydroazulen-1-ol (trivial name: Alimol), 1,4-dimethyl-7-propan-2-ylidene-2,3,4,5,6,8-hexahydro-1H-azulene (trivial name: β-guaiene), and 3,8-dimethyl-5-propan-2-ylidene-2,4,6,7,8,8a-hexahydro-1H-azulene.

[0027] Examples of "compounds having an octahydroazulene skeleton" include: (3S,3αS,5R)-3,8-dimethyl-5-propan-2-yl-1,2,3,3a,4,5,6,7-octahydroazulene (common name: bulnesene) 3,8-dimethyl-5-propan-2-yl-1,2,3,3a,4,5,6,7-octahydroazulene (common name: apitonen 1) (3R,3αS,5S)-3,8-dimethyl-5-propan-2-yl-1,2,3,3a,4,5,6,7-octahydroazulene 1,4-dimethyl-7-propan-2-yl-1,2,3,4,5,6,7,8-octahydroazulene・3,8-dimethyl-5-propan-2-yl-1,2,3,4,5,6,7,8,8a-octahydroazulene ・2-[(3R,5S,8R)-3,8-dimethyl-1,2,3,4,5,6,7,8-octahydroazulen-5-yl]]propan-2-ol (common name: α-guaiol) ・2-[(3S,3αR,5S)-3,8-dimethyl-1,2,3,3a,4,5,6,7-octahydroazulen-5-yl]propan-2-ol (common name: bulnesol) ・2-[(5R,8S,8αS)-3,8-dimethyl-1,2,3,4,5,6,7,8,8a-octahydroazulen-5-yl]propan-2-ol 1,4-dimethyl-7-propan-2-ylidene-1,2,3,3a,5,6,8,8a-octahydroazulen-4-ol

[0028] Examples of "compounds having a decahydro-1H-cyclopropa[e]azulene skeleton" include: 1,1,4,7-tetramethyl-1a,2,3,4,4a,5,6,7,7a,7b-decahydrocyclopropa[e]azulene (trivial name: aromadendren) 1,1,4,7-tetramethyl-2,3,4,5,6,7,7a,7b-octahydro-1aH-cyclopropa[h]azulen-4a-ol (trivial name: palustrol) (1aR,4R,4aS,7R,7aS,7bS)-1,1,4,7-tetramethyl-2,3,4a,5,6,7,7a,7b-octahydro-1aH-cyclopropa[e]azulen-4-ol (trivial name: redol) (1aR,4S,4aS,7R,7aS,7bR)-1,1,4,7-tetramethyl-1a,2,3,4a,5,6,7a,7b-octahydrocyclopropa[h]azulene-4,7-diol 1,1,4,7-tetramethyl-1a,2,3,5,6,7,7a,7b-octahydrocyclopropa[h]azulene-4,4a-diol 1,1,4,7-tetramethyl-2,3,4,4a,5,6,7,7b-octahydro-1aH-cyclopropa[e]azulen-7a-ol (common name: 5-aromadendranolan) (4S,4aS,7S,7aS)-1,1,4,7-tetramethyl-1a,2,3,4,5,6,7a,7b-octahydrocyclopropa[h]azulene-4a,7-diol

[0029] Examples of "compounds having an octahydro-1H-cyclopropa[e]azulene skeleton" include: 1,1,4,7-tetramethyl-1a,2,3,4,4a,5,6,7b-octahydrocyclopropa[e]azulene (common name: α-gurjunene) 1,1,4,7-tetramethyl-1a,2,3,5,6,7,7a,7b-octahydrocyclopropa[e]azulene (common name: 1(10)-aromadendrene) 1,1,4,7-tetramethyl-1a,2,3,4,5,6,7,7b-octahydrocyclopropa[e]azulene (common name: isoleden) 1,1,7-Trimethyl-4-methylidene-2,3,4a,5,6,7,7a,7b-octahydro-1aH-cyclopropa[e]azulene (common name: aromadendrene) 1,1,4,7-Tetramethyl-2,3,6,7,7a,7b-hexahydro-1aH-cyclopropa[e]azulen-4-ol (common name: 1-aromadendrene-10-ol) 1,1,4,7-Tetramethyl-3,4,5,6,7,7b-hexahydro-2H-cyclopropa[e]azulen-1a-ol (common name: 1(5)-aromadendrene-7-ol) Examples include 1,1,4,7-tetramethyl-1a,2,3,4,4a,5,6,7b-octahydrocyclopropa[e]azulen-2-ol (trivial name: 8α-hydroxy-α-gurjunene), (1,4,7-trimethyl-1a,2,3,4,4a,5,6,7b-octahydrocyclopropa[e]azulen-1-yl)methanol (trivial name: 4-aromadendrene-12-ol), and 1,1,4,7-tetramethyl-1a,2,3,4,4a,5,6,7b-octahydrocyclopropa[e]azulen-3-ol.

[0030] The above-mentioned compounds are merely examples, and compounds that can be used in the method for producing azulenes are not limited to these. As will be described in detail later, any compound that has a hydrogenated azulene skeleton and that undergoes a dehydrogenation reaction to produce an azulene skeleton when heated together with at least one disulfide selected from the group consisting of substituted aromatic disulfides and long-chain alkyl disulfides can be used as a starting material in the method for producing azulenes of this embodiment.

[0031] In the method for producing azulenes, the above-mentioned compounds may be used alone or as a composition containing the above-mentioned compounds.

[0032] When the composition of the above-mentioned compounds is used as a raw material in the method for producing azulenes, the composition is preferably a plant-derived component, such as camphor oil, eucalyptus oil, patchouli oil, geranium oil, peppermint oil, Gurjun balsam oil, Guaiac wood oil, Eucalyptus globulus oil, or Wintera colorata oil.

[0033] These plant-derived components are known to contain compounds having a hydrogenated azulene skeleton, and can be used as raw materials in the production of azulenes. The plant-derived components described above may be used alone or in combination of two or more.

[0034] <Disulfide> In the method for producing azulenes of this embodiment, the disulfide used in the dehydrogenation reaction is a disulfide that produces a reaction mixture with a reduced odor compared to the reaction mixture after a dehydrogenation reaction using known diphenyl disulfide.

[0035] Odor evaluation is performed by sensory evaluation using the sense of smell. After dehydrogenation of a compound having a hydrogenated azulene skeleton using each disulfide, the odor of the reaction mixture is confirmed. The odor of the reaction mixture in a reaction system using a known diphenyl disulfide is used as the standard, and judgment is made according to the following criteria. The evaluation result when diphenyl disulfide is used is a C rating based on the following criteria. As a result of the odor evaluation, if the rating is A or B, it is considered to be pass, and if the rating is C, it is considered to be fail. A: There is an odor, but it does not interfere with work. B: There is an odor, but it does not interfere with work if odor control measures are taken. C: The odor is strong and cannot be used.

[0036] Among the disulfides used, the aromatic ring of the "substituted aromatic disulfide" may be an aromatic ring having 6 to 10 carbon atoms or a six-membered heterocyclic ring. Examples of the substituent bonded to the aromatic ring include an alkyl group, an ester group, an alkoxy group, an amino group, and an amide group.

[0037] Examples of such compounds include: di-p-isopropylphenyl disulfide, 2,2'-dithiobis(methyl benzoate), bis(4-methoxyphenyl) disulfide, di-2-naphthyl disulfide, 2,2'-dithiodianiline, and bis(2-benzamidophenyl) disulfide.

[0038] In addition, in the "long-chain alkyl disulfide", the number of carbon atoms in the alkyl group bonded to the sulfur atom may be 8 to 20, 8 to 16, or 8 to 14. In addition, the alkyl group bonded to the sulfur atom may be linear or branched.

[0039] Examples of such compounds include: dinonyl disulfide, didecyl disulfide, diundecyl disulfide, and didodecyl disulfide.

[0040] In the method for producing azulenes, the above disulfides may be used alone or in combination of two or more.

[0041] <Solvent> The compound having a hydrogenated azulene skeleton or a composition containing the compound and the disulfide may dissolve in each other to form a uniform mixture. The mixture may also contain a solvent in addition to the compound having a hydrogenated azulene skeleton and the disulfide. When the mixture is a solution containing a solvent, the disulfide, which is solid at room temperature, can be dissolved in the solvent, making it easier to apply the mixture to a flow reactor, which will be described later.

[0042] In this embodiment, various solvents can be used as long as they can dissolve the compound having a hydrogenated azulene skeleton, the disulfide, and the resulting compound having an azulene skeleton. Usable solvents include triglyme, tetraethylene glycol, and mesitylene.

[0043] In the method for producing azulenes of this embodiment, the dehydrogenation reaction may be carried out in a batch reactor or a flow reactor. The production method of this embodiment is easily applicable to a flow reactor because the dehydrogenation reaction can be carried out by a homogeneous reaction using a mixture in which the compounds used are dissolved in each other.

[0044] 1 to 3 are explanatory diagrams of a flow-type reactor used in a method for producing azulenes. The reactor 100A shown in FIG. 1 includes a storage tank 1 for storing a mixture of raw materials, a heating section 2 for heating the mixture, a cooling section 3 for cooling the heated mixture (reaction mixture), and a recovery tank 4 for recovering and storing the reaction mixture. The storage tank 1, heating section 2, cooling section 3, and recovery tank 4 are connected in this order by piping 5. A liquid feed pump 6 and a back pressure regulator 7 are disposed within the path of piping 5. The liquid feed pump 6 feeds the mixture and reaction mixture toward the downstream recovery tank 4. The back pressure regulator 7 applies back pressure toward the upstream storage tank 1.

[0045] The heating conditions in the heating section 2 can be controlled by the set temperature of the heating section 2 , the length of the piping in the heating section 2 , and the flow rate of the mixture flowing through the piping 5 in the heating section 2 .

[0046] In the reactor 100A, the reaction mixture recovered in the recovery tank 4 may be stored again in the storage tank 1 and passed through the heating section 2 multiple times.

[0047] In the reactor 100A, the compound having a hydrogenated azulene skeleton or a composition containing the compound may be mixed with a preheated disulfide to form a mixture, which may then be supplied from the storage tank 1. The preheating temperature for the disulfide is preferably 250°C or higher and 280°C or lower.

[0048] 2, a storage tank 1, a heating section 2, a cooling section 3, and a recovery tank 4 are also connected in this order by piping 5. In the reactor 100B, a piping following a back pressure adjusting device 7 disposed in the path of piping 5 is connected to the storage tank 1, forming a circulation system.

[0049] Furthermore, between the storage tank 1 and the liquid delivery pump 6 (between the storage tank 1 and the heating section 2), a switching valve 51 is provided in the path of the piping 5, and the recovery tank 4 is connected via a bypass 52 connected to the switching valve 51.

[0050] The reactor 100B can form a closed system reaction section 50 in which a piping 5 including a heating section 2 and a cooling section 3 is connected to a back pressure adjusting device 7 by a switching valve 51. The reaction section 50 has a storage tank 1, a heating section 2, a cooling section 3, a piping 5, and a liquid transfer pump 6. That is, the reactor 100B has the reaction section 50, a switching valve 51 provided in the piping 5 of the reaction section 50, a bypass 52, and a recovery tank 4.

[0051] The reaction section 50 functions as a circulation-type flow reactor by sending a liquid using a liquid sending pump 6 provided in the path of the pipe 5. In the reaction section 50, the dehydrogenation reaction is repeated while circulating the mixture, thereby improving the yield of the target product.

[0052] 3 includes a mixing section 60, a heating section 2, a cooling section 3, and a recovery tank 4. The mixing section 60, the heating section 2, the cooling section 3, and the recovery tank 4 are connected in this order by a pipe 5. A liquid feed pump 6 and a back pressure adjusting device 7 are disposed within the path of the pipe 5, similarly to the reactor 100A.

[0053] The mixing unit 60 mixes the compound having a hydrogenated azulene skeleton or a composition containing the compound with the disulfide to prepare a mixture of raw materials. The mixing unit 60 includes a first supply unit 61, a second supply unit 62, and a mixer 63.

[0054] (First Supply Unit) The first supply unit 61 supplies a compound having a hydrogenated azulene skeleton or a composition containing the compound. Hereinafter, the compound having a hydrogenated azulene skeleton or a composition containing the compound may be referred to as "compound A." In Figure 3, compound A is represented by the symbol A.

[0055] The first supply unit 61 includes a first storage tank 1A for storing compound A, a first pipe 5A connecting the first storage tank 1A and the mixer 63, and a first liquid feed pump 6A and a first check valve 8A provided in the path of the first pipe 5A. The first check valve 8A prevents backflow of compound A.

[0056] Compound A may be in the form of a solution dissolved in the above-mentioned solvent.

[0057] The compound A stored in the first storage tank 1A is caused to flow through the first pipe 5A by the first liquid transfer pump 6A and is supplied to the mixer 63.

[0058] (Second Supply Unit) The second supply unit 62 supplies the disulfide. In Fig. 3, the disulfide is represented by the symbol B.

[0059] The second supply unit 62 includes a second storage tank 1B for storing disulfide, a second pipe 5B connecting the second storage tank 1B and the mixer 63, a second liquid feed pump 6B provided in the path of the second pipe 5B, a second check valve 8B, and a heating unit 25. The second check valve 8B prevents backflow of disulfide.

[0060] The disulfide may be in the form of a solution dissolved in the above-mentioned solvent.

[0061] The heating unit 25 heats (preheats) the disulfide in the second pipe 5B. The heating conditions in the heating unit 25 can be controlled by the set temperature of the heating unit 25, the length of the pipe in the heating unit 25, and the flow rate of the disulfide flowing through the second pipe 5B. The disulfide is heated to a temperature of 250°C or higher and 280°C or lower in the heating unit 25.

[0062] The heating unit 25 can be configured in any known manner as long as it can heat the disulfide in the second pipe 5B.

[0063] The disulfide stored in the second storage tank 1B is caused to flow through the second pipe 5B by the second liquid transfer pump 6B, heated in the heating unit 25, and then supplied to the mixer 63.

[0064] (Mixer) Mixer 63 mixes the compound having a hydrogenated azulene skeleton or a composition containing the compound with the heated disulfide. This produces the mixture (denoted by the symbol "A+B" in FIG. 3). Mixer 63 is an in-line mixer incorporated into the flow paths of compound A and disulfide, and may have a known configuration.

[0065] The mixture obtained in mixer 63 is heated in heating section 2 disposed downstream and cooled in cooling section 3. Thereafter, the obtained reaction mixture is recovered in recovery tank 4.

[0066] In this reactor 100C, the mixture can be adjusted within the flow path, eliminating the need for prior preparation of the mixture. Therefore, the target product can be easily produced. Furthermore, in the reactor 100C, the mixture can be easily prepared using preheated disulfide. By using such heated disulfide, the reaction efficiency can be improved, and the yield of the target product can be improved without the need to circulate the mixture during the reaction as in the reactor 100B.

[0067] The appropriate temperature for the disulfide preheated in the heating section 25 varies depending on the type of disulfide. Therefore, when using the reactor 100C, it is advisable to confirm the heating conditions in the heating section 25 in a preliminary experiment and set heating conditions that result in a relatively high yield.

[0068] Although the reactor 100C is supposed to have the heating unit 25, the heating unit 25 may be omitted if disulfide preheated outside the apparatus is supplied from the second supply unit 62.

[0069] Each of the reactors 100A, 100B, and 100C may have a known configuration.

[0070] The reaction rate of the dehydrogenation reaction of the compound having a hydrogenated azulene skeleton can be controlled by adjusting various conditions, such as the raw material concentration, the ratio of the compound having a hydrogenated azulene skeleton to the disulfide, the reaction temperature (the temperature of heating section 2), and the liquid feed rate.

[0071] Furthermore, when the reactor 100A is used, the reaction rate of the dehydrogenation reaction can be controlled by the number of times that the mixture (reaction mixture) is passed through the heating section 2.

[0072] Furthermore, when the reactor 100B is used, the reaction rate of the dehydrogenation reaction can be controlled by the circulation time in the reaction section 50.

[0073] When the reactor 100C is used, the reaction rate of the dehydrogenation reaction can be controlled by the heating conditions in the heating section 25.

[0074] The target azulenes can be obtained by separating the azulenes contained in the reaction mixture using a known separation method.

[0075] In the method for producing azulenes, the compound having the hydrogenated azulene skeleton described above is heated together with at least one disulfide selected from the group consisting of substituted aromatic disulfides and long-chain alkyl disulfides, thereby causing a dehydrogenation reaction in the compound having the hydrogenated azulene skeleton and obtaining the target compound having the azulene skeleton.

[0076] For example, when α-gurjunene, a compound having an octahydro-1H-cyclopropa[e]azulene skeleton, is used as the compound having the hydrogenated azulene skeleton and heated together with the disulfide, the hydrogenated azulene skeleton undergoes a dehydrogenation reaction as shown in the following formula (A), and guaiazulene, an azulene, is obtained.

[0077]

[0078] In this case, by heating α-gurjunene together with one or more disulfides selected from the group consisting of aromatic disulfides and long-chain alkyl disulfides having the above-mentioned substituents, the odor of the reaction mixture is reduced compared to conventional systems using diphenyl disulfide. From the viewpoint of odor reduction, the following are preferred: 2,2'-dithiobis(methyl benzoate), di-p-isopropylphenyl disulfide, di-2-naphthyl disulfide, bis(4-methoxyphenyl)disulfide, 2,2'-dithiodianiline, bis(2-benzamidophenyl)disulfide, and didodecyl disulfide. Furthermore, due to their high reaction yield, di-p-isopropylphenyl disulfide, 2,2'-dithiobis(methyl benzoate), bis(4-methoxyphenyl)disulfide, and di-2-naphthyl disulfide are more preferred.

[0079] Furthermore, in the production method of this embodiment, the target product can be obtained in a higher yield than in known dehydrogenation reactions using a transition metal catalyst.

[0080] The target azulenes can be easily isolated from the reaction mixture obtained by the production method of this embodiment by known methods.

[0081] Therefore, the method for producing azulenes having the above-described configuration can provide a simple and efficient production method.

[0082] While the preferred embodiments of the present invention have been described above with reference to the accompanying drawings, the present invention is not limited to these examples. The shapes and combinations of the components shown in the above examples are merely examples, and various modifications can be made based on the design, specifications, etc., without departing from the spirit of the present invention.

[0083] The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

[0084] In the examples shown below, a mixture of an α-gurjunene composition (α-gurjunene content: 83%) and each compound was heated to react with each other to obtain guaiazulene (see formula (A) below). α-gurjunene corresponds to the "compound having a hydrogenated azulene skeleton" in the present invention. α-gurjunene: C １５ H ２４ mw204 Guaiazulene: C １５ H １８ mw198

[0085]

[0086] The reaction was evaluated by determining the yield of guaiazulene obtained relative to the amount of α-gurjunene used as a starting material. In calculating the yield, the molecular weight of α-gurjunene was set to 204 and the molecular weight of guaiazulene to 198.

[0087] The above reaction was carried out in both a batch reactor and a flow reactor.

[0088] In addition, the reaction mixture after the reaction was subjected to an odor evaluation by the following method. The odor was evaluated by a sensory evaluation using the sense of smell. After the reaction of formula (A) above was carried out using each disulfide, the odor of the reaction mixture was confirmed. The odor of the reaction mixture in a reaction system using a known diphenyl disulfide was used as the standard, and judgment was made according to the following criteria. The evaluation result when diphenyl disulfide was used was rated C according to the following criteria. As a result of the odor evaluation, an A or B rating was considered pass, and a C rating was considered fail. A: There is an odor, but it does not interfere with work. B: There is an odor, but it does not interfere with work if odor countermeasures are taken. C: The odor is strong and cannot be used.

[0089] [Batch Reactor] Example 1 98.2 g of 2,2′-dithiobis(methyl benzoate) (formula (1) below) was added to a flask and melted by heating to 250° C. with stirring. 20.0 g of an α-gurjunene composition (81.37 mmol of α-gurjunene) was added dropwise to the resulting melt using a dropping funnel, and after the dropwise addition, the mixture was allowed to react at 250° C. for 10 minutes.

[0090]

[0091] After the reaction, post-treatment and isolation were carried out by a separation operation to obtain 9.57 g (48.34 mmol) of guaiazulene in a yield of 59.4 mol %.

[0092] Example 2 73.9 g of di-p-isopropylphenyl disulfide (formula (2) below) was added to a flask and heated to 250° C. with stirring. 10 g of an α-gurjunene composition (40.69 mmol of α-gurjunene) was added dropwise to the heated liquid using a dropping funnel, and after the dropwise addition, the mixture was reacted at 250° C. for 10 minutes.

[0093]

[0094] Isolation was carried out by a separation operation to obtain 4.6 g (23.23 mmol) of guaiazulene in a yield of 57.2 mol %.

[0095] Example 3 4.7 g of di-2-naphthyl disulfide (formula (3) below) was added to a flask and melted by heating to 260°C with stirring. 1.0 g of an α-gurjunene composition (4.07 mmol of α-gurjunene) was added dropwise to the resulting melt using a dropping funnel, and after the dropwise addition, the mixture was allowed to react at 260°C for 10 minutes.

[0096]

[0097] After the reaction, the amount was determined by liquid chromatography, and it was found that 0.46 g (2.30 mmol) of guaiazulene was obtained in a yield of 56.6 mol %.

[0098] Example 4 3.6 g of 2,2′-dithiodianiline (formula (4) below) was added to a flask and melted by heating to 200° C. with stirring. 1.0 g of an α-gurjunene composition (4.07 mmol of α-gurjunene) was added dropwise to the resulting melt using a dropping funnel, and after the dropwise addition, the mixture was allowed to react at 206° C. for 10 minutes.

[0099]

[0100] After the reaction, the amount was determined by liquid chromatography, and it was found that 0.25 g (1.26 mmol) of guaiazulene was obtained in a yield of 31.0 mol %.

[0101] Example 5 6.7 g of bis(2-benzamidophenyl)disulfide (the following formula (5)) was added to a flask and melted by heating to 175°C with stirring. 1.0 g of an α-gurjunene composition (4.07 mmol of α-gurjunene) was added dropwise to the resulting melt using a dropping funnel, and after the dropwise addition, the mixture was allowed to react at 175°C for 10 minutes.

[0102]

[0103] Post-treatment and isolation were carried out by a separation operation to obtain 0.29 g (1.46 mmol) of guaiazulene in a yield of 36.0 mol %.

[0104] ​Example 6 6.8 g of bis(4-methoxyphenyl)disulfide (the following formula (6)) was added to a flask and heated to 240° C. with stirring. 1.0 g of an α-gurjunene composition (4.07 mmol of α-gurjunene) was added dropwise to the heated liquid using a dropping funnel, and after the dropwise addition, the mixture was reacted at 245° C. for 10 minutes.

[0105]

[0106] After the reaction, quantitative analysis by liquid chromatography revealed that 0.51 g (2.59 mmol) of guaiazulene was obtained at 63.7 mol %.

[0107] Example 7 9.8 g of didodecyl disulfide (formula (7) below) was added to a flask and melted by heating to 250°C with stirring. 1.0 g of an α-gurjunene composition (4.07 mmol of α-gurjunene) was added dropwise to the resulting melt using a dropping funnel, and after the dropwise addition, the mixture was allowed to react at 250°C for 10 minutes.

[0108]

[0109] After the reaction, quantitative analysis by gas chromatography revealed that 0.18 g (0.91 mmol) of guaiazulene was obtained in a yield of 22.0 mol %.

[0110] Comparative Example 1 3.6 g of di-p-tolyl disulfide (formula (C1) below) was added to a flask and melted by heating to 250° C. with stirring. To the resulting melt, 1.0 g of an α-gurjunene composition (4.07 mmol of α-gurjunene) was added dropwise using a dropping funnel, and after the dropwise addition, the mixture was allowed to react at 250° C. for 10 minutes.

[0111]

[0112] After the reaction, quantitative analysis by gas chromatography revealed that 0.42 g (2.11 mmol) of guaiazulene was obtained at 52.0 mol %.

[0113] Comparative Example 2 4.9 g of bis(p-tert-butylphenyl) disulfide (the following formula (C2)) was added to a flask and melted by heating to 250° C. with stirring. To the resulting melt, 1.0 g of an α-gurjunene composition (4.07 mmol of α-gurjunene) was added dropwise using a dropping funnel, and after the dropwise addition, the mixture was allowed to react at 250° C. for 10 minutes.

[0114]

[0115] After the reaction, the amount was determined by liquid chromatography, and it was found that 0.412 g (2.08 mmol) of guaiazulene was obtained in a yield of 51.1 mol %.

[0116] Comparative Example 3 6.8 g of bis(2,4-dimethylphenyl) disulfide (formula (C3) below) was added to a flask and heated to 250° C. with stirring. 1.0 g of an α-gurjunene composition (4.07 mmol of α-gurjunene) was added dropwise to the heated liquid using a dropping funnel, and after the dropwise addition, the mixture was allowed to react at 250° C. for 10 minutes.

[0117]

[0118] After the reaction, the amount was determined by liquid chromatography, and it was found that 0.51 g (2.55 mmol) of guaiazulene was obtained in a yield of 62.7 mol %.

[0119] Comparative Example 4 3.2 g of 2,2′-dipyridyl disulfide (the following formula (C4)) and 1.0 g of an α-gurjunene composition (4.07 mmol of α-gurjunene) were added to a flask. The contents of the flask were heated to 230° C. with stirring to dissolve and react the contents.

[0120]

[0121] After the reaction, the amount was determined by liquid chromatography, and it was found that 0.06 g (0.31 mmol) of guaiazulene was obtained in a yield of 7.5 mol %.

[0122] Comparative Example 5 2.2 g of 1,2-benzothiazolin-3-one (the following formula (C5)) and 1.0 g of an α-gurjunene composition (4.07 mmol of α-gurjunene) were added to a flask. The contents of the flask were heated to 250°C with stirring to melt the contents, and the contents were reacted at 250°C for 3 minutes.

[0123]

[0124] After the reaction, the reaction mixture was diluted with 5 mL of toluene and quantitatively determined by gas chromatography. 0.099 g (0.5 mmol) of guaiazulene was obtained in a yield of 11.3%.

[0125] [Flow Reactor] (Example 8) A flow reactor having the same configuration as the reactor 100A shown in Fig. 1 was used. 22.2 g of di-p-isopropylphenyl disulfide (the above formula (2)) and 5.0 g of an α-gurjunene composition (20.34 mmol of α-gurjunene) were mixed, and the heating section 2 was heated to 280°C, and the reaction liquid was passed through the heating section 2 at a flow rate of 2 mL / min without applying back pressure. Thereafter, the reaction liquid was passed through the cooling section 3 whose temperature was controlled to 20°C to 30°C, and cooled.

[0126] The resulting reaction liquid was collected and then passed through the reactor 100A again under the same conditions. After passing the liquid through the reactor 100A a total of 15 times, the reaction was terminated.

[0127] The reaction mixture was quantitatively analyzed by liquid chromatography, and it was found that 2.3 g (11.86 mmol) of guaiazulene was obtained in a yield of 58.3 mol %.

[0128] Example 9 A flow reactor having the same configuration as the reactor 100B shown in FIG. 2 was used. 33.3 g of di-p-isopropylphenyl disulfide (the above formula (2)) and 7.5 g of an α-gurjunene composition (30.51 mmol of α-gurjunene) were mixed to obtain a mixed solution. The heating section 2 was heated to 280°C, and the cooling section 3 was cooled to 20°C to 30°C. After that, the mixed solution was passed through the heating section 2 and the cooling section 3 at a flow rate of 2 mL / min without applying back pressure, and the reaction was terminated after circulating for 250 minutes.

[0129] The reaction mixture was quantitatively analyzed by liquid chromatography, and it was found that 3.5 g (17.52 mmol) of guaiazulene was obtained in a yield of 57.4 mol %.

[0130] Example 10 A flow reactor having the same configuration as the reactor 100B shown in Fig. 2 was used. α-Gurjunene was reacted in the same manner as in Example 8, except that a back pressure of 0.2 to 0.4 MPa was applied by the back pressure adjusting device 7 and the reaction time (circulation time) was set to 150 minutes.

[0131] The reaction mixture was quantitatively analyzed by liquid chromatography, and it was found that 3.0 g (15.25 mmol) of guaiazulene was obtained in a yield of 50.0 mol %.

[0132] (Reference Example) A tubular flow reactor having the same configuration as the reactor 100A shown in FIG. 1 was used. 6 g of di-p-tolyl disulfide (the above formula (C1)) and 1.0 g of an α-gurjunene composition (4.07 mmol of α-gurjunene) were heated to 65°C and melted. 2 mL of triglyme was added to the resulting melt, and the mixture was passed through the flow reactor, the heating section 2 of which was heated to 350°C, at a flow rate of 0.2 mL / min. Thereafter, the reaction liquid was passed through the cooling section 3, which had been cooled to 20°C to 30°C, to cool the reaction liquid.

[0133] The resulting reaction solution was quantitatively analyzed by gas chromatography, and it was found that 0.084 g (0.42 mmol) of guaiazulene was obtained in a yield of 10.3 mol %.

[0134] The evaluation results are shown in the following Tables 1 and 2. Table 1 shows the results using a batch reactor, and Table 2 shows the results using a flow reactor.

[0135]

[0136]

[0137] As a result of the evaluation, it was confirmed that the yield was as high as 20 mol% or more in Examples 1 to 7 using a batch reactor, and the odor of the reaction mixture was not so strong that it interfered with the work. Furthermore, it was found that the yield was 30 mol% or more in Examples 1 to 6, and the target product was obtained in a higher yield.

[0138] On the other hand, in Comparative Examples 1 to 3, the reaction yield was high, but the reaction mixture had a foul odor that interfered with the work. In Comparative Example 4, the odor was not a problem, but the yield was low. In Comparative Example 5, since a disulfide compound was not used, the odor of the reaction mixture was not a problem, but the yield was low.

[0139] In Examples 8 to 10, in which a flow reactor was used, it was confirmed that by repeatedly reacting the reaction mixture, results equivalent to those obtained in a batch reactor (Example 2) could be obtained.

[0140] It should be noted that, by comparing the Reference Example with Example 2, it was confirmed that the target product can be obtained by the target dehydrogenation reaction even by passing the liquid through the flow reactor only once, but the yield is lower than that of the batch reactor.

[0141] [Study on the Effect of Preheating Disulfide] The effect of preheating the disulfide compound before mixing the α-gurjunene composition with the disulfide compound was studied below.

[0142] In the following study, di-p-isopropylphenyl disulfide (the above formula (2)) was used as the disulfide, and a mixture of an α-gurjunene composition and di-p-isopropylphenyl disulfide was heated to react with each other to obtain guaiazulene. In the following description, di-p-isopropylphenyl disulfide is abbreviated as "DIPD."

[0143] Example 11 A flow reactor having the same configuration as the reactor 100A shown in FIG. 1 was used. 22.2 g of DIPD was placed in a 100 mL three-neck flask and heated and stirred in an oil bath. Heating was terminated 5 minutes after the internal temperature reached 280°C. The heated DIPD was mixed with 5.0 g of an α-gurjunene composition (20.34 mmol of α-gurjunene), and the resulting mixture was supplied to heating section 2 heated to 280°C and passed through once. The mixture was flowed at a flow rate of 2 mL / min and a back pressure of 0.8 kPa.

[0144] The reaction mixture was quantitatively analyzed by liquid chromatography, and it was found that 1.8 g (8.97 mmol) of guaiazulene was obtained in a yield of 44.1 mol %.

[0145] Examples 12 to 14 α-Gurjunene was reacted in the same manner as in Example 11, except that the preheating conditions for DIPD and the flow rate (linear velocity) of the mixture were set to the conditions shown in Table 3.

[0146] The evaluation results are shown in Table 3 below. The "reaction time" in the table is the time calculated from the inner diameter and length of pipe 5 of reactor 100A and the flow rate of the mixture, and is the time it takes for the mixture to flow inside heating section 2. Furthermore, the "total time" in the table is the time it takes for the liquid (mixture, reaction mixture) to flow through pipe 5 from storage tank 1 to recovery tank 4 of reactor 100A.

[0147]

[0148] As a result of the evaluation, it was confirmed that the yield was improved in Examples 11 to 13 in which DIPD was preheated compared to when DIPD was not preheated (Example 14). Furthermore, in all of Examples 11 to 13 in which DIPD was preheated, the target product was obtained in a high yield in a much shorter time than in Examples 8 to 10.

[0149] Example 15 A flow reactor having the same configuration as the reactor 100C shown in Fig. 3 was used. 13.5 g of an α-gurjunene composition (54.83 mmol of α-gurjunene) was fed to the first feed section 61. Meanwhile, 59.9 g of DIPD was fed to the second feed section 62 and preheated in the heating section 25 heated to 280°C. The heating time (preheating time) in the heating section 25 is shown in Table 4.

[0150] The heated DIPD and the α-gurjunene composition were mixed in a mixer 63, and then the resulting mixture was supplied to a heating section 2 heated to 280°C and passed through once. The mixture was made to flow at a flow rate of 2 mL / min and a back pressure of 0.8 kPa. Thereafter, the reaction liquid was passed through a cooling section 3 cooled to 20°C to 30°C, whereby the reaction liquid was cooled.

[0151] The reaction mixture was quantitatively analyzed by liquid chromatography, and it was found that 4.3 g (21.71 mmol) of guaiazulene was obtained in a yield of 39.6 mol %.

[0152] Examples 16 to 18 α-Gurjunene was reacted in the same manner as in Example 15, except that the reaction conditions were those shown in Table 4. In the table, the "heating time" of "DIPD preheating" is a time calculated from the inner diameter and length of the second pipe 5B of the heating section 25 and the flow rate of disulfide, and is the time for disulfide to flow inside the heating section 25.

[0153] The preheating time of each of Examples 15 to 18 was adjusted by changing the length of the piping of the heating section. For example, the linear velocity of Example 15 was twice that of Example 17, but the preheating times of Examples 15 and 17 were the same. Therefore, the length of the heating section 25 of Example 15 was adjusted to be twice the length of the heating section 25 of Example 17.

[0154]

[0155] As a result of the evaluation, it was found that the target product could also be obtained in high yield within a short period of time in the reactor 100C having the configuration shown in FIG.

[0156] Examples 19 and 20 α-Gurjunene was reacted in the same manner as in Example 17, except that the reaction conditions were those shown in Table 5. In the table, the "heating time" of "DIPD preheating" is a time calculated from the inner diameter and length of the second pipe 5B of the heating section 25 and the flow rate of disulfide, and is the time during which disulfide flows inside the heating section 25.

[0157]

[0158] The evaluation revealed that the heating temperature of DIPD affects the yield. When using a different disulfide, it is recommended to confirm the preheating temperature that maximizes the yield through preliminary experiments.

[0159] Examples 21 and 22 α-Gurjunene was reacted in the same manner as in Example 17, except that the reaction conditions were changed to those shown in Table 6.

[0160]

[0161] As a result of the evaluation, it was found that, within the confirmed range, the yield did not improve even when the heating time of DIPD was increased, and rather the yield tended to decrease.

[0162] Examples 23 to 27 α-Gurjunene was reacted in the same manner as in Example 18, except that the reaction conditions were those shown in Table 7. In the table, the "heating time" of "DIPD preheating" is a time calculated from the inner diameter and length of the second pipe 5B of the heating section 25 and the flow rate of disulfide, and is the time during which disulfide flows inside the heating section 25.

[0163]

[0164] As a result of the evaluation, within the confirmed range, a positive correlation was observed between the amount of DIPD used and the yield of the target product, guaiazulene, up to 3 equivalents.

[0165] From the above results, it was found that the target product could be obtained in high yield in a short time by preheating the disulfide.

[0166] From the above results, it was confirmed that the present invention is useful.

[0167] DESCRIPTION OF SYMBOLS 1...storage tank, 1A...first storage tank, 1B...second storage tank, 2...heating section, 3...cooling section, 4...recovery tank, 5...piping, 5A...first piping, 5B...second piping, 6...liquid feed pump, 6A...first liquid feed pump, 6B...second liquid feed pump, 7...back pressure adjusting device, 8A...first check valve, 8B...second check valve, 25...heating section, 50...reaction section, 51...switching valve, 52...bypass, 60...mixing section, 61...first supply section, 62...second supply section, 63...mixer, 100A, 100B, 100C...reactor

Claims

1. A method for producing azulenes, comprising a step of heating a mixture containing a compound having a hydrogenated azulene skeleton or a composition containing said compound, and at least one disulfide selected from the group consisting of substituted aromatic disulfides and long-chain alkyl disulfides, to dehydrogenate said compound.

2. The method for producing azulenes according to claim 1, wherein the compound having a hydrogenated azulene skeleton is at least one selected from the group consisting of compounds having a hexahydroazulene skeleton, compounds having an octahydroazulene skeleton, compounds having a decahydro-1H-cyclopropa[e]azulene skeleton, and compounds having an octahydro-1H-cyclopropa[e]azulene skeleton.

3. The method for producing azulenes according to claim 1 or 2, wherein the composition is a plant-derived component.

4. The method for producing azulenes according to claim 1 or 2, wherein the disulfide is at least one selected from the group consisting of 2,2'-dithiobis(methyl benzoate), di-p-isopropylphenyl disulfide, di-2-naphthyl disulfide, 2,2'-dithiodianiline, bis(2-benzamidophenyl) disulfide, bis(4-methoxyphenyl) disulfide and didodecyl disulfide.

5. The method for producing azulenes according to claim 1 or 2, wherein the dehydrogenation step is carried out in a batch reactor.

6. The method for producing azulenes according to claim 1 or 2, wherein the dehydrogenation step is carried out in a flow reactor.

7. The method for producing azulenes according to claim 6, wherein in the dehydrogenation step, the preheated disulfide and the composition are mixed to obtain the mixture, and then the mixture is heated.

8. The method for producing azulenes according to claim 7, wherein the disulfide and the composition are mixed in a flow path of the flow reactor to obtain the mixture.

9. The method for producing azulenes according to claim 8, wherein the disulfide is heated in the flow channel before being mixed with the composition.

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