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WO2015194247A1 - Method for producing cyclopentanol derivative - Google Patents

Method for producing cyclopentanol derivative Download PDF

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Publication number
WO2015194247A1
WO2015194247A1 PCT/JP2015/061886 JP2015061886W WO2015194247A1 WO 2015194247 A1 WO2015194247 A1 WO 2015194247A1 JP 2015061886 W JP2015061886 W JP 2015061886W WO 2015194247 A1 WO2015194247 A1 WO 2015194247A1
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group
formula
general formula
cyclopentanol
producing
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PCT/JP2015/061886
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French (fr)
Japanese (ja)
Inventor
留美 佐野
朋裕 澤
大河 正野
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株式会社クレハ
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a method for producing a cyclopentanol derivative.
  • Patent Document 1 discloses 2- (halogenated hydrocarbon substitution) -5-benzyl-1-, which has low toxicity to human livestock and exhibits a high control effect on a wide range of plant diseases and a high growth effect on various agricultural and horticultural plants.
  • Azolylmethylcyclopentanol derivatives are described.
  • Patent Document 1 discloses an intermediate 2-substituted-5-benzyl as a part of the production process of 2- (halogenated hydrocarbon substituted) -5-benzyl-1-azolylmethylcyclopentanol derivative. It is described that cyclopentanol derivatives are produced by azolylmethylation of cyclopentanone derivatives.
  • Patent Document 2 describes the use of a metal hydride or an alkali metal alkoxide as a base in the azolyl methylation.
  • the conventional method for producing a cyclopentanol derivative is not yet a method that can obtain a cyclopentanol derivative at a sufficiently low cost and in a high yield, and further improvement is required.
  • the present invention has been made in view of the above problems, and its object is to produce azolylmethylation of a 2-substituted-5-benzylcyclopentanone derivative, that is, to produce a cyclopentanol derivative at low cost and in high yield. It is to provide a method that can be done with.
  • the present invention relates to a method for producing a cyclopentanol derivative for producing a cyclopentanol derivative represented by the following general formula (I), wherein the cyclopentanone represented by the following general formula (II) is present in the presence of sulfur ylide.
  • An azolylmethylation reaction step in which the derivative is azolylmethylated using an azole compound represented by the following general formula (III), and the sulfur ylide is a sulfonium compound or a sulfoxonium compound in the reaction system of the azolylmethylation reaction step And a metal hydroxide.
  • R 1 and R 2 each independently represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or —C n H 2n —OG, and G represents a protecting group.
  • N represents an integer of 1 to 4
  • R 1 and R 2 may be bonded to each other to form a ring
  • X is a halogen atom, an alkyl group having 1 to 4 carbon atoms, 1 carbon atom
  • m represents an integer of 0 to 5;
  • m is 2 or more, a plurality of X may be different from each other
  • A represents a nitrogen atom or a methine group.
  • R 1, R 2, X and m are the same as R 1, R 2, X and m in each formula (I).
  • M represents an alkali metal atom
  • A is the same as A in formula (I).
  • a metal hydroxide can be used for the production of sulfur ylide in the reaction system of the azolyl methylation reaction step in the production process of the cyclopentanol derivative, so that it is less expensive than the conventional production method.
  • a cyclopentanol derivative can be produced in a high yield.
  • cyclopentanol derivative (I) a cyclopentanol derivative represented by the following general formula (I) (hereinafter referred to as “cyclopentanol derivative (I)”) is produced.
  • cyclopentanol derivative (I) a cyclopentanol derivative represented by the following general formula (I)
  • cyclopentanol derivative (I) a cyclopentanol derivative represented by the following general formula (I)
  • X is a halogen atom, an alkyl group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a haloalkoxy group having 1 to 4 carbon atoms, It represents a phenyl group, a cyano group or a nitro group.
  • halogen atom examples include a chlorine atom, a fluorine atom, a bromine atom, and an iodine atom.
  • alkyl group having 1 to 4 carbon atoms examples include a methyl group, an ethyl group, an n-propyl group, a 1-methylethyl group, a 2-methylpropyl group, an n-butyl group, and a 1,1-dimethylethyl group. Can be mentioned.
  • haloalkyl group having 1 to 4 carbon atoms examples include trifluoromethyl group, 1,1,2,2,2-pentafluoroethyl group, chloromethyl group, trichloromethyl group, and bromomethyl group. .
  • alkoxy group having 1 to 4 carbon atoms examples include a methoxy group, an ethoxy group, and an n-propoxy group.
  • haloalkoxy group having 1 to 4 carbon atoms examples include a trifluoromethoxy group, a difluoromethoxy group, a 1,1,2,2,2-pentafluoroethoxy group, and a 2,2,2-trifluoroethoxy group. Can be mentioned.
  • X is preferably a halogen atom, a haloalkyl group having 1 to 3 carbon atoms, a haloalkoxy group having 1 to 3 carbon atoms, an alkyl group having 1 to 3 carbon atoms, and an alkoxy group having 1 to 3 carbon atoms, and more preferably Are a halogen atom, a haloalkyl group having 1 to 2 carbon atoms, and a haloalkoxy group having 1 to 2 carbon atoms, more preferably a halogen atom, and particularly preferably a fluorine atom and a chlorine atom.
  • M represents an integer from 0 to 5.
  • m is 2 or more, a plurality of Xs may be the same or different from each other.
  • m is preferably an integer of 0 to 3, more preferably an integer of 0 to 2, and further preferably 0 or 1.
  • the bonding position of X is not particularly limited, but when m is 1, a position where 4-substituted benzyl is formed is preferable.
  • A represents a nitrogen atom or a methine group.
  • A is preferably a nitrogen atom.
  • R 1 and R 2 each independently represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or —C n H 2n —OG. R 1 and R 2 may be bonded to each other to form a ring.
  • alkyl group having 1 to 4 carbon atoms examples include methyl group, ethyl group, n-propyl group, 1-methylethyl group, 1-methylpropyl group, 2-methylpropyl group, n-butyl group, and 1, Examples thereof include a 1-dimethylethyl group.
  • G represents a protecting group.
  • the protecting group is not particularly limited, and examples thereof include alkoxymethyl groups such as methoxymethyl group and ethoxymethyl group, lower alkyl groups such as t-butyl group and methyl group, substituted or unsubstituted benzyl group, substituted or unsubstituted tetrahydropyranyl group. Group, substituted or unsubstituted tetrahydrofuranyl group, and allyl group.
  • n represents an integer of 1 to 4. Among these, n is preferably an integer of 1 to 3, more preferably 1 or 2, and even more preferably 1.
  • —C n H 2n — may be linear or branched. When both R 1 and R 2 are —C n H 2n —OG, the two Gs may be bonded to each other to form a ring.
  • Examples of the protecting group in the case where two G's are bonded to each other to form a ring include methylene acetal, ethylidene acetal, t-butyl methylidene ketal, 1-t-butyl ethylidene ketal, 1-phenyl ethylidene ketal, Acrolein acetal, isopropylidene ketal (acetonide), cyclopentylidene ketal, cyclohexylidene ketal, cycloheptylidene ketal, benzylidene acetal, p-methoxybenzylidene acetal, 2,4-dimethoxybenzylidene ketal, 3,4-dimethoxybenzylidene ketal 2-nitrobenzylidene acetal, 4-nitrobenzylidene acetal, mesitylene acetal, 1-naphthaldehyde acetal, benzophen
  • R 1 and R 2 are each preferably —C n H 2n —OG.
  • the cyclopentanol derivative (I) can be represented by the following general formula (Ic).
  • G 1 and G 2 each represent a protecting group.
  • G 1 and G 2 may be the same as or different from each other.
  • G 1 and G 2 may be bonded to each other to form a ring.
  • Specific examples of G 1 and G 2 are the same as G in the case where R 1 and R 2 in formula (I) are —C n H 2n —OG.
  • n 1 and n 2 each independently represents an integer of 1 to 4 (ie 1, 2, 3 or 4).
  • X, m and A are the same as X, m and A in the formula (I), respectively.
  • the cyclopentanol derivative (I) is more preferably a cyclopentanol derivative represented by the following general formula (Ia) (hereinafter referred to as “cyclopentanol derivative (Ia)”).
  • p and q are each independently 1 or 2. Both p and q are preferably 1.
  • X, m and A are X in each formula (I), the the same as m and A, G 1 and G 2 are the same as G 1 and G 2 in each formula (Ic).
  • the cyclopentanol derivative (I) is more preferably a cyclopentanol derivative represented by the following general formula (Ib) (hereinafter referred to as “cyclopentanol derivative (Ib)”).
  • R 3 and R 4 each independently represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group, or a benzyl group.
  • alkyl group having 1 to 4 carbon atoms examples include methyl group, ethyl group, n-propyl group, 1-methylethyl group, 1-methylpropyl group, 2-methylpropyl group, n-butyl group, and 1, Examples thereof include a 1-dimethylethyl group.
  • One or more hydrogen atoms of the phenyl group in R 3 or R 4 and one or more hydrogen atoms in the phenyl portion of the benzyl group in R 3 or R 4 are an alkyl group having 1 to 4 carbon atoms or an alkyl group having 1 to 4 carbon atoms; It may be substituted with an alkoxy group or a halogen atom.
  • Examples of the alkyl group having 1 to 4 carbon atoms as a substituent include, for example, a methyl group, an ethyl group, an n-propyl group, a 1-methylethyl group, a 1-methylpropyl group, a 2-methylpropyl group, and an n-butyl group.
  • alkoxy group having 1 to 4 carbon atoms as a substituent examples include a methoxy group, an ethoxy group, and an n-propoxy group.
  • a halogen atom as a substituent a fluorine atom, a chlorine atom, a bromine atom, etc. can be mentioned, for example.
  • R 3 and R 4 are each independently preferably a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, more preferably an alkyl group having 1 to 4 carbon atoms, More preferably, it is an alkyl group of ⁇ 2, and it is particularly preferable that both R 3 and R 4 are methyl groups.
  • cyclopentanol derivative (I) for example, a cyclopentanol derivative represented by the following general formula (Id) can be exemplified, but the invention is not limited thereto.
  • X 1 represents a hydrogen atom, a fluorine atom or a chlorine atom.
  • cyclopentanol derivative (I) is suitably used for the production of an azole derivative represented by the following general formula (V) (hereinafter referred to as “azole derivative (V)”).
  • X, m and A are the same as X, m and A in formula (I), respectively.
  • L represents a halogen atom, and the halogen atom is preferably a chlorine atom or a bromine atom.
  • Production of the azole derivative (V) from the cyclopentanol derivative (I) may be based on, for example, the description in Patent Document 2.
  • the azole derivative (V) has an excellent bactericidal action against many bacteria that cause plant diseases.
  • the cyclopentanol derivative (I) itself also has an excellent bactericidal action against bacteria that cause diseases on plants.
  • the azole derivative (V) and the cyclopentanol derivative (I) can also be suitably used as an industrial material protective agent or plant growth regulator.
  • the method for producing the cyclopentanol derivative (I) includes a cyclopentanone derivative represented by the following general formula (II) (hereinafter referred to as “cyclopentanone derivative (II)”) in the presence of sulfur ylide.
  • An azolylmethylation reaction step of azolylmethylation using an azole compound represented by the following general formula (III) hereinafter referred to as “azole compound (III)”.
  • the sulfur ylide is generated from a sulfonium compound or a sulfoxonium compound and a metal hydroxide in the reaction system of the azolyl methylation reaction step.
  • R 1, R 2, X and m are the same as R 1, R 2, X and m in each formula (I).
  • M represents an alkali metal atom.
  • alkali metal atom examples include sodium, potassium, lithium and the like, and M is preferably sodium or potassium, more preferably sodium.
  • A is the same as A in formula (I).
  • the reaction shown in Reaction Scheme 1 includes two reactions shown in Reaction Scheme 2 and Reaction Scheme 3 below.
  • the reaction shown in Reaction Scheme 2 (hereinafter referred to as “Reaction A”) produces a compound represented by the general formula (IV) (hereinafter referred to as “Compound (IV)”) from the cyclopentanone derivative (II). This is an oxirane reaction.
  • the reaction shown in Reaction Scheme 3 (hereinafter referred to as “Reaction B”) is an azolation reaction that produces a cyclopentanol derivative (I) from the compound (IV).
  • R 1, R 2, X and m are the same as R 1, R 2, X and m in each formula (I).
  • Reaction A and reaction B may be performed in the same reaction system or in different reaction systems.
  • the “reaction system” refers to a single reaction occurring in the reaction vessel and a plurality of reactions occurring simultaneously in the reaction vessel, and the same applies to the following description. That is, in the method for producing a cyclopentanol derivative of the present embodiment, even if a product is obtained from a raw material via an intermediate, the reaction from the raw material to the intermediate and the intermediate to the product are performed in the reaction vessel. If these reactions occur simultaneously, they are said to be the same reaction system.
  • the reaction B when the reaction B is caused after the completion of the reaction A, the reaction systems of the reaction A and the reaction B are different. At this time, the container for performing the reaction A and the container for performing the reaction B may be the same or different. On the other hand, when the reaction A occurs while the reaction A occurs, the reaction system is the same because the reaction A and the reaction B occur simultaneously and continuously. At this time, the raw materials for the reaction A and the reaction B may be charged in advance in the reaction vessel, or may be appropriately added during the reaction.
  • reactions in the same reaction system are also referred to as “one pot (reaction)”, and reactions in different reaction systems are also referred to as “stepwise (reaction)”. That is, it can be said that the reaction A and the reaction B may be a one-pot reaction or a stepwise reaction.
  • compound (IV) is produced from cyclopentanone derivative (II) by the action of sulfur ylide.
  • This sulfur ylide is produced in the reaction system by the reaction of a sulfonium compound or a sulfoxonium compound with a metal hydroxide, and the type thereof depends on the sulfonium compound or the sulfoxonium compound used.
  • the sulfur ylide include sulfonium methylides such as dimethylsulfonium methylide and sulfoxonium methylides such as dimethylsulfoxonium methylide.
  • Examples of the sulfonium compound include trimethylsulfonium bromide, trimethylsulfonium chloride, and trimethylsulfonium iodide.
  • Examples of the sulfoxonium compound include trimethylsulfoxonium bromide (TMSOB), trimethylsulfoxonium chloride, and trimethylsulfoxonium iodide.
  • TMSOB trimethylsulfoxonium bromide
  • a sulfoxonium compound is preferably used from the viewpoint of yield, and trimethylsulfoxonium bromide is more preferably used.
  • the sulfonium compound or the sulfoxonium compound may be added in portions.
  • the metal hydroxide functions as a base.
  • the metal hydroxide include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide; .
  • the metal hydroxide is preferably an alkali metal hydroxide, more preferably sodium hydroxide or potassium hydroxide, and even more preferably sodium hydroxide.
  • a metal hydroxide may be used individually by 1 type, and may use 2 or more types together. Further, the metal hydroxide may be added separately.
  • the number of times the metal hydroxide is added is not particularly limited as long as the predetermined purpose can be achieved.
  • the number of times is preferably 1 to 20 times, and more preferably 2 to 10 times.
  • the solvent is not particularly limited.
  • amides such as N, N-dimethylacetamide (DMAc), N, N-dimethylformamide (DMF), and N-methylpyrrolidone (NMP); dimethyl sulfoxide (DMSO); toluene; Ethers such as tetrahydrofuran and dioxane; and the like, and these may be used as a mixture if necessary.
  • water may be contained in the solvent, or water may not be contained. From the viewpoint of easily dissolving the metal hydroxide and improving the yield, it is preferable that water is contained in the solvent.
  • the amount of water contained in the solvent is preferably 0.001 to 0.4 times (volume ratio) of the solvent, and 0.01 to 0.2 times ( The volume ratio is more preferable.
  • a cyclopentanone derivative (II) represented by the following general formula (IIa) is used as the cyclopentanone derivative (II). Cyclopentanone derivative (IIa) ”) is used.
  • G 1, G 2, p, q, X and m are the same as G 1, G 2, p, q, X and m in each formula (Ia).
  • a cyclopentanone derivative (II) represented by the following general formula (IIb) is used as the cyclopentanone derivative (II). Cyclopentanone derivative (IIb) ”) is used.
  • R 3, R 4, p, q, X and m are the same as R 3, R 4, p, q, X and m in each formula (Ib).
  • reaction B compound (IV) produced in reaction A reacts with azole compound (III) present in the reaction system to produce cyclopentanol derivative (I). More specifically, a cyclopentanol derivative (I) is formed by forming a carbon-nitrogen bond between the carbon atom constituting the oxirane ring in compound (IV) and the nitrogen atom of azole compound (III). .
  • the timing of adding the azole compound (III) is not particularly limited. In the case of a one-pot, before reaction A, it may be added to the reaction vessel together with the cyclopentanone derivative (II) or continuously with the cyclopentanone derivative (II). May be added. In the case of stepwise, after completion of the reaction A, it may be added to the reaction vessel (same or different). Alternatively, the azole compound (III) may be prepared in a reactor, and the cyclopentanol derivative (I) may be subsequently produced without isolation.
  • the reaction temperature and reaction time can be appropriately set depending on the type of solvent used, cyclopentanol derivative (I), sulfonium compound or sulfoxonium compound, metal hydroxide, and the like.
  • the reaction temperature is, for example, preferably 0 to 200 ° C., more preferably 20 to 180 ° C.
  • the reaction time is preferably, for example, 0.1 hour to several days, and more preferably 0.5 hour to 2 days.
  • the total amount of the sulfonium compound or the sulfoxonium compound used is preferably 0.5 to 5 times mol and more preferably 0.8 to 2 times mol for the cyclopentanone derivative (II).
  • the amount of the azole compound (III) to be used with respect to the cyclopentanone derivative (II) is preferably 0.5 to 10 times mol, and more preferably 0.8 to 5 times mol.
  • the amount of the metal hydroxide used relative to the cyclopentanone derivative (II) is preferably 0.01 to 5 times mole, for example, 0.1 to 2 times. More preferably, it is a mole.
  • the cyclopentanone derivative (II) may be synthesized based on the description in Patent Document 2, for example.
  • the azole compound (III) is, for example, a compound represented by the following general formula (VI) (hereinafter referred to as “compound (VI)”), N, N-dimethylacetamide (DMAc), N, N-dimethyl In a mixed solvent containing formamide (DMF), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO) and the like and water, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide and lithium hydroxide It can be obtained by reacting.
  • a compound represented by the following general formula (VI) (hereinafter referred to as “compound (VI)”), N, N-dimethylacetamide (DMAc), N, N-dimethyl
  • DMF N-methylpyrrolidone
  • DMSO dimethyl sulfoxide
  • an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide and lithium hydroxide It can be obtained by reacting.
  • A is the same as A in formula (I).
  • the bases such as metal hydride compounds or alkali metal alkoxides used in Patent Documents 1 and 2 require careful handling in industrial use.
  • metal hydride compounds may react violently with water and ignite. is there.
  • a metal hydroxide such as sodium hydroxide used as a base in this embodiment is easy to handle.
  • metal hydroxides such as sodium hydroxide are inexpensive. Therefore, the method for producing the cyclopentanol derivative (I) according to this embodiment is advantageous in terms of safety and cost, particularly on an industrial scale.
  • N, N-dimethylacetamide (DMAc), N, N-dimethylformamide (DMF), N-methylpyrrolidone (NMP) and the like are known to be easily decomposed in the presence of sodium hydroxide and water. ing. Therefore, according to common technical common sense, when the cyclopentanol derivative (I) is produced using a metal hydroxide such as sodium hydroxide as a base, it is expected that a good yield cannot be obtained.
  • sodium hydroxide which is an example of a metal hydroxide
  • a conventional production method using an alkali metal alkoxide as a base surprisingly, compared with a conventional production method using an alkali metal alkoxide as a base.
  • the present invention is a process for producing a cyclopentanol derivative for producing a cyclopentanol derivative represented by the following general formula (I), which is represented by the following general formula (II) in the presence of sulfur ylide.
  • a cyclopentanol derivative for producing a cyclopentanol derivative represented by the following general formula (I), which is represented by the following general formula (II) in the presence of sulfur ylide.
  • R 1 and R 2 each independently represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or —C n H 2n —OG, and G represents a protecting group.
  • N represents an integer of 1 to 4
  • R 1 and R 2 may be bonded to each other to form a ring
  • X is a halogen atom, an alkyl group having 1 to 4 carbon atoms, 1 carbon atom
  • m represents an integer of 0 to 5;
  • m is 2 or more, a plurality of X may be different from each other
  • A represents a nitrogen atom or a methine group.
  • R 1, R 2, X and m are the same as R 1, R 2, X and m in each formula (I).
  • M represents an alkali metal atom
  • A is the same as A in formula (I).
  • the metal hydroxide is preferably an alkali metal hydroxide.
  • the metal hydroxide is more preferably sodium hydroxide.
  • the cyclopentanol derivative represented by the general formula (I) is a cyclopentanol derivative represented by the following general formula (Ia), and the cyclopentanone derivative represented by the general formula (II) is represented by the following general formula ( The cyclopentanone derivative represented by IIa) is preferred.
  • G 1 and G 2 each represent a protecting group, G 1 and G 2 may be bonded to each other to form a ring, and p and q are each independently 1 or 2 X, m and A are the same as X, m and A in formula (I), respectively.
  • G 1, G 2, p, q, X and m are the same as G 1, G 2, p, q, X and m in each formula (Ia).
  • the cyclopentanol derivative represented by the general formula (Ia) is a cyclopentanol derivative represented by the following general formula (Ib), and the cyclopentanone derivative represented by the general formula (IIa) is represented by the following general formula (IIb) It is more preferable that it is the cyclopentanone derivative shown.
  • R 3 and R 4 each independently represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group or a benzyl group, and one or more hydrogen atoms of the phenyl group and One or more hydrogen atoms in the phenyl part of the benzyl group may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms or a halogen atom, and p, q, A, X and m is the same as p, q, A, X and m in formula (Ia), respectively.
  • R 3, R 4, p, q, X and m are the same as R 3, R 4, p, q, X and m in each formula (Ib).
  • R 3 and R 4 are each independently a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.
  • X is preferably a fluorine atom or a chlorine atom, and m is preferably 0 or 1.
  • Example 1 Compound (II-1) (48.6 mmol) was dissolved in N, N-dimethylacetamide (30 mL) and water (2.3 mL), and the temperature was raised to 65 ° C. To this, compound (III-1) (63.3 mmol), TMSOB (58.4 mmol) and sodium hydroxide (9.7 mmol) were added and stirred. After 9 hours, the reaction temperature was raised to 85 ° C. and reacted for 2 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with toluene to obtain compound (I-1). Yield 81.1%.
  • Example 2 Compound (II-1) (48.6 mmol) was dissolved in N, N-dimethylacetamide (30 mL) and water (2.3 mL), and the temperature was raised to 65 ° C. To this, compound (III-1) (63.3 mmol), TMSOB (58.4 mmol) and sodium hydroxide (12.0 mmol) were added and stirred. After 7 hours, the reaction temperature was raised to 85 ° C. and reacted for 2 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with toluene to obtain compound (I-1). Yield 82.0%.
  • Example 3 Compound (II-1) (9.68 mmol) was dissolved in N, N-dimethylacetamide (12.0 mL) and water (0.45 mL), and the temperature was raised to 65 ° C. To this, compound (III-1) (12.6 mmol), TMSOB (11.7 mmol) and sodium hydroxide (9.8 mmol) were added. After 7 hours, the reaction temperature was raised to 85 ° C. and reacted for 2 hours. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off to obtain compound (I-1). Crude yield: 6.008 g. Purity: 52.9%. Yield: 83.8%.
  • Example 4 Compound (II-1) (9.68 mmol) was dissolved in N, N-dimethylacetamide (6.0 mL) and water (0.6 mL), and the temperature was raised to 65 ° C. To this, compound (III-1) (12.6 mmol), TMSOB (11.7 mmol) and sodium hydroxide (2.4 mmol) were added and stirred for 8 hours. Further, sodium hydroxide (2.4 mmol) was added and stirred for 2 hours, and then the reaction temperature was raised to 85 ° C. and reacted for 2 hours. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate.
  • Example 5 Compound (II-1) (9.67 mmol) was dissolved in N, N-dimethylacetamide (6.0 mL), and the temperature was raised to 65 ° C. To this, compound (III-1) (12.62 mmol), TMSOB (11.72 mmol) and sodium hydroxide (2.48 mmol) were added and stirred for 9 hours. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off to obtain compound (I-1). Crude yield: 5.099 g. Purity: 58.7%. Yield: 79.0%.
  • the present invention can be suitably used for the production of compounds that can be used as active ingredients of agricultural and horticultural fungicides.

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Abstract

Provided is a method for producing a cyclopentanol derivative (I) inexpensively and with a high yield. This production method comprises an azolyl methylation reaction step for azolyl methylation of a cyclopentanol derivative (II) in the presence of a sulfur ylide using an azole compound (III). In the reaction system during the azolyl methylation reaction step, the sulfur ylide is produced from a sulfonium compound or sulfoxonium compound and a metal hydroxide compound.

Description

シクロペンタノール誘導体の製造方法Method for producing cyclopentanol derivative
　本発明は、シクロペンタノール誘導体の製造方法に関する。 The present invention relates to a method for producing a cyclopentanol derivative.
　農園芸用病害防除剤および工業用材料保護剤の有効成分として優れた活性を示すアゾリルメチルシクロペンタノール誘導体が知られている。例えば、特許文献１には、人畜に対する毒性が低く、広範な植物病害に対する高い防除効果および種々の農園芸植物に対する高い生長効果を示す２－（ハロゲン化炭化水素置換）－５－ベンジル－１－アゾリルメチルシクロペンタノール誘導体が記載されている。 An azolylmethylcyclopentanol derivative showing excellent activity is known as an active ingredient of agricultural and horticultural disease control agents and industrial material protection agents. For example, Patent Document 1 discloses 2- (halogenated hydrocarbon substitution) -5-benzyl-1-, which has low toxicity to human livestock and exhibits a high control effect on a wide range of plant diseases and a high growth effect on various agricultural and horticultural plants. Azolylmethylcyclopentanol derivatives are described.
　また、特許文献１には、２－（ハロゲン化炭化水素置換）－５－ベンジル－１－アゾリルメチルシクロペンタノール誘導体の製造工程の一部として、中間体である２－置換－５－ベンジルシクロペンタノン誘導体をアゾリルメチル化して、シクロペンタノール誘導体を製造することが記載されている。 Further, Patent Document 1 discloses an intermediate 2-substituted-5-benzyl as a part of the production process of 2- (halogenated hydrocarbon substituted) -5-benzyl-1-azolylmethylcyclopentanol derivative. It is described that cyclopentanol derivatives are produced by azolylmethylation of cyclopentanone derivatives.
　特許文献２には、上記アゾリルメチル化において、塩基として金属水素化合物またはアルカリ金属のアルコキシドを用いることが記載されている。 Patent Document 2 describes the use of a metal hydride or an alkali metal alkoxide as a base in the azolyl methylation.
国際公開第２０１１／０７０７７１号（２０１１年６月１６日公開）International Publication No. 2011/070771 (released on June 16, 2011) 国際公開第２０１２／１６９５５９号（２０１２年１２月１３日公開）International Publication No. 2012/169559 (Released on December 13, 2012)
　しかしながら、従来のシクロペンタノール誘導体の製造方法は、未だ十分に安価に、かつ高収率にシクロペンタノール誘導体を得ることができる方法であるとはいえず、さらなる改良が求められている。 However, the conventional method for producing a cyclopentanol derivative is not yet a method that can obtain a cyclopentanol derivative at a sufficiently low cost and in a high yield, and further improvement is required.
　本発明は、上記課題に鑑みてなされたものであり、その目的は、２－置換－５－ベンジルシクロペンタノン誘導体のアゾリルメチル化、すなわちシクロペンタノール誘導体の製造を、安価に、かつ高収率で行うことができる方法を提供することである。 The present invention has been made in view of the above problems, and its object is to produce azolylmethylation of a 2-substituted-5-benzylcyclopentanone derivative, that is, to produce a cyclopentanol derivative at low cost and in high yield. It is to provide a method that can be done with.
　本発明は、下記一般式（Ｉ）で示されるシクロペンタノール誘導体を製造するシクロペンタノール誘導体の製造方法であって、硫黄イリドの存在下で、下記一般式（ＩＩ）で示されるシクロペンタノン誘導体を、下記一般式（ＩＩＩ）で示されるアゾール化合物を用いてアゾリルメチル化するアゾリルメチル化反応工程を含み、上記硫黄イリドは、上記アゾリルメチル化反応工程の反応系内において、スルホニウム化合物またはスルホキソニウム化合物と、金属水酸化物とから生成されることを特徴とする。 The present invention relates to a method for producing a cyclopentanol derivative for producing a cyclopentanol derivative represented by the following general formula (I), wherein the cyclopentanone represented by the following general formula (II) is present in the presence of sulfur ylide. An azolylmethylation reaction step in which the derivative is azolylmethylated using an azole compound represented by the following general formula (III), and the sulfur ylide is a sulfonium compound or a sulfoxonium compound in the reaction system of the azolylmethylation reaction step And a metal hydroxide.
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
（式（Ｉ）中、Ｒ１およびＲ２は、それぞれ独立に、水素原子、炭素数１～４のアルキル基または－ＣｎＨ２ｎ－Ｏ－Ｇを表しており、Ｇは保護基を表し、ｎは１～４の整数を表しており、Ｒ１およびＲ２が互いに結合して環を形成していてもよく、Ｘは、ハロゲン原子、炭素数１～４のアルキル基、炭素数１～４のハロアルキル基、炭素数１～４のアルコキシ基、炭素数１～４のハロアルコキシ基、フェニル基、シアノ基またはニトロ基を表しており、ｍは０～５の整数を表しており、ｍが２以上である場合には、複数あるＸは互いに異なっていてもよく、Ａは、窒素原子またはメチン基を表している。） (In the formula (I), R 1 and R 2 each independently represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or —C n H 2n —OG, and G represents a protecting group. , N represents an integer of 1 to 4, R 1 and R 2 may be bonded to each other to form a ring, and X is a halogen atom, an alkyl group having 1 to 4 carbon atoms, 1 carbon atom Represents a haloalkyl group having 4 to 4, an alkoxy group having 1 to 4 carbon atoms, a haloalkoxy group having 1 to 4 carbon atoms, a phenyl group, a cyano group or a nitro group, and m represents an integer of 0 to 5; When m is 2 or more, a plurality of X may be different from each other, and A represents a nitrogen atom or a methine group.)
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
（式（ＩＩ）中、Ｒ１、Ｒ２、Ｘおよびｍは、それぞれ式（Ｉ）におけるＲ１、Ｒ２、Ｘおよびｍと同一である。） (In the formula (II), R 1, R 2, X and m are the same as R 1, R 2, X and m in each formula (I).)
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
（式（ＩＩＩ）中、Ｍは、アルカリ金属原子を表しており、Ａは、式（Ｉ）におけるＡと同一である。） (In formula (III), M represents an alkali metal atom, and A is the same as A in formula (I).)
　本発明によれば、シクロペンタノール誘導体の製造過程で、アゾリルメチル化反応工程の反応系内における硫黄イリドの生成に、金属水酸化物を用いることができるため、従来の製造方法に比べて、安価にかつ高収率でシクロペンタノール誘導体を製造することができる。 According to the present invention, a metal hydroxide can be used for the production of sulfur ylide in the reaction system of the azolyl methylation reaction step in the production process of the cyclopentanol derivative, so that it is less expensive than the conventional production method. In addition, a cyclopentanol derivative can be produced in a high yield.
　本発明の一実施形態について説明すれば以下の通りである。 An embodiment of the present invention will be described as follows.
　〔１．シクロペンタノール誘導体〕
　本実施形態に係るシクロペンタノール誘導体の製造方法では、下記一般式（Ｉ）で示されるシクロペンタノール誘導体（以下、「シクロペンタノール誘導体（Ｉ）」と称する）を製造する。製造方法の詳細な説明課題を解決するための手段に先立って、シクロペンタノール誘導体（Ｉ）の構造について以下に説明する。 [1. (Cyclopentanol derivative)
In the method for producing a cyclopentanol derivative according to this embodiment, a cyclopentanol derivative represented by the following general formula (I) (hereinafter referred to as “cyclopentanol derivative (I)”) is produced. Detailed description of the production method Prior to the means for solving the problems, the structure of the cyclopentanol derivative (I) will be described below.
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
　一般式（Ｉ）中、Ｘは、ハロゲン原子、炭素数１～４のアルキル基、炭素数１～４のハロアルキル基、炭素数１～４のアルコキシ基、炭素数１～４のハロアルコキシ基、フェニル基、シアノ基またはニトロ基を表している。 In general formula (I), X is a halogen atom, an alkyl group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a haloalkoxy group having 1 to 4 carbon atoms, It represents a phenyl group, a cyano group or a nitro group.
　ハロゲン原子としては、例えば、塩素原子、フッ素原子、臭素原子、およびヨウ素原子を挙げることができる。 Examples of the halogen atom include a chlorine atom, a fluorine atom, a bromine atom, and an iodine atom.
　炭素数１～４のアルキル基としては、例えば、メチル基、エチル基、ｎ－プロピル基、１－メチルエチル基、２－メチルプロピル基、ｎ－ブチル基、および１，１－ジメチルエチル基等を挙げることができる。 Examples of the alkyl group having 1 to 4 carbon atoms include a methyl group, an ethyl group, an n-propyl group, a 1-methylethyl group, a 2-methylpropyl group, an n-butyl group, and a 1,1-dimethylethyl group. Can be mentioned.
　炭素数１～４のハロアルキル基としては、例えば、トリフルオロメチル基、１，１，２，２，２－ペンタフルオロエチル基、クロロメチル基、トリクロロメチル基、およびブロモメチル基等を挙げることができる。 Examples of the haloalkyl group having 1 to 4 carbon atoms include trifluoromethyl group, 1,1,2,2,2-pentafluoroethyl group, chloromethyl group, trichloromethyl group, and bromomethyl group. .
　炭素数１～４のアルコキシ基としては、例えば、メトキシ基、エトキシ基、およびｎ－プロポキシ基等を挙げることができる。 Examples of the alkoxy group having 1 to 4 carbon atoms include a methoxy group, an ethoxy group, and an n-propoxy group.
　炭素数１～４のハロアルコキシ基としては、例えば、トリフルオロメトキシ基、ジフルオロメトキシ基、１，１，２，２，２－ペンタフルオロエトキシ基、および２，２，２－トリフルオロエトキシ基等を挙げることができる。 Examples of the haloalkoxy group having 1 to 4 carbon atoms include a trifluoromethoxy group, a difluoromethoxy group, a 1,1,2,2,2-pentafluoroethoxy group, and a 2,2,2-trifluoroethoxy group. Can be mentioned.
　Ｘは、好ましくはハロゲン原子、炭素数１～３のハロアルキル基、炭素数１～３のハロアルコキシ基、炭素数１～３のアルキル基、および炭素数１～３のアルコキシ基であり、より好ましくはハロゲン原子、炭素数１～２のハロアルキル基、および炭素数１～２のハロアルコキシ基であり、さらに好ましくはハロゲン原子であり、特に好ましくはフッ素原子および塩素原子である。 X is preferably a halogen atom, a haloalkyl group having 1 to 3 carbon atoms, a haloalkoxy group having 1 to 3 carbon atoms, an alkyl group having 1 to 3 carbon atoms, and an alkoxy group having 1 to 3 carbon atoms, and more preferably Are a halogen atom, a haloalkyl group having 1 to 2 carbon atoms, and a haloalkoxy group having 1 to 2 carbon atoms, more preferably a halogen atom, and particularly preferably a fluorine atom and a chlorine atom.
　ｍは、０～５の整数を表している。ｍが２以上である場合には、複数あるＸは同じであってもよいし、互いに異なっていてもよい。なかでも、ｍは、０～３の整数であることが好ましく、０～２の整数であることがより好ましく、０または１であることがさらに好ましい。 M represents an integer from 0 to 5. When m is 2 or more, a plurality of Xs may be the same or different from each other. Among these, m is preferably an integer of 0 to 3, more preferably an integer of 0 to 2, and further preferably 0 or 1.
　Ｘの結合位置は特に限定されないが、ｍが１である場合には、４－置換ベンジルとなる位置が好ましい。 The bonding position of X is not particularly limited, but when m is 1, a position where 4-substituted benzyl is formed is preferable.
　Ａは、窒素原子またはメチン基を表している。Ａは、好ましくは窒素原子である。 A represents a nitrogen atom or a methine group. A is preferably a nitrogen atom.
　Ｒ１およびＲ２は、それぞれ独立に、水素原子、炭素数１～４のアルキル基または－ＣｎＨ２ｎ－Ｏ－Ｇを表している。Ｒ１およびＲ２は、互いに結合して環を形成していてもよい。 R 1 and R 2 each independently represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or —C n H 2n —OG. R 1 and R 2 may be bonded to each other to form a ring.
　炭素数１～４のアルキル基としては、例えば、メチル基、エチル基、ｎ－プロピル基、１－メチルエチル基、１－メチルプロピル基、２－メチルプロピル基、ｎ－ブチル基、および１，１－ジメチルエチル基等を挙げることができる。 Examples of the alkyl group having 1 to 4 carbon atoms include methyl group, ethyl group, n-propyl group, 1-methylethyl group, 1-methylpropyl group, 2-methylpropyl group, n-butyl group, and 1, Examples thereof include a 1-dimethylethyl group.
　－ＣｎＨ２ｎ－Ｏ－Ｇにおいて、Ｇは保護基を表す。保護基は特に限定されないが、例えば、メトキシメチル基およびエトキシメチル基等のアルコキシメチル基、ｔ－ブチル基およびメチル基等の低級アルキル基、置換または無置換のベンジル基、置換または無置換テトラヒドロピラニル基、置換または無置換テトラヒドロフラニル基、ならびにアリル基等を挙げることができる。ｎは１～４の整数を表している。なかでも、ｎは１～３の整数であることが好ましく、１または２であることがより好ましく、１であることがさらに好ましい。－ＣｎＨ２ｎ－は、直鎖状であってもよいし、分岐鎖状であってもよい。Ｒ１およびＲ２の何れもが－ＣｎＨ２ｎ－Ｏ－Ｇである場合、２つのＧは互いに結合して環を形成していてもよい。 In —C n H 2n —OG, G represents a protecting group. The protecting group is not particularly limited, and examples thereof include alkoxymethyl groups such as methoxymethyl group and ethoxymethyl group, lower alkyl groups such as t-butyl group and methyl group, substituted or unsubstituted benzyl group, substituted or unsubstituted tetrahydropyranyl group. Group, substituted or unsubstituted tetrahydrofuranyl group, and allyl group. n represents an integer of 1 to 4. Among these, n is preferably an integer of 1 to 3, more preferably 1 or 2, and even more preferably 1. —C n H 2n — may be linear or branched. When both R 1 and R 2 are —C n H 2n —OG, the two Gs may be bonded to each other to form a ring.
　２つのＧが互いに結合して環を形成している場合の保護基としては、例えば、メチレンアセタール、エチリデンアセタール、ｔ－ブチルメチリデンケタール、１－ｔ－ブチルエチリデンケタール、１－フェニルエチリデンケタール、アクロレインアセタール、イソプロピリデンケタール（アセトナイド）、シクロペンチリデンケタール、シクロヘキシリデンケタール、シクロヘプチリデンケタール、ベンジリデンアセタール、ｐ－メトキシベンジリデンアセタール、２，４－ジメトキシベンジリデンケタール、３，４－ジメトキシベンジリデンケタール、２－ニトロベンジリデンアセタール、４－ニトロベンジリデンアセタール、メシチレンアセタール、１－ナフトアルデヒドアセタール、ベンゾフェノンケタール、カンファーケタール、メントン、メトキシメチレンアセタール、エトキシメチレンアセタール、ジメトキシメチレンオルトエステル、１－メトキシエチリデンオルトエステル、１－エトキシエチリデンオルトエステル、メチリデンオルトエステル、フタリドオルトエステル、１，２－ジメトキシエチリデンオルトエステル、α－メトキシベンジリデンオルトエステル、２－オキサシクロペンチリデンオルトエステル、ブタン－２，３－ビスアセタール、シクロヘキサン－１，２－ジアセタール、ビスジヒドロピランケタール、ジ－ｔ－ブチルシリレン、１，３－（１，１，３，３－テトライソプロピル）ジシリオキサニリデン、および１，１，３，３－テトラ－ｔ－ブトキシジシロキサニリデン等を挙げることができるが、これらに限定されるものではない。 Examples of the protecting group in the case where two G's are bonded to each other to form a ring include methylene acetal, ethylidene acetal, t-butyl methylidene ketal, 1-t-butyl ethylidene ketal, 1-phenyl ethylidene ketal, Acrolein acetal, isopropylidene ketal (acetonide), cyclopentylidene ketal, cyclohexylidene ketal, cycloheptylidene ketal, benzylidene acetal, p-methoxybenzylidene acetal, 2,4-dimethoxybenzylidene ketal, 3,4-dimethoxybenzylidene ketal 2-nitrobenzylidene acetal, 4-nitrobenzylidene acetal, mesitylene acetal, 1-naphthaldehyde acetal, benzophenone ketal, camphor ketal, Methoxymethylene acetal, ethoxymethylene acetal, dimethoxymethylene orthoester, 1-methoxyethylidene orthoester, 1-ethoxyethylidene orthoester, methylidene orthoester, phthalide orthoester, 1,2-dimethoxyethylidene orthoester, α- Methoxybenzylidene orthoester, 2-oxacyclopentylidene orthoester, butane-2,3-bisacetal, cyclohexane-1,2-diacetal, bisdihydropyranketal, di-t-butylsilylene, 1,3- (1, Examples include, but are not limited to, 1,3,3-tetraisopropyl) disilixanilidene, 1,1,3,3-tetra-t-butoxydisiloxanilidene, and the like.
　Ｒ１およびＲ２は、それぞれ、－ＣｎＨ２ｎ－Ｏ－Ｇであることが好ましい。 R 1 and R 2 are each preferably —C n H 2n —OG.
　なお、Ｒ１およびＲ２が何れも－ＣｎＨ２ｎ－Ｏ－Ｇである場合、シクロペンタノール誘導体（Ｉ）は、下記一般式（Ｉｃ）で表すことができる。 When R 1 and R 2 are both —C n H 2n —OG, the cyclopentanol derivative (I) can be represented by the following general formula (Ic).
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
　一般式（Ｉｃ）中、Ｇ１およびＧ２はそれぞれ保護基を表している。Ｇ１およびＧ２は互いに同一でも異なっていてもよい。また、Ｇ１およびＧ２が互いに結合して環を形成してもよい。Ｇ１およびＧ２の具体例は、式（Ｉ）のＲ１およびＲ２が－ＣｎＨ２ｎ－Ｏ－Ｇである場合におけるＧと同じである。ｎ１およびｎ２は、それぞれ独立に、１～４の整数（すなわち、１、２、３または４）を表している。Ｘ、ｍおよびＡは、それぞれ式（Ｉ）におけるＸ、ｍおよびＡと同一である。 In the general formula (Ic), G 1 and G 2 each represent a protecting group. G 1 and G 2 may be the same as or different from each other. G 1 and G 2 may be bonded to each other to form a ring. Specific examples of G 1 and G 2 are the same as G in the case where R 1 and R 2 in formula (I) are —C n H 2n —OG. n 1 and n 2 each independently represents an integer of 1 to 4 (ie 1, 2, 3 or 4). X, m and A are the same as X, m and A in the formula (I), respectively.
　シクロペンタノール誘導体（Ｉ）は、下記一般式（Ｉａ）で示されるシクロペンタノール誘導体（以下、「シクロペンタノール誘導体（Ｉａ）」と称する）であることがより好ましい。 The cyclopentanol derivative (I) is more preferably a cyclopentanol derivative represented by the following general formula (Ia) (hereinafter referred to as “cyclopentanol derivative (Ia)”).
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
　一般式（Ｉａ）中、ｐおよびｑは、それぞれ独立に、１または２である。ｐおよびｑは、何れも、１であることが好ましい。Ｘ、ｍおよびＡは、それぞれ式（Ｉ）におけるＸ、ｍおよびＡと同一であり、Ｇ１およびＧ２は、それぞれ式（Ｉｃ）におけるＧ１およびＧ２と同一である。 In general formula (Ia), p and q are each independently 1 or 2. Both p and q are preferably 1. X, m and A are X in each formula (I), the the same as m and A, G 1 and G 2 are the same as G 1 and G 2 in each formula (Ic).
　シクロペンタノール誘導体（Ｉ）は、下記一般式（Ｉｂ）で示されるシクロペンタノール誘導体（以下、「シクロペンタノール誘導体（Ｉｂ）」と称する）であることがさらに好ましい。 The cyclopentanol derivative (I) is more preferably a cyclopentanol derivative represented by the following general formula (Ib) (hereinafter referred to as “cyclopentanol derivative (Ib)”).
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
　一般式（Ｉｂ）中、Ｒ３およびＲ４は、それぞれ独立に、水素原子、炭素数１～４のアルキル基、フェニル基またはベンジル基を表している。 In general formula (Ib), R 3 and R 4 each independently represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group, or a benzyl group.
　炭素数１～４のアルキル基としては、例えば、メチル基、エチル基、ｎ－プロピル基、１－メチルエチル基、１－メチルプロピル基、２－メチルプロピル基、ｎ－ブチル基、および１，１－ジメチルエチル基等を挙げることができる。 Examples of the alkyl group having 1 to 4 carbon atoms include methyl group, ethyl group, n-propyl group, 1-methylethyl group, 1-methylpropyl group, 2-methylpropyl group, n-butyl group, and 1, Examples thereof include a 1-dimethylethyl group.
　Ｒ３またはＲ４におけるフェニル基の１以上の水素原子、およびＲ３またはＲ４におけるベンジル基のフェニル部における１以上の水素原子は、炭素数１～４のアルキル基、炭素数１～４のアルコキシ基またはハロゲン原子で置換されていてもよい。置換基としての炭素数１～４のアルキル基としては、例えば、メチル基、エチル基、ｎ－プロピル基、１－メチルエチル基、１－メチルプロピル基、２－メチルプロピル基、ｎ－ブチル基、および１，１－ジメチルエチル基等を挙げることができる。置換基としての炭素数１～４のアルコキシ基としては、例えば、メトキシ基、エトキシ基、およびｎ－プロポキシ基等を挙げることができる。置換基としてのハロゲン原子としては、例えば、フッ素原子、塩素原子、および臭素原子等を挙げることができる。 One or more hydrogen atoms of the phenyl group in R 3 or R 4 and one or more hydrogen atoms in the phenyl portion of the benzyl group in R 3 or R 4 are an alkyl group having 1 to 4 carbon atoms or an alkyl group having 1 to 4 carbon atoms; It may be substituted with an alkoxy group or a halogen atom. Examples of the alkyl group having 1 to 4 carbon atoms as a substituent include, for example, a methyl group, an ethyl group, an n-propyl group, a 1-methylethyl group, a 1-methylpropyl group, a 2-methylpropyl group, and an n-butyl group. And 1,1-dimethylethyl group. Examples of the alkoxy group having 1 to 4 carbon atoms as a substituent include a methoxy group, an ethoxy group, and an n-propoxy group. As a halogen atom as a substituent, a fluorine atom, a chlorine atom, a bromine atom, etc. can be mentioned, for example.
　これらの中でも、Ｒ３およびＲ４は、それぞれ独立に、水素原子または炭素数１～４のアルキル基であることが好ましく、炭素数１～４のアルキル基であることがより好ましく、炭素数１～２のアルキル基であることがさらに好ましく、Ｒ３およびＲ４がともにメチル基であることが特に好ましい。 Among these, R 3 and R 4 are each independently preferably a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, more preferably an alkyl group having 1 to 4 carbon atoms, More preferably, it is an alkyl group of ˜2, and it is particularly preferable that both R 3 and R 4 are methyl groups.
　一般式（Ｉｂ）中、ｐ、ｑ、Ａ、Ｘおよびｍは、それぞれ式（Ｉａ）におけるｐ、ｑ、Ａ、Ｘおよびｍと同一である。 In general formula (Ib), p, q, A, X and m are the same as p, q, A, X and m in formula (Ia), respectively.
　シクロペンタノール誘導体（Ｉ）の好適な例として、例えば下記一般式（Ｉｄ）で示されるシクロペンタノール誘導体を挙げることができるが、これに限定されるものではない。 As a suitable example of the cyclopentanol derivative (I), for example, a cyclopentanol derivative represented by the following general formula (Id) can be exemplified, but the invention is not limited thereto.
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
　一般式（Ｉｄ）中、Ｘ１は、水素原子、フッ素原子または塩素原子を表している。 In the general formula (Id), X 1 represents a hydrogen atom, a fluorine atom or a chlorine atom.
　シクロペンタノール誘導体（Ｉ）は、下記一般式（Ｖ）で示されるアゾール誘導体（以下、「アゾール誘導体（Ｖ）」と称する）の製造に好適に使用される。 The cyclopentanol derivative (I) is suitably used for the production of an azole derivative represented by the following general formula (V) (hereinafter referred to as “azole derivative (V)”).
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
　一般式（Ｖ）中、Ｘ、ｍおよびＡは、それぞれ式（Ｉ）におけるＸ、ｍおよびＡと同一である。Ｌは、ハロゲン原子を表し、ハロゲン原子としては、塩素原子および臭素原子が好ましい。 In general formula (V), X, m and A are the same as X, m and A in formula (I), respectively. L represents a halogen atom, and the halogen atom is preferably a chlorine atom or a bromine atom.
　シクロペンタノール誘導体（Ｉ）からのアゾール誘導体（Ｖ）の製造は、例えば、特許文献２の記載に基づけばよい。 Production of the azole derivative (V) from the cyclopentanol derivative (I) may be based on, for example, the description in Patent Document 2.
　アゾール誘導体（Ｖ）は、植物に病害を引き起こす多くの菌に対して優れた殺菌作用を有する。なお、シクロペンタノール誘導体（Ｉ）自体も、植物に病害を引き起こす菌に対して優れた殺菌作用を有している。また、アゾール誘導体（Ｖ）およびシクロペンタノール誘導体（Ｉ）は、工業用材料保護剤または植物成長調整剤としても好適に利用することができる。 The azole derivative (V) has an excellent bactericidal action against many bacteria that cause plant diseases. The cyclopentanol derivative (I) itself also has an excellent bactericidal action against bacteria that cause diseases on plants. The azole derivative (V) and the cyclopentanol derivative (I) can also be suitably used as an industrial material protective agent or plant growth regulator.
　〔２．シクロペンタノール誘導体（Ｉ）の製造方法の詳細〕
　本実施形態に係るシクロペンタノール誘導体（Ｉ）の製造方法は、硫黄イリドの存在下で、下記一般式（ＩＩ）で示されるシクロペンタノン誘導体（以下、「シクロペンタノン誘導体（ＩＩ）」と称する）を、下記一般式（ＩＩＩ）で示されるアゾール化合物（以下、「アゾール化合物（ＩＩＩ）」と称する）を用いてアゾリルメチル化するアゾリルメチル化反応工程を含む。当該硫黄イリドは、当該アゾリルメチル化反応工程の反応系内において、スルホニウム化合物またはスルホキソニウム化合物と、金属水酸化物とから生成される。 [2. Details of production method of cyclopentanol derivative (I)]
The method for producing the cyclopentanol derivative (I) according to this embodiment includes a cyclopentanone derivative represented by the following general formula (II) (hereinafter referred to as “cyclopentanone derivative (II)”) in the presence of sulfur ylide. An azolylmethylation reaction step of azolylmethylation using an azole compound represented by the following general formula (III) (hereinafter referred to as “azole compound (III)”). The sulfur ylide is generated from a sulfonium compound or a sulfoxonium compound and a metal hydroxide in the reaction system of the azolyl methylation reaction step.
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
　一般式（ＩＩ）中、Ｒ１、Ｒ２、Ｘおよびｍは、それぞれ式（Ｉ）におけるＲ１、Ｒ２、Ｘおよびｍと同一である。 In the general formula (II), R 1, R 2, X and m are the same as R 1, R 2, X and m in each formula (I).
　一般式（ＩＩＩ）中、Ｍは、アルカリ金属原子を表している。アルカリ金属原子としては、例えば、ナトリウム、カリウム、およびリチウム等を挙げることができ、Ｍは、好ましくは、ナトリウムまたはカリウムであり、より好ましくはナトリウムである。Ａは、式（Ｉ）におけるＡと同一である。 In general formula (III), M represents an alkali metal atom. Examples of the alkali metal atom include sodium, potassium, lithium and the like, and M is preferably sodium or potassium, more preferably sodium. A is the same as A in formula (I).
　本実施形態に係るシクロペンタノール誘導体（Ｉ）の製造方法の概略的な反応スキームを、下記反応スキーム１に示す。 A schematic reaction scheme of the method for producing the cyclopentanol derivative (I) according to this embodiment is shown in the following reaction scheme 1.
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
　反応スキーム１に示される反応は、下記反応スキーム２および下記反応スキーム３で示される２つの反応を含んでいる。反応スキーム２で示される反応（以下、「反応Ａ」と称する）は、シクロペンタノン誘導体（ＩＩ）から一般式（ＩＶ）で示される化合物（以下、「化合物（ＩＶ）」と称する）を生成するオキシラン化反応である。また、反応スキーム３で示される反応（以下、「反応Ｂ」と称する）は、化合物（ＩＶ）からシクロペンタノール誘導体（Ｉ）を生成するアゾール化反応である。 The reaction shown in Reaction Scheme 1 includes two reactions shown in Reaction Scheme 2 and Reaction Scheme 3 below. The reaction shown in Reaction Scheme 2 (hereinafter referred to as “Reaction A”) produces a compound represented by the general formula (IV) (hereinafter referred to as “Compound (IV)”) from the cyclopentanone derivative (II). This is an oxirane reaction. The reaction shown in Reaction Scheme 3 (hereinafter referred to as “Reaction B”) is an azolation reaction that produces a cyclopentanol derivative (I) from the compound (IV).
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
　一般式（ＩＶ）中、Ｒ１、Ｒ２、Ｘおよびｍは、それぞれ式（Ｉ）におけるＲ１、Ｒ２、Ｘおよびｍと同一である。 In the general formula (IV), R 1, R 2, X and m are the same as R 1, R 2, X and m in each formula (I).
　反応Ａと反応Ｂとは、同一の反応系内で行ってもよいし、異なる反応系で行ってもよい。ここで、「反応系」とは、反応容器内で起こる単一の反応、および反応容器内で同時に起こる複数の反応を指し、以下の説明においても同様である。すなわち、本実施形態のシクロペンタノール誘導体の製造方法では、原料から中間体を経由して得られる生成物であっても、反応容器内で原料から中間体への反応と中間体から生成物への反応とが同時に起きていれば、同一の反応系という。 Reaction A and reaction B may be performed in the same reaction system or in different reaction systems. Here, the “reaction system” refers to a single reaction occurring in the reaction vessel and a plurality of reactions occurring simultaneously in the reaction vessel, and the same applies to the following description. That is, in the method for producing a cyclopentanol derivative of the present embodiment, even if a product is obtained from a raw material via an intermediate, the reaction from the raw material to the intermediate and the intermediate to the product are performed in the reaction vessel. If these reactions occur simultaneously, they are said to be the same reaction system.
　より具体的に説明すると、反応Ａを完了させた後で、反応Ｂを起こす場合は、反応Ａおよび反応Ｂの反応系は異なる。このとき、反応Ａを行う容器と反応Ｂを行う容器は、同一であってもよいし、異なっていてもよい。一方、反応Ａを起こしつつ、反応Ｂも起こす場合は、反応Ａと反応Ｂとが同時にかつ連続的に起きているため、反応系は同一である。このとき、反応Ａおよび反応Ｂの原料は、予め全量が反応容器内に仕込まれていてもよいし、反応途中で適宜投入するようにしてもよい。 More specifically, when the reaction B is caused after the completion of the reaction A, the reaction systems of the reaction A and the reaction B are different. At this time, the container for performing the reaction A and the container for performing the reaction B may be the same or different. On the other hand, when the reaction A occurs while the reaction A occurs, the reaction system is the same because the reaction A and the reaction B occur simultaneously and continuously. At this time, the raw materials for the reaction A and the reaction B may be charged in advance in the reaction vessel, or may be appropriately added during the reaction.
　本実施形態では、同一の反応系での反応を「ワンポット（反応）」、異なる反応系での反応を「ステップワイズ（の反応）」とも称する。すなわち、反応Ａと反応Ｂとは、ワンポット反応としてもよいし、ステップワイズの反応としてもよいと換言することができる。 In this embodiment, reactions in the same reaction system are also referred to as “one pot (reaction)”, and reactions in different reaction systems are also referred to as “stepwise (reaction)”. That is, it can be said that the reaction A and the reaction B may be a one-pot reaction or a stepwise reaction.
　反応Ａでは、硫黄イリドの作用によってシクロペンタノン誘導体（ＩＩ）から化合物（ＩＶ）が生成される。この硫黄イリドは、スルホニウム化合物またはスルホキソニウム化合物と金属水酸化物とが反応して反応系内において生成されるものであり、その種類は用いられるスルホニウム化合物またはスルホキソニウム化合物に依存する。硫黄イリドとしては、ジメチルスルホニウムメチリド等のスルホニウムメチリド類およびジメチルスルホキソニウムメチリド等のスルホキソニウムメチリド類を挙げることができる。 In reaction A, compound (IV) is produced from cyclopentanone derivative (II) by the action of sulfur ylide. This sulfur ylide is produced in the reaction system by the reaction of a sulfonium compound or a sulfoxonium compound with a metal hydroxide, and the type thereof depends on the sulfonium compound or the sulfoxonium compound used. Examples of the sulfur ylide include sulfonium methylides such as dimethylsulfonium methylide and sulfoxonium methylides such as dimethylsulfoxonium methylide.
　スルホニウム化合物としては、例えば、トリメチルスルホニウムブロマイド、トリメチルスルホニウムクロライドおよびトリメチルスルホニウムヨード等を挙げることができる。スルホキソニウム化合物としては、トリメチルスルホキソニウムブロマイド（ＴＭＳＯＢ）、トリメチルスルホキソニウムクロライドおよびトリメチルスルホキソニウムヨード等を挙げることができる。硫黄イリドの生成には収率の観点からスルホキソニウム化合物を用いることが好ましく、なかでもトリメチルスルホキソニウムブロマイドを用いることがより好ましい。スルホニウム化合物またはスルホキソニウム化合物は、分割して添加してもよい。 Examples of the sulfonium compound include trimethylsulfonium bromide, trimethylsulfonium chloride, and trimethylsulfonium iodide. Examples of the sulfoxonium compound include trimethylsulfoxonium bromide (TMSOB), trimethylsulfoxonium chloride, and trimethylsulfoxonium iodide. For the production of sulfur ylide, a sulfoxonium compound is preferably used from the viewpoint of yield, and trimethylsulfoxonium bromide is more preferably used. The sulfonium compound or the sulfoxonium compound may be added in portions.
　本実施形態に係るシクロペンタノール誘導体の製造方法において、金属水酸化物は塩基として働く。金属水酸化物としては、水酸化リチウム、水酸化ナトリウム、および水酸化カリウム等のアルカリ金属水酸化物；水酸化マグネシウム、および水酸化カルシウム等の水酸化アルカリ土類金属；等を挙げることができる。金属水酸化物は、アルカリ金属水酸化物であることが好ましく、水酸化ナトリウムまたは水酸化カリウムであることがより好ましく、水酸化ナトリウムであることがさらに好ましい。なお、金属水酸化物は、１種類を単独で用いてもよいし、２種類以上を併用してもよい。また、金属水酸化物は、分割して添加してもよい。 In the method for producing a cyclopentanol derivative according to this embodiment, the metal hydroxide functions as a base. Examples of the metal hydroxide include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide; . The metal hydroxide is preferably an alkali metal hydroxide, more preferably sodium hydroxide or potassium hydroxide, and even more preferably sodium hydroxide. In addition, a metal hydroxide may be used individually by 1 type, and may use 2 or more types together. Further, the metal hydroxide may be added separately.
　金属水酸化物を加える回数については、所定の目的を達成することができる回数であれば、特に限定されるものではない。回数としては、１～２０回であることが好ましく、２～１０回であることがより好ましい。スルホニウム化合物またはスルホキソニウム化合物を分割して加える場合も同様である。 The number of times the metal hydroxide is added is not particularly limited as long as the predetermined purpose can be achieved. The number of times is preferably 1 to 20 times, and more preferably 2 to 10 times. The same applies when the sulfonium compound or the sulfoxonium compound is added in portions.
　溶媒は特に限定されないが、例えば、Ｎ，Ｎ－ジメチルアセトアミド（ＤＭＡｃ）、Ｎ，Ｎ－ジメチルホルムアミド（ＤＭＦ）、およびＮ－メチルピロリドン（ＮＭＰ）等のアミド類；ジメチルスルホキシド（ＤＭＳＯ）；トルエン；テトラヒドロフランおよびジオキサン等のエーテル類；等を挙げることができ、これらは必要に応じて混合して使用してもよい。また、溶媒中に水が含まれていてもよいし、水が含まれていなくてもよい。金属水酸化物を容易に溶解させる観点および収率の向上の観点から、溶媒中に水が含まれていることが好ましい。水が含まれている場合、溶媒中に含まれている水の量は、上記溶媒の０．００１～０．４倍（体積比）であることが好ましく、０．０１～０．２倍（体積比）であることがより好ましい。 The solvent is not particularly limited. For example, amides such as N, N-dimethylacetamide (DMAc), N, N-dimethylformamide (DMF), and N-methylpyrrolidone (NMP); dimethyl sulfoxide (DMSO); toluene; Ethers such as tetrahydrofuran and dioxane; and the like, and these may be used as a mixture if necessary. Further, water may be contained in the solvent, or water may not be contained. From the viewpoint of easily dissolving the metal hydroxide and improving the yield, it is preferable that water is contained in the solvent. When water is contained, the amount of water contained in the solvent is preferably 0.001 to 0.4 times (volume ratio) of the solvent, and 0.01 to 0.2 times ( The volume ratio is more preferable.
　シクロペンタノール誘導体（Ｉ）としてより好ましいシクロペンタノール誘導体（Ｉａ）を製造する場合には、シクロペンタノン誘導体（ＩＩ）として、下記一般式（ＩＩａ）で示されるシクロペンタノン誘導体（以下、「シクロペンタノン誘導体（ＩＩａ）」と称する）を用いる。 When producing a cyclopentanol derivative (Ia) more preferable as the cyclopentanol derivative (I), a cyclopentanone derivative (II) represented by the following general formula (IIa) is used as the cyclopentanone derivative (II). Cyclopentanone derivative (IIa) ”) is used.
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
　一般式（ＩＩａ）中、Ｇ１、Ｇ２、ｐ、ｑ、Ｘおよびｍは、それぞれ式（Ｉａ）におけるＧ１、Ｇ２、ｐ、ｑ、Ｘおよびｍと同一である。 In the general formula (IIa), G 1, G 2, p, q, X and m are the same as G 1, G 2, p, q, X and m in each formula (Ia).
　シクロペンタノール誘導体（Ｉ）としてさらに好ましいシクロペンタノール誘導体（Ｉｂ）を製造する場合には、シクロペンタノン誘導体（ＩＩ）として、下記一般式（ＩＩｂ）で示されるシクロペンタノン誘導体（以下、「シクロペンタノン誘導体（ＩＩｂ）」と称する）を用いる。 In the case of producing a cyclopentanol derivative (Ib) that is more preferable as the cyclopentanol derivative (I), a cyclopentanone derivative (II) represented by the following general formula (IIb) is used as the cyclopentanone derivative (II). Cyclopentanone derivative (IIb) ”) is used.
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
　一般式（ＩＩｂ）中、Ｒ３、Ｒ４、ｐ、ｑ、Ｘおよびｍは、それぞれ式（Ｉｂ）におけるＲ３、Ｒ４、ｐ、ｑ、Ｘおよびｍと同一である。 In the general formula (IIb), R 3, R 4, p, q, X and m are the same as R 3, R 4, p, q, X and m in each formula (Ib).
　反応Ｂでは、反応Ａで生成した化合物（ＩＶ）が、反応系内に存在するアゾール化合物（ＩＩＩ）と反応し、シクロペンタノール誘導体（Ｉ）が生成する。より詳細には、化合物（ＩＶ）におけるオキシラン環を構成する炭素原子とアゾール化合物（ＩＩＩ）の窒素原子との間に炭素－窒素結合が生成することによって、シクロペンタノール誘導体（Ｉ）が生成する。 In reaction B, compound (IV) produced in reaction A reacts with azole compound (III) present in the reaction system to produce cyclopentanol derivative (I). More specifically, a cyclopentanol derivative (I) is formed by forming a carbon-nitrogen bond between the carbon atom constituting the oxirane ring in compound (IV) and the nitrogen atom of azole compound (III). .
　アゾール化合物（ＩＩＩ）の添加のタイミングは特に限定されない。ワンポットの場合、反応Ａの前に、シクロペンタノン誘導体（ＩＩ）と一緒に、あるいはシクロペンタノン誘導体（ＩＩ）と連続的に反応容器内に加えられてもよいし、反応Ａの進行中に加えられてもよい。ステップワイズの場合、反応Ａの終了後に、（同一または別の）反応容器内に加えればよい。あるいは、アゾール化合物（ＩＩＩ）を反応器内で調製し、単離することなく、続けてシクロペンタノール誘導体（Ｉ）の製造を行ってもよい。 The timing of adding the azole compound (III) is not particularly limited. In the case of a one-pot, before reaction A, it may be added to the reaction vessel together with the cyclopentanone derivative (II) or continuously with the cyclopentanone derivative (II). May be added. In the case of stepwise, after completion of the reaction A, it may be added to the reaction vessel (same or different). Alternatively, the azole compound (III) may be prepared in a reactor, and the cyclopentanol derivative (I) may be subsequently produced without isolation.
　反応温度および反応時間は、用いられる溶媒、シクロペンタノール誘導体（Ｉ）、スルホニウム化合物またはスルホキソニウム化合物および金属水酸化物の種類等によって適宜設定することができる。反応温度は、例えば、０～２００℃であることが好ましく、２０～１８０℃であることがより好ましい。また、反応時間は、例えば、０．１時間～数日であることが好ましく、０．５時間～２日であることがより好ましい。 The reaction temperature and reaction time can be appropriately set depending on the type of solvent used, cyclopentanol derivative (I), sulfonium compound or sulfoxonium compound, metal hydroxide, and the like. The reaction temperature is, for example, preferably 0 to 200 ° C., more preferably 20 to 180 ° C. The reaction time is preferably, for example, 0.1 hour to several days, and more preferably 0.5 hour to 2 days.
　スルホニウム化合物またはスルホキソニウム化合物の合計の使用量は、シクロペンタノン誘導体（ＩＩ）に対して０．５～５倍モルであることが好ましく、０．８～２倍モルであることがより好ましい。シクロペンタノン誘導体（ＩＩ）に対するアゾール化合物（ＩＩＩ）の使用量は、０．５～１０倍モルであることが好ましく、０．８～５倍モルであることがより好ましい。 The total amount of the sulfonium compound or the sulfoxonium compound used is preferably 0.5 to 5 times mol and more preferably 0.8 to 2 times mol for the cyclopentanone derivative (II). . The amount of the azole compound (III) to be used with respect to the cyclopentanone derivative (II) is preferably 0.5 to 10 times mol, and more preferably 0.8 to 5 times mol.
　シクロペンタノン誘導体（ＩＩ）に対する金属水酸化物の使用量（複数種類を併用する場合は合計の使用量）は、例えば０．０１～５倍モルであることが好ましく、０．１～２倍モルであることがより好ましい。 The amount of the metal hydroxide used relative to the cyclopentanone derivative (II) (the total amount used when a plurality of types are used in combination) is preferably 0.01 to 5 times mole, for example, 0.1 to 2 times. More preferably, it is a mole.
　シクロペンタノン誘導体（ＩＩ）は、例えば、特許文献２の記載に基づいて合成すればよい。 The cyclopentanone derivative (II) may be synthesized based on the description in Patent Document 2, for example.
　また、アゾール化合物（ＩＩＩ）は、例えば、下記一般式（ＶＩ）で示される化合物（以下、「化合物（ＶＩ）」と称する）を、Ｎ，Ｎ－ジメチルアセトアミド（ＤＭＡｃ）、Ｎ，Ｎ－ジメチルホルムアミド（ＤＭＦ）、Ｎ－メチルピロリドン（ＮＭＰ）、またはジメチルスルホキシド（ＤＭＳＯ）等と水とを含む混合溶媒中で、水酸化ナトリウム、水酸化カリウム、および水酸化リチウム等のアルカリ金属水酸化物と反応させることによって得ることができる。 The azole compound (III) is, for example, a compound represented by the following general formula (VI) (hereinafter referred to as “compound (VI)”), N, N-dimethylacetamide (DMAc), N, N-dimethyl In a mixed solvent containing formamide (DMF), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO) and the like and water, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide and lithium hydroxide It can be obtained by reacting.
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024
　一般式（ＶＩ）中、Ａは、式（Ｉ）におけるＡと同一である。 In general formula (VI), A is the same as A in formula (I).
　このアゾール化合物（ＩＩＩ）の合成反応では、反応後の反応系内に水が存在する。本実施形態に係るシクロペンタノール誘導体（Ｉ）の製造方法では、水が含まれていてもよいため、アゾール化合物（ＩＩＩ）の合成反応後に、従来行っていたトルエンによる水の共沸脱水を行わなくてもよい。そのため、本実施形態に係るシクロペンタノール誘導体の製造方法おいて溶媒中に水が含まれている場合には、全体の工程数を削減することができる上、トルエンの使用を回避することができる。 In the synthesis reaction of this azole compound (III), water exists in the reaction system after the reaction. In the method for producing the cyclopentanol derivative (I) according to the present embodiment, water may be contained. Therefore, after the synthesis reaction of the azole compound (III), the conventional azeotropic dehydration of water with toluene is performed. It does not have to be. Therefore, when water is contained in the solvent in the method for producing a cyclopentanol derivative according to this embodiment, the total number of steps can be reduced and the use of toluene can be avoided. .
　特許文献１および２において用いている金属水素化合物またはアルカリ金属のアルコキシド等の塩基は、工業的使用において取り扱いに注意が必要であり、特に金属水素化合物は水と激しく反応して発火する可能性がある。一方、本実施形態において塩基として用いる水酸化ナトリウム等の金属水酸化物は取り扱いが容易である。その上、水酸化ナトリウム等の金属水酸化物は安価である。そのため、本実施形態に係るシクロペンタノール誘導体（Ｉ）の製造方法は、特に工業規模において、安全面およびコスト面で有利である。 The bases such as metal hydride compounds or alkali metal alkoxides used in Patent Documents 1 and 2 require careful handling in industrial use. In particular, metal hydride compounds may react violently with water and ignite. is there. On the other hand, a metal hydroxide such as sodium hydroxide used as a base in this embodiment is easy to handle. In addition, metal hydroxides such as sodium hydroxide are inexpensive. Therefore, the method for producing the cyclopentanol derivative (I) according to this embodiment is advantageous in terms of safety and cost, particularly on an industrial scale.
　また、Ｎ，Ｎ－ジメチルアセトアミド（ＤＭＡｃ）、Ｎ，Ｎ－ジメチルホルムアミド（ＤＭＦ）、およびＮ－メチルピロリドン（ＮＭＰ）等は、水酸化ナトリウムと水との共存下で分解し易いことが知られている。そのため、通常の技術常識では、水酸化ナトリウム等の金属水酸化物を塩基として用いてシクロペンタノール誘導体（Ｉ）を製造すると、良好な収率は得られないと予想される。しかしながら、本願発明者らは、今回、金属水酸化物の一例である水酸化ナトリウムを塩基として用いた場合に、驚くべきことに、塩基としてアルカリ金属のアルコキシドを用いた従来の製造方法と比較して、シクロペンタノール誘導体（Ｉ）の収率が同等あるいは飛躍的に向上するという予想外の効果を見出した（後述の実施例を参照）。 N, N-dimethylacetamide (DMAc), N, N-dimethylformamide (DMF), N-methylpyrrolidone (NMP) and the like are known to be easily decomposed in the presence of sodium hydroxide and water. ing. Therefore, according to common technical common sense, when the cyclopentanol derivative (I) is produced using a metal hydroxide such as sodium hydroxide as a base, it is expected that a good yield cannot be obtained. However, the inventors of the present application, surprisingly, when sodium hydroxide, which is an example of a metal hydroxide, is used as a base, surprisingly, compared with a conventional production method using an alkali metal alkoxide as a base. Thus, an unexpected effect that the yield of the cyclopentanol derivative (I) is equivalently or dramatically improved was found (see Examples described later).
　〔３．まとめ〕
　以上のように、本発明は、下記一般式（Ｉ）で示されるシクロペンタノール誘導体を製造するシクロペンタノール誘導体の製造方法であって、硫黄イリドの存在下で、下記一般式（ＩＩ）で示されるシクロペンタノン誘導体を、下記一般式（ＩＩＩ）で示されるアゾール化合物を用いてアゾリルメチル化するアゾリルメチル化反応工程を含み、上記硫黄イリドは、上記アゾリルメチル化反応工程の反応系内において、スルホニウム化合物またはスルホキソニウム化合物と、金属水酸化物とから生成されることを特徴とする。 [3. (Summary)
As described above, the present invention is a process for producing a cyclopentanol derivative for producing a cyclopentanol derivative represented by the following general formula (I), which is represented by the following general formula (II) in the presence of sulfur ylide. Including an azolylmethylation reaction step of azolylmethylating the cyclopentanone derivative shown below with an azole compound represented by the following general formula (III), wherein the sulfur ylide is a sulfonium compound in the reaction system of the azolylmethylation reaction step Or it produces | generates from a sulfoxonium compound and a metal hydroxide, It is characterized by the above-mentioned.
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
（式（Ｉ）中、Ｒ１およびＲ２は、それぞれ独立に、水素原子、炭素数１～４のアルキル基または－ＣｎＨ２ｎ－Ｏ－Ｇを表しており、Ｇは保護基を表し、ｎは１～４の整数を表しており、Ｒ１およびＲ２が互いに結合して環を形成していてもよく、Ｘは、ハロゲン原子、炭素数１～４のアルキル基、炭素数１～４のハロアルキル基、炭素数１～４のアルコキシ基、炭素数１～４のハロアルコキシ基、フェニル基、シアノ基またはニトロ基を表しており、ｍは０～５の整数を表しており、ｍが２以上である場合には、複数あるＸは互いに異なっていてもよく、Ａは、窒素原子またはメチン基を表している。） (In the formula (I), R 1 and R 2 each independently represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or —C n H 2n —OG, and G represents a protecting group. , N represents an integer of 1 to 4, R 1 and R 2 may be bonded to each other to form a ring, and X is a halogen atom, an alkyl group having 1 to 4 carbon atoms, 1 carbon atom Represents a haloalkyl group having 4 to 4, an alkoxy group having 1 to 4 carbon atoms, a haloalkoxy group having 1 to 4 carbon atoms, a phenyl group, a cyano group or a nitro group, and m represents an integer of 0 to 5; When m is 2 or more, a plurality of X may be different from each other, and A represents a nitrogen atom or a methine group.)
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
（式（ＩＩ）中、Ｒ１、Ｒ２、Ｘおよびｍは、それぞれ式（Ｉ）におけるＲ１、Ｒ２、Ｘおよびｍと同一である。） (In the formula (II), R 1, R 2, X and m are the same as R 1, R 2, X and m in each formula (I).)
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027
（式（ＩＩＩ）中、Ｍは、アルカリ金属原子を表しており、Ａは、式（Ｉ）におけるＡと同一である。） (In formula (III), M represents an alkali metal atom, and A is the same as A in formula (I).)
　上記金属水酸化物は、アルカリ金属水酸化物であることが好ましい。 The metal hydroxide is preferably an alkali metal hydroxide.
　上記金属水酸化物は、水酸化ナトリウムであることがより好ましい。 The metal hydroxide is more preferably sodium hydroxide.
　上記アゾリルメチル化反応工程において、溶媒中に水が含まれていることが好ましい。 In the azolyl methylation reaction step, it is preferable that water is contained in the solvent.
　上記一般式（Ｉ）で示されるシクロペンタノール誘導体は、下記一般式（Ｉａ）で示されるシクロペンタノール誘導体であり、上記一般式（ＩＩ）で示されるシクロペンタノン誘導体は、下記一般式（ＩＩａ）で示されるシクロペンタノン誘導体であることが好ましい。 The cyclopentanol derivative represented by the general formula (I) is a cyclopentanol derivative represented by the following general formula (Ia), and the cyclopentanone derivative represented by the general formula (II) is represented by the following general formula ( The cyclopentanone derivative represented by IIa) is preferred.
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028
（式（Ｉａ）中、Ｇ１およびＧ２はそれぞれ保護基を表し、Ｇ１およびＧ２が互いに結合して環を形成していてもよく、ｐおよびｑは、それぞれ独立に、１または２であり、Ｘ、ｍおよびＡは、それぞれ式（Ｉ）におけるＸ、ｍおよびＡと同一である。） (In Formula (Ia), G 1 and G 2 each represent a protecting group, G 1 and G 2 may be bonded to each other to form a ring, and p and q are each independently 1 or 2 X, m and A are the same as X, m and A in formula (I), respectively.
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
（式（ＩＩａ）中、Ｇ１、Ｇ２、ｐ、ｑ、Ｘおよびｍは、それぞれ式（Ｉａ）におけるＧ１、Ｇ２、ｐ、ｑ、Ｘおよびｍと同一である。） (In the formula (IIa), G 1, G 2, p, q, X and m are the same as G 1, G 2, p, q, X and m in each formula (Ia).)
　上記一般式（Ｉａ）で示されるシクロペンタノール誘導体は、下記一般式（Ｉｂ）示されるシクロペンタノール誘導体であり、上記一般式（ＩＩａ）で示されるシクロペンタノン誘導体は、下記一般式（ＩＩｂ）示されるシクロペンタノン誘導体であることがより好ましい。 The cyclopentanol derivative represented by the general formula (Ia) is a cyclopentanol derivative represented by the following general formula (Ib), and the cyclopentanone derivative represented by the general formula (IIa) is represented by the following general formula (IIb) It is more preferable that it is the cyclopentanone derivative shown.
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030
（式（Ｉｂ）中、Ｒ３およびＲ４は，それぞれ独立に、水素原子、炭素数１～４のアルキル基、フェニル基またはベンジル基を表しており、当該フェニル基の１以上の水素原子および当該ベンジル基のフェニル部における１以上の水素原子は、炭素数１～４のアルキル基、炭素数１～４のアルコキシ基またはハロゲン原子で置換されていてもよく、ｐ、ｑ、Ａ、Ｘおよびｍは、それぞれ式（Ｉａ）におけるｐ、ｑ、Ａ、Ｘおよびｍと同一である。） (In the formula (Ib), R 3 and R 4 each independently represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group or a benzyl group, and one or more hydrogen atoms of the phenyl group and One or more hydrogen atoms in the phenyl part of the benzyl group may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms or a halogen atom, and p, q, A, X and m is the same as p, q, A, X and m in formula (Ia), respectively.
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031
（式（ＩＩｂ）中、Ｒ３、Ｒ４、ｐ、ｑ、Ｘおよびｍは、それぞれ式（Ｉｂ）におけるＲ３、Ｒ４、ｐ、ｑ、Ｘおよびｍと同一である。） (In the formula (IIb), R 3, R 4, p, q, X and m are the same as R 3, R 4, p, q, X and m in each formula (Ib).)
　Ｒ３およびＲ４は、それぞれ独立に、水素原子または炭素数１～４のアルキル基であることがさらに好ましい。 More preferably, R 3 and R 4 are each independently a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.
　Ｘは、フッ素原子または塩素原子であり、ｍは、０または１であることが好ましい。 X is preferably a fluorine atom or a chlorine atom, and m is preferably 0 or 1.
　以下に実施例を示し、本発明の実施の形態についてさらに詳しく説明する。もちろん、本発明は以下の実施例に限定されるものではなく、細部については様々な態様が可能であることはいうまでもない。さらに、本発明は上述した実施形態に限定されるものではなく、請求項に示した範囲で種々の変更が可能であり、それぞれ開示された技術的手段を適宜組み合わせて得られる実施形態についても本発明の技術的範囲に含まれる。また、本明細書中に記載された文献の全てが参考として援用される。 Examples will be shown below, and the embodiments of the present invention will be described 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 detail. Further, the present invention is not limited to the above-described embodiments, and various modifications can be made within the scope shown in the claims, and the present invention is also applied to the embodiments obtained by appropriately combining the disclosed technical means. It is included in the technical scope of the invention. Moreover, all the literatures described in this specification are used as reference.
　様々な条件で、２－（４－クロロベンジル）－８，８－ジメチル－７，９－ジオキサスピロ［４，５］デカン－１－オン（化合物（ＩＩ－１））を、１，２，４－トリアゾール（化合物（ＩＩＩ－１））を用いてアゾリルメチル化し、２－（４－クロロベンジル）－８，８－ジメチル－１－（１Ｈ－１，２，４－トリアゾール－１－イルメチル）－７，９－ジオキサスピロ［４，５］デカン－１－オール（化合物（Ｉ－１））を製造した。 Under various conditions, 2- (4-chlorobenzyl) -8,8-dimethyl-7,9-dioxaspiro [4,5] decan-1-one (compound (II-1)) was converted to 1,2,4 -Azolyl methylation using triazole (compound (III-1)) and 2- (4-chlorobenzyl) -8,8-dimethyl-1- (1H-1,2,4-triazol-1-ylmethyl) -7 , 9-Dioxaspiro [4,5] decan-1-ol (compound (I-1)) was prepared.
Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000032
　〔実施例１〕
　化合物（ＩＩ－１）（４８．６ｍｍｏｌ）をＮ，Ｎ－ジメチルアセトアミド（３０ｍＬ）および水（２．３ｍＬ）に溶解し、６５℃に昇温した。ここに、化合物（ＩＩＩ－１）（６３．３ｍｍｏｌ）、ＴＭＳＯＢ（５８．４ｍｍｏｌ）および水酸化ナトリウム（９．７ｍｍｏｌ）を添加し撹拌した。９時間後、反応温度を８５℃に昇温して２時間反応させた。反応終了後、反応液に水を加え、トルエンで抽出し、化合物（Ｉ－１）を得た。
収率８１．１％。 [Example 1]
Compound (II-1) (48.6 mmol) was dissolved in N, N-dimethylacetamide (30 mL) and water (2.3 mL), and the temperature was raised to 65 ° C. To this, compound (III-1) (63.3 mmol), TMSOB (58.4 mmol) and sodium hydroxide (9.7 mmol) were added and stirred. After 9 hours, the reaction temperature was raised to 85 ° C. and reacted for 2 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with toluene to obtain compound (I-1).
Yield 81.1%.
　〔実施例２〕
　化合物（ＩＩ－１）（４８．６ｍｍｏｌ）をＮ，Ｎ－ジメチルアセトアミド（３０ｍＬ）および水（２．３ｍＬ）に溶解し、６５℃に昇温した。ここに、化合物（ＩＩＩ－１）（６３．３ｍｍｏｌ）、ＴＭＳＯＢ（５８．４ｍｍｏｌ）および水酸化ナトリウム（１２．０ｍｍｏｌ）を添加し撹拌した。７時間後、反応温度を８５℃に昇温して２時間反応させた。反応終了後、反応液に水を加え、トルエンで抽出し、化合物（Ｉ－１）を得た。
収率８２．０％。 [Example 2]
Compound (II-1) (48.6 mmol) was dissolved in N, N-dimethylacetamide (30 mL) and water (2.3 mL), and the temperature was raised to 65 ° C. To this, compound (III-1) (63.3 mmol), TMSOB (58.4 mmol) and sodium hydroxide (12.0 mmol) were added and stirred. After 7 hours, the reaction temperature was raised to 85 ° C. and reacted for 2 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with toluene to obtain compound (I-1).
Yield 82.0%.
　〔実施例３〕
　化合物（ＩＩ－１）（９．６８ｍｍｏｌ）をＮ，Ｎ－ジメチルアセトアミド（１２．０ｍＬ）および水（０．４５ｍＬ）に溶解し、６５℃に昇温した。ここに、化合物（ＩＩＩ－１）（１２．６ｍｍｏｌ）、ＴＭＳＯＢ（１１．７ｍｍｏｌ）および水酸化ナトリウム（９．８ｍｍｏｌ）を添加した。７時間後、反応温度を８５℃に昇温して２時間反応させた。反応終了後、反応液に水を加え、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥した。溶媒を留去し、化合物（Ｉ－１）を得た。
粗収量：６．００８ｇ。純度：５２．９％。収率：８３．８％。 Example 3
Compound (II-1) (9.68 mmol) was dissolved in N, N-dimethylacetamide (12.0 mL) and water (0.45 mL), and the temperature was raised to 65 ° C. To this, compound (III-1) (12.6 mmol), TMSOB (11.7 mmol) and sodium hydroxide (9.8 mmol) were added. After 7 hours, the reaction temperature was raised to 85 ° C. and reacted for 2 hours. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off to obtain compound (I-1).
Crude yield: 6.008 g. Purity: 52.9%. Yield: 83.8%.
　〔実施例４〕
　化合物（ＩＩ－１）（９．６８ｍｍｏｌ）をＮ，Ｎ－ジメチルアセトアミド（６．０ｍＬ）および水（０．６ｍＬ）に溶解し、６５℃に昇温した。ここに、化合物（ＩＩＩ－１）（１２．６ｍｍｏｌ）、ＴＭＳＯＢ（１１．７ｍｍｏｌ）および水酸化ナトリウム（２．４ｍｍｏｌ）を添加し、８時間撹拌した。さらに、水酸化ナトリウム（２．４ｍｍｏｌ）を追加して２時間撹拌した後、反応温度を８５℃に昇温して２時間反応させた。反応終了後、反応液に水を加え、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥した。溶媒を留去し、化合物（Ｉ－１）を得た。
粗収量：５．２０４ｇ。純度：６１．５％。収率：８４．４％。 Example 4
Compound (II-1) (9.68 mmol) was dissolved in N, N-dimethylacetamide (6.0 mL) and water (0.6 mL), and the temperature was raised to 65 ° C. To this, compound (III-1) (12.6 mmol), TMSOB (11.7 mmol) and sodium hydroxide (2.4 mmol) were added and stirred for 8 hours. Further, sodium hydroxide (2.4 mmol) was added and stirred for 2 hours, and then the reaction temperature was raised to 85 ° C. and reacted for 2 hours. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off to obtain compound (I-1).
Crude yield: 5.204 g. Purity: 61.5%. Yield: 84.4%.
　〔実施例５〕
　化合物（ＩＩ－１）（９．６７ｍｍｏｌ）をＮ，Ｎ－ジメチルアセトアミド（６．０ｍＬ）に溶解し、６５℃に昇温した。ここに、化合物（ＩＩＩ－１）（１２．６２ｍｍｏｌ）、ＴＭＳＯＢ（１１．７２ｍｍｏｌ）および水酸化ナトリウム（２．４８ｍｍｏｌ）を添加し、９時間撹拌した。反応終了後、反応液に水を加え、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥した。溶媒を留去し、化合物（Ｉ－１）を得た。
粗収量：５．０９９ｇ。純度：５８．７％。収率：７９．０％。 Example 5
Compound (II-1) (9.67 mmol) was dissolved in N, N-dimethylacetamide (6.0 mL), and the temperature was raised to 65 ° C. To this, compound (III-1) (12.62 mmol), TMSOB (11.72 mmol) and sodium hydroxide (2.48 mmol) were added and stirred for 9 hours. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off to obtain compound (I-1).
Crude yield: 5.099 g. Purity: 58.7%. Yield: 79.0%.
　〔比較例１〕
　化合物（ＩＩ－１）（１０．０ｍｍｏｌ）をＮ，Ｎ－ジメチルアセトアミド（６．０ｍＬ）に溶解し、６５℃に昇温した。ここに、化合物（ＩＩＩ－１）（１３．０７ｍｍｏｌ）、ＴＭＳＯＢ（１１．９５ｍｍｏｌ）およびナトリウムｔ－ブトキシド（２．４ｍｍｏｌ）を添加し、９時間撹拌した。反応終了後、反応液に水を加え、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥した。溶媒を留去し、化合物（Ｉ－１）を得た。
粗収量：４．１２１ｇ。純度：７４．３％。収率：７８．１％。 [Comparative Example 1]
Compound (II-1) (10.0 mmol) was dissolved in N, N-dimethylacetamide (6.0 mL), and the temperature was raised to 65 ° C. To this, compound (III-1) (13.07 mmol), TMSOB (11.95 mmol) and sodium t-butoxide (2.4 mmol) were added and stirred for 9 hours. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off to obtain compound (I-1).
Crude yield: 4.121 g. Purity: 74.3%. Yield: 78.1%.
　〔比較例２〕
　化合物（ＩＩ－１）（９．６９ｍｍｏｌ）をＮ，Ｎ－ジメチルアセトアミド（６．０ｍＬ）に溶解し、６５℃に昇温した。ここに、化合物（ＩＩＩ－１）（１２．６５ｍｍｏｌ）、ＴＭＳＯＢ（１１．６８ｍｍｏｌ）および２８％ナトリウムメトキシドメタノール溶液（２．４ｍｍｏｌ）を添加した、７時間撹拌した。反応終了後、反応液に水を加え、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥した。溶媒を留去し、化合物（Ｉ－１）を得た。
粗収量：３．９３４ｇ。純度：７６．１％。収率：７８．９％。 [Comparative Example 2]
Compound (II-1) (9.69 mmol) was dissolved in N, N-dimethylacetamide (6.0 mL), and the temperature was raised to 65 ° C. To this, compound (III-1) (12.65 mmol), TMSOB (11.68 mmol) and 28% sodium methoxide methanol solution (2.4 mmol) were added and stirred for 7 hours. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off to obtain compound (I-1).
Crude yield: 3.934 g. Purity: 76.1%. Yield: 78.9%.
　〔比較例３〕
　化合物（ＩＩ－１）（９．７０ｍｍｏｌ）をＮ，Ｎ－ジメチルアセトアミド（６．０ｍＬ）および水(０．６ｍＬ)に溶解し、６５℃に昇温した。ここに、化合物（ＩＩＩ－１）（１２．６２ｍｍｏｌ）、ＴＭＳＯＢ（１１．６６ｍｍｏｌ）および２８％ナトリウムメトキシドメタノール溶液（２．４４ｍｍｏｌ）を添加し、１２時間撹拌した。反応終了後、反応液に水を加え、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥した。溶媒を留去し、化合物（Ｉ－１）を得た。
粗収量：３．７９０ｇ。純度：７９．６％。収率：７９．４％。 [Comparative Example 3]
Compound (II-1) (9.70 mmol) was dissolved in N, N-dimethylacetamide (6.0 mL) and water (0.6 mL), and the temperature was raised to 65 ° C. To this, compound (III-1) (12.62 mmol), TMSOB (11.66 mmol) and 28% sodium methoxide methanol solution (2.44 mmol) were added and stirred for 12 hours. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off to obtain compound (I-1).
Crude yield: 3.790 g. Purity: 79.6%. Yield: 79.4%.
　本発明は、農園芸用の殺菌剤の有効成分として利用することができる化合物の製造に好適に利用することができる。 The present invention can be suitably used for the production of compounds that can be used as active ingredients of agricultural and horticultural fungicides.

Claims (8)

  1. 　下記一般式（Ｉ）で示されるシクロペンタノール誘導体を製造するシクロペンタノール誘導体の製造方法であって、
    　硫黄イリドの存在下で、下記一般式（ＩＩ）で示されるシクロペンタノン誘導体を、下記一般式（ＩＩＩ）で示されるアゾール化合物を用いてアゾリルメチル化するアゾリルメチル化反応工程を含み、
    　上記硫黄イリドは、上記アゾリルメチル化反応工程の反応系内において、スルホニウム化合物またはスルホキソニウム化合物と、金属水酸化物とから生成されることを特徴とするシクロペンタノール誘導体の製造方法。
    Figure JPOXMLDOC01-appb-C000001
     （式（Ｉ）中、Ｒ１およびＲ２は、それぞれ独立に、水素原子、炭素数１～４のアルキル基または－ＣｎＨ２ｎ－Ｏ－Ｇを表しており、Ｇは保護基を表し、ｎは１～４の整数を表しており、Ｒ１およびＲ２が互いに結合して環を形成していてもよく、Ｘは、ハロゲン原子、炭素数１～４のアルキル基、炭素数１～４のハロアルキル基、炭素数１～４のアルコキシ基、炭素数１～４のハロアルコキシ基、フェニル基、シアノ基またはニトロ基を表しており、ｍは０～５の整数を表しており、ｍが２以上である場合には、複数あるＸは互いに異なっていてもよく、Ａは、窒素原子またはメチン基を表している。）
    Figure JPOXMLDOC01-appb-C000002
     （式（ＩＩ）中、Ｒ１、Ｒ２、Ｘおよびｍは、それぞれ式（Ｉ）におけるＲ１、Ｒ２、Ｘおよびｍと同一である。）
    Figure JPOXMLDOC01-appb-C000003
     （式（ＩＩＩ）中、Ｍは、アルカリ金属原子を表しており、Ａは、式（Ｉ）におけるＡと同一である。）     A method for producing a cyclopentanol derivative for producing a cyclopentanol derivative represented by the following general formula (I),
    An azolylmethylation reaction step of azolylmethylating a cyclopentanone derivative represented by the following general formula (II) using an azole compound represented by the following general formula (III) in the presence of sulfur ylide,
    The method for producing a cyclopentanol derivative, wherein the sulfur ylide is generated from a sulfonium compound or a sulfoxonium compound and a metal hydroxide in the reaction system of the azolyl methylation reaction step.
    Figure JPOXMLDOC01-appb-C000001
     (In the formula (I), R 1 and R 2 each independently represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or —C n H 2n —OG, and G represents a protecting group. , N represents an integer of 1 to 4, R 1 and R 2 may be bonded to each other to form a ring, and X is a halogen atom, an alkyl group having 1 to 4 carbon atoms, 1 carbon atom Represents a haloalkyl group having 4 to 4, an alkoxy group having 1 to 4 carbon atoms, a haloalkoxy group having 1 to 4 carbon atoms, a phenyl group, a cyano group or a nitro group, and m represents an integer of 0 to 5; When m is 2 or more, a plurality of X may be different from each other, and A represents a nitrogen atom or a methine group.)
    Figure JPOXMLDOC01-appb-C000002
     (In the formula (II), R 1, R 2, X and m are the same as R 1, R 2, X and m in each formula (I).)
    Figure JPOXMLDOC01-appb-C000003
     (In formula (III), M represents an alkali metal atom, and A is the same as A in formula (I).)
  2. 　上記金属水酸化物は、アルカリ金属水酸化物であることを特徴とする請求項１に記載のシクロペンタノール誘導体の製造方法。 The method for producing a cyclopentanol derivative according to claim 1, wherein the metal hydroxide is an alkali metal hydroxide.
  3. 　上記金属水酸化物は、水酸化ナトリウムであることを特徴とする請求項２に記載のシクロペンタノール誘導体の製造方法。 The method for producing a cyclopentanol derivative according to claim 2, wherein the metal hydroxide is sodium hydroxide.
  4. 　上記アゾリルメチル化反応工程において、溶媒中に水が含まれていることを特徴とする請求項１～３の何れか１項に記載のシクロペンタノール誘導体の製造方法。 The method for producing a cyclopentanol derivative according to any one of claims 1 to 3, wherein in the azolylmethylation reaction step, water is contained in the solvent.
  5. 　上記一般式（Ｉ）で示されるシクロペンタノール誘導体は、下記一般式（Ｉａ）で示されるシクロペンタノール誘導体であり、
    　上記一般式（ＩＩ）で示されるシクロペンタノン誘導体は、下記一般式（ＩＩａ）で示されるシクロペンタノン誘導体であることを特徴とする請求項１～４の何れか１項に記載のシクロペンタノール誘導体の製造方法。
    Figure JPOXMLDOC01-appb-C000004
     （式（Ｉａ）中、Ｇ１およびＧ２はそれぞれ保護基を表し、Ｇ１およびＧ２が互いに結合して環を形成していてもよく、ｐおよびｑは、それぞれ独立に、１または２であり、Ｘ、ｍおよびＡは、それぞれ式（Ｉ）におけるＸ、ｍおよびＡと同一である。）
    Figure JPOXMLDOC01-appb-C000005
     （式（ＩＩａ）中、Ｇ１、Ｇ２、ｐ、ｑ、Ｘおよびｍは、それぞれ式（Ｉａ）におけるＧ１、Ｇ２、ｐ、ｑ、Ｘおよびｍと同一である。）     The cyclopentanol derivative represented by the general formula (I) is a cyclopentanol derivative represented by the following general formula (Ia),
    The cyclopentanone derivative represented by the general formula (II) is a cyclopentanone derivative represented by the following general formula (IIa): A method for producing a tanol derivative.
    Figure JPOXMLDOC01-appb-C000004
     (In Formula (Ia), G 1 and G 2 each represent a protecting group, G 1 and G 2 may be bonded to each other to form a ring, and p and q are each independently 1 or 2 X, m and A are the same as X, m and A in formula (I), respectively.
    Figure JPOXMLDOC01-appb-C000005
     (In the formula (IIa), G 1, G 2, p, q, X and m are the same as G 1, G 2, p, q, X and m in each formula (Ia).)
  6. 　上記一般式（Ｉａ）で示されるシクロペンタノール誘導体は、下記一般式（Ｉｂ）示されるシクロペンタノール誘導体であり、
    　上記一般式（ＩＩａ）で示されるシクロペンタノン誘導体は、下記一般式（ＩＩｂ）示されるシクロペンタノン誘導体であることを特徴とする請求項５に記載のシクロペンタノール誘導体の製造方法。
    Figure JPOXMLDOC01-appb-C000006
     （式（Ｉｂ）中、Ｒ３およびＲ４は，それぞれ独立に、水素原子、炭素数１～４のアルキル基、フェニル基またはベンジル基を表しており、当該フェニル基の１以上の水素原子および当該ベンジル基のフェニル部における１以上の水素原子は、炭素数１～４のアルキル基、炭素数１～４のアルコキシ基またはハロゲン原子で置換されていてもよく、ｐ、ｑ、Ａ、Ｘおよびｍは、それぞれ式（Ｉａ）におけるｐ、ｑ、Ａ、Ｘおよびｍと同一である。）
    Figure JPOXMLDOC01-appb-C000007
     （式（ＩＩｂ）中、Ｒ３、Ｒ４、ｐ、ｑ、Ｘおよびｍは、それぞれ式（Ｉｂ）におけるＲ３、Ｒ４、ｐ、ｑ、Ｘおよびｍと同一である。）     The cyclopentanol derivative represented by the general formula (Ia) is a cyclopentanol derivative represented by the following general formula (Ib):
    6. The method for producing a cyclopentanol derivative according to claim 5, wherein the cyclopentanone derivative represented by the general formula (IIa) is a cyclopentanone derivative represented by the following general formula (IIb).
    Figure JPOXMLDOC01-appb-C000006
     (In the formula (Ib), R 3 and R 4 each independently represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group or a benzyl group, and one or more hydrogen atoms of the phenyl group and One or more hydrogen atoms in the phenyl part of the benzyl group may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms or a halogen atom, and p, q, A, X and m is the same as p, q, A, X and m in formula (Ia), respectively.
    Figure JPOXMLDOC01-appb-C000007
     (In the formula (IIb), R 3, R 4, p, q, X and m are the same as R 3, R 4, p, q, X and m in each formula (Ib).)
  7. 　Ｒ３およびＲ４は、それぞれ独立に、水素原子または炭素数１～４のアルキル基であることを特徴とする請求項６に記載のシクロペンタノール誘導体の製造方法。 7. The method for producing a cyclopentanol derivative according to claim 6, wherein R 3 and R 4 are each independently a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.
  8. 　Ｘは、フッ素原子または塩素原子であり、ｍは、０または１であることを特徴とする請求項１～７の何れか１項に記載のシクロペンタノール誘導体の製造方法。 The method for producing a cyclopentanol derivative according to any one of claims 1 to 7, wherein X is a fluorine atom or a chlorine atom, and m is 0 or 1.
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