Isomer Preparation Equipment

Abstract

To provide an isomer preparation device capable of acquiring a desired isomer at high yield, from an isomer mixture.SOLUTION: There is provided an isomer preparation device for selectively preparing one isomer out of an isomer mixture, the device comprises: a division part for dividing the isomer mixture into one isomer and the other isomer; and a light radiation part for radiating light to the other isomer which is divided from the mixture by the division part, for photo-isomerization. The division part divides the isomer mixture subjected to the photo-isomerization by the light radiation part to one isomer and the other isomer, and the light radiation part has a channel in which the other isomer is circulated, and a plurality of light sources which is arranged around the channel.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to an apparatus for preparing isomers. [Background technology]

[0002] It has been known that isomers have different properties. For example, enantiomers of sulfoxide compounds with the sulfur atom of the sulfoxide group as the asymmetric center are known as proton pump inhibitors. These sulfoxide compounds have an asymmetric center at the sulfur atom of the sulfoxide group, and based on the configuration of this asymmetric center, there are S-enantiomers and R-enantiomers.

[0003] It is known that the above-mentioned sulfoxide compounds have different pharmacokinetics between enantiomers. For example, it is known that esomeprazole, which is the S-form of omeprazole, has smaller inter-individual variability in pharmacokinetics and pharmacological action than omeprazole, which is racemic. In addition, dexlansoprazole, which is the R-form of lansoprazole, is known to have better stability against drug metabolizing enzymes and pharmacokinetics than lansoprazole, which is racemic.

[0004] Under these circumstances, various methods have been proposed for efficiently obtaining a desired enantiomer from a racemic sulfoxide compound (see, for example, Patent Documents 1 to 3).

[0005] However, since racemic sulfoxide compounds are an equal mixture of S- and R-isomers, the methods described in Patent Documents 1 to 3 could only obtain the desired enantiomer in a maximum yield of 50%, and the remaining enantiomer was wasted.

[0006] On the other hand, it has been reported that optically active sulfoxide compounds undergo racemization (photoisomerization) when irradiated with light (see, for example, Non-Patent Documents 1 and 2). However, it is difficult to control the irradiated light required for racemization, and there are energy losses and safety issues due to leakage of the irradiated light to the outside. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] Special Publication No. 2009-502906 [Patent Document 2] Special Publication No. 2009-542624 [Patent Document 3] Special Publication No. 7-509499 [Non-patent literature]

[0008] [Non-Patent Document 1] K. Mislow et al.,J. Am. Chem. Soc.,1965,87(21),pp.4958-4959 [Non-Patent Document 2] Tsubasa Kimura et al., "Study on the light-induced racemization phenomenon of sulfoxides contained in pharmaceuticals," Abstracts of the 138th Annual Meeting of the Pharmaceutical Society of Japan, March 2018, 27PA-am001S Summary of the Invention [Problem to be solved by the invention]

[0009] An object of the present invention is to provide an isomer preparation apparatus capable of obtaining a desired isomer in high yield from an isomer mixture. [Means for solving the problem]

[0010] Specific means for solving the above problems include the following embodiments.

[0011] <1> An isomer preparation apparatus for selectively preparing one isomer of an isomer mixture, comprising: a division section for dividing the isomer mixture into the one isomer and the other isomer; a light irradiation unit configured to be capable of irradiating the other isomer split by the splitting unit with light that induces photoisomerization, the splitting unit splits the isomer mixture photoisomerized by the light irradiating unit into the one isomer and the other isomer, the light irradiation unit includes a flow path through which the other isomer flows, a light source disposed along the flow path, and a housing capable of housing the flow path and the light source.

[0012] <2> the splitting unit is capable of repeatedly splitting the isomer mixture photoisomerized by the light irradiating unit into the one isomer and the other isomer multiple times. <1> An apparatus for preparing an isomer as described above.

[0013] <3> The flow channel is filled with a solid-phase photosensitizer in which a photosensitizer is immobilized on a carrier. <1> or <2> An apparatus for preparing an isomer as described above.

[0014] <4> The flow channel is further filled with optically transparent particles. <3> An apparatus for preparing an isomer as described above.

[0015] <5> The flow path is made of a material that can transmit light irradiated from the light source. <1> ~ <4> 13. The apparatus for preparing an isomer according to any one of claims 1 to 12.

[0016] <6> The housing is made of a metal material and prevents leakage of light emitted from the light source to the outside. <1> ~ <5> 13. The apparatus for preparing an isomer according to any one of claims 1 to 12.

[0017] <7> a sensor capable of detecting at least one of a temperature and an illuminance of the surface of the flow path, and an amount of light irradiated from the light source to the flow path is controlled based on a detection result of the sensor; <1> ~ <6> 13. The apparatus for preparing an isomer according to any one of claims 1 to 12.

[0018] <8> The wavelength range of the light irradiated from the light source is within the range of 200 nm to 450 nm. <1> ~ <7> 13. The apparatus for preparing an isomer according to any one of claims 1 to 12. Effect of the Invention

[0019] According to the present invention, it is possible to provide an isomer preparation apparatus capable of obtaining a desired isomer in high yield from an isomer mixture. [Brief description of the drawings]

[0020] [Figure 1] FIG. 1 is a diagram showing an example of a schematic configuration of an isomer preparation apparatus according to an embodiment of the present invention. [Diagram 2] FIG. 2 is a perspective view showing a configuration of a light irradiation unit according to the first embodiment. [Diagram 3] FIG. 2 is a front view showing the configuration of a light irradiation unit according to the first embodiment. [Figure 4] 4 is a cross-sectional view taken along line AA in FIG. [Diagram 5] FIG. 11 is a front view showing the configuration of a light irradiation unit according to the second embodiment. [Figure 6] FIG. 13 is a front view showing the configuration of a light irradiation unit according to a third embodiment. [Figure 7] FIG. 4 is a diagram showing a time change in intensity of isomers detected by a splitting section according to the present embodiment. [Figure 8] FIG. 4 is a diagram showing a time change in intensity of isomers detected by a splitting section according to the present embodiment. [Figure 9] 4 is a graph showing the relationship between input current and irradiance for the light source according to the first embodiment. [Figure 10] 5 is a graph showing the relationship between the light source lighting time and the flow path surface temperature when the input current to the light source according to the first embodiment is changed. [Figure 11] FIG. 1 shows the change over time in enantiomeric excess when a photoracemization reaction of an optically active sulfoxide compound is allowed to proceed in the presence of solid-phase photosensitizer 2 in which the photosensitizer TPT+ is immobilized on a carrier. [Figure 12] FIG. 1 shows the change over time in enantiomeric excess when a photoracemization reaction of an optically active sulfoxide compound is allowed to proceed in the presence of solid-phase photosensitizer 3 in which the photosensitizer TPT+ is immobilized on a carrier. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] The isomer preparation apparatus according to this embodiment includes a division unit that divides an isomer mixture such as enantiomers into one isomer and the other isomer, and a light irradiation unit that irradiates the other isomer obtained in the division unit with light to photoisomerize the isomer.

[0022] First Embodiment <Isomer Preparation Equipment> An example of a schematic configuration of an isomer preparation apparatus according to this embodiment is shown in Fig. 1. As shown in Fig. 1, the isomer preparation apparatus 1 includes a separation unit 10 and a light irradiation unit 20.

[0023] (divided part) The splitting section 10 splits the isomer mixture. The isomer mixture may be an isomer mixture that undergoes photoisomerization as described below, but hereinafter, an enantiomer mixture may be taken as an example of the isomer mixture. The splitting section 10 splits the enantiomer mixture as an isomer into one enantiomer (e.g., S-form) and the other enantiomer (e.g., R-form), separates one enantiomer, and sends the other enantiomer to the light irradiation section 20. The splitting section 10 is not particularly limited as long as it can split isomers. For example, when a chromatography method is employed, the splitting section 10 is provided with a chiral column.

[0024] [Isomers] The isomer separated by the separation unit 10 may be any isomer that is photoisomerized by irradiation with light. Examples of the isomer include enantiomers of sulfoxide compounds, amino acids, amino acid derivatives, carboxylic acids, carboxylic acid derivatives, and the like, and diastereomers such as cis-trans isomers. The other isomer separated by the separation unit 10 may be in a solid state or in a state dissolved in a solvent, but the latter is preferred in terms of photoisomerization efficiency.

[0025] As an isomer, a sulfoxide compound will be described below as an example. A sulfoxide compound is, for example, a compound having an asymmetric center at the sulfur atom of a sulfoxide group, and having S- and R-enantiomers based on the configuration of this asymmetric center. From the viewpoint of efficiently preparing only the desired enantiomer, a sulfoxide compound having only one asymmetric center is preferred.

[0026] A suitable sulfoxide compound is, for example, a compound represented by the following formula (1): The compound represented by the following formula (1) has excellent gastric acid secretion suppression activity, antiulcer activity, mucosal protection activity, anti-Helicobacter pylori activity, etc., and is a useful compound as a proton pump inhibitor.

[0027] [ka] (In the formula, R 1 , R 2 , R 3 R each independently represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, a hydroxy group, a carboxy group, an alkyl group which may have a substituent, an alkoxy group which may have a substituent, an alkoxycarbonyl group, an aryl group, an aryloxy group, an acyl group, an acyloxy group, or a heteroaryl group. 4 , R 5 , R 6 R each independently represents a hydrogen atom, an alkyl group which may have a substituent, an alkoxy group which may have a substituent, or an amino group which may have a substituent. 7 represents a hydrogen atom, a hydrocarbon group which may have a substituent, an acyl group, or an acyloxy group. X, Y, and Z each independently represent a nitrogen atom or CH. * represents an asymmetric center.

[0028] R 1 , R 2 , R 3 Examples of the halogen atom represented by the formula (I) include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

[0029] R 1 , R2 , R 3 Examples of the "alkyl group" in the "alkyl group which may have a substituent" represented by the formula (I) include linear or branched C alkyl groups such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an n-hexyl group, and an n-heptyl group. 1-7 Examples of the "substituted or unsubstituted alkyl group" include a halogen atom, a hydroxyl group, a C 1-6 Alkoxy groups (methoxy, ethoxy, n-propoxy, isopropoxy, etc.), C 1-6 Examples of the substituents include an alkoxy-carbonyl group (such as a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an isopropoxycarbonyl group, etc.), and a carbamoyl group. The number of the substituents is not particularly limited, and may be, for example, 1 to 3. When the number of the substituents is 2 or more, the respective substituents may be the same or different.

[0030] R 1 , R 2 , R 3 Examples of the "alkoxy group" of the "alkoxy group which may have a substituent" represented by the formula (I) include linear or branched C alkoxy groups such as a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, an n-pentoxy group, and an n-hexyloxy group. 1-6 Examples of the "substituent" of the "alkoxy group which may have a substituent" include the same as the "substituent" of the above-mentioned "alkyl group which may have a substituent". The number of the substituents is not particularly limited, and may be, for example, 1 to 3. When the number of the substituents is 2 or more, each of the substituents may be the same or different.

[0031] R 1 , R 2 , R 3Examples of the "alkoxycarbonyl group" represented by the formula (I) include a C alkoxy group in which the alkoxy portion is linear or branched, such as a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an isopropoxycarbonyl group, an n-butoxycarbonyl group, an isobutoxycarbonyl group, a sec-butoxycarbonyl group, a tert-butoxycarbonyl group, an n-pentoxycarbonyl group, or an n-hexyloxycarbonyl group. 1-6 An example of such a group is an alkoxy group.

[0032] R 1 , R 2 , R 3 Examples of the "aryl group" represented by the formula (I) include C aryl groups such as phenyl group, 1-naphthyl group, 2-naphthyl group, biphenylyl group, and 2-anthryl group. 6-14 An example of such an alkyl group is an aryl group.

[0033] R 1 , R 2 , R 3 Examples of the "aryloxy group" represented by the formula (I) include C aryloxy groups such as phenyloxy group, 1-naphthyloxy group, 2-naphthyloxy group, biphenylyloxy group, and 2-anthryloxy group. 6-14 An example of such a group is an aryloxy group.

[0034] R 1 , R 2 , R 3 Examples of the "acyl group" represented by the formula (I) include a formyl group, an acetyl group, a propionyl group, and the like. 1-6 Alkyl-carbonyl group; benzoyl group, naphthalene carbonyl group, etc. 6-14 aryl-carbonyl groups; and the like.

[0035] R 1 , R 2 , R 3 Examples of the "acyloxy group" represented by the formula (I) include an acetyloxy group, a propionyloxy group, and the like. 1-6 Alkyl-carbonyloxy group; benzoyloxy group, naphthalenecarbonyloxy group, etc. 6-14 aryl-carbonyloxy group; and the like.

[0036] R 1 , R 2 , R 3 Examples of the "heteroaryl group" represented by the formula (I) include 5- to 10-membered ring groups containing 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom. Specific examples include 1-, 2-, or 3-thienyl group, 1-, 2-, 3-, or 4-pyridyl group, 2- or 3-furyl group, 1-, 2-, or 3-pyrrolyl group, 2-, 3-, 4-, 5-, or 8-quinolyl group, 1-, 3-, 4-, or 5-isoquinolyl group, and 1-, 2-, or 3-indolyl group.

[0037] R 4 , R 5 , R 6 The "optionally substituted alkyl group" and "optionally substituted alkoxy group" represented by the formula: 1 , R 2 , R 3 Examples of the alkyl group include those similar to the "alkyl group which may have a substituent" and the "alkoxy group which may have a substituent" represented by the following formula:

[0038] R 4 , R 5 , R 6 Examples of the "amino group which may have a substituent" represented by the following formula (1) include an amino group; a mono-C group such as a methylamino group, an ethylamino group, an n-propylamino group, an isopropylamino group, etc. 1-6 Alkylamino groups; mono-C groups such as phenylamino groups, 1-naphthylamino groups, and 2-naphthylamino groups 6-14 Arylamino group; Di-C such as dimethylamino group, diethylamino group, methylethylamino group, and methylisobutylamino group 1-6 Alkylamino groups; di-C such as diphenylamino groups 6-14 arylamino group; and the like.

[0039] R 7Examples of the "hydrocarbon group" of the "hydrocarbon group which may have a substituent" represented by the formula: 1-19 Hydrocarbon groups are included.

[0040] R 7 The alkyl group in the formula (I) is a straight-chain or branched C alkyl group such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an isopentyl group, a sec-pentyl group, a neopentyl group, an n-hexyl group, or an isohexyl group. 1-6 Alkyl groups; cyclic C groups such as cyclopentyl and cyclohexyl groups 3-14 Alkyl groups; and the like.

[0041] R 7 The alkenyl group in the formula (I) is a straight-chain or branched C alkenyl group such as an allyl group, an isopropenyl group, an isobutenyl group, a 2-pentenyl group, or a 2-hexenyl group. 2-6 Alkenyl groups; cyclic C groups such as 2-cyclohexenyl groups 3-14 alkenyl groups; and the like.

[0042] R 7 Examples of the alkynyl group in the formula (I) include linear or branched C alkyl groups such as propargyl, 2-butynyl, 3-butynyl, 3-pentynyl, and 3-hexynyl. 2-6 An example is an alkynyl group.

[0043] R 7 Examples of the aryl group in the formula (I) include C phenyl group, 1-naphthyl group, 2-naphthyl group, biphenylyl group, and 2-anthryl group. 6-14 An example of such an alkyl group is an aryl group.

[0044] R 7 Examples of the aralkyl group in the formula (I) include phenyl-C such as benzyl, phenethyl, and phenylpropyl groups. 1-4 Alkyl group; benzhydryl group; trityl group; etc. 7-19 Examples of such groups include aralkyl groups.

[0045] R 7 When the hydrocarbon group represented by the formula (I) is an alkyl group, an alkenyl group, or an alkynyl group, the hydrocarbon group is preferably an alkylthio group (C such as a methylthio group, an ethylthio group, an n-propylthio group, an isopropylthio group, etc. 1-4 alkylthio groups, etc.), halogen atoms (fluorine atoms, chlorine atoms, bromine atoms, iodine atoms, etc.), alkoxy groups (methoxy groups, ethoxy groups, n-propoxy groups, isopropoxy groups, etc.) 1-6 Alkoxy groups, acyloxy groups (acetyloxy groups, n-propionyloxy groups, etc.) 1-6 Alkyl-carbonyloxy group; benzoyloxy group, naphthalenecarbonyloxy group, etc. 6-14 Aryl-carbonyloxy group; etc.), nitro group, alkoxycarbonyl group (methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, etc. C 1-6 Alkoxy-carbonyl group, etc.), alkylamino group (mono- or di-C such as methylamino group, ethylamino group, n-propylamino group, isopropylamino group, dimethylamino group, diethylamino group, methylethylamino group, methylisobutylamino group, etc. 1-6 alkylamino groups, etc.), alkoxyimino groups (methoxyimino groups, ethoxyimino groups, n-propoxyimino groups, isopropoxyimino groups, etc.) 1-6 It may be substituted with an alkoxy-imino group, a hydroxyimino group, etc. The number of substituents is not particularly limited and may be, for example, 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[0046] In addition, when the hydrocarbon group is an aryl group or an aralkyl group, the hydrocarbon group is preferably an alkyl group (a straight-chain or branched-chain C alkyl group such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an n-hexyl group, etc. 1-6 Alkyl group; cyclic C such as cyclohexyl group 3-6Alkyl groups; etc.), alkenyl groups (allyl group, isopropenyl group, isobutenyl group, 1-methylallyl group, 2-pentenyl group, 2-hexenyl group, etc. 2-6 alkenyl groups, etc.), alkynyl groups (propargyl group, 2-butynyl group, 3-butynyl group, 3-pentynyl group, 3-hexynyl group, etc.) 2-6 Alkynyl groups, etc.), alkoxy groups (methoxy groups, ethoxy groups, n-propoxy groups, isopropoxy groups, etc.) 1-6 Alkoxy groups, etc.), acyl groups (formyl groups, acetyl groups, propionyl groups, etc.) 1-6 Alkyl-carbonyl group; benzoyl group, naphthalene carbonyl group, etc. 6-14 Aryl-carbonyl group; etc.), nitro group, amino group, hydroxy group, cyano group, sulfamoyl group, mercapto group, halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom, etc.), alkylthio group (methylthio group, ethylthio group, n-propylthio group, isopropylthio group, etc. C 1-4 The number of the substituents is not particularly limited and may be, for example, 1 to 5. When the number of the substituents is 2 or more, the respective substituents may be the same or different.

[0047] R 7 The "acyl group" and "acyloxy group" represented by the formula R 1 , R 2 , R 3 Examples of the acyl group include those similar to the "acyl group" and "acyloxy group" represented by the following formula:

[0048] Among the compounds represented by the above formula (1), R 1 is a hydrogen atom, and R 2 C may be substituted with a hydrogen atom or a halogen atom 1-4 C optionally substituted with alkyl or halogen atoms 1-4 an alkoxy group, or a heteroaryl group (preferably a 1-, 2- or 3-pyrrolyl group); R 3 is a hydrogen atom or C 1-4 is an alkoxy-carbonyl group, R 4C may be substituted with a hydrogen atom or a halogen atom 1-4 Alkyl group, halogen atom or C 1-4 C optionally substituted with an alkoxy group 1-4 is an alkoxy group, R 5 is a hydrogen atom, a halogen atom or C 1-4 C optionally substituted with an alkoxy group 1-4 is an alkoxy group, R 6 C may be substituted with a hydrogen atom or a halogen atom 1-4 Alkyl group, halogen atom or C 1-4 C optionally substituted with an alkoxy group 1-4 Alkoxy group or di-C 1-4 is an alkylamino group, R 7 is a hydrogen atom.

[0049] Specific examples of the compound represented by the above formula (1) are shown below. However, the sulfonyl compound in the present embodiment is not limited to these examples.

[0050] [ka]

[0051] The compound represented by the above formula (1) may be in the form of a salt or a hydrate. The salt is preferably a pharma- ceutically acceptable salt, and examples thereof include salts with inorganic bases, salts with organic bases, and salts with basic amino acids. Examples of salts with inorganic bases include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and ammonium salts. Examples of salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, and N,N'-dibenzylethylenediamine. Examples of salts with basic amino acids include salts with arginine, lysine, ornithine, and the like.

[0052] The splitting unit 10 splits the isomer mixture into one isomer and the other isomer. The splitting unit 10 is equipped with a detector capable of detecting the split isomers.

[0053] The isomer mixture is not particularly limited as long as it contains isomers having different structures, and does not have to be an equal mixture. The isomer excess of the isomer mixture may be 0% to 25%, 0% to 10%, or 0% to 5%.

[0054] The method of resolution in the resolution section 10 is not particularly limited, and any method can be adopted. Examples of resolution methods for resolving sulfoxide compounds as isomers include a chromatography method using a chiral column; an inclusion complex method using an optically active host molecule (such as 1,1'-bi-2-naphthol) (see, for example, Patent Documents 1 and 2); and a diastereomer method in which diastereomers are derived using an optical resolution agent and then separated from each other (see, for example, Patent Document 3). Among these, it is preferable to adopt a chromatography method using a chiral column from the viewpoint of simplicity.

[0055] (Light irradiation part) The light irradiation section 20 irradiates the other isomer obtained in the resolution section 10 with light, and photoisomerizes the other isomer. The isomer mixture obtained in the light irradiation section 20 is sent again to the resolution section 10. In this way, according to the isomer preparation apparatus 1, by repeating resolution and photoisomerization in the resolution section 10 and the light irradiation section 20, the yield of the desired isomer can be significantly improved.

[0056] 2, the light irradiation unit 20 according to this embodiment includes a light source 21, a substrate 22, a housing 23, a flow path 24 through which the other isomer flows, and a sensor S. The light irradiation unit 20 also includes support members (not shown) for supporting the flow path 24 at both ends of the flow path 24, and the support members and the housing 23 are configured to prevent leakage of light to the outside. This makes it possible to prevent leakage of light irradiated from the light source 21 to the outside, so that the isomer preparation device 1 can be used safely even if the light has a wavelength that is harmful to the human body.

[0057] [light source] The light source 21 irradiates the other isomer flowing through the flow path 24 with light having a wavelength required for photoisomerization (for example, light having a wavelength of 200 nm to 450 nm, preferably light having a wavelength of 254 nm to 365 nm). The light source 21 is not particularly limited. Specific examples of the light source include a high-pressure mercury lamp, a low-pressure mercury lamp, a xenon lamp, an LED lamp light source, a laser, and an organic electroluminescence (EL). As the LED lamp light source, an SMD (Surface Mount Device) can be preferably applied because of its convenience of mounting in a narrow space and its ability to irradiate at a wide angle. Note that, when a material that absorbs or diffuses the light from the light source or a material that changes the wavelength of the light from the light source is present between the light source and the other isomer, it is preferable to irradiate the light while taking into consideration the absorption or diffusion of light, or the change in the wavelength of light.

[0058] As shown in FIG. 3, a plurality of light sources 21 are provided around the flow path 24. The light sources 21 are preferably arranged so that light enters from the light sources 21 perpendicular to the central axis C of the flow path 24. That is, the optical axis L1 of the light source 21 is preferably perpendicular to the central axis C of the flow path 24. The distance between the plurality of light sources 21 and the central axis C is preferably equal. In addition, the light sources 21 are preferably arranged so that the angles between the adjacent optical axes L1 as viewed from the direction of the central axis C are equal to each other. When a plurality of flow paths 24 are arranged, the above configuration can be applied with the central axis C being the axis located at the center of the flow path cross section of the plurality of flow paths 24. In this embodiment, the light sources 21 are arranged in four directions around the flow path 24 so that the angles between the adjacent optical axes L1 are approximately 90°. With the above configuration, the light sources 21 can uniformly irradiate the other isomer flowing through the flow path 24 with light.

[0059] Fig. 4 is a cross-sectional view taken along line AA in Fig. 3. As shown in Fig. 4, a plurality of light sources 21 (nine in this embodiment) are arranged in a row at equal intervals along the direction of the central axis C of the flow path 24. In this embodiment, nine light sources 21 are provided in each direction around the flow path 24, and light is irradiated onto the flow path 24 from four directions around the flow path 24. This makes it easy to control the amount of light irradiated onto the flow path 24 from the light sources 21. The above control can be performed by changing the input current to the light source 21 and controlling the irradiance of the light irradiated from the light source 21, as described below.

[0060] The irradiance of the light irradiated from the multiple light sources 21 to the flow path 24 is calculated from the input current to the multiple light sources 21. FIG. 9 is a graph showing the relationship between the input current to the light source 21 according to this embodiment and the irradiance on the surface of the flow path 24. During the measurement of FIG. 9, nine light sources 21 were arranged at equal intervals within an installation range of 40 mm in length along the central axis C direction of the flow path 24. The light sources 21 were arranged in four directions around the flow path 24. The distance between the light source 21 and the surface of the flow path 24 was 5 mm. An LED light source with a wavelength of 365 nm was used as the light source 21. A flow path with an outer diameter of 12 mm was used as the flow path 24. The irradiance is a value actually measured by installing a light receiving unit of a 365 nm wavelength irradiance meter on the surface of the flow path 24.

[0061] As shown in FIG. 9, the input current to the multiple light sources 21 according to this embodiment and the irradiance to the flow path 24 are in a nearly proportional relationship. Therefore, by determining the relationship between the input current to the light source 21 and the irradiance in advance, the irradiance can be calculated from the input current to the light source 21. The temperature of the flow path 24 can be adjusted by the above-mentioned irradiance as well as the cross-sectional shape of the housing, the number of light sources 21, the distance between the light source 21 and the surface of the flow path 24, the length of the flow path 24 to which light is irradiated from the light source 21, and the like. Therefore, the multiple light sources 21 having the above-mentioned configuration make it easy to control the amount of light irradiated to the other isomer and the temperature of the flow path 24. The control of the temperature of the flow path 24 will be described in detail later.

[0062] [substrate] The substrate 22 supports a plurality of light sources 21 arranged along the direction of the central axis C of the flow path 24. The substrate 22 is, for example, an aluminum substrate, and is supported by a housing 23. The light sources 21, the substrate 22, and the housing 23 are thermally connected, and heat generated from the light sources 21 is transferred to the housing 23 via the substrate 22.

[0063] [Case] The housing is configured to accommodate the light source 21 and the flow path 24. The housing is a hollow cylindrical member having a space formed therein through which the flow path 24 can be inserted. The light source 21 and the substrate 22 are fixed and disposed on the inner surface side of the housing. The cross-sectional shape of the housing as viewed from the direction of the central axis C of the flow path 24 is not particularly limited and can be appropriately selected from a circle, an ellipse, a polygon, and the like. The material of the housing is not particularly limited as long as it can prevent light from leaking from the housing to the outside, but it is preferable that the housing is made of a metal material with high thermal conductivity such as aluminum. This allows the heat transferred via the substrate 22 to be efficiently dissipated to the outside. In order to further increase the efficiency of heat dissipation, a heat sink or a water-cooling mechanism may be added to the housing, or an opening or an air-cooling fan may be provided to cool the inside of the housing and prevent the light irradiated inside the housing from leaking to the outside.

[0064] In this embodiment, the housing is constructed by combining a plurality of housings 23 having a substantially rectangular parallelepiped shape. The housing 23 has a mounting surface to which the light source 21 and the substrate 22 are attached. One end side of the mounting surface extends toward the end direction to form a connection portion 231. The connection portion 231 is provided with a plurality of holes 232 through which a fastener can be inserted. The connection portion 231 is abutted against the end face of the other end side of the mounting surface of another housing 23, and a fastener (not shown) is connected to the hole 232 to be fixed, so that the plurality of housings 23 are combined so that the mounting surfaces are arranged on the inner surface. In this embodiment, four housings 23 are combined and arranged so that the mounting surfaces having the light source 21 on the inner surface are arranged. With the above configuration, a space having a rectangular cross-sectional shape is formed inside the light irradiation unit 20, into which light is irradiated from the light source 21 and into which the flow path 24 can be inserted. This makes it possible to easily configure the light irradiation unit 20.

[0065] [Flow path] The flow channel 24 is a flow channel through which the other isomer obtained in the division unit 10 flows. The flow channel 24 may be one flow channel or multiple flow channels. The flow channel 24 may be made of any material as long as it is light-transmissive. A photosensitizer is preferably present in the flow channel 24. By irradiating the other isomer with light in the presence of the photosensitizer, the efficiency of photoisomerization can be further increased. As a method for making the photosensitizer present in the flow channel 24, for example, a method of preparing a solid-phase photosensitizer F in which the photosensitizer is immobilized on a carrier such as silica gel and filling the flow channel 24 can be mentioned. As a method for immobilizing the photosensitizer on the carrier, there is no particular limitation, and examples include a method of ionically bonding the photosensitizer to the carrier and a method of covalently bonding the photosensitizer to the carrier. In this embodiment, the solid-phase photosensitizer F is filled within the installation range of the light source 21 having a length of 40 mm along the direction of the central axis C of the flow channel 24 as shown in FIG. 4, but is not limited thereto. The solid-phase photosensitizer may be placed outside the installation range of the light source 21. By immobilizing the photosensitizer on the carrier, it becomes easy to separate the photosensitizer from the isomer mixture obtained by the light irradiation unit 20. The immobilization method for immobilizing the photosensitizer on the carrier is not particularly limited, and may be a covalent bond or an ionic bond.

[0066] It is preferable that the flow channel 24 is filled with light-transmitting particles in addition to the solid-phase photosensitizer F. When the flow channel 24 is filled with only the solid-phase photosensitizer F, there is a concern that the center of the flow channel 24 may not be irradiated with light having sufficient irradiance to advance photoisomerization, depending on the size of the inner diameter of the flow channel 24. By filling the flow channel 24 with light-transmitting particles in addition to the solid-phase photosensitizer F, the light irradiated from the light source 21 can be sufficiently distributed to the center of the flow channel 24. In addition, the amount of the solid-phase photosensitizer F used can be reduced, and the risk of leakage of the solid-phase photosensitizer F can also be reduced. Examples of the light-transmitting particles include, but are not limited to, glass beads, amorphous glass powder, and resin beads. The median diameter (D50) of the light-transmitting particles is, for example, about 10 to 100 μm. The mass ratio of the solid-phase photosensitizer F and the light-transmitting particles filled in the flow path 24 is preferably 1 to 50 mass%, more preferably 5 to 25 mass%, and even more preferably 5 to 10 mass%, of the solid-phase photosensitizer F relative to the total mass of the solid-phase photosensitizer F and the light-transmitting particles.

[0067] (Photosensitizer) The photosensitizer is not particularly limited, and a conventionally known photosensitizer can be used. Among the photosensitizers, photosensitizers having a maximum absorption wavelength in the wavelength region of 365 nm to 450 nm are preferable. Specific examples of the photosensitizer include cyanoarene compounds such as 1,2,4,5-tetracyanobenzene, 6,6'-dicyano-2,2'-bipyridyl, 1,2-dicyanonaphthalene, and 9,10-dicyanoanthracene; pyrylium compounds such as 2,4,6-triphenylpyrylium salts and 2,4,6-triphenylthiopyrylium salts; 10-methyl-9-(2,4,6-trimethylphenyl)acridinium salts and 3,6-diamino-10-methylacridinium salts; Examples of suitable compounds include acridinium compounds such as quinolinium salts, 2,3-dichloro-5,6-dicyano-p-benzoquinone, anthraquinone, and the like; quinolinium compounds such as 1-methylquinolinium salts, 1-methyl-6-methoxyquinolinium salts, and the like; xanthene compounds such as fluorescein, rhodamine B, and the like; thiazine compounds such as 10-phenylphenothiazine, methylthioninium salts, and the like; benzophenone compounds such as benzophenone, thioxanthone, and the like. Among these, cyanoarene compounds, pyrylium compounds, acridinium compounds, quinone compounds, and quinolinium compounds are preferred.

[0068] [Sensor] The sensor S can detect at least one of the temperature and irradiance of the surface of the flow path 24. Based on the temperature and irradiance detected by the sensor S, the temperature and irradiance in the flow path 24 can be estimated from the material constituting the flow path 24, the wall thickness, etc. It is preferable that the amount of light irradiated from the multiple light sources 21 is feedback-controlled based on at least one of the temperature and irradiance detected by the sensor S. This makes it possible to prevent the compound present in the flow path 24, such as an isomer, from being thermally decomposed, and to prevent the solvent in which the other isomer is dissolved from exceeding its boiling point. In addition, the isomer preparation device 1 can be operated with the minimum necessary energy. The sensor S is not particularly limited, and a known temperature sensor and illuminance sensor can be used. For example, a thermocouple thermometer, a thermistor, a radiation thermometer, etc. can be used as the temperature sensor. For example, an illuminance sensor using a photodiode, a phototransistor, a photoconductor, etc. can be used as the illuminance sensor. 4, the location of the sensor S is a location in contact with the inner surface of the housing 23, but is not particularly limited as long as it is capable of detecting the temperature or irradiance of the surface of the flow path 24. For example, the sensor S may be disposed on the surface of the flow path 24 to directly measure the temperature or irradiance of the surface of the flow path 24, or the sensor S capable of remotely measuring the temperature may be disposed at a location other than the surface of the flow path 24 to remotely measure the temperature of the flow path 24. In addition to the above, the sensor S may be disposed at a location other than the surface of the flow path 24, and a correlation between the measured value and the temperature or irradiance of the surface of the flow path 24 may be obtained in advance, and the temperature or irradiance of the surface of the flow path 24 may be calculated from the measured value.

[0069] When a temperature sensor is used as the sensor S, the amount of light irradiated from the multiple light sources 21 can be feedback-controlled so that the surface temperature of the flow path 24 detected by the sensor S does not exceed a predetermined threshold. The feedback control of the amount of light can be performed by controlling the irradiance by changing the input current to the multiple light sources 21, as described with reference to Fig. 9. In addition to the feedback control using the temperature sensor, it is also possible to control the input current and irradiation time to the light source 21 so that the surface temperature of the flow path 24 does not exceed a predetermined threshold.

[0070] Fig. 10 is a graph showing the relationship between the lighting time of the light source 21 and the flow path surface temperature when the input current to the light source 21 is changed. The horizontal axis in Fig. 10 indicates the lighting time (minutes) of the light source 21, and the vertical axis in Fig. 10 indicates the surface temperature (°C) of the flow path 24. The conditions for measurement in Fig. 10 were the same as those in Fig. 9, except that the input current was 50 mA, 100 mA, 200 mA, 300 mA, and 400 mA, and the surface temperature was measured with a thermocouple thermometer.

[0071] 10, the relationship between the illumination time and the flow path surface temperature at a given input current shows a significant correlation. Therefore, by determining the above relationship in advance, even if a temperature sensor is not used as the sensor S, it is possible to estimate the surface temperature of the flow path 24 based on the input current and irradiation time to the light source 21. Therefore, it is possible to control the light source 21 so that the surface temperature of the flow path 24 does not exceed a given threshold value.

[0072] When an illuminance sensor is used as the sensor S, the irradiance of light irradiated from the multiple light sources 21 can be feedback-controlled so that light with the minimum irradiance required for photoisomerization of the other isomer is irradiated. The minimum irradiance required for photoisomerization can be calculated by calculating the time (s) required for the other isomer to pass through the light irradiated portion from the volume of the portion of the flow path 24 where the light is irradiated and the flow rate (ml / s) of the other isomer flowing through the flow path 24, and then calculating the correlation between the previously calculated irradiation time and the irradiance required to obtain a desired degree of isomerization. The irradiance of light irradiated into the flow path 24, which is the irradiance of light actually irradiated to the other isomer, can be calculated from the transmittance of the light irradiated from the light source 21 with respect to the material and wall thickness of the flow path 24. Furthermore, even if an illuminance sensor is not used as the sensor S, the input current to the multiple light sources 21 may be controlled to control the irradiance of the light irradiated from the multiple light sources 21, so that light with the minimum irradiance required for photoisomerization of the other isomer is irradiated.

[0073] It is also possible to perform both control so that the surface temperature of the flow channel 24 does not exceed a predetermined threshold value and control so that light with the minimum irradiance required for photoisomerization of the other isomer is irradiated. For example, control can be performed so that light with the minimum irradiance required for photoisomerization of the other isomer is irradiated within a range in which the surface temperature of the flow channel 24 does not exceed a predetermined threshold value. This makes it possible to optimize the amount of light irradiated from the light source 21.

[0074] The isomer preparation apparatus 1 may have a guard column at the rear of the light irradiation section 20 and between the light irradiation section 20 and the division section 10. This allows the photosensitizer to be adsorbed and removed even if it leaks from the light irradiation section. Therefore, when a chiral column is provided in the division section 10, it is possible to prevent contamination of the chiral column, diffusion into the apparatus, and mixing into the target product. The guard column is not particularly limited, and a known guard column such as a normal phase guard column using silica gel or the like capable of selectively adsorbing the photosensitizer can be used. Note that even if a guard column is provided in the isomer preparation apparatus 1, the peak position of the signal intensity due to each isomer will shift overall, but there is no particular effect on the separation ability and isomerization of the chiral column.

[0075] The isomer preparation apparatus 1 according to this embodiment separates one of the isomers separated by the separation section 10 and sends the other isomer to the light irradiation section 20. The light irradiation section 20 irradiates the other isomer with light to generate an isomer mixture. The isomer mixture is sent to the separation section 10 again. That is, the isomer preparation apparatus 1 is a circulating apparatus, and the yield of one of the isomers can be significantly improved by repeating circulation within the apparatus. If one of the isomers and the other isomers are not sufficiently separated by the separation section 10, a cycle in which separation is not performed may be provided between cycles in which one of the isomers is separated, and separation may be performed only in the cycle in which one of the isomers and the other isomers are completely separated. Since the isomer preparation apparatus 1 is a circulating apparatus, the solvent can be reused, and it is easy to repeat the separation and photoisomerization. Furthermore, the light irradiation section 20 allows the other isomer to be irradiated with light uniformly and efficiently while ensuring safety.

[0076] <Isomer preparation method> The method for preparing an isomer using the above-mentioned isomer preparation apparatus 1 includes the following steps A to C. Step A: A step of separating an isomeric mixture into one isomer and the other isomer. Step B: A step of irradiating the other isomer obtained in step A or step C with light to photoisomerize the isomer. Step C: A step of separating the isomer mixture obtained in Step B into one isomer and the other isomer.

[0077] The resolution method in step A is performed by a resolution unit 10, and the resolution method in step C is performed by the same resolution unit 10 as in step A. When a sulfoxide compound is used as the isomer mixture to be resolved in steps A and C, it is preferable to adopt a chromatography method using a chiral column as the resolution method. The photoisomerization method in step B is performed by a light irradiation unit 20.

[0078] Other preferred embodiments of the present invention will be described below. Descriptions of configurations similar to those of the above embodiment may be omitted.

[0079] Second Embodiment The light irradiation unit 20a according to the second embodiment has six housings 23a, as shown in FIG. 5. One end side of the mounting surface to which the light source 21 and the substrate 22 of the housings 23a are fixed extends toward the end direction, forming a connection portion 231. The connection portion 231 is fixed in contact with an end face 233 on the other end side of the mounting surface of another housing 23, and a plurality of housings 23a are combined to form an internal space having a hexagonal cross-sectional shape. The end face 233 on the other end side is inclined at approximately 60° with respect to the mounting surface. With the above-mentioned configuration of the light irradiation unit 20a, the light sources 21 are evenly arranged in six directions around the flow path 24 so that the angles between the optical axes L2 adjacent to the light source 21 fixed to the housing 23a are approximately 60°.

[0080] Third Embodiment The light irradiation unit 20b according to the third embodiment has eight housings 23b, as shown in FIG. 6. One end side of the mounting surface of the housings 23b to which the light source 21 and the substrate 22 are fixed extends toward the end direction, forming a connection portion 231. The connection portion 231 is fixed in contact with an end face 234 on the other end side of the mounting surface of the other housing 23, and a plurality of housings 23b are combined to form an internal space having an octagonal cross-sectional shape. The end face 234 on the other end side is inclined at approximately 45° with respect to the mounting surface. With the configuration of the light irradiation unit 20b, the light sources 21 are evenly arranged in eight directions around the flow path 24 so that the angles between the optical axes L3 adjacent to the light source 21 fixed to the housing 23b are approximately 45°.

[0081] The configurations of the light irradiation unit in the second and third embodiments are examples, but the number of housings 23 combined in the light irradiation unit can be adjusted arbitrarily. The distance from the light source 21 to the flow path 24 can also be adjusted arbitrarily by adjusting the cross-sectional length of the mounting surface of the housing 23. Therefore, the number of directions in which light is irradiated from the light source 21 to the flow path 24 and the distance to the flow path 24 can be adjusted arbitrarily according to the diameter and number of the flow path 24. EXAMPLES

[0082] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0083] Example 1: Optical resolution of racemic sulfoxide compound In Example 1, an isomer preparation apparatus 1 having a light irradiation unit as shown in Figures 2 to 4 was used to optically resolve a racemic compound as an isomer mixture represented by the following formula, and an S-form compound was selectively prepared. [ka]

[0084] Specifically, a racemic compound was optically resolved by recycling HPLC using a chiral column as the resolution section to separate the S-compound, while the R-compound was returned from the column outlet to the column inlet. In the process of returning the R-compound to the column inlet, the R-compound was photo-racemized by irradiating it with light from the light irradiation section. The same column and solvent as those used in the recycling HPLC were used as the flow path and solvent in the light irradiation section. The conditions for the recycling HPLC and the light irradiation section are as follows.

[0085] -Recycled HPLC conditions- Column: CHIRALPAK ID (10 mm x 250 mm, particle size 5 μm) + CHIRALPAK ID (10 mm x 250 mm, particle size 5 μm) (manufactured by Daicel Corporation) Mobile phase (solvent): Acetonitrile -Light irradiation conditions- Light source: LED lamp (wavelength 365 nm, 100 mA) Solid-phase photosensitizer (PS-0.5): 2,4,6-triphenylpyrylium tetrafluoroborate (TPT + ) (manufactured by Aldrich) immobilized on an ion exchange resin DOWEX 50Wx8 200-400 H (manufactured by Muromachi Technos Co., Ltd.) was used as a carrier (installation range: 70 mm). Flow rate: 2.0mL / min Irradiance: 40.6mW / cm 2 (Calculated from Figure 9) Temperature: 28.7℃ (lighting time 10 minutes, calculated from Figure 10)

[0086] FIG. 7 shows a chromatogram of the signal intensity over time, which is the result of the resolution by recycling HPLC in which the optical resolution and photoisomerization of Example 1 were repeated twice. The vertical axis in FIG. 7 shows the signal intensity, and the horizontal axis shows the time (s). As shown in FIG. 7, peaks P1 and P2 due to each isomer were detected by the first optical resolution, and peaks P3 and P4 due to each isomer were detected by the second optical resolution. Therefore, it was confirmed that the other isomer was isomerized during the second optical resolution. Therefore, it is clear that the yield of the desired isomer can be improved by repeating the optical resolution and photoisomerization.

[0087] Example 2: Optical resolution of racemic sulfoxide compounds (effect of light-transmitting particles) In Example 2, the S-compound was selectively prepared using the same isomer preparation apparatus 1 as in Example 1 and a racemic compound as an isomer mixture, except that in addition to the solid-phase photosensitizer (PS-0.5), glass beads (Fuji Glass Beads FGB-320, median diameter 53 to 38 μm, manufactured by Fuji Manufacturing Co., Ltd.) were filled as light-transmitting particles in the flow path of the light irradiation section in the amounts shown in Table 1 below.

[0088] [Table 1]

[0089] FIG. 8 shows a chromatogram of the signal intensity over time, which is the second resolution result by recycling HPLC in which the optical resolution and photoisomerization of Example 2 were repeated twice. The vertical axis in FIG. 8 indicates signal intensity, and the horizontal axis indicates time (s). The graphs of 100%, 50%, 25%, 10%, and 5% in FIG. 8 correspond to the mass ratio (%) of the solid-phase photosensitizer shown in Table 1 (the mass ratio of the solid-phase photosensitizer to the total mass of the solid-phase photosensitizer and the glass beads). As shown in FIG. 8, compared with the solid-phase photosensitizer having a mass ratio of 100% by mass, the solid-phase photosensitizer having a part (especially 90% by mass or more) replaced with glass beads has peaks P3 and P4 indicating signal intensity that are sharper, and it was confirmed that isomerization has progressed more. Therefore, it is clear that by filling the flow path of the light irradiation section with light-transmitting particles together with a solid-phase photosensitizer, not only can the amount of solid-phase photosensitizer used be reduced, but also the efficiency of photoisomerization can be improved.

[0090] Using a light irradiation section in which the mass ratio of solid-phase photosensitizer was 5 mass% (light-transmitting particles were 95 mass%) filled in the flow path, six cycles of separation of the S-form compound were repeated under the conditions of Example 2, and the enantiomeric excess was calculated by chiral HPLC under the following conditions. As a result, a yield of 96% (enantiomeric excess of 94%ee) of the S-form compound was obtained.

[0091] -Chiral HPLC conditions- Column: CHIRALPACK IG (particle size 5 μm) (manufactured by Daicel Corporation) Mobile phase: Acetonitrile Flow rate: 0.5mL / min

[0092] <Reference Example 1: Study of photosensitizers> [ka]

[0093] As shown in the above scheme, optically active sulfoxide compounds were irradiated with light in the presence of various photosensitizers to examine the effect of the photosensitizer on the photoracemization reaction. The following eight photosensitizers were used.

[0094] [ka]

[0095] A photosensitizer (0.02μmol-2μmol, 0.1mol%-10mol%) was added to an acetonitrile solution (2.0mL, 0.01M) containing an optically active sulfoxide compound ((+)-1) (3.08mg, 0.02mmol), and the mixture was irradiated with light using an 18W LED light (wavelength 365nm-425nm) or a spectrofluorophotometer (wavelength 290nm-330nm, Shimadzu Corporation, RF-5300PC). For comparison, a similar experiment was performed without adding a photosensitizer. During the light irradiation, samples (20μL) were taken over time, and the enantiomeric excess was calculated by chiral HPLC. The chiral HPLC conditions are as follows.

[0096] -Chiral HPLC conditions- Column: CHIRALPACK IH (10 mm x 250 mm, particle size 5 μm) (manufactured by Daicel Corporation) Mobile phase: hexane / isopropanol = 60 / 40 Flow rate: 0.5mL / min Detection: 254nm

[0097] [Table 2]

[0098] As shown in Table 2, in entries 1 to 8, in which light was irradiated in the presence of a photosensitizer, the photoracemization reaction was able to proceed efficiently. On the other hand, in entry 9, in which no photosensitizer was used, the photoracemization reaction did not proceed very much even when irradiated with light at a wavelength of 425 nm for 60 minutes.

[0099] <Reference Example 2: Examination of solvents in photoracemization reaction using 9,10-DCA as a photosensitizer> [ka]

[0100] 9,10-dicyanoanthracene (9,10-DCA) (0.45 mg, 2 μmol, 10 mol%) was added to a solution of the optically active sulfoxide compound ((+)-1) (3.08 mg, 0.02 mmol) dissolved in various solvents (2.0 mL), and the solution was irradiated with light using an 18 W LED light (wavelength 425 nm). During the light irradiation, samples (20 μL) were taken over time, and the enantiomeric excess was calculated by chiral HPLC. The chiral HPLC conditions are as follows.

[0101] -Chiral HPLC conditions- Column: CHIRALPACK IH (10 mm x 250 mm, particle size 5 μm) (manufactured by Daicel Corporation) Mobile phase: hexane / isopropanol = 60 / 40 Flow rate: 0.5mL / min Detection: 254nm

[0102] [Table 3]

[0103] As shown in Table 3, photoracemization was possible when any of the solvents was used, and the photoracemization reaction was particularly fast when acetonitrile was used.

[0104] <Reference Example 3: TPT as a photosensitizer + Examination of solvents in photoracemization reactions using [ka]

[0105] The optically active sulfoxide compound ((+)-1) (3.08 mg, 0.02 mmol) was dissolved in various solvents (2.0 mL) and 2,4,6-triphenylpyrylium tetrafluoroborate (TPT + ) (80μg, 0.2μmol, 1mol%) was added and irradiated with light using an 18W LED light (wavelength 425nm). During the irradiation, samples (20μL) were taken over time and the enantiomeric excess was calculated by chiral HPLC. The chiral HPLC conditions were as follows:

[0106] -Chiral HPLC conditions- Column: CHIRALPACK IH (10 mm x 250 mm, particle size 5 μm) (manufactured by Daicel Corporation) Mobile phase: hexane / isopropanol = 60 / 40 Flow rate: 0.5mL / min Detection: 254nm

[0107] [Table 4]

[0108] As shown in Table 4, photoracemization was possible when any of the solvents was used, and the photoracemization reaction was particularly fast when acetonitrile was used.

[0109] Reference Example 4: Mes-Acr-Me as a photosensitizer + Examination of solvents in photoracemization reactions using [ka]

[0110] The optically active sulfoxide compound ((+)-1) (3.08 mg, 0.02 mmol) was dissolved in various solvents (2.0 mL) and 10-methyl-9-(2,4,6-trimethylphenyl)acridinium perchlorate (Mes-Acr-Me +) (82.3 μg, 0.2 μmol, 1 mol%) was added and irradiated with light using an 18 W LED light (wavelength 425 nm). During the irradiation, samples (20 μL) were taken over time and the enantiomeric excess was calculated by chiral HPLC. The chiral HPLC conditions were as follows.

[0111] -Chiral HPLC conditions- Column: CHIRALPACK IH (10 mm x 250 mm, particle size 5 μm) (manufactured by Daicel Corporation) Mobile phase: hexane / isopropanol = 60 / 40 Flow rate: 0.5mL / min Detection: 254nm

[0112] [Table 5]

[0113] As shown in Table 5, photoracemization was possible when any of the solvents was used, and the photoracemization reaction was particularly fast when acetonitrile was used.

[0114] <Reference example 5: TPT + Preparation of solid-phase photosensitizers by covalently binding to a carrier [ka]

[0115] 2,4,6-Triphenylpyrylium tetrafluoroborate (TPT + Sodium acetate (0.32 g, 4.0 mmol, 4.0 equivalents) and R-Cat-Sil TA (1.0 g, 1.0 mmol, 1.0 equivalents; Kanto Chemical Co., Ltd.) were added to an ethanol solution (10 mL) containing 2-(2-(4-phenylenediamine)-2-propanediol (0.40 g, 1.0 mmol, 1.0 equivalents), and the mixture was stirred at 80° C. overnight. After cooling to 0° C., the mixture was filtered, and the residue was washed with methanol and dichloromethane and then dried to obtain solid-phase photosensitizer 2 (1.12 g).

[0116] [ka]

[0117] Acetic anhydride (0.90 mL, 10.0 mmol, 20 equivalents) and pyridine (0.8 mL, 10.0 mmol, 20 equivalents) were added to a dichloromethane solution (10 mL) containing solid-phase photosensitizer 2 (0.50 g), and the mixture was stirred at room temperature for 5 hours. After filtration, the residue was washed with dichloromethane and dried to obtain solid-phase photosensitizer 3 (478 mg).

[0118] <Reference Example 6: Study of photoracemization using solid-phase photosensitizer 2 or solid-phase photosensitizer 3> [ka]

[0119] Solid-phase photosensitizer 2 (5 mg) or solid-phase photosensitizer 3 (5 mg) was added to an acetonitrile solution (1.0 mL, 0.01 M) containing an optically active sulfoxide compound ((+)-1) (1.54 mg, 0.01 mmol), and the mixture was irradiated with light using a spectrofluorophotometer (wavelength 310 nm, Shimadzu Corporation, RF-5300PC). During the light irradiation, samples (20 μL) were taken over time, and the enantiomeric excess was calculated by chiral HPLC. The chiral HPLC conditions were as follows.

[0120] -Chiral HPLC conditions- Column: CHIRALPACK IH (10 mm x 250 mm, particle size 5 μm) (manufactured by Daicel Corporation) Mobile phase: hexane / isopropanol = 60 / 40 Flow rate: 0.5mL / min Detection: 254nm

[0121] The changes in enantiomeric excess over time when solid-phase photosensitizer 2 and solid-phase photosensitizer 3 were used are shown in Figures 11 and 12, respectively. As shown in Figures 11 and 12, even when the photosensitizer was immobilized on a carrier, the photoracemization reaction was able to proceed efficiently.

[0122] <Reference Example 7: Preparation of a solid-phase photosensitizer in which 9,10-DCA is covalently bound to a carrier> [ka]

[0123] Under an argon atmosphere, trimethylsilyl cyanide (1.71 mL, 13.9 mmol, 2.05 equivalents) was added to an N,N-dimethylformamide solution (6.7 mL) containing 2-methylanthraquinone (1.50 g, 6.75 mmol) and potassium cyanide (22.0 mg, 0.38 mmol, 0.05 equivalents), and the mixture was stirred at room temperature overnight. After the reaction was completed, acetonitrile (30 mL) was added, followed by phosphorus tribromide (1.54 mL, 16.2 mmol, 1.2 equivalents), and the mixture was stirred at room temperature overnight. After the reaction was stopped by adding dichloromethane, the mixture was filtered, and the residue obtained by concentrating the filtrate was purified by column chromatography (developing solvent: hexane / dichloromethane = 1 / 1) to obtain compound 6 (200 mg, 0.826 mmol, yield: 12%).

[0124] [ka]

[0125] Under an argon atmosphere, N-bromosuccinimide (290 mg, 1.90 mmol, 2.0 equivalents) and benzoyl peroxide (10.0 mg, 0.04 mmol, 0.05 equivalents) were added to a carbon tetrachloride solution (10 mL) containing compound 6 (207 mg, 0.86 mmol), and the mixture was stirred under heating and reflux for 7 hours. After the reaction was completed, the residue obtained by concentration was purified by column chromatography (developing solvent: hexane / ethyl acetate = 20 / 1) to obtain compound 7. The obtained compound 7 was dissolved in dichloromethane (9.3 mL), and R-Cat-Sil TA (1.0 g, 1.0 mmol, 1.1 equivalents; Kanto Chemical Co., Ltd.) and triethylamine (0.42 mL, 3.00 mmol, 3 equivalents) were added under an argon atmosphere, and the mixture was stirred overnight at room temperature. After filtration, the residue was washed with water, methanol, dichloromethane, and ethyl acetate, and dried to give solid phase photosensitizer 8 (1.23 g).

[0126] <Reference example 8: TPT + Preparation of solid-phase photosensitizers in which the compound is ionically bound to a carrier> [ka]

[0127] 2,4,6-Triphenylpyrylium tetrafluoroborate (TPT + DOWEX 50Wx8 (2.0 g; Fujifilm Wako Pure Chemical Industries, Ltd.) was added to an aqueous solution (60 mL) containing 1,2-dichloromethane (0.20 g, 0.50 mol) and stirred at room temperature for 17 hours. After filtration, the residue was washed with water, methanol, dichloromethane, and acetonitrile, and dried to obtain solid-phase photosensitizer 9 (1.70 g).

[0128] <Reference Example 9: Study of photoracemization using solid-phase photosensitizer 9> [ka]

[0129] Solid-phase photosensitizer 9 (5 mg) was added to an acetonitrile solution (1.0 mL, 0.01 M) containing an optically active sulfoxide compound ((+)-1) (1.54 mg, 0.01 mmol), and the mixture was irradiated with light using an 18 W LED light (wavelength 425 nm). During the light irradiation, samples (20 μL) were taken over time, and the enantiomeric excess was calculated by chiral HPLC. The chiral HPLC conditions were as follows.

[0130] -Chiral HPLC conditions- Column: CHIRALPACK IH (10 mm x 250 mm, particle size 5 μm) (manufactured by Daicel Corporation) Mobile phase: hexane / isopropanol = 60 / 40 Flow rate: 0.5mL / min Detection: 254nm

[0131] By irradiating the solid-phase photosensitizer 9 with 425 nm light for 10 min, the enantiomeric excess decreased from 99.2% ee to 2.7% ee, confirming that the photoracemization reaction proceeded efficiently.

[0132] <Reference Example 10: Examination of substrate generality> [ka]

[0133] 9,10-dicyanoanthracene (9,10-DCA) (0.70 mg, 0.003 mmol, 10 mol%) was added to an acetonitrile solution (3.0 mL, 0.01 M) containing an optically active sulfoxide compound ((+)-10a) (4.30 mg, 0.03 mmol), and the mixture was irradiated with light using an 18 W LED light (wavelength 425 nm). During the light irradiation, samples (20 μL) were taken over time, and the enantiomeric excess was calculated by chiral HPLC. The same operation as above was performed except that (+)-10b to 10i were used instead of (+)-10a. The chiral HPLC conditions are as follows.

[0134] -Chiral HPLC conditions (10a-10d, 10f-10h)- Column: CHIRALPACK IH (10 mm x 250 mm, particle size 5 μm) (manufactured by Daicel Corporation) Mobile phase: hexane / isopropanol = 60 / 40 Flow rate: 0.5mL / min Detection: 254nm

[0135] -Chiral HPLC conditions (10e)- Column: CHIRALPACK IA (10 mm x 250 mm, particle size 5 μm) (manufactured by Daicel Corporation) Mobile phase: hexane / ethanol = 50 / 50 Flow rate: 0.5mL / min Detection: 254nm

[0136] -Chiral HPLC conditions (10i)- Column: CHIRALPACK IH (10 mm x 250 mm, particle size 5 μm) (manufactured by Daicel Corporation) Mobile phase: hexane / isopropanol = 80 / 20 Flow rate: 0.5mL / min Detection: 254nm

[0137] [Table 6]

[0138] As shown in Table 6, photoracemization was possible when any of the sulfoxide compounds was used. [Explanation of symbols]

[0139] 1 isomer preparation device, 10 division section, 20 light irradiation section, 21 light source, 24 flow path, S sensor, F solid-phase photosensitizer

Claims

1. An isomer preparation apparatus for selectively preparing one isomer of an isomer mixture, comprising: The isomer mixture is a mixture of isomers of a sulfoxide compound having a sulfur atom of a sulfoxide group as an asymmetric center, a division section for dividing the isomer mixture into the one isomer and the other isomer; a light irradiation unit configured to be capable of irradiating the other isomer split by the splitting unit with light that induces photoisomerization, the splitting unit splits the isomer mixture photoisomerized by the light irradiating unit into the one isomer and the other isomer, the light irradiation unit includes a flow path through which the other isomer flows, a light source disposed along the flow path, and a housing capable of housing the flow path and the light source; The flow path is filled with a solid-phase photosensitizer in which a photosensitizer is immobilized on a carrier.

2. 2. The isomer preparation apparatus according to claim 1, wherein the splitting unit is capable of repeatedly splitting the isomer mixture photoisomerized by the light irradiating unit into the one isomer and the other isomer multiple times.

3. The isomer preparation apparatus according to claim 1 , wherein the flow passage is further filled with optically transparent particles.

4. 4. The isomer preparation apparatus according to claim 1, wherein the flow path is made of a material that is transmissible to the light irradiated from the light source.

5. 5. The isomer preparation apparatus according to claim 1, wherein the housing is made of a metal material and prevents leakage of light emitted from the light source to the outside.

6. a sensor capable of detecting at least one of a temperature and an irradiance on the surface of the flow path; 6. The isomer preparation apparatus according to claim 1, wherein the amount of light irradiated from said light source to said flow path is controlled based on the detection result of said sensor.

7. 7. The apparatus for preparing an isomer according to claim 1, wherein the wavelength range of the light irradiated from the light source is within a range of 200 nm to 450 nm.

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