Process for producing the (R) enantiomer of a triazole derivative

Abstract

Provided is a method for producing a triazole derivative enantiomer (R). The method includes: a step for adding, in a solvent, a chiral molecule represented by general formula (IIa) or general formula (IIb) to a triazole derivative represented by general formula (I), and carrying out crystallization; and a step for separating a precipitated crystal and a residual liquid.

Description

Technical Field

[0001] The present invention relates to a method for producing the (R)-enantiomer of a triazole derivative.

Background Art

[0002] Conventionally, there has been a demand for agricultural and horticultural chemicals that are less toxic to humans and livestock, have excellent handling safety, and exhibit a high control effect against a wide range of plant diseases. Under such circumstances, Patent Document 1 discloses a triazole derivative having high antibacterial properties against phytopathogenic bacteria, as well as an agricultural and horticultural chemical and an industrial material protective agent containing the same as an active ingredient. Further, Patent Document 2 discloses the (-)-enantiomer of a more active triazole derivative.

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0004] In Patent Document 2, as a method for preparing the predominantly active (-)-enantiomer, a method of preparative separation by a column for optical resolution from a racemate of a triazole derivative is disclosed. However, from an industrial perspective, a method for obtaining a specific enantiomer other than by column has been desired for cost reduction.

[0005] The present invention has been made in view of the above problems, and an object thereof is to provide a method for producing a specific enantiomer of a triazole derivative.

Means for Solving the Problems

[0006] As a result of intensive studies, the present inventors have found that cocrystallization with the (−)-enantiomer becomes possible by adding a specific chiral molecule to the racemate of the triazole derivative. Further, as a result of another study, the present inventors have found that the (−)-enantiomer of the triazole derivative is the (R)-form of the enantiomer of the triazole derivative, leading to the present invention.

[0007] That is, in order to solve the above problems, a method for producing the (R)-form of the enantiomer of a triazole derivative according to one aspect of the present invention includes 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 and performing crystallization, and a step of separating the precipitated crystals from the remaining liquid. [Chemical formula] [In formula (I), R 1 is -OR 4 or -NR 5 R 6 ; R 4 R 5 and R 6 are each independently hydrogen, a C1-C6-alkyl group, a C2-C6-alkenyl group, a C2-C6-alkynyl group, a C3-C8-cycloalkyl group, a C3-C8-cycloalkyl-C1-C4-alkyl group, a phenyl group, a phenyl-C1-C4-alkyl group, a phenyl-C2-C4-alkenyl group or a phenyl-C2-C4-alkynyl group, and R 5 and R 6 may form a ring together with the nitrogen atom to which they are attached; Here, the aliphatic groups in R 4 R 5 and R 6 may have 1, 2, 3 or the maximum possible number of identical or different groups R a , and R a is independently selected from a halogen group, a cyano group, a nitro group, a C1-C4-alkoxy group and a C1-C4-haloalkoxy group; 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 in the cycloalkyl group and phenyl group moieties and the phenyl group moiety in R 3 may have 1, 2, 3, 4, 5 or the maximum possible number of identical or different groups R b and R b is independently selected from 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; wherein R 7 is a C1-C4-alkyl group or a C1-C4-haloalkyl group; 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.]

Chemical formula

Advantages of the Invention

[0008] According to one aspect of the present invention, the enantiomer (R) form of the triazole derivative can be efficiently produced.

Embodiments for Carrying Out the Invention

[0009] Hereinafter, the method for producing the enantiomer (R) form of the triazole derivative according to the present invention will be described in detail. Note that the embodiments described below show an example of a typical embodiment of the present invention, and the scope of the present invention is not construed narrowly thereby.

[0010] The method for producing the enantiomer (R) form of the triazole derivative according to one embodiment of the present invention includes a step of adding a chiral molecule to the triazole derivative in a solvent to perform co-crystallization, and a step of separating the precipitated crystals and the remaining liquid. Note that "production of enantiomers" in this specification is intended to make a state containing more of the target enantiomer starting from a racemate or a mixture of each enantiomer. Therefore, "production of enantiomers" in this specification can also be expressed as separation of one enantiomer from a mixture of each enantiomer. Note that, in any expression, it is not necessarily intended to obtain a state that does not completely contain other enantiomers. By making a state containing more of the target enantiomer, an agrohorticultural chemical agent having higher activity than that using a racemate can be prepared.

[0011] Here, the enantiomers of the triazole derivative according to the present embodiment are 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 represented by the following general formula (I) (hereinafter referred to as the triazole derivative (I)). The asterisk (*) in the following general formula (I) refers to an asymmetric carbon atom. In this specification, the “(-)-enantiomer” refers to an enantiomer that rotates the plane of vibration of linearly polarized light of sodium D line to the left, and the “(+)-enantiomer” refers to an enantiomer that rotates the plane of vibration of linearly polarized light of sodium D line to the right. Further, as will be clarified in the examples described later, the triazole derivative (-)-enantiomer is the (R)-form of the enantiomer of the triazole derivative (I), and the triazole derivative (+)-enantiomer is the (S)-form of the enantiomer of the triazole derivative (I). In addition, when simply expressed as the “triazole derivative represented by the general formula (I)” or “triazole derivative (I)” in this specification, it is intended to be in a state not separated into the triazole derivative (-)-enantiomer and the triazole derivative (+)-enantiomer. Therefore, the “triazole derivative represented by the general formula (I)” and “triazole derivative (I)” in this specification are intended to be a mixture of the triazole derivative (-)-enantiomer and the triazole derivative (+)-enantiomer, and typically, it is a racemate of the triazole derivative (I). [Chemical formula] In the general formula (I), R 1 is -OR 4 or -NR 5 R 6 and preferably -OR 4 is.

[0012] R 4 、R 5 and R 6is, independently of one another, hydrogen, a C1-C6-alkyl group, a C2-C6-alkenyl group, a C2-C6-alkynyl group, a C3-C8-cycloalkyl group, a C3-C8-cycloalkyl-C1-C4-alkyl group, a phenyl group, a phenyl-C1-C4-alkyl group, a phenyl-C2-C4-alkenyl group or a phenyl-C2-C4-alkynyl group. R 5 and R 6 and R 5 and R 6 may together with the nitrogen atom to which they are attached form a ring.

[0013] The C1-C6-alkyl group is a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, for example, methyl group, ethyl group, 1-methylethyl group, 1,1-dimethylethyl group, propyl group, 1-methylpropyl group, 2-methylpropyl group, 1,1-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, butyl group, 1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, pentyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group and 4-methylpentyl group.

[0014] The C2-C6-alkenyl group is a straight-chain or branched-chain alkenyl group having 2 to 6 carbon atoms, for example, ethenyl group, 2-propenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 1-butenyl group, 2-butenyl group, 3-methyl-2-butenyl group, 1-methyl-2-butenyl group, 3-butenyl group, 1-pentenyl group, 2-pentenyl group, 1-hexenyl group and 5-hexenyl group.

[0015] The C2-C6-alkynyl group is a straight-chain or branched-chain alkynyl group having 2 to 6 carbon atoms, for example, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, pentynyl group and 1-hexynyl group.

[0016] The C3-C8-cycloalkyl group is a cyclic alkyl 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.

[0017] The C3-C8-cycloalkyl-C1-C4-alkyl group indicates that a cyclic cycloalkyl group having 3 to 8 carbon atoms is bonded to a linear or branched alkyl group having 1 to 4 carbon atoms. Examples thereof include a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, a 2-cyclopropylethyl group, a 1-cyclopropylethyl group, a 2-cyclohexylethyl group, a 3-cyclopropylpropyl group, a 2-cyclopropylpropyl group, and a 4-cyclopropylbutyl group.

[0018] The phenyl-C1-C4-alkyl group has a phenyl group substituted on a linear or branched alkyl group having 1 to 4 carbon atoms, and examples thereof include a phenylmethyl group, a 2-phenylethyl group, a 3-phenylpropyl group, and a 4-phenylbutyl group.

[0019] The phenyl-C2-C4-alkenyl group has a linear or branched alkenyl group having 2 to 4 carbon atoms bonded to the phenyl group, and examples thereof include a phenylethenyl group, a phenyl-1-propenyl group, a phenylisopropenyl group, and a phenylbutenyl group.

[0020] The phenyl-C2-C4-alkynyl group has an alkynyl group having 2 to 4 carbon atoms bonded to the phenyl group, and examples thereof include a phenylethynyl group, a phenyl-1-propynyl group, a phenyl-2-propynyl group, a phenyl-1-butynyl group, a phenyl-2-butynyl group, and a phenyl-3-butynyl group.

[0021] R 4 is preferably a C1-C6-alkyl group.

[0022] R1 , R 4 , R 5 , and R 6 The aliphatic groups in, are 1, 2, 3 or the maximum possible number of identical or different groups R a may have, and R a is independently selected from a halogen group, a cyano group, a nitro group, a C1-C4-alkoxy group, and a C1-C4-haloalkoxy group.

[0023] Examples of the halogen group include a chlorine group, a bromine group, an iodine group, or a fluorine group. For example, 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 can be mentioned.

[0024] The C1-C4-alkoxy group is a linear or branched alkoxy group having 1 to 4 carbon atoms. For example, 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 can be mentioned.

[0025] The C1-C4-haloalkoxy group has 1 or more halogen atoms substituted at the substitutable positions of the above-mentioned C1-C4-alkoxy group. When there are 2 or more halogen groups to be substituted, the halogen groups may be the same or different.

[0026] R 2 is a halogen group, a cyano group, a nitro group, a phenyl group, a phenyl-oxy 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.

[0027] The halogen group, the C1-C4-alkyl group, the C1-C4-haloalkyl group, the C1-C4-alkoxy group, and the C1-C4-haloalkoxy group can be the groups exemplified as examples of the organic group represented by R a .

[0028] R 2 is preferably 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, and more preferably a halogen group, a cyano group, a C1-C4-alkyl group, a C1-C4-haloalkyl group or a C1-C4-alkoxy group.

[0029] R 7 is a C1-C4-alkyl group or a C1-C4-haloalkyl group. R 2 is substituted at the 2-position, 3-position, 5-position or 6-position, preferably at the 2-position. n is 0, 1, 2, 3 or 4, preferably 1.

[0030] R 3 is a halogen group, a cyano group, a nitro group, an amino group, a phenyl group, a phenyl-oxy 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, and the halogen group, a C1-C4-alkyl C1-C4-haloalkyl group, a C1-C4-alkoxy group or a C1-C4-haloalkoxy group, and -SOR 7 is as exemplified by the groups listed as examples of the organic groups represented by R 2 above.

[0031] R 3 is preferably a halogen group, a nitro 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, and more 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.

[0032] A 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. Examples include a methylamino group, an ethylamino group, an n-propylamino group, an isopropylamino group, and a tert-butylamino group.

[0033] A C1-C4-dialkylamino group is an amino group in which both of the two hydrogen atoms of the amino group are substituted with linear or branched alkyl groups having 1 to 4 carbon atoms. Examples include an N,N-dimethylamino group, an N,N-diethylamino group, an N,N-di-n-propylamino group, an N,N-diisopropylamino group, and an N,N-di-tert-butylamino group.

[0034] A C1-C4-alkylacylamino group is an amino group in which one or two of the hydrogen atoms of the amino group are substituted with a linear or branched alkylacyl group having 1 to 4 carbon atoms. Examples 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.

[0035] R 4 、R 5 、R 6 The cycloalkyl group or phenyl group moiety in, or the phenyl group moiety in R 3 may have 1, 2, 3, 4, 5, or the maximum possible number of identical or different groups R b . R b is independently selected from 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, C1-C4-alkyl group, C1-C4-alkoxy group, C1-C4-haloalkyl group, and C1-C4-haloalkoxy group are Ra Examples of the organic group represented by the formula include the groups exemplified above.

[0036] From the above, as a preferred embodiment of the triazole derivative, 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, and examples of the triazole derivative include those described above.

[0037] Furthermore, as a more preferred embodiment of the triazole derivative, in the general formula (I), R 1 is -OR 4 and R 4 is a C1-C6-alkyl group; 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, and examples of the triazole derivative include those described above.

[0038] 〔1. Co-crystallization of Triazole Derivative and Chiral Molecule〕 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, according to the method described in Patent Document 1. When the triazole derivative (I) is produced according to the method described in Patent Document 1, the resulting triazole derivative (I) is a racemate. The prepared racemate of the triazole derivative (I) is crystallized by mixing it with a chiral molecule represented by the following general formula (IIa) or (IIb) in a solvent to obtain a cocrystal of one enantiomer of the triazole derivative (I) and the chiral molecule. [Chemical formula]

[0039] Here, in the general formulas (IIa) and (IIb), R 8 and R 9 are C1-C6-alkyl groups, and R 8 and R 9 may form a ring together with the carbon atom to which they are attached.

[0040] The C1-C6-alkyl group is a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, for example, methyl group, ethyl group, 1-methylethyl group, 1,1-dimethylethyl group, propyl group, 1-methylpropyl group, 2-methylpropyl group, 1,1-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, butyl group, 1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, pentyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group and 4-methylpentyl group.

[0041] The chiral molecule represented by the general formula (IIa) is preferably a chiral molecule represented by the following general formula (IIIa) or (IVa). [Chemical formula] ((2R,3R)-1,4-Dioxaspiro[4.5]decane-2,3-diyl)bis(diphenylmethanol) (General formula (IIIa))

Chemical formula

[0042] The chiral molecule represented by the general formula (IIb) is preferably a chiral molecule represented by the following general formula (IIIb) or (IVb).

Chemical formula

Chemical formula

[0043] The amount of the chiral molecule to be added is preferably 0.01 to 100 moles, more preferably 0.1 to 10 moles, and even more preferably 0.5 to 5 moles, per 1 mole of the triazole derivative (I).

[0044] The solvent to be 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-dimethylformaldehyde, and dimethyl sulfoxide. Since the soluble range of the triazole derivative (I) may vary depending on the type of solvent, the amount of the solvent to be used may be appropriately determined according to the soluble range of the triazole derivative (I). For example, when methanol is used as the solvent, the amount of methanol is preferably 10 to 1,000,000 moles, more preferably 50 to 500,000 moles, and even more preferably 100 to 10,000 moles per mole of the triazole derivative (I).

[0045] The solvent may or may not be heated. When the solvent is not heated, after dissolving the triazole derivative enantiomer, crystals will precipitate by allowing it to stand for a while. By performing crystallization without heating, crystals with a higher abundance ratio of one enantiomer can be obtained. When the solvent is heated, it may be pre-heated before adding the triazole derivative (I), or it may be heated after adding the triazole derivative (I). When heating after adding the triazole derivative (I), it may be heated after adding both the triazole derivative (I) and the chiral molecule. Then, crystallization is carried out by cooling the heated solvent to which the chiral molecule has been added. The temperature of the solvent after heating is not particularly limited, but it can be, for example, 25 to 64°C, preferably 40 to 64°C, and more preferably 45 to 60°C. The temperature of the solvent after cooling is not particularly limited, but it is preferably, for example, -50 to 25°C, more preferably 0 to 25°C. Typically, it can be room temperature (e.g., 25°C). When the temperature is above room temperature, an excessive cooling operation is not necessary, and it can be allowed to stand at room temperature, for example.

[0046] The method of crystallization after mixing the triazole derivative (I) and the chiral molecule, that is, the method of precipitating the cocrystal, is not limited to this, and conventionally known precipitation methods such as the preferential crystallization method, the diastereomer method, the asymmetric crystallization method, and the method of evaporating the solvent can be adopted. For example, in the method of precipitating the cocrystal by evaporating the solvent, the ratio of one enantiomer in the obtained crystal becomes larger.

[0047] All triazole derivative enantiomers are amorphous compounds, but by adding the above-mentioned chiral molecule to the triazole derivative (I), it can be crystallized as a cocrystal of one enantiomer of the triazole derivative (I) and the chiral molecule. As a result, by separating the obtained crystal from the mother liquor, a state containing more of one enantiomer can be obtained. On the other hand, since the mother liquor obtained by separating the crystal contains more of the other enantiomer of the triazole derivative (I), by fractionating the mother liquor after crystal formation, a state containing more of the other enantiomer can be obtained.

[0048] Also, by selecting the chiral molecule, the enantiomer of the triazole derivative (I) that forms the cocrystal can be changed. For example, when a chiral molecule represented by the general formula (IIa) is used as the chiral molecule, a cocrystal with the (R)-enantiomer of the triazole derivative (I) is formed. On the other hand, when a chiral molecule represented by the general formula (IIb) which is a mirror isomer of this chiral molecule is used, a cocrystal with the (S)-enantiomer of the triazole derivative (I) is formed.

[0049] The cocrystal and the mother liquor of the triazole derivative (I) and the chiral molecule obtained as described above are separated, for example, by filtration.

[0050] [2. Generation of (R)-Enantiomer of Triazole Derivative 1] As described above, depending on the chiral molecule used, either the enantiomer (R) form or the enantiomer (S) form of the triazole derivative (I) co-crystallizes with the chiral molecule. In this section, the case of using a chiral molecule represented by the general formula (IIa) in which the enantiomer (R) form of the triazole derivative (I) co-crystallizes will be described. When using this chiral molecule, the step of separating the precipitated crystals from the mother liquor can be referred to as the step of separating the precipitated crystals from the mother liquor to obtain the crystals. Note that depending on the chiral molecule, the chiral molecule represented by the general formula (IIa) can also co-crystallize with the enantiomer (S) form of the triazole derivative (I). However, when co-crystallization is performed on the racemate, the enantiomer (R) form is preferentially co-crystallized.

[0051] The separated crystals may contain not only the enantiomer (R) form of the triazole derivative (I) but also the enantiomer (S) form of the triazole derivative, but the content of the (R) form is higher than that of the (S) form. Typically, the ratio of the content of the (R) form to the total amount of the content of the (R) form and the (S) form can exceed 50%, can be 70% or more, can be 95% or more, and can even be 100%.

[0052] The ratio of the (R) form and the (S) form contained in the separated crystals can be confirmed by a method of dissolving the obtained crystals in a solvent and fractionating and separating each enantiomer by chiral chromatography. The preparative separation by chiral chromatography may be performed, for example, with reference to the method described in Patent Document 2.

[0053] In order to increase the content ratio of the enantiomer (R) form of the target triazole derivative (I) from the obtained co-crystal, a step of removing the chiral molecule in the crystal may be added. Examples of the method for removing the chiral molecule include silica gel chromatography. Thereby, the enantiomer (R) form of the triazole derivative (I) from which the chiral molecule has been removed can be produced.

[0054] 〔3. Generation of Enantiomer (R) of Triazole Derivative 2〕 As described above, depending on the chiral molecule used, either the enantiomer (R) or the enantiomer (S) of the triazole derivative (I) co-crystallizes with the chiral molecule. In this section, the case of using a chiral molecule represented by the general formula (IIb) in which the enantiomer (S) of the triazole derivative (I) co-crystallizes will be described. When using this chiral molecule, the step of separating the precipitated crystals from the residual liquid can be referred to as the step of separating the precipitated crystals from the residual liquid and collecting the filtrate after crystallization.

[0055] When using a chiral molecule represented by the general formula (IIb), more of the enantiomer (S) forms crystals compared to the enantiomer (R). By filtering this crystal and removing the obtained crystal, the filtrate after filtering the crystal (i.e., the residual liquid after crystal formation) will consequently contain more of the enantiomer (R). Therefore, by generating an amorphous solid from this filtrate, a solid containing more of the enantiomer (R) of the triazole derivative can be obtained. Examples of methods for generating an amorphous solid include solvent evaporation and column chromatography.

[0056] The obtained amorphous solid may contain not only the enantiomer (R) of the triazole derivative (I) but also the enantiomer (S) of the triazole derivative, but the content of the (R) form is higher compared to the (S) form. Typically, the ratio of the content of the (R) form to the total content of the (R) and (S) forms can exceed 50%, can be 70% or more, can be 95% or more, and can even be 100%.

[0057] Also, the obtained amorphous solid or the filtrate after filtering the co-crystal may contain the chiral molecule used for co-crystallization. By separating the chiral molecule by silica gel chromatography or the like, a triazole derivative (I) that does not contain the chiral molecule can be obtained.

[0058] <Summary> The method for producing the (R)-enantiomer of the triazole derivative according to Embodiment 1 of the present invention includes a step of adding a chiral molecule represented by the above general formula (IIa) or (IIb) to the triazole derivative represented by the above general formula (I) in a solvent for crystallization, and a step of separating the precipitated crystals from the remaining liquid.

[0059] The method for producing the (R)-enantiomer of the triazole derivative according to Embodiment 2 of the present invention, in addition to the configuration of Embodiment 1 of the present invention, the chiral molecule is a chiral molecule represented by the above general formula (IIa), and the (R)-enantiomer of the triazole derivative is generated from the separated crystals.

[0060] The method for producing the (R)-enantiomer of the triazole derivative according to Embodiment 3 of the present invention, in addition to the configuration of Embodiment 2 of the present invention, removes the chiral molecule in the separated crystals by silica gel chromatography to generate the (R)-enantiomer of the triazole derivative.

[0061] The method for producing the (R)-enantiomer of the triazole derivative according to Embodiment 4 of the present invention, in addition to the configuration of Embodiment 2 of the present invention, the chiral molecule represented by the above 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).

[0062] The method for producing the (R)-enantiomer of the triazole derivative according to Embodiment 5 of the present invention, in addition to the configuration of Embodiment 1 of the present invention, the chiral molecule is a chiral molecule represented by the above general formula (IIb), and the (R)-enantiomer of the triazole derivative is generated from the separated remaining liquid.

[0063] The method for producing the (R)-enantiomer of the triazole derivative according to Embodiment 6 of the present invention, in addition to the configuration of Embodiment 5 of the present invention, generates an amorphous solid from the remaining liquid and separates the amorphous solid as the (R)-enantiomer of the triazole derivative.

[0064] The method for producing the (R)-enantiomer of the triazole derivative according to Embodiment 7 of the present invention, in addition to the configuration of Embodiment 5 of the present invention, 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).

[0065] The method for producing the (R)-enantiomer of the triazole derivative according to Embodiment 8 of the present invention, in addition to the configuration of Embodiment 1 of the present invention, includes heating the solvent before or after adding the chiral molecule, and performing the crystallization by cooling the heated solvent to which the chiral molecule has been added.

[0066] The method for producing the (R)-enantiomer of the triazole derivative according to Embodiment 9 of the present invention, in addition to the configuration of any one of Embodiments 1 to 8 of the present invention, 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.

[0067] The method for producing the (R)-enantiomer of the triazole derivative according to Embodiment 10 of the present invention, in addition to the configuration of Embodiment 9 of the present invention, in the general formula (I), R 4 is a C1-C6-alkyl group; R 2is 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.

[0068] Examples are shown below to explain the embodiments of the present invention in more detail. Of course, the present invention is not limited to the following examples, and it goes without saying that various aspects are possible in terms of details. Furthermore, the present invention is not limited to the above-described embodiments, and various modifications are possible within the scope shown in the claims. Embodiments obtained by appropriately combining the disclosed technical means are also included in the technical scope of the present invention. Also, all the documents described in this specification are incorporated by reference.

Example

[0069] <Reference Example 1: Examination of Chiral Molecules> In order to search for a compound that preferentially forms a co-crystal 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 co-crystallization with the (-)-enantiomer of Compound 1 and co-crystallization with the (+)-enantiomer of Compound 1.

[0070] Compound 1 was synthesized with reference to the method described in Patent Document 1. Each enantiomer was separated and purified from the racemate of Compound 1 by chiral chromatography according to the method described in Patent Document 2. According to the formulations shown in Table 1 or Table 2 below, one enantiomer was dissolved in methanol. One of the chiral molecules 1 to 13 was added and dissolved according to the formulations shown in Table 1 or Table 2, and the mixture was allowed to stand at 25 °C to attempt crystallization. The results are shown in Tables 1 and 2. Those that became oils were determined to be unable to form co-crystals ("not possible" in the table). When crystals or solids precipitated, if peaks different from those derived from the chiral molecule were detected by powder X-ray diffraction (PXRD) measurement, it was determined that co-crystal formation was possible ("possible" in the table), and if peaks derived from the chiral molecule were detected, it was determined that co-crystals were not formed and co-crystal formation was not possible ("not possible" in the table).

[0071] As shown in Table 1, it was found that only chiral molecules 7 and 10 were able to co-crystallize with the (−)-enantiomer. Also, as shown in Table 2, it was found that only chiral molecules 7 and 10 were able to co-crystallize with the (+)-enantiomer. · Chiral molecule 1: (R)-(+)-1,1'-bi-2-naphthol

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Table 1

Table 2

[0072] <Reference Example 2: Determination of the Structure of the Absolute Configuration of the (-)-Enantiomer> Since the enantiomers of Compound 1 are amorphous compounds, they could not be crystallized until now, and the structure of the absolute configuration could not be determined by crystal structure analysis. As shown in Reference Example 1, the crystallization of the (-)-enantiomer as a cocrystal with a specific chiral molecule became possible, so crystal structure analysis was carried out. Specifically, 20 mg of the (-)-enantiomer of Compound 1 was dissolved in 3 mL of methanol, 24.8 mg of chiral molecule 10 was added thereto, and the mixture was allowed to stand at 25 °C until white crystals precipitated. Single crystal X-ray crystal structure analysis was performed on the precipitated white needle crystals. As a result of the structure analysis, the (-)-enantiomer of Compound 1 was determined to be the (R)-form of Compound 1. Therefore, in the following examples, the (-)-enantiomer is described as the (R)-form and the (+)-enantiomer is described as the (S)-form.

[0073] <Example 1> 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 and dissolved, and the mixture was allowed to stand at 25 °C to obtain a precipitated white solid. The obtained white solid was fractionated and separated into the (R)-form and the (S)-form using CHIRALPAK IG, and the content ratio was analyzed based on the peak area ratio. As a result, (R)-form:(S)-form = 21:8.

[0074] (Analysis Conditions) Column: CHIRALPAK IG (manufactured by Daicel) 4.6×250 mm Particle size: 5 μm Mobile phase: MeOH Flow rate: 1.0 mL / min Column temperature: 40 °C Injection volume: 10 μL.

[0075] <Example 2> 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 to obtain a precipitated white solid. The obtained white solid was washed with cold methanol, and the washed white solid was fractionated and separated into the (R)-form and the (S)-form in the same manner as in Example 1, and the content ratio was analyzed based on the peak area ratio. As a result, the ratio of the (R)-form was 99% or more.

[0076] <Example 3> 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 an enantiomer of chiral molecule 10, was added thereto and dissolved, and the mixture was allowed to stand at 25°C to obtain a precipitated white solid. The obtained white solid was washed with cold methanol, and the filtrate obtained by filtering and separating this was fractionated and separated into the (R)-form and the (S)-form in the same manner as in Example 1, and the content ratio was analyzed based on the peak area ratio. As a result, (R)-form:(S)-form = 4.6:1.

Industrial Applicability

[0077] The method for producing the (R)-form enantiomer of the triazole derivative according to the present invention can be used for agricultural and horticultural fungicides and industrial material protectants containing the enantiomer as an active ingredient.

Claims

1. 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 and performing crystallization, and A method for producing the (R)-enantiomer of a triazole derivative, comprising a step of separating the precipitated crystals from the remaining liquid. 【Chemical Formula 1】 [In formula (I), R １ is -OR4; R4 is C １ -C ６ -alkyl group; R ２ is a halogen group, a cyano group, C １ -C ４ -alkyl group, C １ -C ４ -haloalkyl group, C １ -C ４ -alkoxy group or C １ -C ４ -haloalkoxy group; R ３ is a halogen group, a cyano group, C １ -C ４ -alkyl group, C １ -C ４ -haloalkyl group, C １ -C ４ -alkoxy group or C １ -C ４ -haloalkoxy group; Here, n is 0 or 1; m is 1 or 2, The asterisk (*) indicates an asymmetric carbon atom. ] 【Chemical Formula 2】 [In formulas (IIa) and (IIb), R ８ and R ９ are C １ -C ６ -alkyl group, R ８ and R ９They may form a ring together with the carbon atoms to which they are attached.

2. The chiral molecule is a chiral molecule represented by the general formula (IIa), A method for producing an enantiomer (R) form of a triazole derivative according to claim 1, which produces an enantiomer (R) form of a triazole derivative from the separated crystals.

3. A method for producing an enantiomer (R) form of a triazole derivative according to claim 2, which removes the chiral molecule in the separated crystals by silica gel chromatography to produce an enantiomer (R) form of a triazole derivative.

4. 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). A method for producing an enantiomer (R) form of a triazole derivative according to claim 2.

5. The chiral molecule is a chiral molecule represented by the general formula (IIb), A method for producing an enantiomer (R) form of a triazole derivative according to claim 1, which produces an enantiomer (R) form of a triazole derivative from the separated residue.

6. A method for producing an enantiomer (R) form of a triazole derivative according to claim 5, which produces an amorphous solid from the residue and separates the amorphous solid as an enantiomer (R) form of a triazole derivative.

7. 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). A method for producing an enantiomer (R) form of a triazole derivative according to claim 5. Claim 8 The method for producing the (R)-enantiomer of the triazole derivative according to claim 1, which comprises heating the solvent before or after adding the chiral molecule, and performing the crystallization by cooling the heated solvent to which the chiral molecule has been added.

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