Method for producing enantiomer (R) configuration of triazole derivative

Abstract

The present invention provides a method of making an enantiomer (R) configuration of a triazole derivative. The method for producing an enantiomer (R) configuration of a triazole derivative comprises: a step in which a chiral molecule represented by general formula (IIa) or (IIb) is added to a triazole derivative represented by general formula (I) in a solvent, and crystallization is performed; and a step for separating the precipitated crystals from the residual liquid.

Description

Technical Field

[0001] The present invention relates to a method for preparing the enantiomer (R) configuration of a triazole derivative. Background Art

[0002] Conventionally, agricultural and horticultural agents have been required to have low toxicity to humans and animals, excellent handling safety, and high control effects on a wide range of plant diseases. Under such circumstances, Patent Document 1 discloses triazole derivatives having high antibacterial properties against plant pathogens, and agricultural and horticultural agents and industrial material protective agents containing the triazole derivatives as active ingredients. In addition, Patent Document 2 discloses a (-)-enantiomer of a triazole derivative having higher activity.

[0003] Prior art literature

[0004] Patent Literature

[0005] Patent Document 1: International Publication WO2019 / 093522

[0006] Patent Document 2: International Publication No. WO2021 / 230382 Summary of the invention

[0007] Problem that the invention aims to solve

[0008] Patent Document 2 discloses a method for separating a triazole derivative racemate by using an optical resolution column as a method for preparing a (-)-enantiomer having a predominant activity. However, from an industrial point of view, in order to reduce costs, it has been ideal to obtain a specific enantiomer by a method other than a column.

[0009] The present invention has been made in view of the above-mentioned problems, and an object of the present invention is to provide a method for producing a specific enantiomer of a triazole derivative.

[0010] Technical Solution

[0011] The present inventors have conducted intensive research and found that by adding a specific chiral molecule to a racemic form of a triazole derivative, it can be co-crystallized with the (-)-enantiomer. In addition, the present inventors found from another research result that the (-)-enantiomer of a triazole derivative is the enantiomer (R) configuration of the triazole derivative, thereby completing the present invention.

[0012] That is, in order to solve the above-mentioned problems, a method for producing an enantiomeric (R) configuration of a triazole derivative according to one embodiment of the present invention comprises: a step of adding a chiral molecule represented by the following general formula (IIa) or (IIb) to a triazole derivative represented by the following general formula (I) in a solvent to carry out crystallization; and a step of separating the precipitated crystals from the residual liquid.

[0013] [Chemical formula 1]

[0014]

[0015] [In formula (I), R 1 For-OR 4 or -NR 5 R 6 ; R 4 , R 5 and R 6 are each independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C8-cycloalkyl, C3-C8-cycloalkyl-C1-C4-alkyl, phenyl, phenyl-C1-C4-alkyl, phenyl-C2-C4-alkenyl or phenyl-C2-C4-alkynyl, R 5 and R 6 Optionally, together with the nitrogen atom to which they are bound, form a ring; wherein R 4 , R 5 and R 6 The aliphatic radical in optionally has 1, 2, 3 or the maximum possible number of identical or different radicals R a , R a are independently selected from halogen groups, cyano groups, nitro groups, C1-C4-alkoxy groups and C1-C4-haloalkoxy groups; R 2 is a halogen group, a cyano group, a nitro group, a phenyl group, a phenyloxy group, a C1-C4-alkyl group, a C1-C4-haloalkyl group, a C1-C4-alkoxy group, a C1-C4-haloalkoxy group, -SOR 7 or -SF5;R 3 is a halogen group, a cyano group, a nitro group, an amino group, a phenyl group, a phenyloxy group, a C1-C4-alkyl group, a C1-C4-haloalkyl group, a C1-C4-alkoxy group or a C1-C4-haloalkoxy group, a C1-C4-alkylamino group, a C1-C4-dialkylamino group, a C1-C4-alkylacylamino group, -SOR 7 or -SF5;R 4 , R 5 and R 6 The cycloalkyl and phenyl parts and R 3 The phenyl moiety in the group optionally has 1, 2, 3, 4, 5 or the maximum possible number of identical or different groups R b , R b are independently selected from halogen groups, cyano groups, nitro groups, C1-C4-alkyl groups, C1-C4-alkoxy groups, C1-C4-haloalkyl groups and C1-C4-haloalkoxy groups; wherein R 7is C1-C4-alkyl or C1-C4-haloalkyl; n is 0, 1, 2, 3 or 4; m is 1, 2, 3, 4 or 5, and the asterisk (*) refers to an asymmetric carbon atom.]

[0016] [Chemical formula 2]

[0017]

[0018] [In formula (IIa) and (IIb), R 8 and R 9 is C1-C6-alkyl, R 8 and R 9 Optionally, together with the carbon atoms to which they are bound, they form a ring.]

[0019] Beneficial Effects

[0020] According to one embodiment of the present invention, the enantiomeric (R) configuration of a triazole derivative can be efficiently produced. DETAILED DESCRIPTION

[0021] The following is a detailed description of the method for producing the enantiomeric (R) configuration of the triazole derivative of the present invention. It should be noted that the embodiments described below are merely examples of representative embodiments of the present invention and are not to be construed as narrowing the scope of the present invention.

[0022] The method for manufacturing the enantiomer (R) configuration of a triazole derivative according to one embodiment of the present invention comprises: adding a chiral molecule to a triazole derivative in a solvent to perform a co-crystallization step; and separating the precipitated crystals from the residual liquid. It should be noted that the "manufacturing of enantiomers" in this specification refers to a state in which a racemate or a mixture of each enantiomer is used as a starting material to contain more target enantiomers. Therefore, the "manufacturing of enantiomers" in this specification can also be expressed as separating one enantiomer from a mixture of each enantiomer. It should be noted that any expression does not necessarily mean that it is obtained in a state completely free of other enantiomers. By becoming a state containing more target enantiomers, agricultural and horticultural agents with higher activity than using racemates can be prepared.

[0023] Among them, the enantiomer of the triazole derivative of the present embodiment is the (-)-enantiomer (hereinafter referred to as the triazole derivative (-)-enantiomer) or the (+)-enantiomer (hereinafter referred to as the triazole derivative (+)-enantiomer) in the triazole derivative (hereinafter referred to as the triazole derivative (I)) shown in the following general formula (I). The asterisk (*) in the following general formula (I) refers to an asymmetric carbon atom. It should be noted that in this specification, "(-)-enantiomer" refers to the enantiomer that rotates the vibration plane of the linear polarized light of the sodium D line to the left, and "(+)-enantiomer" refers to the enantiomer that rotates the vibration plane of the linear polarized light of the sodium D line to the right. In addition, as shown in the examples described later, the triazole derivative (-)-enantiomer is the enantiomer (R) configuration of the triazole derivative (I), and the triazole derivative (+)-enantiomer is the enantiomer (S) configuration of the triazole derivative (I). In addition, in the present specification, when only "the triazole derivative represented by the general formula (I)" or "the triazole derivative (I)" is expressed, it refers to the state in which the triazole derivative (-)-enantiomer and the triazole derivative (+)-enantiomer are not separated. Therefore, the "triazole derivative represented by the general formula (I)" and "triazole derivative (I)" in the present specification refer to a mixture of the triazole derivative (-)-enantiomer and the triazole derivative (+)-enantiomer, typically, a racemate of the triazole derivative (I).

[0024] [Chemical formula 3]

[0025]

[0026] In the general formula (I), R 1 For-OR 4 or -NR 5 R 6 , preferably -OR 4 .

[0027] R 4 , R 5 and R 6 R is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C8-cycloalkyl, C3-C8-cycloalkyl-C1-C4-alkyl, phenyl, phenyl-C1-C4-alkyl, phenyl-C2-C4-alkenyl or phenyl-C2-C4-alkynyl. 5 and R 6 Optionally with R 5 and R 6 The bound nitrogen atoms together form a ring.

[0028] The C1-C6-alkyl group is a straight-chain or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, butyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, pentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl and 4-methylpentyl.

[0029] The C2-C6-alkenyl group is a straight-chain or branched alkenyl group having 2 to 6 carbon atoms, and examples thereof include vinyl, 2-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-butenyl, 2-butenyl, 3-methyl-2-butenyl, 1-methyl-2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 1-hexenyl and 5-hexenyl.

[0030] The C2-C6-alkynyl group is a straight-chain or branched alkynyl group having 2 to 6 carbon atoms, and examples thereof include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, pentynyl and 1-hexynyl.

[0031] The C3-C8-cycloalkyl group is a cyclic alkyl group having 3 to 8 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.

[0032] C3-C8-cycloalkyl-C1-C4-alkyl means a cyclic cycloalkyl group having 3 to 8 carbon atoms bonded to a linear or branched alkyl group having 1 to 4 carbon atoms. Examples thereof include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 1-cyclopropylethyl, 2-cyclohexylethyl, 3-cyclopropylpropyl, 2-cyclopropylpropyl, and 4-cyclopropylbutyl.

[0033] The phenyl-C1-C4-alkyl group is a phenyl group substituted on a linear or branched alkyl group having 1 to 4 carbon atoms, and examples thereof include phenylmethyl, 2-phenylethyl, 3-phenylpropyl and 4-phenylbutyl.

[0034] The phenyl-C2-C4-alkenyl group is a linear or branched alkenyl group having 2 to 4 carbon atoms bonded to a phenyl group, and examples thereof include phenylvinyl, phenyl-1-propenyl, phenylisopropenyl, and phenylbutenyl.

[0035] The phenyl-C2-C4-alkynyl group is an alkynyl group having 2 to 4 carbon atoms bonded to a phenyl group, and examples thereof include phenylethynyl, phenyl-1-propynyl, phenyl-2-propynyl, phenyl-1-butynyl, phenyl-2-butynyl and phenyl-3-butynyl.

[0036] R 4 Preference is given to C1-C6-alkyl.

[0037] R 1 , R 4 , R 5 and R 6 The aliphatic radical in optionally has 1, 2, 3 or the maximum possible number of identical or different radicals R a , R a are independently selected from the group consisting of halogen groups, cyano groups, nitro groups, C1-C4-alkoxy groups and C1-C4-haloalkoxy groups.

[0038] Examples of the halogen group include a chloro group, a bromo group, an iodo group, and a fluoro group, and examples thereof include a chloromethyl group, a 2-chloroethyl group, a 2,3-dichloropropyl group, a bromomethyl group, a chlorodifluoromethyl group, a trifluoromethyl group, and a 3,3,3-trifluoropropyl group.

[0039] The C1-C4-alkoxy group is a linear or branched alkoxy group having 1 to 4 carbon atoms, and examples thereof include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, a sec-butoxy group, and a tert-butoxy group.

[0040] The C1-C4-halogenated alkoxy group is a group in which the substitutable positions of the above-mentioned C1-C4-alkoxy group are substituted by one or two or more halogen atoms. When there are two or more substituted halogen groups, the halogen groups may be the same or different.

[0041] R 2 is a halogen group, a cyano group, a nitro group, a phenyl group, a phenyloxy group, a C1-C4-alkyl group, a C1-C4-haloalkyl group, a C1-C4-alkoxy group, a C1-C4-haloalkoxy group, -SOR 7 or -SF5.

[0042] As R, there can be mentioned halogen groups, C1-C4-alkyl groups, C1-C4-haloalkyl groups, C1-C4-alkoxy groups and C1-C4-haloalkoxy groups. a The groups are listed as examples of the organic groups shown.

[0043] R 2 Preferred are halogen groups, cyano groups, C1-C4-alkyl groups, C1-C4-haloalkyl groups, C1-C4-alkoxy groups, -SOR 7or -SF5, further preferably a halogen group, a cyano group, a C1-C4-alkyl group, a C1-C4-haloalkyl group or a C1-C4-alkoxy group.

[0044] R 7 is C1-C4-alkyl or C1-C4-haloalkyl. 2 The substitution position of is 2, 3, 5 or 6, preferably 2. n is 0, 1, 2, 3 or 4, preferably 1.

[0045] R 3 is a halogen group, a cyano group, a nitro group, an amino group, a phenyl group, a phenyloxy group, a C1-C4-alkyl group, a C1-C4-haloalkyl group, a C1-C4-alkoxy group, a C1-C4-haloalkoxy group, a C1-C4-alkylamino group, a C1-C4-dialkylamino group, a C1-C4-alkylacylamino group, -SOR 7 or -SF5, halogen group, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy or C1-C4-haloalkoxy and -SOR 7 R 2 The groups are listed as examples of the organic groups shown.

[0046] R 3 Preferred are halogen groups, nitro groups, amino groups, C1-C4-alkyl groups, C1-C4-haloalkyl groups, C1-C4-alkoxy groups, C1-C4-haloalkoxy groups, C1-C4-alkylamino groups, C1-C4-dialkylamino groups, C1-C4-alkylacylamino groups, -SOR 7 or -SF5, further preferably a halogen group, a C1-C4-alkyl group, a C1-C4-haloalkyl group, a C1-C4-alkoxy group or a C1-C4-haloalkoxy group.

[0047] The C1-C4-alkylamino group is an amino group in which one of the hydrogen atoms of the amino group is substituted with a linear or branched alkyl group having 1 to 4 carbon atoms, and examples thereof include methylamino, ethylamino, n-propylamino, isopropylamino and tert-butylamino.

[0048] The C1-C4-dialkylamino group is an amino group in which both hydrogen atoms possessed by the amino group are substituted with a linear or branched alkyl group having 1 to 4 carbon atoms, and examples thereof include N,N-dimethylamino, N,N-diethylamino, N,N-di-n-propylamino, N,N-diisopropylamino and N,N-di-tert-butylamino.

[0049] The C1-C4-alkylacylamino group is an amino group in which one or two hydrogen atoms possessed by an amino group are substituted by a linear or branched alkylacyl group having 1 to 4 carbon atoms, and examples thereof include a methylacylamino group, an ethylacylamino group, an n-propylacylamino group, an isopropylacylamino group, a tert-butylacylamino group, an N,N-dimethylacylamino group, an N,N-diethylacylamino group, an N,N-di-n-propylacylamino group, an N,N-diisopropylacylamino group and an N,N-di-tert-butylacylamino group.

[0050] R 4 , R 5 , R 6 The cycloalkyl or phenyl part in R 3 The phenyl moiety in the group optionally has 1, 2, 3, 4, 5 or the maximum possible number of identical or different groups R b , R b are independently selected from the group consisting of a halogen group, a cyano group, a nitro group, a C1-C4-alkyl group, a C1-C4-alkoxy group, a C1-C4-haloalkyl group and a C1-C4-haloalkoxy group. The halogen group, the C1-C4-alkyl group, the C1-C4-alkoxy group, the C1-C4-haloalkyl group and the C1-C4-haloalkoxy group can be cited as R a The groups are listed as examples of the organic groups shown.

[0051] Based on the above, as a preferred embodiment of the triazole derivative, the following triazole derivatives can be listed: In the general formula (I), R 1 For-OR 4 ; R 2 is a halogen group, a cyano group, a C1-C4-alkyl group, a C1-C4-haloalkyl group, a C1-C4-alkoxy group, -SOR 7 or -SF5;R 3 is a halogen group, a nitro group, a cyano group, an amino group, a C1-C4-alkyl group, a C1-C4-haloalkyl group, a C1-C4-alkoxy group, a C1-C4-haloalkoxy group, a C1-C4-alkylamino group, a C1-C4-dialkylamino group, a C1-C4-alkylacylamino group, -SOR 7 or -SF5.

[0052] In addition, as a more preferred embodiment of the triazole derivative, the following triazole derivatives can be cited: In the general formula (I), R 1 For-OR 4 And R 4 is C1-C6-alkyl; R 2 is a halogen group, a cyano group, a C1-C4-alkyl group, a C1-C4-haloalkyl group or a C1-C4-alkoxy group; R 3is a halogen group, a cyano group, a C1-C4-alkyl group, a C1-C4-haloalkyl group, a C1-C4-alkoxy group or a C1-C4-haloalkoxy group.

[0053] 〔1. Co-crystallization of triazole derivatives and chiral molecules〕

[0054] As described above, the triazole derivative (I) is typically a racemate of the triazole derivative (I). The racemate of the triazole derivative (I) can be prepared, for example, by the method described in Patent Document 1. It should be noted that, when the triazole derivative (I) is prepared by the method described in Patent Document 1, the obtained triazole derivative (I) is a racemate. By mixing the prepared racemate of the triazole derivative (I) with a chiral molecule represented by the following general formula (IIa) or (IIb) in a solvent and crystallizing it, a co-crystal of one enantiomer of the triazole derivative (I) and the chiral molecule can be obtained.

[0055] [Chemical formula 4]

[0056]

[0057] Among them, in the general formula (IIa) and (IIb), R 8 and R 9 is C1-C6-alkyl, R 8 and R 9 Optionally, together with the carbon atoms to which they are bonded, they form a ring.

[0058] The C1-C6-alkyl group is a straight-chain or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, butyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, pentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl and 4-methylpentyl.

[0059] The chiral molecule represented by the general formula (IIa) is preferably a chiral molecule represented by the following general formula (IIIa) or (IVa).

[0060] [Chemical formula 5]

[0061]

[0062] (General formula (IIIa): ((2R,3R)-1,4-dioxaspiro[4.5]decane-2,3-diyl)bis(diphenylmethanol))

[0063] [Chemical formula 6]

[0064]

[0065] (General formula (IVa): ((4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)bis(diphenylmethanol))

[0066] The chiral molecule represented by the general formula (IIb) is preferably a chiral molecule represented by the following general formula (IIIb) or (IVb).

[0067] [Chemical formula 7]

[0068]

[0069] (General formula (IIIb): ((2S,3S)-1,4-dioxaspiro[4.5]decane-2,3-diyl)bis(diphenylmethanol))

[0070] [Chemical formula 8]

[0071]

[0072] (General formula (IVb): ((4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)bis(diphenylmethanol))

[0073] The amount of the chiral molecule added is preferably 0.01 mol to 100 mol, more preferably 0.1 mol to 10 mol, and further preferably 0.5 mol to 5 mol, based on 1 mol of the triazole derivative (I).

[0074] The solvent used is not particularly limited, but alcohols such as methanol and ethanol are preferred. Other examples include: aromatic hydrocarbons such as benzene, toluene, xylene and chlorobenzene; amides such as N,N-dimethylacetamide, N-methylpyrrolidone and N,N-dimethylformamide; and dimethyl sulfoxide. Since the solubility range of the triazole derivative (I) may vary depending on the type of solvent, the amount of the solvent used may be appropriately determined based on the solubility range of the triazole derivative (I). For example, when methanol is used as the solvent, the amount of methanol is preferably 10 mol to 1,000,000 mol, more preferably 50 mol to 500,000 mol, and even more preferably 100 mol to 10,000 mol, relative to 1 mol of the triazole derivative (I).

[0075] The solvent may be heated or not. When the solvent is not heated, the enantiomer of the triazole derivative is dissolved and then temporarily left to stand for a period of time, thereby crystals are precipitated. By crystallizing without heating, a crystal with a higher abundance ratio of one enantiomer can be obtained. When the solvent is heated, it can be preheated before adding the triazole derivative (I), or it can be heated after adding the triazole derivative (I). When the solvent is heated after adding the triazole derivative (I), it can be heated after adding both the triazole derivative (I) and the chiral molecule. The heated solvent to which the chiral molecule is added is then cooled, thereby crystallizing. There is no particular limitation on the temperature of the heated solvent, for example, it can be 25°C to 64°C, preferably 40°C to 64°C, and more preferably 45°C to 60°C. There is no particular limitation on the temperature of the cooled solvent, for example, it is preferably -50°C to 25°C, and more preferably 0°C to 25°C. Typically, it can be room temperature (e.g., 25°C). When the temperature is higher than room temperature, there is no need for excessive cooling operation, and the sample may be left to stand at room temperature, for example.

[0076] The method of crystallizing the mixture of the triazole derivative (I) and the chiral molecule, i.e., the method of precipitating the cocrystal is not limited thereto, and conventionally known precipitation methods such as the preferential crystallization method, the diastereoisomer method, the asymmetric crystallization method, and the method of evaporating the solvent may be used. For example, in the method of precipitating the cocrystal by evaporating the solvent, the ratio of one enantiomer in the obtained crystal is greater.

[0077] The triazole derivative enantiomers are all amorphous compounds, but by adding the above-mentioned chiral molecule to the triazole derivative (I), it can be crystallized in the form of a cocrystal of one enantiomer of the triazole derivative (I) and the chiral molecule. As a result, by separating the obtained crystals from the residual liquid, it can be made into a state containing more of one enantiomer. On the other hand, since the residual liquid obtained by separating the crystals contains more of the other enantiomer of the triazole derivative (I), by fractionating the residual liquid after the crystals are formed, it can be made into a state containing more of the other enantiomer.

[0078] In addition, the enantiomer of the triazole derivative (I) that forms the cocrystal can be changed according to the selection of the chiral molecule. For example, when a chiral molecule represented by the general formula (IIa) is used as the chiral molecule, a cocrystal with the enantiomer (R) configuration of the triazole derivative (I) is formed. On the other hand, when a chiral molecule represented by the general formula (IIb) is used as the enantiomer of the chiral molecule, a cocrystal with the enantiomer (S) configuration of the triazole derivative (I) is formed.

[0079] The co-crystal of the triazole derivative (I) and the chiral molecule obtained above and the residual liquid are separated, for example, by filtration.

[0080] 〔2. Formation of the enantiomeric (R) configuration of triazole derivatives 1〕

[0081] As described above, which of the enantiomer (R) configuration and the enantiomer (S) configuration of the triazole derivative (I) is co-crystallized with the chiral molecule varies depending on the chiral molecule used. In this item, the case of using a chiral molecule represented by the general formula (IIa) for co-crystallization of the enantiomer (R) configuration of the triazole derivative (I) is described. In the case of using this chiral molecule, the step of separating the precipitated crystals from the residual liquid can be a step of separating the precipitated crystals from the residual liquid to obtain the crystals. It should be noted that, depending on the chiral molecule, the chiral molecule represented by the general formula (IIa) can also be co-crystallized with the enantiomer (S) configuration of the triazole derivative (I). However, in the case of co-crystallization of a racemic form, the enantiomer (R) configuration is preferentially co-crystallized.

[0082] The separated crystals contain not only the enantiomer (R) configuration of the triazole derivative (I), but also the enantiomer (S) configuration of the triazole derivative, but the content of the (R) configuration is greater than that of the (S) configuration. Typically, the ratio of the content of the (R) configuration to the total content of the content of the (R) configuration and the content of the (S) configuration may exceed 50%, may be above 70%, may be above 95%, or may be 100%.

[0083] The ratio of the (R) configuration to the (S) configuration contained in the isolated crystals can be confirmed by dissolving the obtained crystals in a solvent and fractionating each enantiomer using chiral chromatography. The fractionation using chiral chromatography can be performed, for example, by referring to the method described in Patent Document 2.

[0084] In order to increase the content ratio of the enantiomeric (R) configuration of the target triazole derivative (I) from the obtained cocrystal, a step of removing the chiral molecule in the crystal can be added. As a method for removing the chiral molecule, silica gel chromatography can be cited. In this way, the enantiomeric (R) configuration of the triazole derivative (I) with the chiral molecule removed can be generated.

[0085] 〔3. Formation of the enantiomeric (R) configuration of triazole derivatives 2〕

[0086] As described above, which of the enantiomer (R) configuration and the enantiomer (S) configuration of the triazole derivative (I) is co-crystallized with the chiral molecule varies depending on the chiral molecule used. In this item, the case of using a chiral molecule represented by the general formula (IIb) for co-crystallization of the enantiomer (S) configuration of the triazole derivative (I) is described. When using this chiral molecule, the step of separating the precipitated crystals from the residual liquid can be a step of separating the precipitated crystals from the residual liquid and collecting the filtrate after crystallization.

[0087] When using the chiral molecule shown in the general formula (IIb), more enantiomer (S) configurations form crystals compared to enantiomer (R) configurations. The obtained crystals are removed by filtering the crystals, and as a result, more enantiomer (R) configurations are contained in the filtrate after filtering the crystals (i.e., the residual liquid after the crystals are formed). Therefore, by generating an amorphous solid from the filtrate, a solid containing more enantiomer (R) configurations of triazole derivatives can be obtained. As a method for generating an amorphous solid, distillation to remove the solvent and column chromatography can be cited.

[0088] The obtained amorphous solid contains not only the enantiomer (R) configuration of the triazole derivative (I) but also the enantiomer (S) configuration of the triazole derivative, but the content of the (R) configuration is greater than that of the (S) configuration. Typically, the ratio of the content of the (R) configuration to the total content of the content of the (R) configuration and the content of the (S) configuration may exceed 50%, may be 70% or more, may be 95% or more, and may be 100%.

[0089] Furthermore, the filtrate after filtering the amorphous solid or co-crystal obtained may contain a chiral molecule used for co-crystallization. By separating the chiral molecule by silica gel chromatography or the like, a triazole derivative (I) free of the chiral molecule can be obtained.

[0090] <Conclusion>

[0091] The method for producing the enantiomeric (R) configuration of a triazole derivative of scheme 1 of the present invention comprises: adding a chiral molecule represented by the general formula (IIa) or (IIb) to the triazole derivative represented by the general formula (I) in a solvent to carry out crystallization; and separating the precipitated crystals from the residual liquid.

[0092] The method for producing the enantiomeric (R) configuration of a triazole derivative according to scheme 2 of the present invention is based on the constitution of scheme 1 of the present invention, wherein the chiral molecule is a chiral molecule represented by the general formula (IIa), and the enantiomeric (R) configuration of a triazole derivative is generated from the separated crystals.

[0093] The method for producing the enantiomeric (R) configuration of a triazole derivative according to Scheme 3 of the present invention is based on the constitution of Scheme 2 of the present invention, wherein the chiral molecule in the separated crystal is removed by silica gel chromatography to produce the enantiomeric (R) configuration of a triazole derivative.

[0094] The method for producing the enantiomeric (R) configuration of a triazole derivative according to scheme 4 of the present invention is based on the constitution of scheme 2 of the present invention, wherein the chiral molecule represented by the general formula (IIa) is ((2R,3R)-1,4-dioxaspiro[4.5]decane-2,3-diyl)bis(diphenylmethanol) or ((4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)bis(diphenylmethanol).

[0095] The method for producing the enantiomeric (R) configuration of a triazole derivative of scheme 5 of the present invention is based on the structure of scheme 1 of the present invention, wherein the chiral molecule is a chiral molecule represented by the general formula (IIb) and the enantiomeric (R) configuration of the triazole derivative is generated from the separated residual liquid.

[0096] The method for producing the enantiomeric (R) configuration of a triazole derivative according to aspect 6 of the present invention is based on the constitution of aspect 5 of the present invention, wherein an amorphous solid is generated from the residual liquid, and the amorphous solid is separated as the enantiomeric (R) configuration of a triazole derivative.

[0097] The method for producing the enantiomeric (R) configuration of a triazole derivative of scheme 7 of the present invention is based on the constitution of scheme 5 of the present invention, wherein the chiral molecule represented by the general formula (IIb) is ((2S,3S)-1,4-dioxaspiro[4.5]decane-2,3-diyl)bis(diphenylmethanol) or ((4S,5S)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)bis(diphenylmethanol).

[0098] The method for producing the enantiomeric (R) configuration of a triazole derivative of scheme 8 of the present invention is based on the structure of scheme 1 of the present invention, and further includes a step of heating the solvent before or after adding the chiral molecule, and the crystallization is performed by cooling the heated solvent to which the chiral molecule is added.

[0099] The method for producing the enantiomeric (R) configuration of a triazole derivative according to Scheme 9 of the present invention is based on the constitution of any one of Schemes 1 to 8 of the present invention, wherein in the general formula (I), R 1 For-OR 4 ; R 2 is a halogen group, a cyano group, a C1-C4-alkyl group, a C1-C4-haloalkyl group, a C1-C4-alkoxy group, -SOR 7 or -SF5;R 3is a halogen group, a nitro group, a cyano group, an amino group, a C1-C4-alkyl group, a C1-C4-haloalkyl group, a C1-C4-alkoxy group, a C1-C4-haloalkoxy group, a C1-C4-alkylamino group, a C1-C4-dialkylamino group, a C1-C4-alkylacylamino group, -SOR 7 or -SF5.

[0100] The method for producing the enantiomeric (R) configuration of a triazole derivative according to Scheme 10 of the present invention is based on the constitution of Scheme 9 of the present invention, wherein in the general formula (I), R 4 is C1-C6-alkyl; R 2 is a halogen group, a cyano group, a C1-C4-alkyl group, a C1-C4-haloalkyl group or a C1-C4-alkoxy group; R 3 is a halogen group, a cyano group, a C1-C4-alkyl group, a C1-C4-haloalkyl group, a C1-C4-alkoxy group or a C1-C4-haloalkoxy group.

[0101] The following examples are shown to further illustrate the embodiments of the present invention. Of course, the present invention is not limited to the following examples, and it is beyond doubt that various schemes can be adopted for details. Moreover, the present invention is not limited to the above-mentioned embodiments, and various changes can be made within the scope shown in the claims, and the embodiments obtained by appropriately combining the respectively disclosed technical means are also included in the technical scope of the present invention. In addition, all the documents recorded in this specification are cited as references.

[0102] Example

[0103] <Reference Example 1: Research on Chiral Molecules>

[0104] In order to find a compound that preferentially forms a cocrystal with the (-)-enantiomer of methyl 2-(2-chloro-4-(4-chlorophenoxyphenyl)phenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propanoate (hereinafter referred to as compound 1), the following chiral molecules 1 to 13 were used to attempt cocrystallization with the (-)-enantiomer of compound 1 and cocrystallization with the (+)-enantiomer of compound 1.

[0105] Compound 1 was synthesized with reference to the method described in Patent Document 1. In addition, each enantiomer was separated from the racemate of Compound 1 by chiral chromatography according to the method described in Patent Document 2. One enantiomer was dissolved in methanol according to the formulation shown in Table 1 or Table 2 below. One of the chiral molecules 1 to 13 was added thereto according to the formulation shown in Table 1 or Table 2 and dissolved, and the mixture was allowed to stand at 25°C to try to precipitate crystals. The results are shown in Tables 1 and 2. The sample that became oil was judged to be unable to form a cocrystal ("unable" in the table). In the case of precipitation of crystals or solids, by their powder X-ray diffraction (PXRD) measurement, when a peak different from that derived from the chiral molecule was detected, it was judged that a cocrystal could be formed ("able" in the table), and when a peak derived from the chiral molecule was detected, a cocrystal was not formed and it was judged that a cocrystal could not be formed ("unable" in the table).

[0106] As shown in Table 1, it can be seen that only chiral molecules 7 and 10 can co-crystallize with the (-)-enantiomer. In addition, as shown in Table 2, it can be seen that only chiral molecules 7 and 10 can co-crystallize with the (+)-enantiomer.

[0107] Chiral molecule 1: (R)-(+)-1,1-bi-2-naphthol

[0108] [Chemical formula 9]

[0109]

[0110] Chiral molecule 2: (R)-3,3-dibromo-1,1-bi-2-naphthol

[0111] [Chemical formula 10]

[0112]

[0113] Chiral molecule 3: (R)-2,2,3,3-tetrahydro-1,1-spirobi[indene]-7,7-diol

[0114] [Chemical formula 11]

[0115]

[0116] Chiral molecule 4: (R)-(-)-1-phenylethane-1,2-diol

[0117] [Chemical formula 12]

[0118]

[0119] Chiral molecule 5: (R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol

[0120] [Chemical formula 13]

[0121]

[0122] Chiral molecule 6: (3S,4S)-(phenylmethyl)-3,4-pyrrolidinediol

[0123] [Chemical formula 14]

[0124]

[0125] Chiral molecule 7: ((4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)bis(diphenylmethanol)

[0126] [Chemical formula 15]

[0127]

[0128] Chiral molecule 8: (1R,2R)-N,N-bis(3,5-diphenylbutyl salicylidene)

[0129] [Chemical formula 16]

[0130]

[0131] Chiral molecule 9: (11bR)-4-hydroxy-dinaphtho[2,1-d:1,2-f][1,3,2]dioxaphosphapine 4-oxide

[0132] [Chemical formula 17]

[0133]

[0134] Chiral molecule 10: ((2R,3R)-1,4-dioxaspiro[4.5]decane-2,3-diyl)bis(diphenylmethanol)

[0135] [Chemical formula 18]

[0136]

[0137] Chiral molecule 11: (1R,2R)-1,2-diphenylethylenediamine

[0138] [Chemical formula 19]

[0139]

[0140] Chiral molecule 12: 4-Fluoro-L-phenylalanine

[0141] [Chemical formula 20]

[0142]

[0143] Chiral molecule 13: (R)-(+)-1,1'-binaphthyl-2,2'-diamine

[0144] [Chemical formula 21]

[0145]

[0146] [Table 1]

[0147] Co-crystallization with the (-)-enantiomer

[0148]

[0149]

[0150] [Table 2]

[0151] Co-crystallization with the (+)-enantiomer

[0152] Chiral molecules (+)-enantiomer added amount (mg) Chiral molecule addition amount (mg) Methanol addition amount (mg) result 1 20.4 14.3 3 cannot 2 20.1 22.1 3 cannot 3 20.1 12.5 3 cannot 4 19.9 6.8 3 cannot 5 19.9 12.7 3 cannot 6 20.2 9.5 3 cannot 7 19.9 22.9 3 able 8 20.2 26.9 4 cannot 9 19.9 16.9 3 cannot 10 19.9 25.0 3 able 11 20.1 10.2 3 cannot 12 19.8 8.9 3 cannot 13 19.7 14.0 3 cannot

[0153] <Reference Example 2: Structural determination of absolute configuration of (-)-enantiomer>

[0154] Since the enantiomer of compound 1 is an amorphous compound, it has not been possible to crystallize so far, and the structure of the absolute configuration cannot be known by the crystal structure. As shown in Reference Example 1, by using a specific chiral molecule, the (-)-enantiomer can be crystallized in the form of a cocrystal with the chiral molecule, so the crystal structure analysis is implemented. Specifically, 20 mg of the (-)-enantiomer of compound 1 was dissolved in 3 mL of methanol, 24.8 mg of the chiral molecule 10 was added thereto, and the mixture was allowed to stand at 25 ° C until white crystals precipitated. The precipitated white needle-shaped crystals were subjected to single crystal X-ray crystal structure analysis. As a result of the structural analysis, the (-)-enantiomer of compound 1 was determined to be the (R) configuration of compound 1. Therefore, in the following examples, the (-)-enantiomer is recorded as the (R) configuration, and the (+)-enantiomer is recorded as the (S) configuration.

[0155] <Example 1>

[0156] 100 mg of the racemate of compound 1 was dissolved in 3 mL of methanol at 60° C. 123 mg of chiral molecule 10 was added thereto, dissolved, and allowed to stand at 25° C., thereby obtaining a precipitated white solid. The obtained white solid was fractionated and separated into (R) configuration and (S) configuration using CHIRALPAK IG, and the content ratio was analyzed based on the peak area ratio, and the result was (R) configuration: (S) configuration = 21:8.

[0157] (Analysis conditions)

[0158] Column: CHIRALPAK IG (manufactured by Daicel), 4.6 mm×250 mm.

[0159] Particle size: 5μm.

[0160] Mobile phase: MeOH.

[0161] Flow rate: 1.0mL / min.

[0162] Column temperature: 40℃.

[0163] Injection volume: 10 μL.

[0164] <Example 2>

[0165] 50 mg of the racemate of compound 1 was dissolved in 1 mL of methanol at 25°C. 93 mg of chiral molecule 10 was added thereto and dissolved, and the mixture was allowed to stand at 25°C, thereby obtaining a precipitated white solid. The obtained white solid was washed with cold methanol, and the washed white solid was separated into (R) configuration and (S) configuration in the same manner as in Example 1. The content ratio was analyzed based on the peak area ratio, and the result showed that the ratio of the (R) configuration was 99% or more.

[0166] <Example 3>

[0167] 50 mg of the racemate of compound 1 was dissolved in 0.5 ml of methanol at 60°C. 62 mg of ((2S,3S)-1,4-dioxaspiro[4.5]decane-2,3-diyl)bis(diphenylmethanol), which is the enantiomer of the chiral molecule 10, was added thereto and dissolved, and the mixture was allowed to stand at 25°C, thereby obtaining a precipitated white solid. The obtained white solid was washed with cold methanol and separated by filtration. The obtained filtrate was separated into (R) configuration and (S) configuration in the same manner as in Example 1. The content ratio was analyzed based on the peak area ratio, and the result was (R) configuration: (S) configuration = 4.6:1.

[0168] Industrial Applicability

[0169] The method for producing the enantiomer (R) configuration of the triazole derivative of the present invention can be used for agricultural and horticultural fungicides and industrial material protective agents containing the enantiomer as an active ingredient.

Claims

1. A method for preparing an R-configuration enantiomer of a triazole derivative, comprising: A step of adding a chiral molecule represented by the following general formula (IIa) or (IIb) to a triazole derivative represented by the following general formula (I) in a solvent to carry out crystallization; as well as The process of separating the precipitated crystals from the residual liquid, In formula (I), R 1 For-OR 4 or -NR 5 R 6 ; R 4 , R 5 and R 6 are each independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C8-cycloalkyl, C3-C8-cycloalkyl-C1-C4-alkyl, phenyl, phenyl-C1-C4-alkyl, phenyl-C2-C4-alkenyl or phenyl-C2-C4-alkynyl, R 5 and R 6 optionally together with the nitrogen atom to which they are bound, form a ring; Among them, R 4 , R 5 and R 6 The aliphatic radical in optionally has 1, 2, 3 or the maximum possible number of identical or different radicals R a , R a are independently selected from the group consisting of halogen groups, cyano groups, nitro groups, C1-C4-alkoxy groups and C1-C4-haloalkoxy groups; R 2 is a halogen group, a cyano group, a nitro group, a phenyl group, a phenoxy group, a C1-C4-alkyl group, a C1-C4-haloalkyl group, a C1-C4-alkoxy group, a C1-C4-haloalkoxy group, -SOR 7 or -SF5; R 3 is a halogen group, a cyano group, a nitro group, an amino group, a phenyl group, a phenoxy group, a C1-C4-alkyl group, a C1-C4-haloalkyl group, a C1-C4-alkoxy group or a C1-C4-haloalkoxy group, a C1-C4-alkylamino group, a C1-C4-dialkylamino group, a C1-C4-alkylacylamino group, -SOR 7 or -SF5; R 4 , R 5 and R 6 The cycloalkyl and phenyl parts and R 3 The phenyl moiety in the group optionally has 1, 2, 3, 4, 5 or the maximum possible number of identical or different groups R b , R b are independently selected from the group consisting of halogen groups, cyano groups, nitro groups, C1-C4-alkyl groups, C1-C4-alkoxy groups, C1-C4-haloalkyl groups and C1-C4-haloalkoxy groups; Among them, R 7 is C1-C4-alkyl or C1-C4-haloalkyl; n is 0, 1, 2, 3 or 4; m is 1, 2, 3, 4 or 5, The asterisk * indicates an asymmetric carbon atom. In formula (IIa) and (IIb), R 8 and R 9 is C1-C6-alkyl, R 8 and R 9 Optionally, together with the carbon atoms to which they are bonded, they form a ring.

2. The method for producing the R-configuration enantiomer of a triazole derivative according to claim 1, wherein: The chiral molecule is the chiral molecule represented by the general formula (IIa), The R-configuration enantiomer of the triazole derivative is produced from the isolated crystals.

3. The method for producing the R-configuration enantiomer of a triazole derivative according to claim 2, wherein: The chiral molecule in the separated crystals is removed by silica gel chromatography to generate the R-configuration enantiomer of the triazole derivative.

4. The method for producing the R-configuration enantiomer of a triazole derivative according to claim 2, wherein: The chiral molecule represented by the general formula (IIa) is ((2R,3R)-1,4-dioxaspiro[4.5]decane-2,3-diyl)bis(diphenylmethanol) or ((4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)bis(diphenylmethanol).

5. The method for producing the R-configuration enantiomer of a triazole derivative according to claim 1, wherein: The chiral molecule is the chiral molecule represented by the general formula (IIb), The R-configuration enantiomer of the triazole derivative is generated from the separated residual liquid.

6. The method for producing the R-configuration enantiomer of a triazole derivative according to claim 5, wherein: An amorphous solid is generated from the residual liquid, and the amorphous solid is isolated as an R-configuration enantiomer of the triazole derivative.

7. The method for producing the R-configuration enantiomer of a triazole derivative according to claim 5, wherein: The chiral molecule represented by the general formula (IIb) is ((2S,3S)-1,4-dioxaspiro[4.5]decane-2,3-diyl)bis(diphenylmethanol) or ((4S,5S)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)bis(diphenylmethanol).

8. The method for producing the R-configuration enantiomer of a triazole derivative according to claim 1, wherein: include: The step of heating the solvent before or after adding the chiral molecule, wherein the crystallization is performed by cooling the heated solvent to which the chiral molecule is added.

9. The method for producing an R-configuration enantiomer of a triazole derivative according to any one of claims 1 to 8, wherein: In the general formula (I), R 1 is -OR 4 ; R 2 is a halogen group, a cyano group, a C1-C4-alkyl group, a C1-C4-haloalkyl group, a C1-C4-alkoxy group, -SOR 7 or -SF5; R 3 is a halogen group, a nitro group, a cyano group, an amino group, a C1-C4-alkyl group, a C1-C4-haloalkyl group, a C1-C4-alkoxy group, a C1-C4-haloalkoxy group, a C1-C4-alkylamino group, a C1-C4-dialkylamino group, a C1-C4-alkylacylamino group, -SOR 7 or -SF5.

10. The method for producing the R-configuration enantiomer of a triazole derivative according to claim 9, wherein: In the general formula (I), R 4 is C1-C6-alkyl; R 2 is a halogen group, a cyano group, a C1-C4-alkyl group, a C1-C4-haloalkyl group or a C1-C4-alkoxy group; R 3 is a halogen group, a cyano group, a C1-C4-alkyl group, a C1-C4-haloalkyl group, a C1-C4-alkoxy group or a C1-C4-haloalkoxy group.

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