Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
  • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B57/00—Separation of optically-active compounds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/07—Optical isomers
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
  • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
  • C07D317/20—Free hydroxyl or mercaptan

Definitions

• the present invention relates to a method for producing an enantiomeric (R) form of a triazole derivative.
• Patent Document 1 discloses a triazole derivative having high antibacterial properties against plant pathogens, and agricultural and horticultural agents and industrial material protection agents containing the triazole derivative as an active ingredient.
• Patent Document 2 discloses a (-)-enantiomer of a triazole derivative with higher activity.
• Patent Document 2 discloses a method for preparative separation of a racemic form of a triazole derivative using an optical resolution column as a method for preparing a dominantly active (-)-enantiomer.
• Patent Document 2 discloses a method for preparative separation of a racemic form of a triazole derivative using an optical resolution column as a method for preparing a dominantly active (-)-enantiomer.
• methods for obtaining specific enantiomers other than through columns have been desired to reduce costs.
• the present invention has been made in view of the above problems, and its purpose is to provide a method for producing a specific enantiomer of a triazole derivative.
• the present inventors discovered that by adding a specific chiral molecule to the racemic form of a triazole derivative, co-crystallization with the (-)-enantiomer becomes possible. Further, the present inventors found from other study results that the (-)-enantiomer of the triazole derivative is the enantiomer (R) form of the triazole derivative, and came up with the present invention.
• a method for producing an enantiomeric (R) form of a triazole derivative includes adding a triazole derivative represented by the following general formula (I) to a triazole derivative represented by the following general formula (I) in a solvent.
• the method includes a step of adding a chiral molecule represented by (IIa) or (IIb) to perform crystallization, and a step of separating precipitated crystals from a residual liquid.
• R 1 is -OR 4 or -NR 5 R 6 ;
• R 4 , R 5 and R 6 each independently represent hydrogen, C 1 -C 6 -alkyl group, C 2 -C 6 -alkenyl group, C 2 -C 6 -alkynyl group, C 3 -C 8 -cyclo Alkyl group, C 3 -C 8 -cycloalkyl-C 1 -C 4 -alkyl group, phenyl group, phenyl-C 1 -C 4 -alkyl group, phenyl-C 2 -C 4 -alkenyl group or phenyl-C 2 -C 4 -alkynyl group, R 5 and R 6 may form a ring together with the nitrogen atom to which they are bonded;
• the aliphatic groups in R 4 , R 5 and R 6 may have 1, 2, 3 or the maximum possible number of the same or different groups R a , and R a is a hal
• R 2 is a halogen group, a cyano group, a nitro group, a phenyl group, a phenyl-oxy group, a C 1 -C 4 -alkyl group, a C 1 -C 4 -haloalkyl group, a C 1 -C 4 -alkoxy group, a C 1 - C 4 -haloalkoxy group, -SOR 7 or -SF 5 ;
• R 3 is a halogen group, a cyano group, a nitro group, an amino group, a phenyl group, a phenyl-oxy group, a C 1 -C 4 -alkyl group, a C 1 -C 4 -haloalkyl group, a C 1 -C 4 -alkoxy group or C 1 -C 4 -haloalkoxy;
• R 7 is a C 1 -C 4 -alkyl group or a C 1 -C 4 -haloalkyl group; n is 0, 1, 2, 3, or 4; m is 1, 2, 3, 4 or 5;
• the asterisk (*) indicates an asymmetric carbon atom.
• R 8 and R 9 are C 1 -C 6 -alkyl groups, and R 8 and R 9 may form a ring together with the carbon atom to which they are bonded.
• enantiomeric (R) forms of triazole derivatives can be efficiently produced.
• a method for producing an enantiomer (R) form of a triazole derivative includes a step of adding a chiral molecule to a triazole derivative in a solvent to perform co-crystallization, and a step of co-crystallizing the precipitated crystal and the residual liquid. It includes a step of separating. Note that "manufacture of enantiomers" in this specification is intended to use a racemate or a mixture of each enantiomer as a starting material, and to produce a state containing a larger amount of the desired enantiomer.
• enantiomers in this specification can also be expressed as separation of one enantiomer from a mixture of each enantiomer. Note that any of the expressions does not necessarily mean that the product is obtained in a state completely free of other enantiomers. By containing a larger amount of the desired enantiomer, it is possible to prepare agricultural and horticultural chemicals with higher activity than when using a racemate.
• the enantiomer of the triazole derivative according to the present embodiment is the (-)-enantiomer (hereinafter referred to as triazole derivative (-)) in the triazole derivative represented by the following general formula (I) (hereinafter referred to as triazole derivative (I)).
• triazole derivative (I) the triazole derivative represented by the following general formula (I)
• - enantiomer or (+)-enantiomer
• triazole derivative (+)-enantiomer hereinafter referred to as triazole derivative (+)-enantiomer.
• the asterisk (*) in the following general formula (I) indicates an asymmetric carbon atom.
• the "(-)-enantiomer” refers to an enantiomer that rotates the plane of vibration of linearly polarized light of the sodium D line to the left
• the "(+)-enantiomer” refers to an enantiomer that rotates the vibration plane of linearly polarized light of the sodium D line. refers to an enantiomer that rotates the plane of vibration of linearly polarized light to the right.
• the triazole derivative (-)-enantiomer is the enantiomer (R) form of the triazole derivative (I)
• the triazole derivative (+)-enantiomer is the enantiomer (R) form of the triazole derivative (I).
• triazole derivative represented by general formula (I) when simply expressed as "triazole derivative represented by general formula (I)" or “triazole derivative (I)", it is separated into triazole derivative (-)-enantiomer and triazole derivative (+)-enantiomer. It is intended to be in a state where it is not. Therefore, in this specification, "triazole derivative represented by general formula (I)” and “triazole derivative (I)” mean a mixture of triazole derivative (-)-enantiomer and triazole derivative (+)-enantiomer. , typically a racemic form of triazole derivative (I).
• R 1 is -OR 4 or -NR 5 R 6 , preferably -OR 4 .
• R 4 , R 5 and R 6 each independently represent hydrogen, C 1 -C 6 -alkyl group, C 2 -C 6 -alkenyl group, C 2 -C 6 -alkynyl group, C 3 -C 8 -cyclo Alkyl group, C 3 -C 8 -cycloalkyl-C 1 -C 4 -alkyl group, phenyl group, phenyl-C 1 -C 4 -alkyl group, phenyl-C 2 -C 4 -alkenyl group or phenyl-C 2 -C 4 -alkynyl group.
• R 5 and R 6 may form a ring together with the nitrogen atom to which R 5 and R 6 are bonded.
• a C 1 -C 6 -alkyl group is a straight-chain or branched alkyl group having 1 to 6 carbon atoms, for example methyl, ethyl, 1-methylethyl, 1,1-dimethyl Ethyl 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.
• a C 2 -C 6 -alkenyl group is a linear or branched alkenyl group having 2 to 6 carbon atoms, such as 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- Examples include pentenyl, 1-hexenyl and 5-hexenyl.
• a C 2 -C 6 -alkynyl group is a linear or branched alkynyl group having 2 to 6 carbon atoms, such as ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group. 2-butynyl, 3-butynyl, pentynyl and 1-hexynyl.
• the C 3 -C 8 -cycloalkyl group is a cyclic alkyl group having 3 to 8 carbon atoms, and includes, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group. It will be done.
• a C 3 -C 8 -cycloalkyl-C 1 -C 4 -alkyl group is a group in which a cyclic cycloalkyl group having 3 to 8 carbon atoms is replaced with a linear or branched alkyl group having 1 to 4 carbon atoms. Indicates that they are connected.
• cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, 2-cyclopropylethyl group, 1-cyclopropylethyl group, 2-cyclohexylethyl group, 3-cyclopropylpropyl group, 2-cyclo Examples include propylpropyl group and 4-cyclopropylbutyl group.
• a phenyl-C 1 -C 4 -alkyl group is a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a phenyl group, such as a phenylmethyl group, a 2-phenylethyl group, Examples include 3-phenylpropyl group and 4-phenylbutyl group.
• a phenyl-C 2 -C 4 -alkenyl group has a linear or branched alkenyl group having 2 to 4 carbon atoms bonded to a phenyl group, such as phenylethenyl group, phenyl-1-propenyl group, etc. phenylisopropenyl group, and phenylbutenyl group.
• a phenyl-C 2 -C 4 -alkynyl group has an alkynyl group having 2 to 4 carbon atoms bonded to a phenyl group, such as a phenylethynyl group, a phenyl-1-propynyl group, a phenyl-2-propynyl group. , phenyl-1-butynyl group, phenyl-2-butynyl group, and phenyl-3-butynyl group.
• R 4 is preferably a C 1 -C 6 -alkyl group.
• the aliphatic groups in R 1 , R 4 , R 5 and R 6 may have 1, 2, 3 or the maximum possible number of identical or different groups R a , R a being a halogen group. , cyano, nitro, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy.
• halogen group examples include a chlorine group, a bromine group, an iodine group, and a fluorine group.
• examples include chloromethyl group, 2-chloroethyl group, 2,3-dichloropropyl group, bromomethyl group, chlorodifluoromethyl group, trifluoromethyl group, and 3,3,3-trifluoropropyl group.
• the C 1 -C 4 -alkoxy group is a linear or branched alkoxy group having 1 to 4 carbon atoms, such as methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group. group, sec-butoxy group, and tert-butoxy group.
• halogen atoms are substituted at the substitutable positions of the above-mentioned C 1 -C 4 -alkoxy group, and when there are two or more halogen groups to be substituted,
• the halogen groups may be the same or different.
• R 2 is a halogen group, a cyano group, a nitro group, a phenyl group, a phenyl-oxy group, a C 1 -C 4 -alkyl group, a C 1 -C 4 -haloalkyl group, a C 1 -C 4 -alkoxy group, a C 1 -C 4 -haloalkoxy group, -SOR 7 or -SF 5 .
• the halogen group, C 1 -C 4 -alkyl group, C 1 -C 4 -haloalkyl group, C 1 -C 4 -alkoxy group, and C 1 -C 4 -haloalkoxy group are organic groups represented by R a
• the groups mentioned above can be mentioned as examples.
• R2 is preferably a halogen group, a cyano group, a C1 - C4 -alkyl group, a C1 - C4 -haloalkyl group, a C1 - C4 -alkoxy group, -SOR7 or -SF5 , More preferred are a halogen group, a cyano group, a C 1 -C 4 -alkyl group, a C 1 -C 4 -haloalkyl group or a C 1 -C 4 -alkoxy group.
• R 7 is a C 1 -C 4 -alkyl group or a C 1 -C 4 -haloalkyl group.
• the substitution position of R 2 is the 2nd, 3rd, 5th or 6th position, preferably the 2nd position.
• n is 0, 1, 2, 3 or 4, preferably 1.
• R 3 is a halogen group, a cyano group, a nitro group, an amino group, a phenyl group, a phenyl-oxy group, a C 1 -C 4 -alkyl group, a C 1 -C 4 -haloalkyl group, a C 1 -C 4 -alkoxy group , C 1 -C 4 -haloalkoxy group, C 1 -C 4 -alkylamino group, C 1 -C 4 -dialkylamino group, C 1 -C 4 -alkylacylamino group, -SOR 7 or -SF 5 halogen group, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, or C 1 -C 4 -haloalkoxy , and -SOR 7 is represented by R 2 Examples of organic groups include the groups listed above.
• R 3 is preferably a halogen group, a nitro group, an amino group, a C 1 -C 4 -alkyl group, a C 1 -C 4 -haloalkyl group, a C 1 -C 4 -alkoxy group, a C 1 -C 4 -halo Alkoxy group, C 1 -C 4 -alkylamino group, C 1 -C 4 -dialkylamino group, C 1 -C 4 -alkylacylamino group, -SOR 7 or -SF 5 , more preferably halogen 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.
• a C 1 -C 4 -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, such as methylamino group, ethylamino group, n-propylamino group, isopropylamino group, and tert-butylamino group.
• a C 1 -C 4 -dialkylamino group is an amino group in which both of the hydrogen atoms possessed by the amino group are substituted with a linear or branched alkyl group having 1 to 4 carbon atoms, for example, N , N-dimethylamino group, N,N-diethylamino group, N,N-di-n-propylamino group, N,N-diisopropylamino group, and N,N-di-tert-butylamino group.
• a C 1 -C 4 -alkylacyl amino group is an amino group in which one or two hydrogen atoms of the amino group are substituted with a linear or branched alkylacyl group having 1 to 4 carbon atoms.
• Examples include N,N-di-n-propylacylamino group, N,N-diisopropylacylamino group, and N,N-di-tert-butylacylamino group.
• the cycloalkyl group or phenyl group moiety in R 4 , R 5 , R 6 or the phenyl group moiety in R 3 has 1, 2, 3, 4, 5 or the maximum possible number of the same or different groups
• R b and R b is a halogen group, a cyano group, a nitro group, a C 1 -C 4 -alkyl group, a C 1 -C 4 -alkoxy group, a C 1 -C 4 -haloalkyl group, and a C 1 -C 4 -alkyl group. 4 -haloalkoxy groups independently of each other.
• the halogen group, C 1 -C 4 -alkyl group, C 1 -C 4 -alkoxy group, C 1 -C 4 -haloalkyl group and C 1 -C 4 -haloalkoxy group are the organic groups represented by R a Mention may be made of the groups mentioned as examples.
• R 1 is -OR 4
• R 2 is a halogen group, a cyano group, a C 1 -C 4 -alkyl group, or a C 1 -C 4 -haloalkyl group, C 1 -C 4 -alkoxy group, -SOR 7 or -SF 5
• R 3 is a halogen group, nitro group, cyano group, amino group, C 1 -C 4 -alkyl group , C 1 -C 4 -haloalkyl group, C 1 -C 4 -alkoxy group, C 1 -C 4 -haloalkoxy group, C 1 -C 4 -alkylamino group, C 1 -C 4 -dialkylamino group, C Mention may be made of triazole derivatives which are a 1 -C 4 -alkyl acylamino group, -SOR 7 or
• R 1 is -OR 4 and R 4 is a C 1 -C 6 -alkyl group
• R 2 is a halogen group, cyano group, C 1 -C 4 -alkyl group, C 1 -C 4 -haloalkyl group or C 1 -C 4 -alkoxy group
• R 3 is a halogen group, cyano group, C 1 -C 4 - Mention may be made of triazole derivatives which are alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy or C 1 -C 4 -haloalkoxy groups.
• triazole derivative (I) is typically a racemate of triazole derivative (I).
• the racemic form of triazole derivative (I) can be prepared, for example, according to the method described in Patent Document 1. Note that when the triazole derivative (I) is produced according to the method described in Patent Document 1, the triazole derivative (I) obtained is a racemate.
• the racemic form of the prepared triazole derivative (I) is crystallized by mixing it with a chiral molecule represented by the following general formula (IIa) or (IIb) in a solvent, and one enantiomer of the triazole derivative (I) is crystallized. Cocrystals with chiral molecules can be obtained.
• R 8 and R 9 are C 1 -C 6 -alkyl groups, and R 8 and R 9 form a ring together with the carbon atom to which they are bonded. Good too.
• a C 1 -C 6 -alkyl group is a straight-chain or branched alkyl group having 1 to 6 carbon atoms, for example methyl, ethyl, 1-methylethyl, 1,1-dimethyl Ethyl 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.
• the chiral molecule represented by the general formula (IIa) is preferably a chiral molecule represented by the following general formula (IIIa) or (IVa).
• the chiral molecule represented by the general formula (IIb) is preferably a chiral molecule represented by the following general formula (IIIb) or (IVb).
• the amount of chiral molecules added is preferably 0.01 to 100 mol, more preferably 0.1 to 10 mol, and even more preferably 0.5 to 5 mol, per 1 mol of triazole derivative (I).
• the solvent to be used is not particularly limited, but alcohols such as methanol and ethanol are preferred, as well as aromatic hydrocarbons such as benzene, toluene, xylene and chlorobenzene, N,N-dimethylacetamide, N-methylpyrrolidone and N, Mention may be made of amides such as N-dimethylformaldehyde, as well as dimethyl sulfoxide. Since the solubility 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 depending on the solubility range of the triazole derivative (I).
• the amount of methanol is preferably 10 to 1,000,000 mol, more preferably 50 to 500,000 mol, and more preferably 100 to 10,000 mol, per 1 mol of triazole derivative (I). More preferred is molar.
• the solvent may or may not be heated. If the solvent is not heated, crystals will precipitate if the triazole derivative enantiomer is dissolved and left to stand for a while. By performing crystallization without heating, it is possible to obtain crystals with a higher abundance ratio of one enantiomer.
• heating the solvent it may be heated in advance before adding the triazole derivative (I), or may be heated after adding the triazole derivative (I). When heating after adding the triazole derivative (I), heating may be performed after adding both the triazole derivative (I) and the chiral molecule. Crystallization is then carried out by cooling the heated solvent to which the chiral molecules have been added.
• the temperature of the solvent after heating is not particularly limited, but may 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 is preferably -50 to 25°C, more preferably 0 to 25°C. Typically, it may be at room temperature (eg, 25°C). When the temperature is above room temperature, there is no need for excessive cooling operation, and for example, it may be left standing at room temperature.
• the method of crystallization after mixing the triazole derivative (I) and the chiral molecule is not limited to this, but may include a preferential crystallization method, a diastereomer method, an asymmetric crystallization method, and a method using a solvent.
• Conventionally known precipitation methods such as evaporation can be employed. For example, in a method in which a cocrystal is precipitated by evaporating the solvent, the ratio of one enantiomer in the resulting crystal becomes larger.
• All of the triazole derivative enantiomers are amorphous compounds, but by adding the chiral molecule described above to the triazole derivative (I), one enantiomer of the triazole derivative (I) and the chiral molecule can be crystallized as a co-crystal. can be made into As a result, by separating the obtained crystals from the residual liquid, it is possible to obtain a state containing a larger amount 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 separating the residual liquid after crystal formation, a larger amount of the other enantiomer can be obtained. It can be in a state that includes.
• the enantiomer of the triazole derivative (I) that forms the cocrystal can be changed by selecting the chiral molecule.
• a chiral molecule represented by the general formula (IIa) is used as the chiral molecule, a cocrystal with the enantiomer (R) form of the triazole derivative (I) is formed.
• a chiral molecule represented by the general formula (IIb) which is an enantiomer of this chiral molecule, is used, a cocrystal with the enantiomer (S) form of the triazole derivative (I) is formed.
• the co-crystal of triazole derivative (I) and chiral molecule obtained above and the residual liquid are separated, for example, by filtration.
• the step of separating the precipitated crystals and the residual liquid can be said to be a step of separating the precipitated crystals and the residual liquid to obtain the crystals.
• the chiral molecule represented by the general formula (IIa) can also be co-crystallized with the enantiomer (S) form of the triazole derivative (I).
• the enantiomer (R) form is preferentially co-crystallized.
• the separated crystals may contain not only the enantiomeric (R) form of the triazole derivative (I) but also the enantiomeric (S) form of the triazole derivative, but the content of the (R) form is higher than that of the (S) form.
• the quantity is large.
• the ratio of the content of the (R) isomer to the total content of the (R) isomer and the content of the (S) isomer may be more than 50%, and may be 70% or more, and 95 % or more, and even 100%.
• the ratio of the (R) form and the (S) form contained in the separated crystals can be confirmed by dissolving the obtained crystals in a solvent and preparatively separating each enantiomer using chiral chromatography. Preparative separation by chiral chromatography may be performed, for example, with reference to the method described in Patent Document 2.
• a step of removing chiral molecules in the crystal may be added.
• methods for removing chiral molecules include silica gel chromatography. Thereby, an enantiomeric (R) form of the triazole derivative (I) from which the chiral molecule has been removed can be produced.
• the obtained amorphous solid may contain not only the enantiomeric (R) form of the triazole derivative (I) but also the enantiomeric (S) form of the triazole derivative, but the (R) form is smaller than the (S) form. It has a high content of.
• the ratio of the content of the (R) isomer to the total content of the (R) isomer and the content of the (S) isomer may be more than 50%, and may be 70% or more, and 95 % or more, and even 100%.
• the filtrate after filtering the obtained amorphous solid or co-crystal may also contain the chiral molecules used for co-crystallization.
• a triazole derivative (I) that does not contain the chiral molecule can be obtained.
• the method for producing the enantiomer (R) form of a triazole derivative according to aspect 1 of the present invention includes adding a triazole derivative represented by the above general formula (I) to a triazole derivative represented by the above general formula (IIa) or (IIb) in a solvent.
• the method includes a step of adding a chiral molecule to perform crystallization, and a step of separating the precipitated crystals from the residual liquid.
• the method for producing the enantiomer (R) form of a triazole derivative according to Aspect 3 of the present invention includes, in addition to the constitution of Aspect 2 of the present invention, the chiral molecules in the separated crystals are removed by silica gel chromatography to produce a triazole derivative.
• the enantiomeric (R) form of is produced.
• a method for producing an enantiomer (R) form of a triazole derivative according to Aspect 4 of the present invention includes, in addition to the constitution of Aspect 2 of the present invention, a chiral molecule represented by the above general formula (IIa) ((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).
• the method for producing the enantiomer (R) form of a triazole derivative according to Aspect 6 of the present invention in addition to the constitution of Aspect 5 of the present invention, generates an amorphous solid from the above-mentioned residual liquid, and converts the amorphous solid into an enantiomer (R) form of a triazole derivative. Separate as enantiomers (R).
• a method for producing an enantiomeric (R) form of a triazole derivative according to Aspect 7 of the present invention includes, in addition to the structure of Aspect 5 of the present invention, a chiral molecule represented by the general formula (IIb) ((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 chiral molecule represented by the general formula (IIb) ((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(diphenylm
• the method for producing an enantiomeric (R) form of a triazole derivative according to Aspect 8 of the present invention includes, in addition to the constitution of Aspect 1 of the present invention, heating a solvent before or after adding a chiral molecule, and The crystallization is performed by cooling the heated solvent to which the molecules have been added.
• the method for producing the enantiomeric (R) form of a triazole derivative according to aspect 9 of the present invention includes, in addition to the constitution of any one of aspects 1 to 8 of the present invention, in general formula (I),
• R 1 is -OR 4
• R 2 is a halogen group, a cyano group, a C 1 -C 4 -alkyl group, a C 1 -C 4 -haloalkyl group, a C 1 -C 4 -alkoxy group, -SOR 7 or -SF 5
• R 3 is a halogen group, a nitro group, a cyano group, an amino group, a C 1 -C 4 -alkyl group, a C 1 -C 4 -haloalkyl group, a C 1 -C 4 -alkoxy group, a C 1 -C 4 -halo an alkoxy group, a C 1 -C 4 -alkylamino group, a C
• the method for producing the enantiomer (R) form of a triazole derivative according to aspect 10 of the present invention includes, in addition to the constitution of aspect 9 of the present invention, in the general formula (I), R 4 is a C 1 -C 6 -alkyl group; R 2 is a halogen group, a cyano group, a C 1 -C 4 -alkyl group, a C 1 -C 4 -haloalkyl group or a C 1 -C 4 -alkoxy group; R 3 is a halogen group, a cyano group, a C 1 -C 4 -alkyl group, a C 1 -C 4 -haloalkyl group, a C 1 -C 4 -alkoxy group or a C 1 -C 4 -haloalkoxy group.
• ⁇ Reference example 1 Examination of chiral molecules> 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) )
• compound 1 Methyl 2-(2-chloro-4-(4-chlorophenoxyphenyl)phenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propanoate
• ⁇ Chiral molecule 1 (R)-(+)-1,1-bi-2-naphthol ⁇ Chiral molecule 2: (R)-3,3-dibromo-1,1-bi-2-naphthol ⁇ Chiral molecule 3: (R)-2,2,3,3-tetrahydro-1,1-spirobi[indene]-7,7-diol ⁇ Chiral molecule 4: (R)-(-)-1-phenylethane-1,2-diol ⁇ Chiral molecule 5: (R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol ⁇ Chiral molecule 6: (3S,4S)-(phenylmethyl)-3,4-pyrrolidinediol ⁇ Chiral molecule 7: ((4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)bis(diphenylmethanol) ⁇ Ch
• ⁇ Reference example 2 Determination of the structure of the absolute configuration of the (-)-enantiomer> Since the enantiomer of Compound 1 is an amorphous compound, it has not been possible to crystallize it so far, and the absolute configuration of the structure could not be determined by crystal structure analysis. As shown in Reference Example 1, by using a specific chiral molecule, it became possible to crystallize the (-)-enantiomer as a co-crystal with the chiral molecule, so crystal structure analysis was performed. 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.
• the (-)-enantiomer of Compound 1 was determined to be the (R) form of Compound 1. Therefore, in the following examples, the (-)-enantiomer is referred to as the (R) form, and the (+)-enantiomer is referred to as the (S) form.
• Example 2 50 mg of racemic compound 1 was dissolved in 1 mL of methanol at 25°C. 93 mg of chiral molecule 10 was added thereto, dissolved, and 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 preparatively separated into the (R) form and the (S) form in the same manner as in Example 1, and the content ratio was calculated based on the area ratio of the peaks. When analyzed, the ratio of (R) isomer was 99% or more.
• the method for producing the enantiomer (R) form of a triazole derivative according to the present invention can be used in agricultural and horticultural fungicides and industrial material protection agents that contain the enantiomer as an active ingredient.

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• 2023
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