Method for producing inclusion complex of bicycloalkane compound

Abstract

A production method for an encapsulation of a bicycloalkane compound, the method comprising mixing a bicycloalkane compound and a cyclodextrin compound in a mixed solvent of water and an organic solvent.

Description

[Technical field]

[0001] The present invention relates to a method for producing an inclusion complex of a bicycloalkane compound. [Background technology]

[0002] Bicyclo[1.1.1]pentane (BCP) compounds have attracted attention as biologically active compounds. The BCP motif has the same biofunctionality as para-substituted phenyl, alkynyl, and tert-butyl groups, while being highly three-dimensional and biologically safe, and is therefore expected to be applied to drug delivery. In addition, BCP halides (halogenoBCPs) are useful compounds as building blocks, and 1,3-diiodoBCP in particular has been introduced into the synthesis of candidate pharmaceutical compounds.

[0003] In the synthesis of compounds having a BCP motif, BCP compounds obtained by halogenating, alkylating, acetylating, etc., are used as intermediates. It is desirable to store these compounds stably as synthetic raw materials. That is, chemical stability in air, as well as thermal stability and light stability, are required. Stable storage techniques for such BCP compounds have been proposed. For example, Non-Patent Document 1 describes that a water-insoluble inclusion complex is obtained by mixing a 1,3-disubstituted BCP compound with α-cyclodextrin in water, and that the storage stability of the 1,3-disubstituted BCP compound is greatly improved in the state of this inclusion complex. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Angew.Chem.Int.Ed.,2021, Vol.60, pp.2578-2582 Summary of the Invention [Problem to be solved by the invention]

[0005] According to the technology described in the above Non-Patent Document 1, it is said that an inclusion complex of a BCP compound can be obtained quickly and easily by simply mixing the BCP compound with α-cyclodextrin in water. However, the inventors of the present invention have found that when a bicycloalkane compound such as a BCP compound is mixed with a cyclodextrin compound in water, the efficiency of inclusion is not necessarily sufficient, and that the production efficiency of the inclusion complex is significantly reduced when the amount of the compound is increased.

[0006] An object of the present invention is to provide a method for producing an inclusion complex of a bicycloalkane compound, which can sufficiently increase the yield of the inclusion complex obtained by including a bicycloalkane compound with a cyclodextrin compound to obtain the inclusion complex. [Means for solving the problem]

[0007] The object of the present invention has been achieved by the following means.

[0008] [1] A method for producing an inclusion complex of a bicycloalkane compound, comprising mixing a bicycloalkane compound with a cyclodextrin compound in a mixed solvent of water and an organic solvent. [2] The method according to [1], wherein the bicycloalkane compound is a bicyclo[1.1.1]pentane compound represented by the following general formula (1): [ka] In the formula, R 1 and R 2 each independently represents a hydrogen atom or a substituent. [3] Above R 1 and R 2 each independently represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an aryl group, an acyl group, a cyano group, a nitro group, an amino group, or a carboxy group. [4] The method according to any one of [1] to [3], wherein the cyclodextrin compound is an α-cyclodextrin compound. [5] The method according to any one of [1] to [4], wherein the organic solvent is one or more of an ester solvent, an ether solvent, a ketone solvent, a nitrile solvent, an alcohol solvent, an amide solvent, and a hydrocarbon solvent. [6] The method according to any one of [1] to [5], wherein the content of the organic solvent in the mixed solvent is 80 volume % or less. [7] The method according to any one of [1] to [6], wherein the bicycloalkane compound and the cyclodextrin compound are mixed in a state where light with a wavelength of 400 nm or less is blocked. [8] The method according to any one of [1] to [7], wherein the mixing of the bicycloalkane compound and the cyclodextrin compound in the mixed solvent of water and an organic solvent is carried out by mixing a solution in which the bicycloalkane compound is dissolved with a solution in which the cyclodextrin compound is dissolved. [9] The method according to [8], wherein the solution in which the cyclodextrin compound is dissolved is an aqueous solution in which the cyclodextrin compound is dissolved in water.

[0009] In the present invention and the specification, a numerical range expressed using "to" means a range including the numerical values ​​before and after "to" as the lower and upper limits. In the present invention, the term "compound" refers to a compound having a skeleton. For example, a "bicyclo[1.1.1]pentane compound" refers to not only bicyclo[1.1.1]pentane itself, but also bicyclo[1.1.1]pentane in which at least a portion of the hydrogen atoms has been substituted. In the present invention, for a substituent that is not specified as substituted or unsubstituted, it means that the group may further have an appropriate substituent. Therefore, even when it is simply described as "group" (e.g., "alkyl group" or "amino group") in the present specification, this "group" (e.g., "alkyl group") includes not only an embodiment having no substituent (e.g., "unsubstituted alkyl group" or "unsubstituted amino group"), but also an embodiment having a further substituent (e.g., "substituted alkyl group" or "substituted amino group"). Similarly, when it refers to a "carboxy group", it means the form including -COOR (R is a substituent) in addition to -COOH. Effect of the Invention

[0010] According to the method for producing a bicycloalkane compound inclusion complex of the present invention, when a bicycloalkane compound is encapsulated with a cyclodextrin compound to obtain an inclusion complex of a bicycloalkane compound, the yield of the resulting inclusion compound can be sufficiently increased. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The method for producing an inclusion complex of a bicycloalkane compound of the present invention (hereinafter also referred to as the production method of the present invention) includes mixing a bicycloalkane compound with a cyclodextrin compound in a mixed solvent of water and an organic solvent. By this mixing, the bicycloalkane compound is included by the cyclodextrin compound, and the resulting inclusion complex precipitates in the mixed solvent. In other words, an inclusion complex insoluble in the mixed solvent is obtained.

[0012] [Bicycloalkane compounds] The bicycloalkane compound used in the manufacturing method of the present invention is not particularly limited as long as it is an alkane compound having a bicyclo structure. For example, bicyclo[1.1.1]pentane (BCP) compound, bicyclo[2.2.1]heptane (norbornane) compound, bicyclo[4.4.0]decane (decalin) compound, bicyclo[3.3.1]heptane (norpinane) compound, etc. can be mentioned. Among them, BCP compound is preferable from the viewpoint of making the inclusion more efficient. The BCP compound is a compound represented by the following general formula (1).

[0013] [ka]

[0014] In general formula (1), R 1 and R 2 R each independently represents a hydrogen atom or a substituent. 1 and R 2 When both are substituents, R 1 and R 2 may be the same or different from each other. R 1 and R 2 There are no particular limitations on the substituents that can be used as R 1 and R 2 For example, a group having a chemical formula weight of 400 or less is preferred, a group having a chemical formula weight of 300 or less is more preferred, a group having a chemical formula weight of 200 or less is even more preferred, and a group having a chemical formula weight of 150 or less is even more preferred. R 1 and R 2Preferred examples of the substituent that can be taken as the substituent include a halogen atom (e.g., a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom), an alkyl group (preferably an alkyl group having 1 to 10 carbon atoms, more preferably an alkyl group having 1 to 6 carbon atoms, and even more preferably an alkyl group having 1 to 3 carbon atoms, and even more preferably a methyl or trifluoromethyl), an alkoxy group (preferably an alkoxy group having 1 to 10 carbon atoms, more preferably an alkoxy group having 1 to 6 carbon atoms, and even more preferably a methoxy group), an aryl group (preferably a phenyl), an acyl group (including an alkylcarbonyl group, an arylcarbonyl group, a formyl group, and a halogenocarbonyl group. The alkylcarbonyl group preferably has 2 to 10 carbon atoms, more preferably has 2 to 6 carbon atoms, and even more preferably has 2 or 3 carbon atoms. The arylcarbonyl group is preferably a phenylcarbonyl group.), a cyano group, a nitro group, an amino group, and a carboxy group. Among them, from the viewpoint of making the inclusion more efficient, a halogen atom, a cyano group, a phenyl group, or an acetyl group is preferable, and a halogen atom or an acetyl group is more preferable. The halogen atom is preferably a chlorine atom, a bromine atom or an iodine atom, and more preferably an iodine atom. R 1 and R 2 It is also preferable that one or both of

[0015] BCP compounds can be derived, for example, from [1.1.1]propellane, which can be obtained, for example, by reacting 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane with an organometallic reagent. As the organometallic compound, a wide variety of alkyllithiums, aryllithiums, etc. can be used. The reaction of 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane with an organometallic reagent to obtain [1.1.1]propellane is already known, and reference can be made, for example, to Chem. Commun., 2021, Vol. 57, pp. 2871-2874. In addition, BCP compounds derived from [1.1.1]propellane can also be obtained by a conventional method using [1.1.1]propellane as a starting material. For example, 1,3-diacetyl BCP can be obtained by subjecting [1.1.1]propellane and a 2,3-butanedione compound to a photoreaction. In addition, 1,3-halogeno BCP can be obtained by reacting BCP with a halogen atom. These synthesis reactions themselves are known, and can be appropriately referred to, for example, Chem.Commun., 2021, Vol. 57, p. 2871-2874, JP2020-533330A, JP2019-510012A, and the like.

[0016] [Cyclodextrin compounds] Cyclodextrin (CD) compounds used in the production method of the present invention include α-CD compounds, β-CD compounds, and γ-CD compounds (i.e., α-CD, β-CD, γ-CD, and compounds derived from these CDs), and one or more of these can be used. Among these, α-CD compounds are preferred from the viewpoint of pore size. α-CD compounds include α-CD, mono-2-O-(p-toluenesulfonyl)-α-CD, mono-6-O-(p-toluenesulfonyl)-α-CD, 3A-amino-3A-deoxy-(2AS,3AS)-α-CD, and the like, and one or more of these can be used.

[0017] [Mixed solvent] In the production method of the present invention, a bicycloalkane compound and a CD compound are mixed in a mixed solvent of water and an organic solvent to form a bicycloalkane compound inclusion complex. The organic solvent is preferably one that can dissolve the bicycloalkane compound. That is, it is preferable that the CD compound can be dissolved without precipitating by the action of at least the water in the mixed solvent, and that the bicycloalkane compound can be dissolved by the action of at least the organic solvent. The organic solvent may be compatible or incompatible with water. That is, the water and the organic solvent may be miscible or phase-separated. It is preferable that the water and the organic solvent are miscible.

[0018] Examples of the organic solvent include ester solvents, ether solvents, ketone solvents, nitrile solvents, alcohol solvents, amide solvents and hydrocarbon solvents, and one or more of these can be used. The organic solvent is preferably at least one of an ester solvent and an ether solvent. The ester solvent is preferably a fatty acid ester compound. The ether solvent is preferably a cyclic ether compound. Among them, at least one of a tetrahydrofuran compound and a fatty acid alkyl ester compound is preferable. The number of carbon atoms of the fatty acid and the number of carbon atoms of the alkyl group of the fatty acid alkyl ester are both preferably 1 to 10, more preferably 1 to 6, and further preferably 1 to 3. Specific examples of the ester solvent include methyl acetate, ethyl acetate, propyl acetate, phenyl acetate, methyl propionate, ethyl propionate, propyl propionate, phenyl propionate, methyl 3-methoxypropionate, methyl 3-ethoxypropionate, and methyl lactate. Specific examples of the ether solvent include diethyl ether, ethylene glycol dimethyl ether, dibutyl ether, tetrahydrofuran, methylcyclopentyl ether, and dioxane. Specific examples of the ketone solvent include acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclopentanone, and cyclohexanone. Specific examples of the nitrile solvent include acetonitrile, propionitrile, and benzonitrile. Specific examples of the alcohol solvent include methanol, ethanol, propanol, butanol, and the like. Specific examples of the amide solvent include N-methylpyrrolidone, 2-pyrrolidone, dimethylformamide, dimethylimidazolidinone, and dimethylacetamide. Specific examples of the hydrocarbon solvent include butane, pentane, hexane, heptane, cyclopentane, cyclohexane, methylcyclopentane, methylcyclohexane, benzene, toluene, and xylene.

[0019] In order to obtain an inclusion complex of higher purity, the content of the organic solvent in the mixed solvent is preferably 80% by volume or less. The content of the organic solvent in the mixed solvent is preferably 1 to 80% by volume, more preferably 2 to 80% by volume, even more preferably 4 to 75% by volume, even more preferably 8 to 70% by volume, even more preferably 15 to 65% by volume, even more preferably 16 to 60% by volume, even more preferably 18 to 55% by volume, and even more preferably 20 to 50% by volume.

[0020] [Preparation of inclusion complexes of bicycloalkane compounds] In the production method of the present invention, the mixing of the bicycloalkane compound and the CD compound in the mixed solvent is preferably carried out while the mixed solvent is in a liquid state. For example, it is preferably carried out at -5 to 60°C, more preferably at 0 to 50°C, more preferably at 5 to 50°C, and even more preferably at 10 to 45°C. The mixing time is not particularly limited as long as the desired amount of the target inclusion compound is obtained. For example, the total amount of the bicycloalkane compound and the CD compound can be mixed for 5 to 500 minutes, and it is also preferable to mix for 10 to 300 minutes. The mixing time may be 5 to 60 minutes, 5 to 30 minutes, 5 to 20 minutes, or 5 to 15 minutes. Even with such a short mixing time, the target inclusion compound can be obtained in a sufficiently high yield.

[0021] In a preferred embodiment of the mixing of the bicycloalkane compound and the CD compound in the mixed solvent, a CD compound solution in which the CD compound is dissolved and a bicycloalkane compound solution in which the bicycloalkane compound is dissolved are prepared in advance, and the CD compound solution and the bicycloalkane compound solution are mixed. More preferably, a CD compound aqueous solution in which the CD compound is dissolved in water and a bicycloalkane compound solution in which the bicycloalkane compound is dissolved in an organic solvent are prepared in advance, and the CD compound aqueous solution and the bicycloalkane compound solution are mixed. This makes it possible to obtain the desired inclusion complex more efficiently.

[0022] In this way, by simply mixing a bicycloalkane compound and a CD compound in the above-mentioned mixed solvent, the inclusion complex of the bicycloalkane compound can be produced with high efficiency. The produced bicycloalkane compound inclusion complex does not dissolve in the above-mentioned mixed solvent, but precipitates. The precipitated inclusion complex can be recovered, for example, by filtration. The recovered inclusion complex can be washed with water, an organic solvent, etc., if necessary, and subjected to drying treatment if necessary to isolate the bicycloalkane compound inclusion complex.

[0023] It is also preferable that the mixing of the bicycloalkane compound and the CD compound in the above mixed solvent is carried out under conditions where light with a wavelength of 400 nm or less is blocked. For example, when the bicycloalkane compound is an iodine compound (e.g., 1,3-diiodo BCP), the yield of the inclusion compound obtained can be further increased by performing the mixing under conditions where light with a wavelength of 400 nm or less is blocked.

[0024] The present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples. EXAMPLES

[0025] [Example 1] An inclusion complex comprising 1,3-diiodoBCP and α-CD was prepared as follows. Water (30.1 mL) and α-CD (3.04 g, 2.0 eq) were placed in a 100 mL three-neck flask, and the mixture was stirred at room temperature to dissolve α-CD in water to obtain an α-CD aqueous solution. In addition, 1,3-diiodoBCP (0.5 g, 1.0 eq) was dissolved in tetrahydrofuran (THF) (4.9 mL) to obtain a 1,3-diiodoBCP solution. The 1,3-diiodoBCP solution was added dropwise to the α-CD aqueous solution while blocking light of 400 nm or less and keeping the temperature at 25°C. The mixture was then stirred for 1 hour. The ratio of water to the mixed solvent was 86 vol. %, and the ratio of THF to the mixed solvent was 14 vol. %. After this stirring, a precipitate was observed in the mixed solvent. The mixed solvent containing the precipitate was filtered, and the precipitate was washed with water (10 mL) and then with THF (5 mL). The washed precipitate was dried to obtain an inclusion complex in which 1,3-diiodo BCP was encapsulated with α-CD (an inclusion complex of 1,3-diiodo BCP).

[0026] The fact that the precipitate contained inclusion complexes of 1,3-diiodoBCP was confirmed by the following data. 1 H-NMR (400 MHz, solvent: DMSO-d6, internal standard: tetramethylsilane (TMS)) chemical shifts σ (ppm) = 2.71 (s, 6H), 3.25-3.80 (m, 72H), 4.49-4.51 (m, 12H), 4.79-4.80 (m, 12H), 5.45-5.46 (m, 12H), 5.52-5.54 (m, 12H).

[0027] The mass of the obtained precipitate was measured, and the crude yield was calculated according to the following formula. Crude yield (mol%) = 100 × (crude yield / theoretical yield of inclusion complex)

[0028] The purity of the inclusion complex of 1,3-diiodo BCP in the precipitate was determined by the absolute calibration curve method (external standard method) using the peak area value calculated from high performance liquid chromatography (HPLC) under the following conditions. This purity is called LC purity. Measuring equipment: Shimadzu LC-2040C 3D Plus Column: Tosoh TSKgel ODS-100Z, 5 μm, 150 × 4.6 mm, Column temperature: 40℃ Detection wavelength: 254 nm Flow rate: 1.0mL / min Injection volume: 10μL Inclusion retention time: 6.95 min Solvent composition: Solution A was water, Solution B was acetonitrile, and acetic acid was added to both Solutions A and B to a concentration of 0.1% by volume. Gradient conditions (B solution concentration): B solution concentration 20% to 100% from 0 to 5.0 min, B solution concentration 100% from 5.0 to 8.0 min

[0029] The product of the crude yield (mol %) and the LC purity (%) (i.e., crude yield (mol %)×LC purity (%) / 100) was defined as the actual yield (%) and was evaluated according to the following criteria. <Recovery rate evaluation criteria> A: 60% or more B: 50% or more but less than 60% C: 40% or more but less than 50% D: 30% or more but less than 40% E: 20% or more but less than 30% F: Less than 20%

[0030] [Example 2] An inclusion complex of 1,3-diiodoBCP was obtained in the same manner as in Example 1, except that ethyl acetate (EtOAc) was used instead of THF as the organic solvent.

[0031] [Example 3] An inclusion complex of 1,3-diiodoBCP was obtained in the same manner as in Example 2, except that the temperature for dropwise addition and stirring was 0°C.

[0032] [Example 4] An inclusion complex of 1,3-diiodoBCP was obtained in the same manner as in Example 2, except that the temperature for dropwise addition and stirring was 40°C.

[0033] [Example 5] An inclusion complex of 1,3-diiodoBCP was obtained in the same manner as in Example 1, except that light of 400 nm or less was not blocked.

[0034] [Example 6] An inclusion complex of 1,3-diiodoBCP was obtained in the same manner as in Example 2, except that light of 400 nm or less was not blocked.

[0035] [Comparative Example 1] The procedure of Example 1 was repeated to obtain an inclusion complex of 1,3-diiodoBCP, except that the amount of water in the α-CD aqueous solution was 35 mL, and instead of adding the 1,3-diiodoBCP solution dropwise to the α-CD aqueous solution, 1,3-diiodoBCP was added directly to the α-CD aqueous solution.

[0036] The results are shown in the table below.

[0037] [Table 1]

[0038] The results in Table 1 show that the recovery rate of the inclusion complex of 1,3-diiodoBCP can be significantly increased by using a mixed solution of water and an organic solvent.

[0039] [Example 7] An inclusion complex of 1,3-diiodoBCP was obtained in the same manner as in Example 1, except that the total amount of the mixed solvent was 120 mL and the proportion of THF in the mixed solvent was 10 volume %.

[0040] [Example 8] An inclusion complex of 1,3-diiodoBCP was obtained in the same manner as in Example 1, except that the total amount of the mixed solvent was 120 mL and the ratio of THF in the mixed solvent was 20 volume %.

[0041] [Example 9] An inclusion complex of 1,3-diiodoBCP was obtained in the same manner as in Example 1, except that the total amount of the mixed solvent was 120 mL and the ratio of THF in the mixed solvent was 30 volume %.

[0042] [Example 10] An inclusion complex of 1,3-diiodoBCP was obtained in the same manner as in Example 1, except that the total amount of the mixed solvent was 120 mL and the proportion of THF in the mixed solvent was 40 volume %.

[0043] [Example 11] An inclusion complex of 1,3-diiodoBCP was obtained in the same manner as in Example 1, except that the total amount of the mixed solvent was 120 mL and the proportion of THF in the mixed solvent was 50 volume %.

[0044] [Example 12] An inclusion complex of 1,3-diiodoBCP was obtained in the same manner as in Example 1, except that the total amount of the mixed solvent was 120 mL and the proportion of THF in the mixed solvent was 60% by volume.

[0045] [Example 13] An inclusion complex of 1,3-diiodoBCP was obtained in the same manner as in Example 1, except that the total amount of the mixed solvent was 120 mL and the proportion of THF in the mixed solvent was 70 volume %.

[0046] [Example 14] An inclusion complex of 1,3-diiodoBCP was obtained in the same manner as in Example 1, except that the total amount of the mixed solvent was 120 mL and the proportion of THF in the mixed solvent was 80 volume %.

[0047] [Comparative Example 2] The procedure of Example 7 was repeated to obtain an inclusion complex of 1,3-diiodoBCP, except that the amount of water in the α-CD aqueous solution was 120 mL, and instead of adding the 1,3-diiodoBCP solution dropwise to the α-CD aqueous solution, 1,3-diiodoBCP was added directly to the α-CD aqueous solution.

[0048] The results are shown in the table below.

[0049] [Table 2]

[0050] The results in Table 2 show that the recovery rate of the inclusion complex of 1,3-diiodoBCP can be increased by using water and an organic solvent, regardless of the mixing ratio of water and an organic solvent.

[0051] [Example 15] An inclusion complex of 1,3-diiodoBCP was obtained in the same manner as in Example 1, except that the total amount of the mixed solvent was 60 mL, the ratio of THF in the mixed solvent was 30 volume %, and the stirring time after dropwise addition was 10 minutes.

[0052] [Example 16] An inclusion complex of 1,3-diiodoBCP was obtained in the same manner as in Example 1, except that the total amount of the mixed solvent was 60 mL, the ratio of THF in the mixed solvent was 30 volume %, and the stirring time after dropwise addition was 180 minutes.

[0053] [Comparative Example 3] The procedure of Example 15 was repeated to obtain an inclusion complex of 1,3-diiodoBCP, except that the amount of water in the α-CD aqueous solution was 60 mL, and instead of adding the 1,3-diiodoBCP solution dropwise to the α-CD aqueous solution, 1,3-diiodoBCP was added directly to the α-CD aqueous solution.

[0054] [Comparative Example 4] The procedure of Example 16 was repeated to obtain an inclusion complex of 1,3-diiodoBCP, except that the amount of water in the α-CD aqueous solution was 60 mL, and instead of adding the 1,3-diiodoBCP solution dropwise to the α-CD aqueous solution, 1,3-diiodoBCP was added directly to the α-CD aqueous solution.

[0055] The results are shown in the table below.

[0056] [Table 3]

[0057] The results in Table 3 show that the use of water and an organic solvent can increase the yield of the inclusion complex of high purity 1,3-diiodoBCP in a short period of time and at a sufficiently high yield.

[0058] Although the present invention has been described in conjunction with embodiments thereof, we do not intend to limit our invention to any of the details of the description unless specifically stated otherwise, and believe that the appended claims should be construed broadly without departing from the spirit and scope of the invention as set forth in the appended claims.

[0059] This application claims priority based on Patent Application No. 2021-148841, filed in Japan on September 13, 2021, the contents of which are incorporated herein by reference as part of the present specification.

Claims

1. The method includes mixing a bicycloalkane compound, which is a bicyclo[1.1.1]pentane compound represented by the following general formula (1), with a cyclodextrin compound in a mixed solvent of water and an organic solvent, A method for producing an inclusion complex of a bicycloalkane compound, wherein, in the mixed solvent during the mixing, the cyclodextrin compound is in a dissolved state due to the action of at least the water, and the bicycloalkane compound is in a dissolved state due to the action of at least the organic solvent. 【Chemistry 1】 In the formula, R １ and R ２ each independently represents a hydrogen atom or a substituent.

2. The R １ and R ２ The method according to claim 1 , wherein each independently represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an aryl group, an acyl group, a cyano group, a nitro group, an amino group, or a carboxy group.

3. The method according to claim 1 or 2, wherein the cyclodextrin compound is an α-cyclodextrin compound.

4. The method according to claim 1 or 2, wherein the organic solvent is one or more of an ester solvent, an ether solvent, a ketone solvent, a nitrile solvent, an alcohol solvent, an amide solvent, and a hydrocarbon solvent.

5. The method according to claim 1 or 2, wherein the content of the organic solvent in the mixed solvent is 80% by volume or less.

6. The method according to claim 1 or 2, wherein the bicycloalkane compound and the cyclodextrin compound are mixed in a state where light having a wavelength of 400 nm or less is blocked.

7. 3. The method according to claim 1, wherein the mixing of the bicycloalkane compound and the cyclodextrin compound in the mixed solvent of water and the organic solvent is carried out by mixing a solution in which the bicycloalkane compound is dissolved with a solution in which the cyclodextrin compound is dissolved.

8. The method according to claim 7, wherein the solution in which the cyclodextrin compound is dissolved is an aqueous solution in which the cyclodextrin compound is dissolved in water.

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