Cyclopentenone derivatives and a method for producing the same

Abstract

To provide a cyclopentenone derivative that can be useful as an intermediate of a medicament and a fine chemical, and a simple and convenient production method thereof.SOLUTION: A cyclopentenone derivative is a compound represented by a formula (I) or an optically active substance thereof. A production method thereof comprises subjecting a compound represented by a formula (II) to a hydrothermal reaction.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a cyclopentenone derivative that can be useful as an intermediate for fine chemicals and pharmaceuticals, and a method for producing the same.

Background Art

[0002] Cyclopentenone derivatives are considered to be promising synthetic blocks that can serve as raw materials for fine chemicals, pharmaceuticals such as prostaglandins, pentenomycin, and vertimycin. There is a long-felt need for the provision of novel cyclopentenone derivatives and methods for producing the same.

[0003] Cellulose resources, which are plant biomass, are composed of monosaccharides and exist in the largest quantities. These monosaccharides, as fossil resource-free materials attracting attention in connection with global environmental problems, are the subject of active research and development worldwide for chemical and biological conversion into fuels and materials. Furthermore, research and development are also underway to use compounds obtained by the conversion of monosaccharides as raw materials for fine chemicals and pharmaceuticals (Non-Patent Document 1). In the chemical conversion of monosaccharides, furan compounds in which four carbon atoms and one oxygen atom form a five-membered ring can be obtained in high yields. On the other hand, in synthetic chemistry, it is known that furan having a hydroxymethyl group can be converted into a cyclopentenone compound in which five carbon atoms form a five-membered ring. Such cyclopentenone compounds are being studied for application as skeletal compounds (building blocks) for agricultural chemicals, fragrances, pharmaceuticals, etc. (Non-Patent Document 2).

[0004] 5-Hydroxymethylfurfural (the compound of formula (II)) is obtained by the chemical conversion of glucose (grape sugar), which is the most abundant monosaccharide. Although 5-hydroxymethylfurfural is a furan having a hydroxymethyl group, since it also has an aldehyde group bonded thereto, it is not a cyclopentenone compound as it is, and is converted into levulinic acid (a linear compound) or benzene triol (an aromatic six-membered ring compound).

[0005] The production pathway of 5-HMF from monosaccharides (D-glucose) derived from plant biomass is shown below. JPEG0007716888000001.jpg45123

[0006] However, it has been reported that when an aqueous solution of 5-hydroxymethylfurfural is reduced with a metal catalyst and hydrogen, 4-hydroxy-4-hydroxymethyl-2-cyclopentenone is produced as an intermediate (Non-Patent Document 3).

[0007] Patent Document 1 describes a method for producing cyclopentenone from a furan derivative. Patent Document 2 describes a method for producing cyclopentenone from furan using an aqueous solution with adjusted pH.

[0008] Non-Patent Document 4 states that when an aqueous solution of 5-hydroxymethylfurfural is reduced at 140 °C for 12 hours under a hydrogen pressure of 8 MPa using a gold nanoparticle catalyst, 3-hydroxymethyl-cyclopentanone (HCPN) is obtained, and 4-hydroxy-4-hydroxymethyl-2-cyclopentenone is detected (maximum yield 13%) as a reaction intermediate. 5-Hydroxymethylfurfural is a compound in which an aldehyde group and a hydroxymethyl group side chain are bonded to a furan ring, but a cyclopentenone compound cannot be obtained from it. On the other hand, when an aqueous solution of 5-hydroxymethylfurfural is catalytically reduced with hydrogen under temperature conditions of 100 °C or higher, it is reduced to 2,5-bis(hydroxymethyl)furan, and 4-hydroxy-4-hydroxymethyl-2-cyclopentenone is produced by ring opening and ring rearrangement. However, it has been reported that this cyclopentenone is reduced to 3-hydroxymethyl-cyclopentanone because the reduction reaction takes precedence. JPEG0007716888000002.jpg85105

[0009] In Non-Patent Document 5, when Ta2O5 is used as a solid acid catalyst (solid catalyst), the yield of 3-hydroxymethyl-cyclopentanone is improved, but 3-hydroxymethyl-2-cyclopentenone is detected as an intermediate. On the other hand, when a lanthanoid oxide is used as a catalyst, it is described that 3-hydroxymethyl-cyclopentanone is reduced to obtain 3-hydroxymethyl-cyclopentanol in which the ketone group has become a hydroxyl group.

[0010] However, none of the prior art documents disclose or suggest the compound represented by the formula (I) or its optically active form and the method for producing the same according to the present invention.

Prior Art Documents

Patent Documents

[0011]

Patent Document 1

Patent Document 2

Non-Patent Documents

[0012]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Disclosure of the Invention

Problems to be Solved by the Invention

[0013] There is a long-felt need for providing a novel cyclopentenone derivative such as 4-hydroxy-3-hydroxymethyl-2-cyclopenten-1-one represented by formula (I) and developing a simple production method.

Means for Solving the Problems

[0014] In view of the above circumstances, the present inventors have conducted intensive studies. As a result, after subjecting the aldehyde group of readily available 5-hydroxymethylfurfural to a selective reduction reaction to obtain 2,5-bis(hydroxymethyl)furan, and then subjecting the obtained 2,5-bis(hydroxymethyl)furan to a hydrothermal reaction, it has been found that a compound having a novel cyclopentenone skeleton (4-hydroxy-3-hydroxymethyl-2-cyclopentenone) can be provided, and thus the present invention has been completed.

[0015] That is, the present invention solves the above problems by providing the inventions described below. (1) Formula (I): The compound represented by JPEG0007716888000003.jpg5259 or its optically active form. (2) A method for producing the compound represented by formula (I) or its optically active form, which comprises subjecting the compound represented by formula (II) to a hydrothermal reaction. JPEG0007716888000004.jpg54170(3) The production method according to (2) above, wherein the temperature of the hydrothermal reaction is 90°C or higher. (4) The production method according to (2) above, wherein the hydrothermal reaction includes putting the compound represented by formula (II) and into a hydrothermal reaction apparatus and controlling the hydrothermal reaction temperature range to 90 to 200°C and the reaction time to 1 to 50 hours. (5) Furthermore, the production method according to (2) above, which includes a step of converting the compound represented by formula (III) into the compound represented by formula (II) in the presence of a reducing agent. JPEG0007716888000005.jpg27118(6) The production method according to (5) above, wherein the reducing agent includes an organic reducing agent, an inorganic reducing agent, or a combination thereof. (7) The production method according to (6) above, wherein the reducing agent is an inorganic reducing agent. (8) A method for producing a compound represented by formula (I) or an optically active form thereof, characterized by subjecting the compound represented by formula (IV) to an isomerization reaction in the presence of a metal catalyst. JPEG0007716888000006.jpg57133(9) The production method according to (8) above, wherein the metal catalyst is a metal oxide. (10) The production method according to (8) above, wherein the metal catalyst is an alumina catalyst. (11) The production method according to any one of (8) to (10) above, wherein the isomerization reaction includes controlling the reaction temperature range to 20 to 50 °C and the reaction time to 1 to 50 hours.

Advantages of the Invention

[0016] According to the present invention, a novel cyclopentenone derivative that can be useful as an intermediate for fine chemicals and pharmaceuticals can be provided.

[0017] According to the present invention, by selectively reducing only the aldehyde group of 5-hydroxymethylfurfural, 4-hydroxy-4-hydroxymethyl-2-cyclopentenone and 4-hydroxy-3-hydroxymethyl-2-cyclopentenone can be obtained in good yields. This reduction operation can be carried out at room temperature by adding sodium borohydride (powder), which is a reducing agent, to 5-hydroxymethylfurfural in an organic solvent. The subsequent steps only require solvent extraction and solvent removal. A catalyst (metal catalyst) for the reduction operation is not necessary, and in particular, there is no need to prepare and regenerate metal nanoparticles that are particularly time-consuming. The hydrothermal operation only requires the steps of filtration (removing polymers), extraction, and solvent removal, and there is no need for neutralization and desalting operations. Both the reduction operation and the hydrothermal operation are easy to scale up and can be realized as an industrial manufacturing method.

[0018] According to the present invention, it is possible to avoid a long reaction time for suppressing the decomposition and polymerization of cyclopentenone derivatives in the hydrothermal reaction. For the cyclopentenone derivatives obtained by the hydrothermal reaction, it is possible to improve the yield of 4-hydroxy-3-hydroxymethyl-2-cyclopentenone by isomerization of 4-hydroxy-4-hydroxymethyl-2-cyclopentenone. In addition, the ratio of 4-hydroxy-4-hydroxymethyl-2-cyclopentenone and 4-hydroxy-3-hydroxymethyl-2-cyclopentenone in the cyclopentenone derivatives can be adjusted by isomerization.

Brief Description of the Drawings

[0019]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

[0020] Hereinafter, an embodiment of the present invention will be described. The embodiment is an example of implementing the present invention, and the present invention is not limited to this embodiment.

[0021] In one embodiment of the present invention, a compound of formula (I): The compound represented by JPEG0007716888000007.jpg5155 or an optically active substance thereof can be provided. The compound of formula (I) (4-hydroxy-3-hydroxymethyl-2-cyclopentenone) may be either a racemic or optically active compound. The R- and S-isomers of the optically active compound of formula (I) can be distinguished from each other based on the polarimeter readings.

[0022] In one embodiment of the present invention, there can be provided a method for producing a compound represented by formula (I) or an optically active substance thereof, which comprises subjecting a compound represented by formula (II) to a hydrothermal reaction. JPEG0007716888000008.jpg54170

[0023] The compound represented by formula (II), which is used as a raw material for the hydrothermal reaction, can be produced by a known method (e.g., Tetrahedron 64 (2008)) by subjecting the compound represented by formula (III) to a reduction reaction in the presence of a reducing agent. JPEG0007716888000009.jpg30118

[0024] reduction reaction The compound represented by formula (III) can be converted to the compound represented by formula (II) in the presence of a reducing agent. JPEG0007716888000010.jpg27119As reaction conditions for subjecting the compound represented by formula (III) to reduction to obtain the compound represented by formula (II), any conditions under which the compound represented by formula (II) can be produced may be used. For example, it can be carried out in the above-mentioned inert solvent in the presence of an organic reducing agent, an inorganic reducing agent, or a combination thereof, and preferably in the presence of an inorganic reducing agent such as a metal hydride salt. Examples of the metal hydride salt as a reducing agent include sodium borohydride, zinc borohydride, sodium cyanoborohydride, and the like. The amount of the reducing agent used is, for example, 1.0 to 2.0 equivalents, preferably about 1.0 to 1.2 equivalents, relative to the compound represented by formula (III). The reaction temperature is usually -30°C to 50°C, preferably -25°C to 25°C, more preferably -10°C to 10°C, particularly preferably -10°C to -5°C, and the reaction time is usually 15 minutes to 10 hours, preferably 30 minutes to 5 hours, more preferably 30 minutes to 1.5 hours. In the above reaction, the 3-position aldehyde group of the furan represented by formula (III) is regioselectively reduced to obtain the compound represented by (III).

[0025] Hydrothermal reaction The "hydrothermal reaction" employed in this embodiment refers to a chemical reaction that occurs in subcritical water, which is hot water with a temperature and pressure lower than the critical point of water (374°C, 22 MPa), or in supercritical water with a temperature and pressure exceeding the critical point of water. Further, the "hydrothermal reaction" is carried out, for example, in a hydrothermal reaction apparatus and is usually about 100°C or higher and 250°C or lower. Since the pressure may be the vapor pressure of water as the solvent, the reaction is carried out in a sealed container. Also, the reaction time may be about 20 hours or longer and 150 hours or shorter. Also, the reaction temperature may be increased continuously or sequentially.

[0026] Examples of the water used in the hydrothermal reaction include tap water, pure water such as ion-exchanged water, and ultrapure water. However, in order to improve the yield of the product, it is preferable to use pure water such as ion-exchanged water with few impurities or ultrapure water. In order to prevent the oxidation reaction by oxygen contained in the air, it is more preferable to use ion-exchanged water or ultrapure water in a deaerated state. The pH of the water is preferably in the range of weakly acidic to near neutral, from 4 to 8. Under strongly acidic conditions or alkaline conditions, side reactions may proceed more, and the yield of the target compound of formula (I) may decrease. When using tap water at a high temperature, trace compounds (such as calcium carbonate and silica gel) contained in tap water may generate scale etc. in the reaction apparatus, so inspection of the apparatus is necessary. Also, the amount of water used in the hydrothermal reaction may be any amount as long as the reaction proceeds. From the viewpoints of yield and economic efficiency etc., for each 1 mol of the compound of formula (II), a range of 10 to 100 L (liters), preferably 20 to 50 L can be exemplified, but the amount of the solvent used can be appropriately adjusted by those skilled in the art.

[0027] When subjecting the compound represented by (II) to a hydrothermal reaction, it is preferably carried out in a pressure-resistant container. The reaction temperature when subjecting to the hydrothermal reaction is 100 °C or higher, preferably 100 to 200 °C, and more preferably 100 to 160 °C. Also, the time for subjecting to the hydrothermal reaction is preferably 10 minutes to 24 hours, and more preferably 30 minutes to 18 hours. The atmosphere of the hydrothermal reaction is preferably air or an inert gas (such as nitrogen gas).

[0028] The obtained hydrothermal reaction product can be isolated by filtering, washing with water, and drying. When washing such a hydrothermal reaction product with water, it is preferable to use 5 to 100 parts by mass of water with respect to 1 part by mass of the hydrothermal reaction product. Also, as the drying means, freeze drying or vacuum drying is used, and among these, freeze drying is preferable.

[0029] The obtained mixture of 4-hydroxy-4-hydroxymethyl-2-cyclopentenone and 4-hydroxy-3-hydroxymethyl-2-cyclopentenone can be separated by ordinary separation methods (e.g., HPLC).

[0030] In one aspect of the present invention, there can be provided a method for producing a compound represented by formula (I) or an optically active form thereof, which comprises subjecting the compound represented by formula (IV) to an isomerization reaction in the presence of a metal catalyst. JPEG0007716888000011.jpg58136

[0031] Isomerization reaction The "isomerization reaction" employed in the present embodiment means a reaction in which the compound represented by formula (IV) is changed to the compound represented by formula (I) in the presence of a metal catalyst.

[0032] That is, 4-hydroxy-4-hydroxymethyl-2-cyclopentenone contained in the cyclopentenone derivative can be converted to 4-hydroxy-3-hydroxymethyl-2-cyclopentenone by the isomerization reaction.

[0033] The isomerization mechanism of 4-hydroxy-4-hydroxymethyl-2-cyclopentenone is as follows. The oxygen atom of the carbonyl group becomes negative by the catalyst, the hydrogen atom is removed, and the hydroxyl group and the double bond move to be isomerized to 4-hydroxy-3-hydroxymethyl-2-cyclopentenone. JPEG0007716888000012.jpg82159

[0034] The metal catalyst has a catalytic action on the isomerization reaction. Examples of the metal catalyst include metals (metallic elements or alloys), metal oxides, metal halides, etc. The metal catalyst may be used alone or in combination of two or more. Among these, metal oxides are preferred because the isomerization reaction proceeds particularly efficiently.

[0035] The metal oxides include hydroxides, and examples thereof include magnesium oxide, calcium oxide, titanium oxide, zirconium oxide, tin oxide, aluminum oxide (e.g., activated alumina, alumina gel, activated bauxite, etc.), iron oxide, and the like.

[0036] The metals constituting the metal catalyst include transition metal elements, Group 12 metal elements, Group 13 metal elements, Group 14 metal elements, and Group 15 metal elements. Among them, Group 4 metal elements, Group 6 metal elements, Group 8 metal elements, Group 9 metal elements, Group 10 metal elements, Group 11 metal elements, Group 12 metal elements, Group 13 metal elements, Group 14 metal elements, and Group 15 metal elements are preferred, and Group 4 metal elements, Group 6 metal elements, Group 8 metal elements, Group 10 metal elements, Group 11 metal elements, Group 12 metal elements, and Group 13 metal elements are more preferred.

[0037] When the metal constituting the metal catalyst is a transition metal element, a Group 12 metal element, a Group 13 metal element, a Group 14 metal element, or a Group 15 metal element, specifically, it is more preferably at least one element selected from the group consisting of titanium (Ti), zirconium (Zr), hafnium (Hf) (Group 4 metal elements), niobium (Nb), tantalum (Ta) (Group 5 metal elements), chromium (Cr), tungsten (W) (Group 6 metal elements), rhenium (Re) (Group 7 metal elements), iron (Fe), ruthenium (Ru) (Group 8 metal elements), cobalt (Co), rhodium (Rh) (Group 9 metal elements), nickel (Ni), palladium (Pd), platinum (Pt) (Group 10 metal elements), copper (Cu) (Group 11 metal elements), zinc (Zn) (Group 12 elements), boron (B), aluminum (Al), gallium (Ga), indium (In) (Group 13 metal elements), tin (Sn) (Group 14 metal elements), and antimony (Sb) (Group 15 metal elements).

[0038] The metal catalyst may be one of the above-described metals or an alloy of two or more metals. The metal oxide may be an oxide of one of the above-described metals or a composite oxide of two or more metals. The metal halide may be a halide of one of the above-described metals or a composite halide of two or more metals.

[0039] Also, the metal catalyst may be supported on a carrier. Examples of the carrier include an alumina carrier, a zirconia carrier, a silica carrier, a silica-alumina carrier, a carbon carrier typified by activated carbon, a barium sulfate carrier, a calcium carbonate carrier, etc. Examples of the activated carbon include activated carbon prepared from raw materials such as wood, charcoal, fruit shells, coconut shells, peat, lignite, coal, etc. When the carrier is a compound of the same type as the metal catalyst, it may have the function as a metal catalyst.

[0040] The usage amount of the metal catalyst is, for example, 1.0 to 5.0 equivalents, preferably 1.0 to 3.0 equivalents, more preferably about 2.0 equivalents, relative to the compound represented by formula (IV). The reaction temperature is usually 20°C to 60°C, preferably 25°C to 55°C, more preferably 30°C to 50°C, particularly preferably 40°C to 50°C, and the reaction time is usually 10 hours to 200 hours, preferably 50 to 180 hours, more preferably 80 hours to 160 hours. In the above reaction, the compound represented by formula (IV) is isomerized to the compound represented by formula (I).

Examples

[0041] Examples are given below to explain the present invention in more detail, but the present invention is not limited to these examples. In this specification, room temperature indicates 10°C to 35°C. In addition, the following instruments were used for measuring each physical property of the examples and reference examples. Melting point: Yanaco Mp-500V (manufactured by Anatech Yanaco). 1 1H nuclear magnetic resonance spectrum ( 1 1H-NMR): AVANCE-400 (Burker) Internal reference substance: Tetramethylsilane. Mass spectrometry: mircOTOF-Q II-S1 (Burker)

Example

[0042] Method for producing 2,5-bis(hydroxymethyl)furan (compound of formula (II)) JPEG0007716888000013.jpg34157 Selective reduction reaction 3 g of 5-hydroxymethylfurfural (manufactured by Combi-Blocks) was dissolved in 80 mL of methanol (manufactured by FUJIFILM Wako Pure Chemical Corporation) in a 200 mL eggplant-shaped flask. While stirring the methanol solution with a stirrer, 0.9 g of sodium borohydride (manufactured by Sigma-Aldrich) was slowly added while confirming the generation of steady bubbles (hydrogen). After all was supplied, it was left for a while, and it was confirmed by TLC operation that the reaction was completed. Next, a saturated aqueous ammonium chloride solution was added, transferred to a separatory funnel, and the product was extracted with ethyl acetate (manufactured by FUJIFILM Wako Pure Chemical Corporation) (extracted twice). The water in the ethyl acetate phase was removed (dried) with magnesium sulfate (anhydrous, manufactured by Kokusan Chemical Co., Ltd.). By removing the solvent from the ethyl acetate phase, 2.6 g of 2,5-bis(hydroxymethyl)furan (crude) was obtained. Purification of 2,5-bis(hydroxymethyl)furan 8 mL of ethyl acetate was added to 0.75 g of 2,5-bis(hydroxymethyl)furan (crude) and dissolved in a water bath at 35 - 38°C. When left standing overnight in a freezer (-20°C), a precipitate (yellowish-white) was observed. The solution was removed, the remaining precipitate was washed with an organic solvent, and the solvent was removed with an evaporator to obtain 0.59 g of a powder of 2,5-bis(hydroxymethyl)furan (greenish-white). 1 1H NMR (CDCl3, 400 MHz): 4.45 (4 H, s), 6.14 (2 H, s) ppm.

Example

[0043] Production of the compound represented by formula (I) or its stereoisomer by hydrothermal reaction JPEG0007716888000014.jpg53169The hydrothermal reaction of the present invention can be carried out using the hydrothermal reaction apparatus shown in FIG. 8.

[0044] The hydrothermal reaction apparatus main body (manufactured by Autoclave Engineers) has an internal volume of 40 mL. Inside the reaction apparatus main body, 0.2 g of 2,5-bis(hydroxymethyl)furan powder (manufactured by selective reduction of 5-HMF) was dissolved in 25 g of distilled water (manufactured by FUJIFILM Wako Pure Chemical Corporation) to prepare an aqueous solution. A stir bar was added, filled with argon gas, and the reaction apparatus main body was sealed. The reaction apparatus main body was heated using an oil bath (manufactured by Advantec, TBX222SA). Stirring of the reaction part (liquid phase) inside the sealed reaction apparatus was performed by rotating the stir bar with a magnetic stirrer (manufactured by Advantec, hot plate stirrer, SRS710HA).

[0045] Production by hydrothermal reaction The hydrothermal reaction is initiated by placing the hydrothermal reaction apparatus main body containing the 2,5-bis(hydroxymethyl)furan aqueous solution in a heated oil bath (90 - 200 °C). After a predetermined time has elapsed (1 - 50 hours), the reaction apparatus main body is taken out of the oil bath and immersed in water to lower the temperature of the apparatus main body to room temperature to stop the reaction. The hydrothermal reaction apparatus main body was opened and the contents were recovered. The solid (water-insoluble residue) was removed by filtration (filter paper pore size 0.2 μm) to obtain a filtrate (aqueous solution containing 4-hydroxy-4-hydroxymethyl-2-cyclopentenone and 4-hydroxy-3-hydroxymethyl-2-cyclopentenone). The filtrate was frozen and the moisture was removed using a freeze dryer (manufactured by Tokyo Rikakikai Co., Ltd., FDU-1200). 10 mL of 2-propanol was added to the paste-like solid to dissolve it once, and then 14 mL of n-hexane was added. The solid residue insoluble in the 2-propanol·hexane mixed solvent was removed, and the filtrate was removed using an evaporator to obtain a paste-like solid containing cyclopentenone derivatives (4-hydroxy-4-hydroxymethyl-2-cyclopentenone and 4-hydroxy-3-hydroxymethyl-2-cyclopentenone). Table 1 shows the production amount of cyclopentenone derivatives by the hydrothermal reaction for 8 hours. The temperatures in the table are the reaction temperatures respectively. The solids term is the amount of the paste-like solids containing the cyclopentenone derivative. The raw materials, 4-hm, and 3-hm are the amounts of 2,5-bis(hydroxymethyl)furan, 4-hydroxy-4-hydroxymethyl-2-cyclopentenone, and 4-hydroxy-3-hydroxymethyl-2-cyclopentenone, respectively. These were obtained by dissolving the solids in an organic solvent and performing quantitative analysis by gas chromatography. The subtotal is the sum of the raw materials, 4-hm (4-hydroxy-4-hydroxymethyl-2-cyclopentenone) and 3-hm (4-hydroxy-3-hydroxymethyl-2-cyclopentenone). Since it includes fractions less than 1 mg and is totaled, there are places where it does not match the value obtained by adding the three numbers in the table. The residue is the amount of the solid separated by two filtration operations and shows the total value of the water-insoluble content and the 2-propanol·hexane mixed solvent-insoluble content. It is the amount of impurities (such as polymers) generated by the progress of the decomposition and polymerization reactions. (Table 1) It can be seen that the cyclopentenone derivatives (4-hydroxy-4-hydroxymethyl-2-cyclopentenone, 4-hydroxy-3-hydroxymethyl-2-cyclopentenone) can be obtained under any of the hydrothermal reaction conditions in Table 1 of JPEG0007716888000015.jpg57134. Quantitative analysis by gas chromatography The analysis conditions for gas chromatography are as follows: column: HPINNOWAX, inlet and FID temperature: 250 °C, He flow rate: 9 mL / min, hydrogen flow rate: 40 mL / min, air flow rate: 450 mL / min, oven temperature: 100 °C (5 min) - 20 °C / min - 260 °C (15 min). The GC system used is manufactured by Agilent Technologies, 7890B and 5977A MSD (simultaneous measurement of GC-MS and GC-FID). As a standard sample for quantitative analysis, commercially available 2,5-bis(hydroxymethyl)furan manufactured by Combi-Blocks was used. Since 4-hydroxy-4-hydroxymethyl-2-cyclopentenone and 4-hydroxy-3-hydroxymethyl-2-cyclopentenone are not commercially available, a fractionated HPLC (liquid chromatography) was used to separate and purify the cyclopentenone derivative (mixture), which was then used. Separation of 4-hydroxy-4-hydroxymethyl-2-cyclopentenone and 4-hydroxy-3-hydroxymethyl-2-cyclopentenone using preparative HPLC Similar to the above-described examples, 0.3 g of 2,5-bis(hydroxymethyl)furan powder was dissolved in 25 g of distilled water in the hydrothermal reaction apparatus main body 1 to prepare an aqueous solution. The assembly of the reaction apparatus main body and the procedure of the hydrothermal reaction were the same. The reaction temperature was 160°C and the reaction time was 4 hours. After the reaction, the contents were recovered from the reaction apparatus main body 1, and a filtrate (aqueous solution containing 4-hydroxy-4-hydroxymethyl-2-cyclopentenone and 4-hydroxy-3-hydroxymethyl-2-cyclopentenone) was obtained by a filtration operation (filter paper pore size 0.2 μm) of the aqueous solution containing solids. The water of the solvent was removed with an evaporator to obtain 0.22 g of a paste-like solid. This solid was dissolved in a 2-propanol·hexane mixed solvent (10 mL of 2-propanol, 14 mL of n-hexane), and the mixed solvent-insoluble matter (7 mg) was removed by a filtration operation (filter paper pore size 0.2 μm). The solution of the mixed solvent obtained after the filtration operation was used as a sample solution (sample) for fractionated HPLC. The fractionation conditions for HPLC were as follows: column: CHIRAL ART Cellulose-SC (particle size 5 μm, φ30.0 mm I.D., length 250 mm, manufactured by YMC), density of 2-propanol·hexane mixed solvent 0.70 g / mL (room temperature) (n-hexane:2-propanol = 58:42 <v v>Corresponding to), detection wavelength 220 nm (UV), temperature: room temperature, solvent flow rate: 20 mL / min, injection volume of the sample solution is 2.5 - 3.0 mL. The HPLC chart of the cyclopentenone derivative obtained by the hydrothermal reaction (160 °C, 4 hours) (I: 4-hydroxy-4-hydroxymethyl-2-cyclopentenone, II·III: 4-hydroxy-3-hydroxymethyl-2-cyclopentenone) is shown in Figure 1. Using preparative HPLC, peaks I, II, and III can be separated respectively. For the solutions obtained by separating each peak, the organic solvent was removed with an evaporator. Then, GC-MS analysis and NMR measurement of gas chromatography were performed respectively. The analysis conditions of gas chromatography are the same as described above. In NMR analysis, 1 1H-NMR measurement (measurement device: Bruker AVANCE-400 III spectrometer, measurement solvent: deuterated acetone (manufactured by FUJIFILM Wako Pure Chemical Corporation)) was performed. The GC-MS charts of peaks I, II, and III are shown in Figures 2, 3, and 4 respectively, and the 1 1H-NMR charts of peaks I, II, and III are shown in Figures 5, 6, and 7 respectively. Peaks II and III in Figure 1 form peaks at the same retention time in GC-MS analysis, and the mass spectra in Figures 3 and 4 also almost coincide. The same is true for the 1 1H-NMR charts in Figures 6 and 7. 4-Hydroxy-3-hydroxymethyl-2-cyclopentenone has two structures depending on whether the hydroxyl group bonded to the carbon atom at the 4-position is above or below the cyclopentenone skeleton. Therefore, peaks II and III are formed in Figure 1. The weights of peaks I, II, and III after removing the organic solvent were 89, 26, and 29 mg respectively. That is, by separation and purification using preparative HPLC, 89 mg of 4-hydroxy-4-hydroxymethyl-2-cyclopentenone and 55 mg of 4-hydroxy-3-hydroxymethyl-2-cyclopentenone were obtained as cyclopentenone derivatives respectively. 4-Hydroxy-4-hydroxymethyl-2-cyclopentenone 1 1H NMR (400 Mz, acetone-d6): δ2.23 (d, J = 18.0 Hz, 1H), 2.52 (d, J = 18.0 Hz, 1H), 3.64 (q, J = 10.6 Hz, 2H), 4.13 (brs, 1H), 4.51 (brs, 1H), 4.99 (brs, 1H), 6.08 (d, J = 5.7 Hz, 1H), 7.50 (d, J = 5.7 Hz, 1H) ppm 4-Hydroxy-3-hydroxymethyl-2-cyclopentenone 1 1H NMR (400 Mz, acetone-d6): δ2.18 (dd, J = 2.2, 18.0 Hz, 1H), 2.70 (dd, J = 6.3, 18.0 Hz, 1H), 2.89 (brs, 1H), 4.44 (d, J = 18.3 Hz, 1H) 4.66 (d, J = 1.4, 18.2 Hz, 1H), 4.91 (d, J = 5.2 Hz, 1H), 6.02-6.03 (m, 1H) ppm

Example

[0046] Method for producing 4-hydroxy-3-hydroxymethyl-2-cyclopentenone by isomerization of 4-hydroxy-4-hydroxymethyl-2-cyclopentenone in a cyclopentenone derivative JPEG0007716888000016.jpg53127 First stage (hydrothermal reaction) Similar to Example 2 above, 0.2 of 2,5-bis(hydroxymethyl)furan powder was dissolved in 25 g of distilled water in the hydrothermal reaction apparatus main body 1 to prepare an aqueous solution. The assembly of the reaction apparatus main body and the procedure of the hydrothermal reaction were the same. The reaction temperature was 140°C and the reaction time was 4 hours. After the reaction, the contents were recovered from the main body of the reactor 1, and a filtrate (an aqueous solution containing 4-hydroxy-4-hydroxymethyl-2-cyclopentenone and 4-hydroxy-3-hydroxymethyl-2-cyclopentenone) was obtained by filtering the aqueous solution containing solids (pore size of the filter paper: 0.2 μm). The water as the solvent was removed with an evaporator to obtain a paste-like solid substance. Second stage (isomerization reaction) Alumina (manufactured by Sigma-Aldrich, basic, Brockmann I) was placed in a minivial, and a solution prepared by dissolving the paste-like solid substance obtained by the hydrothermal reaction in a small amount of distilled water was added. The amount of the paste-like solid substance loaded was 0.16 - 0.19 g, the amount of distilled water was 0.11 - 0.14 g, and the amount of alumina was twice the amount of the paste-like solid substance loaded. The lid of the minivial was closed and it was placed in a dryer (manufactured by Yamato Scientific Co., Ltd., DY400) whose internal temperature was set to the reaction temperature, and the isomerization reaction was started. After a predetermined time elapsed, it was taken out from the dryer and extracted from the alumina particles using acetone (manufactured by Fujifilm Wako Pure Chemical Corporation) (using an ultrasonic cleaner). The acetone solution containing alumina was filtered (pore size of the filter paper: 0.2 μm). The solvent was removed from the filtrate using an evaporator, and the amount of the remaining solid was taken as the recovery amount. Table 2 shows the amounts of cyclopentenone derivatives by the isomerization reaction. The temperature and time are the conditions of the isomerization reaction. 4-hm and 3-hm are the amounts of 4-hydroxy-4-hydroxymethyl-2-cyclopentenone and 4-hydroxy-3-hydroxymethyl-2-cyclopentenone, respectively. These were determined by quantitative analysis by gas chromatography in the same manner as described above. The subtotal is the sum of 4-hm and 3-hm. The amount adhered is the amount of the solid adhered to the alumina particles in the isomerization reaction (the amount that cannot be recovered by extraction). The 3 / 4 ratio is the ratio of 4-hydroxy-3-hydroxymethyl-2-cyclopentenone (3-hm) to 4-hydroxy-4-hydroxymethyl-2-cyclopentenone (4-hm). It can be seen that the ratio of 4-hydroxy-3-hydroxymethyl-2-cyclopentenone increases due to the isomerization reaction, and the 3 / 4 ratio exceeds 1 in any of the isomerization reaction experiments. (Table 2) The paste-like solid obtained in the first stage (hydrothermal reaction), JPEG0007716888000017.jpg71144, is crude and contains a cyclopentenone derivative. In the second stage, the isomerization treatment of 4-hydroxy-4-hydroxymethyl-2-cyclopentenone does not start in a purified state. It was confirmed that the isomerization reaction of 4-hydroxy-4-hydroxymethyl-2-cyclopentenone proceeds even when using the unpurified crude.< / v>

Claims

1. Formula (I): A compound represented by the formula or an optically active form thereof.

2. A method for producing a compound represented by formula (I) or an optically active form thereof, characterized by subjecting a compound represented by formula (II) to a hydrothermal reaction.

3. The production method according to claim 2, wherein the temperature of the hydrothermal reaction is 90 °C or higher.

4. The hydrothermal reaction in the production method according to claim 2 includes putting a compound represented by formula (II) into a hydrothermal reaction apparatus and controlling the hydrothermal reaction temperature range to 90 - 200 °C and the reaction time to 1 - 50 hours.

5. The production method according to claim 2, further comprising a step of converting a compound represented by formula (III) into a compound represented by formula (II) in the presence of a reducing agent.

6. The reducing agent in the production method according to claim 5 includes an organic reducing agent, an inorganic reducing agent, or a combination thereof.

7. The production method according to claim 6, wherein the reducing agent is an inorganic reducing agent.

8. A method for producing a compound represented by formula (I) or an optically active form thereof, characterized by subjecting a compound represented by formula (IV) to an isomerization reaction in the presence of a metal catalyst.

9. The production method according to claim 8, wherein the metal catalyst is a metal oxide.

10. The production method according to claim 8, wherein the metal catalyst is an alumina catalyst.

11. The isomerization reaction in the production method according to any one of claims 8 to 10 includes controlling the reaction temperature range to 20 - 50 °C and the reaction time to 1 - 50 hours.

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