METHOD FOR PREPARING ENANTIOMER OF SULFOXIDE COMPOUND, AND SYSTEM FOR PREPARING ENANTIOMER

Abstract

An enantiomer preparation method in which one enantiomer of a sulfoxide compound is selectively prepared, the sulfoxide compound having a sulfur atom of a sulfoxide group as an asymmetric center, the method including a step A for optically resolving an enantiomer mixture of a sulfoxide compound into one enantiomer and the other enantiomer; a step B for irradiating with light the other enantiomer obtained in step A or step C to racemize the enantiomer; and step C for optically resolving the enantiomer mixture of the sulfoxide compound obtained in step B into one enantiomer and the other enantiomer. A system for preparing an enantiomer which is used in the enantiomer preparation method.

Claims

1. A method for selectively preparing one of enantiomers of a sulfoxide compound having a sulfur atom in a sulfoxide group as an asymmetric center by using recycle HPLC provided with a chiral column, the method comprising: a step A for introducing an enantiomer mixture of the sulfoxide compound into the chiral column to optically resolve the enantiomer mixture into one enantiomer and the other enantiomer and collect the one enantiomer, a step B for irradiating the other enantiomer which is a residue after collecting in Step A or Step C with light to racemize the enantiomer, during a process of returning the other enantiomer from the column outlet to the column inlet of the chiral column, and a step C for introducing the enantiomer mixture of the sulfoxide compound obtained by racemization in Step B into the chiral column to optically resolve the enantiomer mixture into the one enantiomer and the other enantiomer and collect the one enantiomer, wherein Step B and Step C are continuously repeated.

2. (canceled)

3. (canceled)

4. The method for preparing an enantiomer according to claim 1, wherein the sulfoxide compound is a compound represented by formula (1) below: ##STR00021## wherein, R.sup.1, R.sup.2 and R.sup.3 are each independently a hydrogen atom, a halogen atom, a cyano group, a nitro group, a hydroxy group, a carboxy group, an alkyl group which optionally has a substituent, an alkoxy group which optionally has a substituent, an alkoxycarbonyl group, an aryl group, an aryloxy group, an acyl group, an acyloxy group or a heteroaryl group, R.sup.4, R.sup.5 and R.sup.6 are each independently a hydrogen atom, an alkyl group which optionally has a substituent, an alkoxy group which optionally has a substituent, or an amino group which optionally has a substituent, R.sup.7 is a hydrogen atom, a hydrocarbon group which optionally has a substituent, an acyl group or an acyloxy group, X, Y and Z are each independently a nitrogen atom or CH, and * represents an asymmetric center.

5. The method for preparing an enantiomer according claim 1, wherein in Step B the other enantiomer is irradiated with light in the presence of a photosensitizer to racemize the enantiomer.

6. An enantiomer preparation system using recycle HPLC provided with a chiral column, wherein the enantiomer preparation system is used in the method for preparing an enantiomer according to claim 1, comprising: an optical resolution part having the chiral column to optically resolve the enantiomer mixture of the sulfoxide compound into one enantiomer and the other enantiomer, and collect the one enantiomer, and a light irradiation part for irradiating the other enantiomer which is a residue after collecting in the optical resolution part with light to racemize the enantiomer, during a process of returning the other enantiomer from the column outlet to the column inlet of the chiral column, wherein the optical resolution part optically resolves the enantiomer mixture of the sulfoxide compound obtained in the light irradiation part into one enantiomer and the other enantiomer, and collect the one enantiomer.

7. (canceled)

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0022] FIG. 1 is a drawing which shows an example of the schematic constitution of an enantiomer preparation system according to the present embodiment.

[0023] FIG. 2 is a graph which shows changes in enantiomeric excess with time when a photoracemization reaction of an optically active sulfoxide compound is allowed to proceed in the presence of a solid photosensitizer 2 in which TPT.sup.+, a photosensitizer, is covalently bound to a carrier.

[0024] FIG. 3 is a graph which shows changes in enantiomeric excess with time when a photoracemization reaction of an optically active sulfoxide compound is allowed to proceed in the presence of a solid photosensitizer 3 in which TPT.sup.+, a photosensitizer, is covalently bound to a carrier.

PREFERRED MODE FOR CARRYING OUT THE INVENTION

<Method for Preparing Enantiomer>

[0025] The method for preparing an enantiomer according to the present embodiment is a method for preparing an enantiomer, in which one enantiomer of a sulfoxide compound having the sulfur atom in a sulfoxide group as an asymmetric center is selectively prepared, the method including the following Step A to Step C:

Step A for optically resolving an enantiomer mixture of the sulfoxide compound into one enantiomer and the other enantiomer;
Step B for irradiating the other enantiomer obtained in Step A or Step C with light to racemize the enantiomer; and
Step C for optically resolving an enantiomer mixture of the sulfoxide compound obtained in Step B into one enantiomer and the other enantiomer.

(Sulfoxide Compound)

[0026] The sulfoxide compound is not particularly restricted as long as it is a compound which has an asymmetric center at the sulfur atom in a sulfoxide group and has S- and R-enantiomers based on the configuration of this asymmetric center. The sulfoxide compound is preferably a compound having only one asymmetric center from the viewpoint of efficiently preparing only a desired enantiomer.

[0027] A suitable sulfoxide compound is, for example, a compound represented by formula (1) below. The compound represented by formula (1) below has e.g. excellent gastric antisecretory, anti-ulcer, mucosal protective, anti-Helicobacter pylori actions, and is a compound useful as a proton pump inhibitor.

##STR00002##

[0028] In the formula (1), R.sup.1, R.sup.2 and R.sup.3 are each independently 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; R.sup.4, R.sup.5 and R.sup.6 are each independently 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; R.sup.7 is a hydrogen atom, a hydrocarbon group which may have a substituent, an acyl group or an acyloxy group; X, Y and Z are each independently a nitrogen atom or CH; and represents an asymmetric center.

[0029] Examples of the halogen atom represented by R.sup.1, R.sup.2 and R.sup.3 include fluorine atom, chlorine atom, bromine atom, iodine atom and the like.

[0030] Examples of the “alkyl group” in the “alkyl group which may have a substituent” represented by R.sup.1, R.sup.2 and R.sup.3 include linear or branched C.sub.1-7 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. Examples of the “substituent” in the “alkyl group which may have a substituent” include a halogen atom, a hydroxy group, C.sub.1-6 alkoxy groups (e.g. a methoxy group, an ethoxy group, an n-propoxy group and an isopropoxy group), C.sub.1-6 alkoxy-carbonyl groups (e.g. a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group and an isopropoxycarbonyl group), a carbamoyl group and the like. The number of substituents is not particularly restricted, and may be, for example, one to three. When the number of substituents is two or more, the substituents may be the same or different.

[0031] Examples of the “alkoxy group” in the “alkoxy group which may have a substituent” represented by R.sup.1, R.sup.2 and R.sup.3 include linear or branched C.sub.1-6 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. Examples of the “substituent” in the “alkoxy group which may have a substituent” include the same as the above-described “substituent” in the “alkyl group which may have a substituent”. The number of substituents is not particularly restricted and may be, for example, one to three. When the number of substituents is two or more, the substituents may be the same or different.

[0032] Examples of the “alkoxycarbonyl group” represented by R.sup.1, R.sup.2 and R.sup.3 include groups in which the alkoxy moiety is a linear or branched C.sub.1-6 alkoxy group 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 and an n-hexyloxycarbonyl group.

[0033] Examples of the “aryl group” represented by R.sup.1, R.sup.2 and R.sup.3 include C.sub.6-14 aryl groups such as a phenyl group, a 1-naphthyl group, a 2-naphthyl group, a biphenylyl group and a 2-anthryl group.

[0034] Examples of the “aryloxy group” represented by R.sup.1, R.sup.2 and R.sup.3 include C.sub.6-14 aryloxy groups such as a phenyloxy group, a 1-naphthyloxy group, a 2-naphthyloxy group, a biphenylyloxy group and a 2-anthryloxy group.

[0035] Examples of the “acyl group” represented by R.sup.1, R.sup.2 and R.sup.3 include a formyl group; C.sub.1-6 alkyl-carbonyl groups such as an acetyl group and a propionyl group; C.sub.6-14 aryl-carbonyl groups such as a benzoyl group and a naphthalenecarbonyl group; and the like.

[0036] Examples of the “acyloxy group” represented by R.sup.1, R.sup.2 and R.sup.3 include C.sub.1-6 alkyl-carbonyloxy groups such as an acetyloxy group and a propionyloxy group; C.sub.6-14 aryl-carbonyloxy groups such as a benzoyloxy group and a naphthalenecarbonyloxy group; and the like.

[0037] Examples of the “heteroaryl group” represented by R.sup.1, R.sup.2 and R.sup.3 include 5-membered to 10-membered ring groups including one to three hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom. Specific examples thereof include a 1-, 2- or 3-thienyl group, a 1-, 2-, 3- or 4-pyridyl group, a 2- or 3-furyl group, a 1-, 2- or 3-pyrrolyl group, a 2-, 3-, 4-, 5- or 8-quinolyl group, a 1-, 3-, 4- or 5-isoquinolyl group, a 1-, 2- or 3-indolyl group and the like.

[0038] Examples of the “alkyl group which may have a substituent” and “alkoxy group which may have a substituent” represented by R.sup.4, R.sup.5 and R.sup.6 include the same as the “alkyl group which may have a substituent” and “alkoxy group which may have a substituent” represented by R.sup.1, R.sup.2 and R.sup.3.

[0039] Examples of the “amino group which may have a substituent” represented by R.sup.4, R.sup.5 and R.sup.6 include an amino group; mono-C.sub.1-6 alkylamino groups such as a methylamino group, an ethylamino group, an n-propylamino group and an isopropylamino group; mono-C.sub.6-14 arylamino groups such as a phenylamino group, a 1-naphthylamino group and a 2-naphthylamino group; di-C.sub.1-6 alkylamino groups such as a dimethylamino group, a diethylamino group, a methylethylamino group and a methylisobutylamino group; di-C.sub.6-14 arylamino groups such as a diphenylamino group; and the like.

[0040] Examples of the “hydrocarbon group” in the “hydrocarbon group which may have a substituent” represented by R.sup.7 include C.sub.1-19 hydrocarbon groups such as an alkyl group, an alkenyl group, an alkynyl group, an aryl group and an aralkyl group.

[0041] Examples of the alkyl group in R.sup.7 include linear or branched C.sub.1-6 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 isopentyl group, a sec-pentyl group, a neopentyl group, an n-hexyl group and an isohexyl group; cyclic C.sub.3-14 alkyl groups such as a cyclopentyl group and a cyclohexyl group; and the like.

[0042] Examples of the alkenyl group in R.sup.7 include linear or branched C.sub.2-6 alkenyl groups such as an allyl group, an isopropenyl group, an isobutenyl group, a 2-pentenyl group and a 2-hexenyl group; cyclic C.sub.3-14 alkenyl groups such as a 2-cyclohexenyl group; and the like.

[0043] Examples of the alkynyl group in R.sup.7 include linear or branched C.sub.2-6 alkynyl groups such as a propargyl group, a 2-butynyl group, a 3-butynyl group, a 3-pentynyl group and a 3-hexynyl group.

[0044] Examples of the aryl group in R.sup.7 include C.sub.6-14 aryl groups such as a phenyl group, a 1-naphthyl group, a 2-naphthyl group, a biphenylyl group and a 2-anthryl group.

[0045] Examples of the aralkyl group in R.sup.7 include C.sub.7-19 aralkyl groups such as phenyl-C.sub.1-4 alkyl groups, e.g. a benzyl group, a phenethyl group and a phenylpropyl group; a benzhydryl group; and a trityl group.

[0046] When the hydrocarbon group represented by R.sup.7 is an alkyl group, an alkenyl group or an alkynyl group, the hydrocarbon group may be substituted by an alkylthio group (e.g. a C.sub.1-4 alkylthio group such as a methylthio group, an ethylthio group, an n-propylthio group or an isopropylthio group), a halogen atom (e.g. fluorine atom, chlorine atom, bromine atom or iodine atom), an alkoxy group (e.g. a C.sub.1-6 alkoxy group such as a methoxy group, an ethoxy group, an n-propoxy group or an isopropoxy group), an acyloxy group (e.g. a C.sub.1-6 alkyl-carbonyloxy group such as an acetyloxy group or an n-propionyloxy group; a C.sub.6-14 aryl-carbonyloxy group such as a benzoyloxy group or a naphthalenecarbonyloxy group), a nitro group, an alkoxycarbonyl group (e.g. a C.sub.1-6 alkoxy-carbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group or an isopropoxycarbonyl group), an alkylamino group (e.g. a mono- or di-C.sub.1-6 alkylamino group such as a methylamino group, an ethylamino group, an n-propylamino group, an isopropylamino group, a dimethylamino group, a diethylamino group, a methylethylamino group or a methylisobutylamino group), an alkoxyimino group (e.g. a C.sub.1-6 alkoxy-imino group such as a methoxyimino group, an ethoxyimino group, an n-propoxyimino group or an isopropoxyimino group), a hydroxyimino group or the like. The number of substituents is not particularly restricted and may be, for example, one to three. When the number of substituents is two or more, the substituents may be the same or different.

[0047] In addition, when the above hydrocarbon group is an aryl group or an aralkyl group, the hydrocarbon group may be substituted by an alkyl group (e.g. a linear or branched C.sub.1-6 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 or an n-hexyl group; a cyclic C.sub.3-6 alkyl group such as a cyclohexyl group), an alkenyl group (e.g. a C.sub.2-6 alkenyl group such as an allyl group, an isopropenyl group, an isobutenyl group, a 1-methylallyl group, a 2-pentenyl group or a 2-hexenyl group), an alkynyl group (e.g. a C.sub.2-6 alkynyl group such as a propargyl group, a 2-butynyl group, a 3-butynyl group, a 3-pentynyl group or a 3-hexynyl group), an alkoxy group (e.g. a C.sub.1-6 alkoxy group such as a methoxy group, an ethoxy group, an n-propoxy group or an isopropoxy group), an acyl group (e.g. a formyl group; a C.sub.1-6 alkyl-carbonyl group such as an acetyl group or a propionyl group; a C.sub.6-14 aryl-carbonyl group such as a benzoyl group or a naphthalenecarbonyl group), a nitro group, an amino group, a hydroxy group, a cyano group, a sulfamoyl group, a mercapto group, a halogen atom (e.g. fluorine atom, chlorine atom, bromine atom or iodine atom), an alkylthio group (e.g. a C.sub.1-4 alkylthio group such as a methylthio group, an ethylthio group, an n-propylthio group or an isopropylthio group) or the like. The number of substituents is not particularly restricted and may be, for example, one to five. When the number of substituents is two or more, the substituents may be the same or different.

[0048] Examples of the “acyl group” and “acyloxy group” represented by R.sup.7 include the same as the “acyl group” and “acyloxy group” represented by R.sup.1, R.sup.2 and R.sup.3.

[0049] Among compounds represented by the above formula (1), preferred are compounds wherein R.sup.1 is a hydrogen atom, R.sup.2 is a hydrogen atom, a C.sub.1-4 alkyl group which may be substituted by a halogen atom, a C.sub.1-4 alkoxy group which may be substituted by a halogen atom, or a heteroaryl group (preferably a 1-, 2- or 3-pyrrolyl group), R.sup.3 is a hydrogen atom or a C.sub.1-4 alkoxy-carbonyl group, R.sup.4 is a hydrogen atom, a C.sub.1-4 alkyl group which may be substituted by a halogen atom, or a C.sub.1-4 alkoxy group which may be substituted by a halogen atom or a C.sub.1-4 alkoxy group, R.sup.5 is a hydrogen atom, or a C.sub.1-4 alkoxy group which may be substituted by a halogen atom or a C.sub.1-4 alkoxy group, R.sup.6 is a hydrogen atom, a C.sub.1-4 alkyl group which may be substituted by a halogen atom, a C.sub.1-4 alkoxy group which may be substituted by a halogen atom or a C.sub.1-4 alkoxy group, or a di-C.sub.1-4 alkylamino group, and R.sup.7 is a hydrogen atom.

[0050] 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.

##STR00003## ##STR00004##

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

(Step A)

[0052] In Step A, an enantiomer mixture of a sulfoxide compound is optically resolved into one enantiomer and the other enantiomer.

[0053] The enantiomer mixture is not particularly restricted as long as it includes R- and S-forms, and is not required to be a racemate. The enantiomeric excess of the enantiomer mixture may be 0% ee to 25% ee, may be 0% ee to 10% ee, or may be 0% ee to 5% ee.

[0054] The optical resolution method is not particularly restricted, and an optional method can be used. Examples of the optical resolution method include a chromatography method using a chiral column; an inclusion complex method using an optically active host molecule (e.g. 1,1′-bi-2-naphthol) (see e.g. Patent Documents 1 and 2); a diastereomer method in which after induction into two types of diastereomers using an optical resolution agent, the diastereomers are separated (see e.g. Patent Document 3); and the like. Among these, a chromatography method using a chiral column is preferably used in at least one of Step A and Step C described below in terms of convenience, and a chromatography method using a chiral column is more preferably used in both Step A and Step C.

(Step B)

[0055] In Step B, the other enantiomer obtained in Step A or Step C described below is irradiated with light to racemize (photoracemize) the enantiomer.

[0056] It has been reported that an optically active sulfoxide compound is racemized by light irradiation (see e.g. Non-Patent Document 1). Because of this, by irradiating the other enantiomer obtained in Step A or Step C with light, the enantiomer can be racemized.

[0057] The other enantiomer to be irradiated with light may be in a solid state or a state of being dissolved in a solvent, and the latter is preferred in terms of racemization efficiency. When using a chromatography method in Step A, the eluate including the other enantiomer can be irradiated with light.

[0058] It should be noted that a photosensitizer may be used as needed in Step B as described below.

[0059] It is preferred that the wavelength of irradiation light be properly adjusted depending on the type of the sulfoxide compound and the presence or absence of a sensitizer, and, for example, the wavelength may be 200 nm to 450 nm, may be 200 nm to 400 nm, or may be 254 nm to 365 nm. The time for light irradiation varies depending on e.g. the type of the sulfoxide compound, the wavelength of irradiation light, and the presence or absence of a sensitizer; however, in general, racemization can be sufficiently achieved by light irradiation for 5 minutes to 2 hours.

(Step C)

[0060] In Step C, an enantiomer mixture of the sulfoxide compound obtained in Step B is optically resolved into one enantiomer and the other enantiomer. The enantiomeric excess of the enantiomer mixture obtained in Step B may be 0% ee to 25% ee, may be 0% ee to 10% ee, or may be 0% ee to 5% ee.

[0061] The optical resolution method in Step C may be the same as or different from the method in Step A, and is preferably the same method. In particular, the chromatography method using a chiral column is more preferably used in both Step A and Step C.

[0062] By the above Step B and Step C, the yield of a desired enantiomer can be largely improved compared to a case where only Step A is carried out. The yield of a desired enantiomer can be further improved by repeating the above Step B and Step C as needed.

(Photosensitizer)

[0063] In the above Step B, an optically active sulfoxide compound may be irradiated with light in the presence of a photosensitizer. The efficiency of racemization can be further increased by light irradiation in the presence of a photosensitizer.

[0064] The photosensitizer is not particularly restricted, and conventionally known photosensitizers can be used. Among photosensitizers, those with the maximum absorption wavelength in a wavelength range of 365 nm to 450 nm are preferred. 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; acridinium compounds such as 10-methyl-9-(2,4,6-trimethylphenyl)acridinium salts and 3,6-diamino-10-methylacridinium salts; quinone compounds such as 2,3-dichloro-5,6-dicyano-p-benzoquinone and anthraquinone; quinolinium compounds such as 1-methylquinolinium salts and 1-methyl-6-methoxyquinolinium salts; xanthene compounds such as fluorescein and rhodamine B; thiazine compounds such as 10-phenylphenothiazine and methylthioninium salts; benzophenone compounds such as benzophenone and thioxanthone; and the like. Among these, cyanoarene compounds, pyrylium compounds, acridinium compounds, quinone compounds and quinolinium compounds are preferred.

[0065] The photosensitizer may be a solid photosensitizer which is immobilized to a carrier such as silica gel. By using the solid photosensitizer, an enantiomer mixture of the sulfoxide compound obtained in Step B and the photosensitizer can be easily separated. The method for immobilizing a photosensitizer to a carrier is not particularly restricted, and may be a covalent bond or ion bond.

<Enantiomer Preparation System>

[0066] The enantiomer preparation system according to the present embodiment is an enantiomer preparation system which is used in the above-described method for preparing an enantiomer, and includes an optical resolution part to optically resolve an enantiomer mixture of a sulfoxide compound into one enantiomer and the other enantiomer, and a light irradiation part to irradiate the other enantiomer obtained in the optical resolution part with light to racemize the enantiomer.

[0067] One example of the schematic constitution of the enantiomer preparation system according to the present embodiment is shown in FIG. 1. As shown in FIG. 1, the enantiomer preparation system 1 includes an optical resolution part 10 and a light irradiation part 20.

[0068] The optical resolution part 10 optically resolves, for example, an enantiomer mixture of a sulfoxide compound into one enantiomer (e.g. S-form) and the other enantiomer (e.g. R-form), and isolates one enantiomer and also sends the other enantiomer to the light irradiation part 20. The optical resolution part 10 is not particularly restricted as long as it can optically resolve an enantiomer mixture of a sulfoxide compound. When a chromatography method, for example, is used as an optical resolution method, the optical resolution part 10 is provided with a chiral column.

[0069] The light irradiation part 20 irradiates the other enantiomer obtained in the optical resolution part 10 (e.g. R-form) with light to racemize (photoracemize) the enantiomer. The light source of the light irradiation part 20 is not particularly restricted as long as the other enantiomer is irradiated with light at a wavelength required for racemization (e.g. light at a wavelength of 200 nm to 450 nm, preferably light at a wavelength of 254 nm to 365 nm). Specific examples of the light source include a high-pressure mercury lamp, a low-pressure mercury lamp, a xenon lamp, a LED lamp and the like. It should be noted that when a material which absorbs light from the light source or a material which changes the wavelength of light from the light source exists between the light source and the other enantiomer, it is preferred that the other enantiomer be irradiated with light in view of the absorption of light or changes in the wavelength of light. The light irradiation part 20 sends an enantiomer mixture of the sulfoxide compound obtained by racemization to the optical resolution part 10 again.

[0070] As described above, according to the enantiomer preparation system 1, the yield of a desired enantiomer can be largely improved by repeating optical resolution and photoracemization in the optical resolution part 10 and the light irradiation part 20.

[0071] It should be noted that a recirculating system, in which an enantiomer mixture of the sulfoxide compound obtained in the light irradiation part 20 is sent to the optical resolution part 10 again, is described in the above-described embodiment; however, the system is not limited thereto. For example, an enantiomer mixture of the sulfoxide compound obtained in the light irradiation part 20 is sent to another optical resolution part, which is not the optical resolution part 10, and the mixture may be optically resolved into one enantiomer and the other enantiomer in the part. However, the recycling system is preferred because a solvent can be reused and optical resolution and photoracemization are easily repeated.

EXAMPLES

[0072] The present invention will now be described in more detail by way of examples thereof. It should be noted, however, that the present invention is not restricted to these examples.

Example 1: Optical Resolution of Sulfoxide Compound, Racemate

[0073] In Example 1, a compound, a racemate, represented by formula below was optically resolved using an enantiomer preparation system with the constitution shown in FIG. 1 to selectively prepare an S-compound.

##STR00005##

[0074] Specifically, the compound, a racemate, was optically resolved to isolate the S-compound by recycle HPLC using a chiral column, and the R-compound was returned from the column outlet to the column inlet. During the process of returning the R-compound to the column inlet, a region with a length of 200 cm in a channel with an internal diameter of 0.5 mm was irradiated with light to photoracemize the R-compound. The recycle HPLC conditions are as described below.

—Recycle HPLC Conditions—

[0075] Column: CHIRALPAK IC (10 mm×250 mm, particle diameter 5 mm)+CHIRALPAK IH (10 mm×250 mm, particle diameter 5 mm) (manufactured by Daicel Corporation),

[0076] Mobile phase: hexane/ethanol=1/1,

[0077] Flow rate: 2.0 mL/min, and

[0078] Light irradiation part: LED lamp (wavelength 365 nm).

[0079] When the S-compound was isolated four times by repeating optical resolution and photoracemization, 4.3 mg (0.01634 mmol) of the S-compound was obtained from 5.0 mg of the compound, a racemate, (0.01900 mmol) (yield: 86%). The enantiomeric excess of the obtained S-compound was 96.4% ee.

Example 2: Optical Resolution of Sulfoxide Compound, Racemate

[0080] In Example 2, (±)-omeprazole, a racemate, was optically resolved to selectively prepare (S)-omeprazole.

[0081] Specifically, (S)-omeprazole and (R)-omeprazole were each isolated from 1.0 mL of a solution of (±)-omeprazole in acetonitrile (3.5 mg, 0.01 mmol, 0.01 M) by chiral HPLC. The chiral HPLC conditions are as described below.

—Chiral HPLC Conditions—

[0082] Column: CHIRALPAK IA (10 mm×250 mm, particle diameter 5 mm) (manufactured by Daicel Corporation),

[0083] Mobile phase: hexane/ethanol=1/1, and

[0084] Flow rate: 2.4 mL/min.

[0085] The solvent of (R)-omeprazole was distilled off, and acetonitrile was added thereto to prepare a 0.01 M acetonitrile solution. This acetonitrile solution was put in a quartz cell, and irradiated with light at a wavelength of 254 nm using a UV lamp for 10 minutes to photoracemize the (R)-omeprazole. After light irradiation, the solvent was distilled off, and (S)-omeprazole and (R)-omeprazole were each isolated again by chiral HPLC. Photoracemization and optical resolution are repeatedly carried out on (R)-omeprazole to isolate (S)-omeprazole and (R)-omeprazole. The obtained (S)-omeprazole were all combined and the solvent was distilled off to obtain 2.0 mg of (S)-omeprazole (0.00580 mmol) (yield 58%). The enantiomeric excess of the obtained (S)-omeprazole was 97.1% ee.

Reference Example 1: Consideration of Photosensitizer

[0086] ##STR00006##

[0087] As shown in the above scheme, an optically active sulfoxide compound was irradiated with light in the presence of a variety of photosensitizers, and influences of photosensitizers on the photoracemization reaction were considered. The following 8 types of photosensitizers are used.

##STR00007##

[0088] To an acetonitrile solution (2.0 mL, 0.01 M) containing an optically active sulfoxide compound ((+)-1) (3.08 mg, 0.02 mmol), a photosensitizer (0.02 mmol to 2 mmol, 0.1 mol % to 10 mol %) was added, and the obtained mixture was irradiated with light using an 18 W LED light (wavelength 365 nm to 425 nm) or a spectrofluorophotometer (wavelength 290 nm to 330 nm, RF-5300 PC manufactured by SHIMADZU CORPORATION). The same experiment was carried out without adding a photosensitizer for comparison. During light irradiation, sampling (20 mL) was carried out over time to calculate the enantiomeric excess thereof by chiral HPLC. The chiral HPLC conditions are as described below.

—Chiral HPLC Conditions—

[0089] Column: CHIRALPACK IH (10 mm×250 mm, particle diameter 5 mm) (manufactured by Daicel Corporation),

[0090] Mobile phase: hexane/isopropanol=60/40,

[0091] Flow rate: 0.5 mL/min, and

[0092] Detection: 254 nm.

TABLE-US-00001 TABLE 1 Amount of added Time photosensitizer Light required for Entry Photosensitizer (mol %) wavelength racemization 1 1,2,4,5-TCB 10 330 nm  15 min 2 6,6′-Dicyano- 10 290 nm  60 min 2,2′-bipyridyl 3 1,4-DCN 10 330 nm  15 min 4 9,10-DCA 0.1 425 nm   1 min 5 TPT.sup.+ 1 425 nm 0.5 min 6 Mes-Acr-Me.sup.+ 1 425 nm   6 min 7 DDQ 10 380 nm   2 min 8 6MeO-NMQ.sup.+ 1 365 nm   2 min 9 — — 425 nm —

[0093] As shown in Table 1, in Entries 1 to 8 which was irradiated with light in the presence of a photosensitizer, the photoracemization reaction could be allowed to efficiently proceed. Contrarily, in Entry 9 in which a photosensitizer was not used, the photoracemization reaction did not proceed very well even by irradiation with light at a wavelength of 425 nm for 60 minutes.

Reference Example 2: Consideration of Solvent in Photoracemization Reaction Using 9,10-DCA as Photosensitizer

[0094] ##STR00008##

[0095] An optically active sulfoxide compound ((+)-1) (3.08 mg, 0.02 mmol) was dissolved in a variety of solvents (2.0 mL). To the obtained solution, 9,10-dicyanoanthracene (9,10-DCA) (0.45 mg, 2 mmol, 10 mol %) was added, and the obtained mixture was irradiated with light using an 18 W LED light (wavelength 425 nm). During light irradiation, sampling (20 mL) was carried out over time to calculate the enantiomeric excess thereof by chiral HPLC. The chiral HPLC conditions are as described below.

—Chiral HPLC Conditions—

[0096] Column: CHIRALPACK IH (10 mm×250 mm, particle diameter 5 mm) (manufactured by Daicel Corporation),

[0097] Mobile phase: hexane/isopropanol=60/40,

[0098] Flow rate: 0.5 mL/min, and

[0099] Detection: 254 nm.

TABLE-US-00002 TABLE 2 Time required for Entry Solvent racemization 1 Acetonitrile  0.5 min 2 Acetone <15 min

[0100] As shown in Table 2, photoracemization could proceed even when any solvent was used, and the photoracemization reaction was fast particularly when acetonitrile was used.

Reference Example 3: Consideration of Solvent in Photoracemization Reaction Using TPT.SUP.+ as Photosensitizer

[0101] ##STR00009##

[0102] An optically active sulfoxide compound ((+)-1) (3.08 mg, 0.02 mmol) was dissolved in a variety of solvents (2.0 mL). To the obtained solution, 2,4,6-triphenylpyrylium tetrafluoroborate (TPT.sup.+) (80 mg, 0.2 mmol, 1 mol %) was added, and the obtained mixture was irradiated with light using an 18 W LED light (wavelength 425 nm). During light irradiation, sampling (20 mL) was carried out over time to calculate the enantiomeric excess thereof by chiral HPLC. The chiral HPLC conditions are as described below.

—Chiral HPLC Conditions—

[0103] Column: CHIRALPACK IH (10 mm×250 mm, particle diameter 5 mm) (manufactured by Daicel Corporation),

[0104] Mobile phase: hexane/isopropanol=60/40,

[0105] Flow rate: 0.5 mL/min, and

[0106] Detection: 254 nm.

TABLE-US-00003 TABLE 3 Time required for Enantiomer ratio Entry Solvent racemization after 10 min 1 Acetonitrile  0.5 min 50:50 2 Toluene >10 min 61:39 3 Dichloromethane <10 min 50:50 4 Acetone >10 min 56:44

[0107] As shown in Table 3, photoracemization could proceed even when any solvent was used, and the photoracemization reaction was fast particularly when acetonitrile was used.

Reference Example 4: Consideration of Solvent in Photoracemization Reaction Using Mes-Acr-Me.SUP.+ as Photosensitizer

[0108] ##STR00010##

[0109] An optically active sulfoxide compound ((+)-1) (3.08 mg, 0.02 mmol) was dissolved in a variety of solvents (2.0 mL). To the obtained solution, 10-methyl-9-(2,4,6-trimethylphenyl)acridinium perchlorate (Mes-Acr-Me.sup.+) (82.3 mg, 0.2 mmol, 1 mol %) was added, and the obtained mixture was irradiated with light using an 18 W LED light (wavelength 425 nm). During light irradiation, sampling (20 mL) was carried out over time to calculate the enantiomeric excess thereof by chiral HPLC. The chiral HPLC conditions are as described below.

—Chiral HPLC Conditions—

[0110] Column: CHIRALPACK IH (10 mm×250 mm, particle diameter 5 mm) (manufactured by Daicel Corporation),

[0111] Mobile phase: hexane/isopropanol=60/40,

[0112] Flow rate: 0.5 mL/min, and

[0113] Detection: 254 nm.

TABLE-US-00004 TABLE 4 Time required for Enantiomer ratio Entry Solvent racemization after 10 min 1 Acetonitrile    6 min 50:50 2 Ethyl acetate >10 min 72:28 3 Dichloromethane <10 min 50:50

[0114] As shown in Table 4, photoracemization could proceed even when any solvent was used, and the photoracemization reaction was fast particularly when acetonitrile was used.

Reference Example 5: Preparation of Solid Photosensitizer in which TPT.SUP.+ is Covalently Bound to Carrier

[0115] ##STR00011##

[0116] To an ethanol solution (10 mL) containing 2,4,6-triphenylpyrylium tetrafluoroborate (TPT.sup.+) (0.40 g, 1.0 mmol, 1.0 equiv.), sodium acetate (0.32 g, 4.0 mmol, 4.0 equiv.) and R-Cat-Sil TA (1.0 g, 1.0 mmol, 1.0 equiv.; manufactured by KANTO CHEMICAL CO., INC.) were added, and the obtained mixture was stirred overnight at 80° C. The mixture was cooled to 0° C. and then filtered. The obtained residue was washed with methanol and dichloromethane and then dried to obtain a solid photosensitizer 2 (1.12 g).

##STR00012##

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

Reference Example 6: Consideration of Photoracemization Using Solid Photosensitizer 2 or Solid Photosensitizer 3

[0118] ##STR00013##

[0119] To an acetonitrile solution (1.0 mL, 0.01 M) containing an optically active sulfoxide compound ((+)-1) (1.54 mg, 0.01 mmol), the solid photosensitizer 2 (5 mg) or solid photosensitizer 3 (5 mg) was added, and the obtained mixture was irradiated with light using a spectrofluorophotometer (wavelength 310 nm, RF-5300PC manufactured by SHIMADZU CORPORATION). During light irradiation, sampling (20 mL) was carried out over time to calculate the enantiomeric excess thereof by chiral HPLC. The chiral HPLC conditions are as described below.

—Chiral HPLC Conditions—

[0120] Column: CHIRALPACK IH (10 mm×250 mm, particle diameter 5 mm) (manufactured by Daicel Corporation),

[0121] Mobile phase: hexane/isopropanol=60/40,

[0122] Flow rate: 0.5 mL/min, and

[0123] Detection: 254 nm.

[0124] Changes in the enantiomeric excess with time when using the solid photosensitizer 2 and the solid photosensitizer 3 are shown in FIGS. 2 and 3 respectively. As shown in FIG. 2 and FIG. 3, the photoracemization reaction could be allowed to efficiently proceed even when a photosensitizer is immobilized to a carrier.

Reference Example 7: Preparation of Solid Photosensitizer in which 9,10-DCA is Covalently Bound to Carrier

[0125] ##STR00014##

[0126] To a 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 equiv.), trimethylsilyl cyanide (1.71 mL, 13.9 mmol, 2.05 equiv.) was added under an argon flow, and the obtained mixture was stirred overnight at room temperature. After completion of the reaction, acetonitrile (30 mL) and then phosphorus tribromide (1.54 mL, 16.2 mmol, 1.2 equiv.) were added thereto, and the obtained mixture was stirred overnight at room temperature. Dichloromethane was added thereto to stop the reaction, followed by filtration. The residue obtained by condensing the filtrate was purified by column chromatography (eluent: hexane/dichloromethane=1/1) to obtain a compound 6 (200 mg, 0.826 mmol, yield: 12%).

##STR00015##

[0127] To a carbon tetrachloride solution (10 mL) containing the compound 6 (207 mg, 0.86 mmol), N-bromosuccinimide (290 mg, 1.90 mmol, 2.0 equiv.) and benzoyl peroxide (10.0 mg, 0.04 mmol, 0.05 equiv.) were added under an argon flow, and the obtained mixture was stirred under heat reflux for 7 hours. After completion of the reaction, the residue obtained by condensation was purified by column chromatography (eluent: hexane/ethyl acetate=20/1) to obtain a 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 equiv.; manufactured by KANTO CHEMICAL CO., INC.) and triethylamine (0.42 mL, 3.00 mmol, 3 equiv.) were added thereto under an argon flow, and the obtained mixture was stirred overnight at room temperature. After filtration, the residue was washed with water, methanol, dichloromethane and ethyl acetate, and dried to obtain a solid photosensitizer 8 (1.23 g).

Reference Example 8: Preparation of Solid Photosensitizer in which TPT.SUP.+ is Ionically Bound to Carrier

[0128] ##STR00016##

[0129] To an aqueous solution (60 mL) containing 2,4,6-triphenylpyrylium tetrafluoroborate (TPT.sup.+ (0.20 g, 0.50 mol), DOWEX 50 W×8 (2.0 g; manufactured by FUJIFILM Wako Pure Chemical Corporation) was added, and the obtained mixture was stirred at room temperature for 17 hours. After filtration, the residue was washed with water, methanol, dichloromethane and acetonitrile, and dried to obtain a solid photosensitizer 9 (1.70 g).

Reference Example 9: Consideration of Photoracemization Using Solid Photosensitizer 9

[0130] ##STR00017##

[0131] To an acetonitrile solution (1.0 mL, 0.01 M) containing an optically active sulfoxide compound ((+)-1) (1.54 mg, 0.01 mmol), the solid photosensitizer 9 (5 mg) was added, and the obtained mixture was irradiated with light using an 18 W LED light (wavelength 425 nm). During light irradiation, sampling (20 mL) was carried out over time to calculate the enantiomeric excess thereof by chiral HPLC. The chiral HPLC conditions are as described below.

—Chiral HPLC Conditions—

[0132] Column: CHIRALPACK IH (10 mm×250 mm, particle diameter 5 mm) (manufactured by Daicel Corporation),

[0133] Mobile phase: hexane/isopropanol=60/40,

[0134] Flow rate: 0.5 mL/min, and

[0135] Detection: 254 nm.

[0136] The enantiomeric excess was reduced from 99.2% ee to 2.7% ee by irradiation with light at a wavelength of 425 nm in the presence of the solid photosensitizer 9 for 10 minutes, and it was observed that the photoracemization reaction efficiently proceeded.

Reference Example 10: Consideration of Substrate Generality

[0137] ##STR00018##

[0138] To an acetonitrile solution (3.0 mL, 0.01 M) containing an optically active sulfoxide compound ((+)-10a) (4.30 mg, 0.03 mmol), 9,10-dicyanoanthracene (9,10-DCA) (0.70 mg, 0.003 mmol, 10 mol %) was added, and the obtained mixture was irradiated with light using an 18 W LED light (wavelength 425 nm). During light irradiation, sampling (20 mL) was carried out over time to calculate the enantiomeric excess thereof by chiral HPLC. The same operation as above was carried out except that (+)-10b to 10i were used in place of (+)-10a. The chiral HPLC conditions are as described below.

—Chiral HPLC Conditions (10a to 10d, 10f to 10h)—

[0139] Column: CHIRALPACK IH (10 mm×250 mm, particle diameter 5 mm) (manufactured by Daicel Corporation),

[0140] Mobile phase: hexane/isopropanol=60/40,

[0141] Flow rate: 0.5 mL/min, and

[0142] Detection: 254 nm.

—Chiral HPLC Conditions (10e)—

[0143] Column: CHIRALPACK IA (10 mm×250 mm, particle diameter 5 mm) (manufactured by Daicel Corporation),

[0144] Mobile phase: hexane/ethanol=50/50,

[0145] Flow rate: 0.5 mL/min, and

[0146] Detection: 254 nm.

—Chiral HPLC Conditions (10i)—

[0147] Column: CHIRALPACK IH (10 mm×250 mm, particle diameter 5 mm) (manufactured by Daicel Corporation),

[0148] Mobile phase: hexane/isopropanol=80/20,

[0149] Flow rate: 0.5 mL/min, and

[0150] Detection: 254 nm.

TABLE-US-00005 TABLE 5 Time required for Entry R.sup.5 R.sup.6 racemization 1 10a Me H 1 min 2 10b Et H 0.5 min 3 10c [00019] H 0.5 min 4 10d —CHCH.sub.2 H 5 min 5 10e [00020] H 1 min 6 10f —CH.sub.2CCOEt H 45 min 7 10g Me F 2 min 8 10h Me Cl 2 min 9 10i Me —OMe 0.5 min

[0151] As shown in Table 5, photoracemization could proceed even when any sulfoxide compound was used.

EXPLANATION OF REFERENCE NUMERALS

[0152] 1: Enantiomer preparation system, 10: optical resolution part, and 20: light irradiation part.