JPH0135A - Inclusion compounds of cholic acid or its ester derivatives - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Retired Emperor Hado Branch 1
The present invention relates to four novel clathrate compounds that use cholic acid or its lower alkyl dimethyl derivative as a host compound, and these clathrate compounds can be used, for example, in the purification and separation of various organic compounds as Gesl-compounds, Furthermore, it is usefully used for the optical resolution of optically active T-lactones.

Purification and separation of organic compounds is often carried out by precision distillation or chroma-togelafy, but these methods are generally cumbersome and expensive. Moreover, even when precision distillation is used, for example, it is not easy to separate organic compounds with close boiling points from each other, and in the case of alcohol, for example, it azeotropes with organic compounds having polar groups, so alcohol It is usually difficult to purify and distribute to high purity.

Further, for example, many aldehydes, amines, nitriles, nitro compounds, etc. are easily altered by heat, so it may be difficult to apply the aforementioned distillation as a means for purifying and separating them. Additionally, carb/acids generally have high boiling points and therefore require a large amount of energy for precision distillation.

Furthermore, in particular, the synthesis of optically active lactones has conventionally been carried out using a ring-closing reaction of heptagonically active oxyacids and the like. However, in this method, the racemic form of lacto/ is ring-opened, an artificial chile or salt is formed with an optically active resolving reagent to form a diastereomer, and the difference in solubility of e is utilized to perform fractional crystallization. After fractionation, an optically active oxyacid is obtained by neutralization or hydrolysis, and an optically active lactone is obtained by ring-closing this, so there is a problem that some racemic forms occur during the ring-closing reaction of the optically active oxyacid. There is.

5. As a result of intensive research to solve the above-mentioned problems in purification separation and optical resolution of organic compounds, the present inventors found that cholic acid and its derivatives selectively target specific organic compounds. It forms a new clathrate compound, which is difficult to dissolve in organic solvents such as acetone and diethyl ether, or non-polar organic solvents such as hydrocarbons. The present invention was achieved by discovering that by including the compound in cholic acid or its derivatives, the target organic compound can be easily and efficiently purified and separated to a high degree of purity.

Furthermore, as a result of intensive research to solve the above-mentioned problems in the synthesis of optically active lactones, the present inventors discovered that cholic acid selectively clathrates one enantiomer of optically active T-lactone, The present invention was achieved by discovering that optically active T-lactone can be easily and efficiently optically resolved by utilizing this selective inclusion reaction.

That is, an object of the present invention is to provide a novel clathrate compound containing cholic acid or its ester derivative as a post compound, which is useful for the purification and separation of various organic compounds.

A further object of the present invention is to provide a novel clathrate of optically active T-lactone with cholic acid.

A clathrate compound having cholic acid or an ester derivative thereof as a host compound according to the present invention has a general formula (wherein R is an alkyl group having 1 to 8 carbon atoms or a cycloalkyl group). (b) alcohol represented by the general formula % (in the formula, R1 and R2 each independently represent a group having 1 or 3 carbon atoms);
~8 alkyl group, cycloalkyl group, or aryl group. ), a chain ether represented by (C1 general formula (in the formula, R1 and R2 represent an ethylene group, and X represents an oxygen atom or a carbon-carbon bond)), (dl general formula % formula % (wherein, R represents an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group, or an atomyl group), (e) General formula % formula % (wherein, R is hydrogen or an alkyl group, a cycloalkyl group, or an aryl group having 1 to 8 carbon atoms.) (f) General formula (wherein, R represents an alkyl group having 2 to 8 carbon atoms). A lactone represented by (gl general formula % formula % (wherein R1 represents hydrogen, an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group, or an aryl group, and R2 represents an alkyl group having 2 to 8 carbon atoms or a cyclo an alkyl group or an aryl group), (h) a carbonyl compound represented by the general formula (wherein R1 and R2 are each independently hydrogen, an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group, or a cycloalkyl group having 6 to 8 carbon atoms); 8 aryl group, and R3 represents an alkyl group or cycloalkyl group having 1 to 8 carbon atoms, or an aryl group having 6 to 8 carbon atoms.However, R2 and R3 are jointly an alkylene group having 4 or 5 carbon atoms. or may form an aromatic heterocycle with nitrogen. -8 aryl group), a nitrile compound represented by the general formula ('') (wherein R is an alkyl group or cycloalkyl group having 1 to 8 carbon atoms, or an aryl group having 6 to 8 carbon atoms) nitro compound (kl) represented by the general formula (wherein R is an alkyl group or cycloalkyl group having 1 to 8 carbon atoms, which may be substituted with a halogen atom, or an aryl group having 6 to 8 carbon atoms) It is characterized in that an organic compound selected from the group consisting of organic halides represented by the following formula is included in cholic acid or its lower alkyl ester derivative.

Furthermore, the novel optically active γ-lactone clathrate compound according to the present invention is characterized in that the γ-optically active lactone represented by the structural formula is included in cholic acid.

The host compound in the clathrate compound according to the present invention is cholic acid or its lower alkyl ester represented by the following general formula, and such lower alkyl esters include, for example, methyl ester, ethyl ester, propyl ester, etc. Preferably used.

Most preferably methyl esters are used.

Next, preferred specific examples of the organic compound as a guest compound to be included in the cholic acid or lower alkyl ester are listed below.

(a) Alcohol methanol, ethanol, propatool, butanol,
benzyl alcohol etc.

Chain ethers dimethyl ether, dibutyl ether, diphenyl ether, methyl phenyl ether, diphenyl ether, etc.

(C) Cyclic ether dioxane, tetrahydropyran, tetrahydrofuran, etc.

(d) Carboxylic acids formic acid, acetic acid, propionic acid, #acid, valeric acid, caproic acid, benzoic acid, etc.

(e) Carboxylic acid ester Lower alkyl esters of the above-mentioned carboxylic acids are preferred, such as methyl formate, ethyl formate, methyl acetate, ethyl acetate, ethyl propionate, methyl benzoate, and ethyl benzoate.

(f) Lactones δ-valerolactone, γ-valerolactone, butyrolactone, etc.

(a) Carbonyl compounds Aldehydes such as acetaldehyde, propylaldehyde, butyraldehyde, valeroaldehyde, benzaldehyde, and ketones such as methyl ethyl ketone, methyl isopropyl ketone, methyl-t-butyl ketone, acetophenone, and benzophenone.

(h) Amine ethylamine, propylamine, butylamine, hexylamine, octylamine, piperidine, aniline, toluidine, pyridine, etc.

(i) Nitro compounds nitromethane, nitroethane, nitrobenzene, chloramphenicol, etc.

(Month) Nitrile compounds acetonitrile, propionitrile, butyronitrile,
Malonitrile, adiponitrile, benzonitrile, etc.

(k) Organic halides chloroform, carbon tetrachloride, ethyl bromide, butyl bromide,
Octyl bromide etc.

For example, when the guest compound is liquid at room temperature, the clathrate compound according to the present invention can be prepared by adding cholic acid or its lower alkyl ester to the liquid guest compound, heating it, dissolving it, and then allowing it to stand. As a result, the clathrate compound precipitates as a crystal. In addition, even if the guest compound is liquid, if cholic acid or its lower alkyl ester does not dissolve therein, or if the guest compound is solid, the guest compound and cholic acid or its lower alkyl ester are dissolved together. When dissolved in a solvent and then cooled, the clathrate compound precipitates as crystals.

As the above-mentioned solvent, acetone, diethyl ether, or a mixed solvent thereof is usually suitably used. In addition, even if a compound alone is included in cholic acid or its derivatives, it has a stronger affinity with cholic acid or its derivatives than itself and is easily included in cholic acid or its derivatives. There are also compounds that can be used as solvents. Examples of such compounds include, for example:
Examples include sec, -butanol, tert, -butanol, and tetrahydrofuran. Furthermore, in general, ketones form stronger hydrogen bonds than ethers and are more easily included in cholic acid or its derivatives, so ketones are preferentially included than ethers.

Therefore, cholic acid or its lower alkyl ester selectively includes benzophenone in a mixture of benzophenone and dibenzyl ether, for example. Also,
In -a, organic halides are included more preferentially than ethers.

The amount of such a solvent used may be any amount sufficient to dissolve the host and guest compounds. In addition, the host/guest reaction molar ratio is usually in the range of 10/1 to 1/10,
Preferably it is in the range of 1/1 to 1/4.

Cholic acid or its lower alkyl ester usually forms an clathrate compound in which the host molecule/guest molecule molar ratio is 1/1 or 1/2 using the above-mentioned organic compound as a host compound. The molar ratio of host molecules/guest molecules in this clathrate compound is confirmed by thermal analysis and elemental analysis such as thermogravimetry (TG) and differential thermal analysis (DTA).

The clathrate compound according to the present invention can be suitably used for purifying and separating various organic compounds as guest compounds.

Typically, two methods can be used to purify and separate an organic compound as a guest compound using the clathrate compound according to the present invention. That is, the first step is to add cholic acid or its ester derivative to a solution containing an organic compound to be purified and separated, dissolve it, and then remove the solvent as necessary to precipitate the clathrate as a crystal. After separation, the clathrate is decomposed by heating, and the organic compound to be purified and separated is liberated from the clathrate as a gas or liquid, which is then collected and cooled.

Preferred organic compounds to which this first method can be applied are alcohols, ethers, carboxylic acid esters, lactones,
aldehydes, ketones, and halogenated methane.

The second method is to first add cholic acid or its ester derivative to a solution containing the organic compound to be purified and separated;
After dissolving, the solvent is removed if necessary, and the clathrate is precipitated as crystals, which are collected by filtration. Next, this clathrate compound is added to a guest exchange compound that has a stronger affinity for cholic acid or its ester derivative than the organic compound that is a guest compound in this clathrate compound and easily guest-exchanges with the guest compound. The mixture is dissolved, heated if necessary, and the clathrated guest compound is exchanged with the guest exchange compound, thereby liberating the organic compound for purification and separation. After this, further hexane,
Add a hydrocarbon solvent such as pentane to precipitate cholic acid or its ester derivative and methanol clathrate, filter this, and distill the filtrate under reduced pressure as necessary to obtain the desired organic compound. This is the way to obtain. Methanol is usually preferably used as the guest exchange compound.

Preferred organic compounds to which this second method can be applied are carboxylic acids, amines, nitrile compounds and nitro compounds, and generally this method is suitable for organic compounds with high boiling points,
Suitable for organic compounds that are easily decomposed by heat.

Next, the inclusion compound of optically active γ-lactone with cholic acid according to the present invention is represented by the above-mentioned structural formula, and therefore, according to the present invention, (S)-T-valerolactone, (S
)-r-hexalaph 1-one and (R)-γ-heptalactone are included in cholic acid. The cholic acid used here is a compound having the above-mentioned structural formula. This cholic acid selectively uses one enantiomer of the optically active γ-lactone as a host molecule to form an clathrate compound in which the molar ratio of host molecule/guest molecule is usually 1/1.

To obtain the above-mentioned clathrate compound according to the present invention, typically,
This can be done in two ways. According to the first method,
Add cholic acid to T-lactone or a solution containing it, heat as necessary to dissolve the cholic acid, then cool as necessary or remove the solvent to form the clathrate compound as a crystal. Precipitate and separate it.

According to the second method, cholic acid is added to T-lactone or a solution containing it, allowed to stand, and dissolved, and then the clathrate compound formed as crystals is separated.

In the first method, as a solvent that can be used to dissolve cholic acid or γ-lactone for optical resolution, for example, acetone, diethyl ether, or a mixed solvent thereof is preferably used. Furthermore, in the second method, a hydrocarbon solvent such as hexane is preferably used as a solvent that can be used to dissolve the γ-lactone. In both of these first and second methods, cholic acid is used in an amount of 0.5 times the molar amount or less of T-lactone.

By using such an inclusion compound of optically active γ-lactone, optically active γ-lactone can be easily optically resolved.

One method to obtain the desired optically active γ-lactone from the clathrate compound of cholic acid that includes the optically active γ-lactone is to thermally decompose the clathrate to form the optically active γ-lactone.
A method can be used in which the lactone is liberated as a gas or liquid, and then collected and cooled.

Another method is to add a compound that easily guest-exchanges with optically active γ-lactone to a solution of the obtained clathrate compound, and by causing guest exchange, the target optically active γ-lactone can be obtained.
You can get lactones. That is, a compound or a solution thereof that easily guest-exchanges an clathrate compound having an optically active γ-lactone as a guest compound with the above guest compound by having a stronger affinity for cholic acid than T-lactone in the clathrate compound. is added to the clathrate solution,
Dissolve and heat if necessary to remove the clathrated γ-
By guest-exchanging the lactone, the desired optically active γ-
The lactone is liberated, and then a hydrocarbon solvent such as hexane or pentane is added to precipitate the clathrate after guest exchange, which is filtered off and the filtrate is reduced under reduced pressure if necessary. The desired optically active γ-lactone is obtained by distillation. This guest exchange reaction is usually carried out at room temperature, but may be carried out with heating if necessary.

In this second method, examples of the compound for guest-exchanging with the optically active T-lactone include acetonitrile, diethyl ether, methanol, acetone, and mixtures thereof, and acetonitrile is particularly preferably used. It will be done. These compounds are used as such or as an aqueous solution.

As described above, by repeating the production of an inclusion compound of an optically active γ-lactone with cholic acid, its separation and decomposition, or the optical resolution of the optically active γ-lactone by guest exchange, the optical properties of the optically active γ-lactone obtained are Activity purity can be increased. For example, taking T-valerolactone as an example, by repeating the above operation three times, the optical purity can be increased to about 60% ee, and by repeating the above operation four times, the optical purity is almost 100% ee. γ-lactone can be obtained.

The clathrate compound according to the present invention is useful, for example, in the purification and separation of organic compounds as guest compounds.

That is, according to purification separation using such a clathrate, cholic acid or its ester derivative forms a clathrate of an organic compound for the purpose of purification and separation, and after separating this, the target clathrate is extracted from the clathrate Since the target organic compound is liberated and purified and separated, it is possible to efficiently purify and separate the target organic compound with high purity without requiring complicated operations such as precision distillation or column chromatography. can.

Furthermore, by using the optically active γ-lactone clathrate compound according to the present invention, optically active γ-lactone having high optical purity can be easily and efficiently obtained without any complicated or troublesome operations. Can be done.

EXAMPLES The present invention will be explained below with reference to Examples, but the present invention is not limited to these Examples in any way. In addition, several examples of purification and separation of organic compounds using the clathrate compound according to the present invention will be listed as reference examples.

Example 1 100 μm of cholic acid was added to 1 ml of methanol, heated to dissolve, and then left in the apparatus overnight. Filter the precipitated crystals,
It was air-dried to obtain 75 ml of a clathrate compound of cholic acid and methanol. The yield relative to the host compound (hereinafter the same) is 6
It was 5%.

The elemental analysis values of this clathrate compound are shown in Table 1, as well as the weight loss curve by thermogravimetry (TG) and differential thermal analysis (DTA).
) is shown in FIG. 1, and the infrared absorption spectrum is shown in FIG. 2. In the DTA-TG diagram, the peak at 133° C. indicates the decomposition temperature of the clathrate compound, and the peak on the higher temperature side indicates the decomposition temperature of cholic acid.

Therefore, it is shown that the molar ratio of host molecule/guest molecule in this clathrate compound of methanol and cholic acid is 1/2, and its decomposition temperature is 172°C.

Example 2 With respect to various guest compounds shown in Tables 1 and 2, except for benzophenone, clathrate compounds were obtained using cholic acid or its methyl ester as a host compound.

The elemental analysis values of these clathrate compounds are shown in Tables 1 and 2, respectively. Also shown is its infrared absorption spectrum.

Figure numbers are listed in the table.

Example 3 500 μl of benzophenone was dissolved in 10 ml of acetone, 100 mg of cholic acid was added thereto, and the mixture was heated and dissolved. After standing for one day, the clathrate compound precipitated as crystals. This was collected by filtration and dried to obtain a clathrate compound of cholic acid and benzophenone.

The elemental analysis values are shown in Table 1, and the infrared absorption spectrum is shown in FIG.

Reference Example 1 15 g of methyl cholate was added to 100 ml of an equal weight mixed solution of methanol and acetone and dissolved. Thereafter, this was concentrated to precipitate an inclusion compound of methanol and methyl cholate as crystals. The crystals were filtered off and dried.

The above clathrate compound was heated to 117° C. to vaporize methanol, which was then introduced into a cooling tube to obtain 1.0 g of 100% pure methanol. The recovery rate was 90%.

Reference Example 2 Add 1.51 g of acetone to a 64% acetic acid aqueous solution Log containing 6.4 g of acetic acid (boiling point 116-117°C), further dissolve 81.6 g of cholic acid, and leave it at room temperature overnight to form an clathrate. 40.5 g of the compound was precipitated as white crystals.

After filtering these crystals, add them to 600ml of methanol,
After heating to dissolve, the mixture was cooled to room temperature.

Thereafter, 600 ml of hexane was added to this to obtain a white precipitate. This was collected by filtration, and the filtrate was distilled under reduced pressure to remove the solvent to obtain 5.5 g of clear, colorless acetic acid with a purity of 100%. The recovery rate was 86%.

Reference example 3 Benzaldehyde (boiling point 178-185°C) 10.6g
and 1,2-dichlorobenzene (boiling point 179-180°C)
1.51 g of acetone was added to a mixed solution of 14.7 g, and 81.6 g of cholic acid was added thereto, dissolved, and allowed to stand at room temperature overnight, resulting in the precipitation of 42.7 g of the clathrate compound as white crystals.

After filtering these crystals, add them to 600ml of methanol,
After heating to dissolve, the mixture was cooled to room temperature.

Thereafter, 600 ml of hexane was added to this to obtain a white precipitate. This was collected by filtration, and the filtrate was distilled under reduced pressure to remove the solvent, yielding 8.8 g of colorless and transparent benzaldehyde with a purity of 100%, with a zero recovery rate of 83%.

Reference Example 4 750ml of acetone was added to a mixed solution of 6.1g of nitromethane (boiling point 110°C) and 13.7g of 1-bromobutane (boiling point 101°C), and 84.4ml of methyl cholate was added to this.
When the mixture was dissolved and left overnight at room temperature, 39.1 g of the clathrate compound was precipitated as white crystals. This was collected by filtration and dried.

The above clathrate compound was added to 600 ml of methanol, heated to dissolve it, and then cooled to room temperature. After that, 600+++1 hexane was added to this, and a white precipitate was obtained. This was collected by filtration, and the filtrate was distilled under reduced pressure to remove the solvent, resulting in colorless and transparent 100% pure nitromethane4.
9g was obtained. The recovery rate was 81%.

Example 4 2 ml of T-valerolactone was dissolved in 10 ml of hexane, and to this solution was added 4.0 ml of cholic acid recrystallized from methanol.
3g was dissolved and incubated overnight. The generated crystals were filtered, washed with a small amount of ether, and then air-dried to obtain 5.3 g of the clathrate compound.

Next, this clathrate compound was dissolved in acetonitrile 20+ at room temperature.
*I was immersed in I for 10 minutes to allow guest exchange.

By filtering off the crystals and concentrating the resulting solution,
0.9 ml of (S)-7-valerolactone was obtained.

Its optical rotation (ff) is -11.3° (neat,
d = 1°057), and the optical purity was 38%ee compared to the literature value.

By repeating the above operation three more times, a clathrate compound was obtained in the same manner. The infrared absorption spectrum of this clathrate compound is shown in Figure 35, and its thermogravimetric measurement (TG
) and the differential thermal analysis (DTA) are shown in Figure 36.

Elemental analysis value (as CzJ4sOt) CI Theoretical value 68.47 9.51 Actual value 68.54 9.43 Optical rotation [α]. "+23.0" (c=1, ethanol) This clathrate compound was treated in the same manner as above to obtain optically active (S)-γ-valerolactone with an optical purity of 100% ee.

Optical rotation [α), -30.1° (neat) Example 5 2 ml of T-hexalactone was dissolved in 10 ml of hexane, and in this solution was added 3.0 ml of cholic acid recrystallized from methanol.
7 g was dissolved and left overnight. The generated crystals were filtered, washed with a small amount of ether, and then air-dried to obtain 4.7 g of the clathrate compound.

Next, this clathrate compound was dissolved in 20 ml of acetonitrile at room temperature.
1 for 1 day, and guests were exchanged.

By filtering off the crystals and concentrating the resulting solution,
0.9 ml of (S)-r-hexalactone was obtained.

Its optical rotation [α] D20 is -18.3° (neat)
Compared with the literature value, the optical purity is 34.4% e
It was e.

By repeating the above operation three more times, a clathrate compound was obtained in the same manner. The infrared absorption spectrum of this clathrate compound is shown in Figure 37, and its thermogravimetry (TG)
Figure 38 shows the weight loss curve and differential thermal analysis (DTA).

Elemental analysis value (CS. H2゜0.) H Theoretical value 68.93 9.64 Actual value 69.02 9.55 Optical rotation CcX〕o” + 16.5° (c=1, ethanol) This inclusion The compound was treated in the same manner as above to obtain optically active (S)-r-hexalactone with optical purity of 100% ee.

Optical rotation [α)o” 53.2° (neat) Example 6 2IIIll of T-heptalactone was dissolved in 10ml of hexane, 3.4g of cholic acid recrystallized from methanol was dissolved in this solution, and the mixture was heated overnight. The resulting crystals were separated by filtration, washed with ether, and air-dried to obtain 4.4 g of the clathrate compound.

Next, this clathrate compound was dissolved in 20 ml of acetonitrile at room temperature.
1 for 1 day, and guests were exchanged.

By filtering off the crystals and concentrating the resulting solution,
0.9 ml of (R)-r-heptalactone was obtained.

Its optical rotation [α] l1to is +1.4° (neat)
Compared with the literature value, the optical purity is 3.8%ee.
Met.

By repeating the above operation 13 more times, a clathrate compound was obtained in the same manner. The infrared absorption spectrum of this clathrate compound is shown in Figure 39, and its thermogravimetric measurement (TG
) and the differential thermal analysis (DTA) are shown in Figure 40.

Elemental analysis value (Cz + Hsz (as lr) I Theoretical value 69.37 9.77 Actual value 69.45 9.62 Optical rotation [α) o” + 36.2° (c = 1, ethanol) This clathrate compound is In the same manner as above, optically active (R)-γ-heptalactone with optical purity of 100%ee was obtained.

Optical rotation [α) o” + 36.8° (neat) Example 7 3 g of cholic acid was added to 25 ml of γ-valerolactone, and 1
After heating to 70 to 180°C to dissolve cholic acid,
It was cooled to precipitate crystals. The crystals were filtered, washed with ether, and air-dried to obtain 4 g of the clathrate compound.

This clathrate was the same as that obtained in Example 1.

This clathrate is heated under reduced pressure to liberate γ-valerolactone, which is collected and cooled to give an optical rotation of [α]o”
0.9 ml of (S)-r-valerolactone of 9.3° (neat) was obtained. Compared to the literature value, the optical purity is 2.
It was 7.5%ee. By repeating the above operation three more times, optically active (S)-
γ-valerolactone was obtained.

[Brief explanation of the drawing]

FIG. 1 shows a thermogravimetric (TO) weight loss curve and a differential thermal analysis (DTA) diagram of an clathrate compound of cholic acid and methanol, and FIG. 2 shows an infrared absorption spectrum. 3 to 34 show infrared absorption spectra of clathrate compounds containing various organic compounds shown in Tables 1 and 2 as guest compounds. Figure 35 shows the infrared absorption spectrum of the clathrate of (S)-γ-valerolactone with cholic acid, and Figure 36 shows the
Its weight loss curve by thermogravimetry (TG) and differential thermal analysis (
DTA), Figure 37 is the infrared absorption spectrum of the clathrate of (S)-r-heptalactone with cholic acid, and Figure 38 is its weight loss curve by thermogravimetry (TG) and differential thermal analysis. Graph showing (DTA), No. 39
The figure shows the infrared absorption spectrum of the clathrate compound of (R)-γ-hexalactone with cholic acid, and Figure 40 shows its weight loss curve by thermogravimetry (TG) and differential thermal analysis (DTA
). Procedural amendment (voluntary) February 16, 1988

Claims (2)

[Claims] (1) (a) Alcohol represented by the general formula R-OH (wherein R represents an alkyl group or cycloalkyl group having 1 to 8 carbon atoms, or an aryl group having 6 to 8 carbon atoms); (b) Represented by the general formula R^1-O-R^2 (wherein R^1 and R^2 each independently represent an alkyl group, a cycloalkyl group, or an aryl group having 1 or 3 to 8 carbon atoms.) Chain ether, (c) General formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 and R^2 represent an ethylene group, and X represents an oxygen atom or a carbon-carbon bond.) cyclic ether represented by (d) a carboxylic acid represented by the general formula R-COOH (wherein R represents an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group, or an aryl group); (e) a carboxylic acid represented by the general formula R ^1-COOR^2 (In the formula, R represents hydrogen, an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group, or an aryl group.) (f) General formula ▲ Numerical formula, chemical formula, There are tables, etc. ▼ (In the formula, R represents an alkylene group having 2 to 8 carbon atoms.) Lactone represented by (g) General formula R^1-CO-R^2 (In the formula, R^1 is hydrogen or an alkyl group, a cycloalkyl group, or an aryl group having 1 to 8 carbon atoms, and R^2 represents an alkyl group, cycloalkyl group, or aryl group having 2 to 8 carbon atoms; h) General formula▲ Numerical formula, chemical formula, table, etc.▼ (In the formula, R^1 and R^2 each independently represent hydrogen, an alkyl group or cycloalkyl group having 1 to 8 carbon atoms, or a It represents an aryl group, and R^3 represents an alkyl group or cycloalkyl group having 1 to 8 carbon atoms, or an aryl group having 6 to 8 carbon atoms.However, R^2 and R^3 are combined to form a group having 4 or 8 carbon atoms. (i) an amine represented by the general formula R-CN (wherein R is an alkyl group having 1 to 8 carbon atoms); or a cycloalkyl group or an aryl group having 6 to 8 carbon atoms.) A nitrile compound represented by the general formula R-NO_2 (wherein R is an alkyl group having 1 to 8 carbon atoms or a cycloalkyl group, or nitro compound (k) represented by the general formula R-X (wherein R is an alkyl group having 1 to 8 carbon atoms which may be substituted with a halogen atom or a cyclo aryl group having 6 to 8 carbon atoms) It represents an alkyl group or an aryl group having 6 to 8 carbon atoms. ) A clathrate compound formed by including an organic compound selected from the group consisting of organic halides represented by the following formula into cholic acid or its lower alkyl ester derivative. (2) A clathrate compound formed by including an optically active lactone represented by the structural formula ▲Mathematical formula, chemical formula, table, etc. available▼ or ▲Mathematical formula, chemical formula, table, etc. available▼ in which an optically active lactone is included in cholic acid.