Method for producing 2-alkylthio-1-imidazoylethanone compounds

Abstract

Provided is a method for producing a compound represented by formula (3) (wherein R1, R2, R3 and Rb are the same as those in formulae (1) and (2)), the method including chemically reacting a compound represented by formula (1) (wherein R1 represents a C1-C6 alkyl group, R2 represents a hydrogen atom, a halogeno group, an (un)substituted C1-C6 alkyl group, an (un)substituted C2-C6 alkenyl group, or a 1,3-dioxolan-2-yl group, and Ra represents a C1-C6 alkyl group) with a compound represented by formula (2) (wherein R3 represents a C1-C6 alkyl group, and Rb represents a C1-C6 alkyl group) in the presence of a Lewis acid and a base.

Description

Technical Field

[0001] The present invention relates to a method for producing a 2-alkylthio-1-imidazolylethanone compound. This application claims priority based on Japanese Patent Application No. 2021-188983 filed in Japan on November 19, 2021, and incorporates its content herein.

Background Art

[0002] Nitrogen-containing heterocycles are a major substructure (building block) that constitutes compounds serving as the basis for pharmaceuticals and agricultural chemicals. In recent years, the development of harmful arthropod control agents having an imidazole ring, a pyridine ring, etc. has been actively carried out. For example, Patent Document 1 discloses an ethylsulfonyl-substituted imidazolylpyrimidine compound and shows a compound represented by formula (A) as an intermediate for its production.

[0003]

Chemical Formula

[0004] Patent Document 1 discloses that the compound represented by formula (A) was produced in the following steps.

[0005]

Chemical Formula

[0006] Further, Patent Document 2 discloses that an imidazole compound was produced in the following steps.

[0007]

Chemical Formula

[0008] Also, Patent Document 3 discloses that an imidazole compound was produced in the following steps.

[0009]

Chemical Formula

[0010] [Patent Document 1] WO 2020 / 071304 A [Patent Document 2] WO 2005 / 090333 A [Patent Document 3] Japanese Patent Publication No. 2017-66077 A [Overview of the Initiative] [Problems that the invention aims to solve]

[0011] The object of the present invention is to provide a method for producing a 2-alkylthio-1-imidazoylethanone compound, which is one of the building blocks. Furthermore, it is also to provide an imidazoylethanone compound that serves as a raw material for this method. [Means for solving the problem]

[0012] As a result of repeated considerations to achieve the above objectives, we have completed the present invention, which encompasses the following aspects. [1] Compounds represented by formula (1):

[0013] [ka]

[0014] (In formula (1) above, R 1 R represents a C1-6 alkyl group, 2 R represents a hydrogen atom, a halogen group, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, or a 1,3-dioxolan-2-yl group. a This represents a C1-6 alkyl group.) Compound represented by formula (2):

[0015] [Chemical formula]

[0016] (In the above formula (2), R 3 represents a C1-6 alkyl group, and R b represents a C1-6 alkyl group.) Reacting the above with a Lewis acid and a base in the presence of a chemical reaction, A compound represented by formula (3) containing ))

[0017] [Chemical formula] )

[0018] (In the above formula (3), R 1 , R 2 , R 3 , and R b represent the same as those in the above formula (1) and the above formula (2).) The manufacturing method. [2] The Lewis acid is a Ti compound represented by formula (4):

[0019] [Chemical formula]

[0020] (In the above formula (4), X represents a halogeno group, R c represents a C1-6 alkyl group, m is any integer from 0 to 4, n is any integer from 0 to 4, and m + n = 4.) The manufacturing method according to the above [1]. [3] A compound represented by formula (3a):

[0021] [Chemical formula]

[0022] (In the above formula (3a), R 1a represents a C1-6 alkyl group, R 2a represents a C2-6 haloalkenyl group, R3a R represents a C1-6 alkyl group, ba (This indicates a C1-6 alkyl group). [4] Compound represented by formula (1a):

[0023] [ka]

[0024] (In formula (1a) above, R 1a R represents a C1-6 alkyl group, 2a This shows a C2-6 haloalkenyl group, R aa (This indicates a C1-6 alkyl group). [5] Equation: ClCO2R aa (In the formula, R aa The chloroformate ester represented by formula (7) is a compound represented by formula (7):

[0025] [ka]

[0026] (In formula (7) above, R 1a R represents a C1-6 alkyl group, 2a (This indicates a C2-6 haloalkenyl group.) The addition step involves adding it to a mixture of diisopropylethylamine and chloroform, The compound represented by formula (7) and the chloroformate ester are reacted in the presence of the diisopropylethylamine to form the compound represented by formula (1a):

[0027] [ka]

[0028] (In formula (1a) above, R 1a R represents a C1-6 alkyl group, 2a This shows a C2-6 haloalkenyl group, R aa (This indicates a C1-6 alkyl group.) A method for producing a compound represented by formula (1a), comprising a reaction step to obtain [the compound]. [Effects of the Invention]

[0029] According to the manufacturing method of the present invention, the compound represented by formula (3) can be obtained in high yield. Furthermore, the compound represented by formula (1), particularly the compound represented by formula (1a), which serves as a raw material, can be obtained in high yield. [Modes for carrying out the invention]

[0030] In this invention, the term "unsubstituted" means that only the core group is present. When the term "substituted" is not used and only the name of the core group is given, it means "unsubstituted" unless otherwise specified. On the other hand, the term "substitution" means that one of the hydrogen atoms of the core group is substituted by a group (substituent) that has the same or a different structure as the core group. Therefore, a "substituent" is another group bonded to the core group. There may be one substituent or two or more substituents. The two or more substituents may be the same or different. Terms such as "C1-6" indicate that the parent group has 1 to 6 carbon atoms. This number of carbon atoms does not include the number of carbon atoms in substituents. For example, a butyl group with an ethoxy group as a substituent is classified as a C2 alkoxy C4 alkyl group. The "substituents" are chemically acceptable and not particularly limited insofar as they have the effects of the present invention.

[0031] The following are examples of groups that can act as "substituents". C1-6 alkyl groups such as methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, s-butyl group, i-butyl group, t-butyl group, n-pentyl group, and n-hexyl group; C2-6 alkenyl groups such as vinyl group, 1-propenyl group, 2-propenyl group (allyl group), 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-methyl-2-propenyl group, and 2-methyl-2-propenyl group; C2-6 alkynyl groups such as ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, and 1-methyl-2-propynyl group;

[0032] C3-6 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups; Phenyl group; A heterocyclyl group with 3 to 6 members;

[0033] C1-6 alkoxy groups such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, i-butoxy, and t-butoxy groups; C6-10 aryloxy groups such as phenoxy and naphthoxy groups; Five- to six-membered heteroaryloxy groups such as thiazolyloxy and pyridyloxy groups;

[0034] C1-6 alkoxycarbonyl groups such as methoxycarbonyl groups, ethoxycarbonyl groups, n-propoxycarbonyl groups, i-propoxycarbonyl groups, n-butoxycarbonyl groups, and t-butoxycarbonyl groups;

[0035] Halogeno groups such as fluoro groups, chloro groups, bromo groups, and iod groups; C1-6 haloalkyl groups such as chloromethyl, chloroethyl, trifluoromethyl, 1,2-dichloro-n-propyl, 1-fluoro-n-butyl, and perfluoro-n-pentyl groups; C1-6 haloalkoxy groups such as trifluoromethoxy, 2-chloro-n-propoxy, and 2,3-dichlorobutoxy;

[0036] Formylamino group; C1-6 alkylcarbonylamino groups such as acetylamino groups, propanoylamino groups, butyrylamino groups, and i-propylcarbonylamino groups; C1-6 alkoxycarbonylamino groups such as methoxycarbonylamino groups, ethoxycarbonylamino groups, n-propoxycarbonylamino groups, and i-propoxycarbonylamino groups; Unsubstituted or substituted aminocarbonyl groups such as aminocarbonyl groups, dimethylaminocarbonyl groups, phenylaminocarbonyl groups, and N-phenyl-N-methylaminocarbonyl groups;

[0037] C1-6 alkylthio groups such as methylthio group, ethylthio group, n-propylthio group, i-propylthio group, n-butylthio group, i-butylthio group, s-butylthio group, and t-butylthio group; C1-6 haloalkylthio groups such as trifluoromethylthio group and 2,2,2-trifluoroethylthio group; C1-6 alkylsulfonyl groups such as methylsulfonyl groups, ethylsulfonyl groups, and t-butylsulfonyl groups; C1-6 haloalkylsulfonyl groups such as trifluoromethylsulfonyl group and 2,2,2-trifluoroethylsulfonyl group;

[0038] Cyano group; nitro group.

[0039] Furthermore, in these "substituents," any hydrogen atom in the substituent may be substituted with a group of a different structure. Examples of substituents in this case include C1-6 alkyl groups, C1-6 haloalkyl groups, C1-6 alkoxy groups, C1-6 haloalkoxy groups, halogeno groups, cyano groups, and nitro groups.

[0040] Furthermore, the above-mentioned "3-6 membered heterocyclyl group" refers to a group that contains 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms as constituent atoms of the ring. The heterocyclyl group may be monocyclic or polycyclic. In a polycyclic heterocyclyl group, at least one ring may be heterocyclic, and the remaining rings may be saturated alicyclic, unsaturated alicyclic, or aromatic rings. Examples of "3-6 membered heterocyclyl groups" include 3-6 membered saturated heterocyclyl groups, 5-6 membered heteroaryl groups, and 5-6 membered partially unsaturated heterocyclyl groups. Examples of 3-6 member saturated heterocyclyl groups include azilidinyl group, epoxy group, pyrrolidinyl group, tetrahydrofuranyl group, thiazolidinyl group, piperidyl group, piperazinyl group, morpholinyl group, dioxolanyl group, and dioxanyl group. Examples of five-membered heteroaryl groups include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, and tetrazolyl groups. Examples of six-membered heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, and triazinyl groups. Examples of five-membered partially unsaturated heterocyclyl groups include pyrrolinyl, dihydrofuranyl, imidazolinyl, pyrazolinyl, oxazolinyl, and isoxazolinyl groups. Examples of six-membered partially unsaturated heterocyclyl groups include the dihydropyranyl group.

[0041] The method for producing compound (3) of the present invention includes chemically reacting compound (1) and compound (2) in the presence of a Lewis acid and a base.

[0042] The compound (1) is represented by the following formula (1).

[0043] [ka]

[0044] In equation (1) above, R 1 This represents a C1-6 alkyl group. R 1 The C1-6 alkyl group in R may be a straight chain or a branched chain. 1 Examples of C1-6 alkyl groups in this compound include methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, i-propyl group, i-butyl group, s-butyl group, t-butyl group, i-pentyl group, neopentyl group, 2-methylbutyl group, 2,2-dimethylpropyl group, and i-hexyl group.

[0045] In equation (1) above, R 2 This represents a hydrogen atom, a halogeno group, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, or a 1,3-dioxolan-2-yl group.

[0046] R 2 Examples of "halogeno groups" in this context include fluoro groups, chloro groups, bromo groups, and iod groups.

[0047] R 2 In this context, "C1-6 alkyl groups" are R 1 We can cite the same thing as in [the previous example].

[0048] R 2 Examples of "C2-6 alkenyl groups" in this context include vinyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1-methyl-2-butenyl group, 2-methyl-2-butenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, and 5-hexenyl group.

[0049] R 2Substituents on the "C1-6 alkyl group" and "C2-6 alkenyl group" in the above include halogen groups such as fluoro, chloro, bromo, and iod groups; hydroxyl groups; C1-6 alkoxy groups such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, i-butoxy, and t-butoxy groups; C1-6 haloalkoxy groups such as 2-chloro-n-propoxy, 2,3-dichlorobutoxy, and trifluoromethoxy; phenyl groups; phenyl groups substituted with halogen groups, C1-6 haloalkyl groups, or C1-6 haloalkoxy groups, such as 4-chlorophenyl, 4-trifluoromethylphenyl, and 4-trifluoromethoxyphenyl; or cyano groups. Of these, halogen groups are preferred.

[0050] R 2 In this context, "halogeno-substituted C1-6 alkyl groups (sometimes called C1-6 haloalkyl groups)" include fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, 3,3,3-trifluoropropyl group, 2,2,3,3,3-pentafluoropropyl group, 1-chloro-2,2,3,3,3-pentafluoropropyl group, 1,2,2,3,3,3-hexafluoropropyl group, perfluoropropyl group, 2,2,2-trifluoro-1-trifluoromethylethyl group, perfluoro Examples include luteoisopropyl group, 4-fluorobutyl group, 1,4,4,4-tetrafluorobutyl group, 2,2,3,3,4,4,4-heptafluorobutyl group, 1,2,2,3,3,4,4,4-octafluorobutyl group, perfluorobutyl group, 3,3,3-trifluoro-2-trifluoromethylpropyl group, 1-chloro-2,3,3,3-tetrafluoro-2-trifluoromethylpropyl group, 1,2,3,3,3-pentafluoro-2-trifluoromethylpropyl group, perfluoropentyl group, and perfluorohexyl group.

[0051] R 2Examples of "halogeno-substituted C2-6 alkenyl groups (sometimes called C2-6 haloalkenyl groups)" in this context include 2,3,3,3-tetrafluoro-1-propenyl group, 3,3,3-trifluoro-1-propenyl group, 2-chloro-3,3,3-trifluoro-1-propenyl group, 2-bromo-3,3,3-trifluoro-1-propenyl group, 3,3,3-trifluoro-2-trifluoromethyl-1-propenyl group, 3,3,4,4,4-pentafluoro-1-butenyl group, 2,3,3,4,4,4-hexafluoro-1-butenyl group, and 2-chloro-3,3,4,4,4-pentafluoro-1-butenyl group.

[0052] In equation (1) above, R a This represents a C1-6 alkyl group.

[0053] R a In this context, "C1-6 alkyl groups" are R 1 We can cite the same thing as in [the previous example].

[0054] The compound (1) is preferably a compound represented by the following formula (1a) (hereinafter sometimes referred to as compound (1a)).

[0055] [ka]

[0056] In the above formula (1a), R 1a R represents a C1-6 alkyl group, 2a This shows a C2-6 haloalkenyl group, R aa This represents a C1-6 alkyl group. The aforementioned compound (1a) is a novel compound and is useful as a substrate in the production method of the present invention. R 1a The C1-6 alkyl groups in R 1 The same thing as in [the previous example] can be cited, preferably a methyl group. R aa The C1-6 alkyl groups in R aThe same thing as in the above can be cited, preferably an ethyl group. R 2a In this, the C2-6 haloalkenyl group is R 2 The same group as in the above can be cited, preferably the 2-chloro-3,3,3-trifluoro-1-propenyl group. The 2-chloro-3,3,3-trifluoro-1-propenyl group may be a mixture of E / Z groups, or it may be Z-only or E-only in terms of stereoisomerism.

[0057] The compound (1) used in the present invention may be synthesized by the present inventor using known methods, or it may be synthesized by another party using some method and commercially available. Specifically, the following compounds can be given as compound (1).

[0058] [ka]

[0059] The following notation in the above chemical formula represents an undefined double stereo bond.

[0060] [ka]

[0061] The aforementioned compound (2) is represented by the following formula (2).

[0062] [ka]

[0063] In equation (2) above, R 3 R represents a C1-6 alkyl group, b This represents a C1-6 alkyl group. R 3 and R b The C1-6 alkyl groups in R aThe same thing as in the above can be cited, preferably an ethyl group.

[0064] The compound (2) used in the present invention may be synthesized by the present inventors using known methods, or it may be synthesized by others and commercially available.

[0065] The amount of compound (2) used is, for example, 1.0 to 5.0 moles, preferably 1.1 to 2.0 moles, per mole of compound (1).

[0066] The Lewis acid present in the aforementioned chemical reaction consists of a central metal element and an electron-withdrawing group bonded to the metal. Examples of central metallic elements include boron (B), aluminum (Al), scandium (Sc), titanium (Ti), iron (Fe), zinc (Zn), arsenic (As), zirconium (Zr), niobium (Nb), cadmium (Cd), indium (In), tin (Sn), antimony (Sb), hafnium (Hf), mercury (Hg), and lanthanides. Of these, titanium (Ti) is preferred. Examples of electron-withdrawing groups include halogeno groups and triflate groups. In the present invention, a Ti compound represented by the following formula (4) (hereinafter sometimes referred to as compound (4)) can preferably be used as the Lewis acid.

[0067] [ka]

[0068] In formula (4) above, X represents a halogeno group, and R c Here, represents a C1-6 alkyl group, m is an integer from 0 to 4, n is an integer from 0 to 4, and m+n=4. The "halogeno group" in X is R 2 We can cite the same thing as in [the previous example]. R cIn this context, "C1-6 alkyl groups" are R 1 We can cite the same thing as in [the previous example].

[0069] Compound (4) may be a commercially available compound, or a tetrahalogeno titanium (TiX4) and an alcohol (R) may be used in the chemical reaction. c It may also be prepared by mixing OH). Compound (4), which is preferably used in the present invention, is TiCl3(O i It is Pr. i Pr is an isopropyl group.

[0070] The amount of Lewis acid used is, for example, 1.0 to 5.0 moles, preferably 1.1 to 4.0 moles, per mole of compound (1).

[0071] Examples of bases to be present in the aforementioned chemical reaction include inorganic bases such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride, and potassium hydride; and organic bases such as triethylamine, tetramethylethylenediamine, N,N-diisopropylamine, N,N-dimethylaniline, N,N-diethylaniline, 4-methylmorpholine, 1-azabicyclo[2.2.2]octane, 1,4-diazabicyclo[2.2.2]octane (abbreviation: DABCO), 1,8-diazabicyclo[5.4.0]undeca-7-ene, 1,5-diazabicyclo[4.3.0]nona-5-ene, pyridine, 4-(dimethylamino)pyridine, and 2,6-dimethylpyridine, with organic bases such as triethylamine being preferred.

[0072] The amount of base used is, for example, 1.0 to 5.0 moles, preferably 1.0 to 3.0 moles, per mole of Lewis acid.

[0073] The aforementioned chemical reaction can be carried out without a solvent or in a solvent. Considering ease of operation, it is preferable to carry out the chemical reaction in an organic solvent. The organic solvent is not particularly limited as long as it is inert to the Lewis acid. Examples of organic solvents include ethers such as diethyl ether, diisopropyl ether, diethylene glycol dimethyl ether (product name: Diglyme), and tetrahydrofuran (abbreviation: THF); halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane (abbreviation: DCE); aliphatic hydrocarbons such as pentane, hexane, cyclohexane, heptane, and octane; aromatic hydrocarbons such as toluene and xylene; aproton polar solvents such as N,N-dimethylformamide (abbreviation: DMF), N,N'-dimethylpropylene urea (abbreviation: DMPU), and hexamethylphosphate triamide (abbreviation: HMPA); and acetonitrile, with halogenated hydrocarbons such as chloroform being preferred.

[0074] The amount of the organic solvent used is preferably 5 to 500 parts by weight per 1 part by weight of compound (1).

[0075] The order in which the compound (1), the compound (2), the base, the Lewis acid, and the organic solvent used as needed are added to the reaction site in the aforementioned chemical reaction is not particularly limited.

[0076] One embodiment involves adding a Lewis acid in an organic solvent or without a solvent, adding compound (2) thereto, adding compound (1) to obtain a mixture, and then adding a base to this mixture while stirring to complete the chemical reaction. Another embodiment involves preparing a Lewis acid by dropwise adding tetrahalogenotitanium and an alcohol in an organic solvent, then dropwise adding compound (2) to it, and then dropwise adding compound (1) to the resulting mixture, followed by dropwise adding of a base and allowing the reaction to proceed with stirring. After the reaction is cooled, an organic solvent is added, tetrahalogenotitanium and an alcohol are added dropwise, and then the base is added dropwise and the reaction to proceed with stirring. The dropwise adding operation is carried out while stirring is performed. Each substance may be added either all at once or in small amounts gradually, but it is preferable to add it dropwise in small amounts, and it is preferable to do so while stirring. Furthermore, while there are no particular restrictions on the temperature at which each substance is added (dropped in), it is preferable that it be 0°C. The temperature in the aforementioned chemical reaction is not particularly limited, and is, for example, 0°C to 60°C, preferably 30°C to 50°C. The pressure in the aforementioned chemical reaction is, for example, 0.1 to 1 MPa, preferably 0.1 to 0.5 MPa, and more preferably 0.1 MPa. The reaction time in the aforementioned chemical reaction is not particularly limited, and is, for example, 0.5 hours to 24 hours. The aforementioned chemical reaction is preferably carried out under an inert gas atmosphere.

[0077] After the chemical reaction is complete, the resulting organic layer can be extracted with an organic solvent and then dried and concentrated for post-treatment. Furthermore, if necessary, the product of the chemical reaction may be purified by operations such as recrystallization and chromatography.

[0078] The compound (3) obtained by the production method of the present invention is represented by the following formula (3).

[0079] [ka]

[0080] In the above equation (3), R 1 , R 2 , R 3 , and R b These represent the same things as those in formula (1) and formula (2) above.

[0081] Of the compounds (3) obtained by the manufacturing method of the present invention, the compound represented by the following formula (3a) (hereinafter sometimes referred to as compound (3a)) is a novel compound and is particularly useful as an intermediate in the manufacture of pharmaceuticals and agrochemicals.

[0082] [ka]

[0083] In the above formula (3a), R 1a This represents a C1-6 alkyl group, preferably a methyl group. R 2a This group exhibits a C2-6 haloalkenyl group, preferably a 2-chloro-3,3,3-trifluoro-1-propenyl group. R 3a This represents a C1-6 alkyl group, preferably an ethyl group. R ba This represents a C1-6 alkyl group, preferably an ethyl group.

[0084] Examples of the aforementioned compound (3a) include the following compounds.

[0085] [ka]

[0086] The aforementioned compound (3) can be converted by a decarboxylation reaction to a compound represented by the following formula (5) (hereinafter sometimes referred to as compound (5)).

[0087] [ka]

[0088] In equation (5) above, R 1 , R 2 , and R 3 These represent the same terms as those in equation (3) above. Among these, R 1 A methyl group is preferred as R. 2 A 2-chloro-3,3,3-trifluoro-1-propenyl group is preferred. 3 An ethyl group is preferred as the component. Specifically, the following compounds can be cited as the aforementioned compound (5).

[0089] [ka]

[0090] The aforementioned decarboxylation reaction may be carried out according to known methods. For example, a method in which decarboxylation is performed in the presence of an acid.

[0091] Acids used in the aforementioned decarboxylation reaction include carboxylic acids such as acetic acid, formic acid, oxalic acid, benzoic acid, and 4-chlorobenzoic acid; phosphoric acid; sulfonic acids such as methanesulfonic acid, 4-toluenesulfonic acid monohydrate, and trifluoromethanesulfonic acid; hydrogen halides such as hydrogen chloride, hydrogen bromide, hydrogen iodide, and hydrogen fluoride; and sulfuric acid, nitric acid, and tetrafluoroboric acid. The amount of acid used is, for example, 0.5 to 3.0 moles, preferably 1.0 to 2.0 moles, per mole of compound (3).

[0092] The decarboxylation reaction is preferably carried out in a solvent. For example, the decarboxylation reaction can be carried out by adding the acid dropwise to a mixture of compound (3) and a solvent at room temperature while stirring, and then heating while continuing to stir. Suitable solvents include water, organic solvents, mixed solvents of water and organic solvents, and mixed solvents of different organic solvents. Examples of the aforementioned organic solvents include alcohols such as methanol and ethanol; ethers such as diethyl ether, diisopropyl ether, diethylene glycol dimethyl ether (product name: Digrime), and tetrahydrofuran (abbreviation: THF); esters such as ethyl acetate; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane (abbreviation: DCE); aliphatic hydrocarbons such as pentane, hexane, cyclohexane, heptane, and octane; aromatic hydrocarbons such as toluene and xylene; aproton polar solvents such as N,N-dimethylformamide (abbreviation: DMF), N,N'-dimethylpropylene urea (abbreviation: DMPU), and hexamethylphosphate triamide (abbreviation: HMPA); and acetonitrile. The amount of solvent used is preferably 5 to 500 parts by weight per 1 part by weight of compound (3).

[0093] The temperature in the decarboxylation reaction is preferably carried out under heating and depends on the boiling point of the solvent used, but is, for example, 40 to 110°C. The reaction time in the decarboxylation reaction is not particularly limited, and is, for example, 0.5 hours to 24 hours.

[0094] The aforementioned compound (5) can be converted by an oxidation reaction to a compound represented by the following formula (6) (hereinafter sometimes referred to as compound (6)).

[0095] [ka]

[0096] In the above formula (6), R 1 , R 2 , and R 3 These represent the same terms as those in equation (5) above. Specifically, the following compounds can be cited as the aforementioned compound (6).

[0097] [ka]

[0098] The method for producing the compound (1a) is: Formula:ClCO2R aa (In the formula, R aa The method includes an addition step of adding a chloroformate ester represented by the following formula (7) (hereinafter sometimes referred to as compound (7)), diisopropylethylamine, and chloroform, and a reaction step of reacting compound (7) and the chloroformate ester in the presence of the diisopropylethylamine to obtain compound (1a).

[0099] [ka]

[0100] In equation (7) above, R 1a R represents a C1-6 alkyl group, 2a This represents a C2-6 haloalkenyl group. R in equation (7) 1a R in equation (1) 1a It is the same as, and preferably, it exhibits a methyl group. R in equation (7) 2a R in equation (1) 2a It is the same as, and preferably exhibits a 2-chloro-3,3,3-trifluoro-1-propenyl group. The following compounds are examples of the aforementioned compound (7).

[0101] [ka]

[0102] The amount of diisopropylethylamine used is, for example, 0.9 to 3.0 moles, preferably 1.0 to 2.5 moles, per mole of compound (7).

[0103] The amount of chloroform used is preferably 5 to 500 parts by weight per 1 part by weight of compound (7).

[0104] For ease of operation, in the addition step, other organic solvents may be further added to the mixture to form a mixed solvent, and the reaction step may be carried out in the mixed solvent. The aforementioned organic solvent is not particularly limited as long as it is inert to chloroformate ester. Examples of organic solvents include ethers such as diethyl ether, diisopropyl ether, diethylene glycol dimethyl ether (product name: Diglyme), and tetrahydrofuran (abbreviation: THF); halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane (abbreviation: DCE); aliphatic hydrocarbons such as pentane, hexane, cyclohexane, heptane, and octane; aromatic hydrocarbons such as toluene and xylene; N,N-dimethylformamide (abbreviation: DMF), N,N'-dimethylpropylene urea (abbreviation: DMPU), hexamethyl phosphate triamide (abbreviation: HMPA); and aprotonate solvents such as acetonitrile.

[0105] The above formula: ClCO2R aa Specific examples of chloroformate esters represented by include methyl chloroformate, ethyl chloroformate, and n-propyl chloroformate. Ethyl chloroformate is particularly preferred.

[0106] The amount of chloroformate ester used is, for example, 0.9 to 3.0 moles, preferably 1.0 to 2.5 moles, per mole of compound (7). The chloroformate ester may be added either all at once or in small amounts gradually, but it is preferable to add it dropwise in small amounts, and it is preferable to add it dropwise while stirring. The temperature at which the chloroformate ester is added is not particularly limited, but is room temperature to 45°C, preferably 40°C.

[0107] The temperature in the reaction step is not particularly limited, and is, for example, 0°C to 60°C, preferably room temperature to 45°C, and more preferably 40°C. The pressure in the reaction step is, for example, 0.1 to 1 MPa, preferably 0.1 to 0.5 MPa, and more preferably 0.1 MPa. The reaction time in the reaction step is not particularly limited, and is, for example, 0.5 hours to 24 hours. The reaction step is preferably carried out under an inert gas atmosphere.

[0108] After the reaction step is completed, the resulting organic layer can be extracted with an organic solvent and then dried and concentrated for post-treatment. Furthermore, if necessary, the product from the reaction step may be purified by operations such as recrystallization and chromatography.

[0109] The present invention will be described in more detail below with reference to examples. However, the present invention is not limited to the following examples.

[0110] [Example 1] Ethyl 3-[5-(2-chloro-3,3,3-trifluoropropa-1-en-1-yl)-1-methyl-1H-imidazole-2-yl]-2-(ethylthio)-3-oxopropanoate was obtained by the following procedure.

[0111] [ka]

[0112] Chloroform (32 ml) was added to a 200 ml four-neck flask purged with nitrogen, and cooled to 0°C. Then, titanium tetrachloride (6.8 g) and isopropyl alcohol (2.1 g) were added dropwise while stirring. Stirring was continued at 0°C for 30 minutes. Next, ethyl 2-(ethyl thio)acetate (5.5 g) was added dropwise at 0°C while stirring, followed by ethyl 5-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-1-methyl-1H-imidazole-2-carboxylate (9.5 g) (E / Z: 14.5 / 85.5) dropwise at 0°C while stirring. Stirring continued at 0°C for 30 minutes. Then, triethylamine (10.8 g) was added dropwise at 0°C while stirring, and after the addition was complete, stirring was continued at room temperature for 24 hours. Next, it was cooled to 0°C. To this, 32 ml of chloroform was added, and titanium tetrachloride (6.8 g) and isopropyl alcohol (2.1 g) were added dropwise while stirring. After the addition was complete, the mixture was stirred at 0°C for 30 minutes. Subsequently, triethylamine (10.8 g) was added dropwise at 0°C while stirring, and stirring was continued at room temperature for 4 hours. To the obtained solution, chloroform (93 ml) and 13% hydrochloric acid (121 g) were added dropwise while stirring under ice cooling, and stirring was continued for a while. Then, the solution was separated, and the organic layer (lower layer of the separatory) was concentrated under reduced pressure. The obtained concentrate was purified by column to obtain ethyl 3-[5-(2-chloro-3,3,3-trifluoropropa-1-en-1-yl)-1-methyl-1H-imidazole-2-yl]-2-(ethylthio)-3-oxopropanoate (5.40 g) (E / Z: 19.4 / 80.6) (purity 98.1 wt%, yield 44.5 mol%).

[0113] [Reference example 1] 1-[5-(2-chloro-3,3,3-trifluoropropane-1-en-1-yl)-1-methyl-1H-imidazole-2-yl]-2-(ethylthio)-ethane-1-one was obtained by the following procedure.

[0114] [ka]

[0115] In a 200 ml four-neck flask, ethyl 3-[5-(2-chloro-3,3,3-trifluoropropa-1-en-1-yl)-1-methyl-1H-imidazole-2-yl]-2-(ethylthio)-3-oxopropanoate (5.40 g) (E / Z: 19.4 / 80.6) and ethyl alcohol (25 ml) were added. 8.3 wt% sulfuric acid (18.0 g) was then added dropwise at room temperature while stirring. The mixture was then heated to 100°C and stirred for 14 hours. The obtained solution was cooled to 30°C, water (39 ml) was added, and a first extraction was performed with chloroform (39 ml), followed by a second extraction with chloroform (13 ml). The organic layers obtained from the extractions were combined, concentrated under reduced pressure, and allowed to dry to obtain 1-[5-(2-chloro-3,3,3-trifluoropropane-1-en-1-yl)-1-methyl-1H-imidazole-2-yl]-2-(ethylthio)-ethane-1-one (3.90 g) (E / Z: 24.5 / 75.5) (purity 95.1 wt%, yield 91.2 mol%).

[0116] [Reference example 2] 1-[5-(2-chloro-3,3,3-trifluoropropane-1-en-1-yl)-1-methyl-1H-imidazole-2-yl]-2-(ethylsulfonyl)-ethane-1-one was obtained by the following procedure.

[0117] [ka]

[0118] In a 100 ml four-neck flask, 1-[5-(2-chloro-3,3,3-trifluoropropane-1-en-1-yl)-1-methyl-1H-imidazole-2-yl]-2-(ethylthio)-ethane-1-one (3.90 g) (E / Z: 24.5 / 75.5), ethyl acetate (12 ml), and sodium tungstate dihydrate (0.063 g) were placed and cooled to 0°C. 30% hydrogen peroxide solution (3.0 g) was then added dropwise while stirring. The mixture was then heated to room temperature and stirred for 3 hours. To the obtained solution, 27 g of 6.4% sodium bisulfite aqueous solution was added, and the first extraction was performed with 25 ml of ethyl acetate, the second extraction with 15 ml of ethyl acetate, and the third extraction with 10 ml of ethyl acetate. The organic layers obtained from the extractions were combined, concentrated under reduced pressure, and allowed to dry. The dry material was subjected to crystallization with a solvent mixture of n-hexane and ethyl acetate in a volume ratio of 8:2 (n-hexane:ethyl acetate) to obtain 1-[5-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-1-methyl-1H-imidazole-2-yl]-2-(ethylsulfonyl)-ethane-1-one (2.67 g) (E / Z: 12.4 / 87.6) (purity 97.9 wt%, yield 64.0 mol%). Furthermore, the filtrate obtained from the crystallization treatment was concentrated under reduced pressure and allowed to dry. The dried material was purified by column chromatography to recover secondary crystals (0.7g) (E / Z: 45.7 / 54.3) (purity 93.7 wt%, yield 16.1 mol%).

[0119] [Example 2] Preparation of Ethyl (Z)-5-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-1-methyl-1H-imidazole-2-carboxylate

[0120] [ka]

[0121] 1.413 g (96.0% purity, 5.00 mmol) of (Z)-5-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-1-methyl-1H-imidazole and 0.904 g (7.00 mmol) of diisopropylethylamine were dissolved in 5.0 mL of chloroform. The mixture was heated to 40°C in a water bath, and 0.760 g (7.00 mmol) of ethyl chloroformate was added dropwise while stirring, followed by continued stirring at the same temperature for 2.0 hours. After confirming the disappearance of the raw materials and performing a quantitative analysis of the reaction solution, the production rate of ethyl(Z)-5-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-1-methyl-1H-imidazole-2-carboxylate was found to be 95.2%.

[0122] [Example 3] Preparation of Ethyl (Z)-5-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-1-methyl-1H-imidazole-2-carboxylate 1.413 g (96.0% purity, 5.00 mmol) of (Z)-5-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-1-methyl-1H-imidazole and 1.422 g (11.00 mmol) of diisopropylethylamine were dissolved in 5.0 mL of chloroform. This mixture was added dropwise to a 5.0 mL solution of 1.194 g (11.00 mmol) of ethyl chloroform in chloroform at 40°C while stirring, and stirring was continued at the same temperature for 2.0 hours. After the reaction was stopped, quantitative analysis of the reaction solution revealed that the production rate of ethyl(Z)-5-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-1-methyl-1H-imidazole-2-carboxylate was 95.7%.

[0123] Next, an example of production using triethylamine instead of diisopropylethylamine is shown below.

[0124] [Reference example 3] Preparation of Ethyl (Z)-5-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-1-methyl-1H-imidazole-2-carboxylate 1.000 g (96.0% purity, 4.70 mmol) of (Z)-5-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-1-methyl-1H-imidazole and 1.057 g (10.40 mmol) of triethylamine were dissolved in 9.5 mL of chloroform. The mixture was added dropwise to a 7.0 mL solution of 1.134 g (10.40 mmol) of ethyl chloroform in chloroform at 0°C while stirring, and stirring was continued at room temperature for 6.0 hours. After stopping the reaction, quantitative analysis of the reaction solution revealed that the production rate of ethyl(Z)-5-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-1-methyl-1H-imidazole-2-carboxylate was 39.3%. [Industrial applicability]

[0125] The manufacturing method of the present invention can efficiently produce 2-alkylthio-1-imidazoylethanone compounds, which are major substructures constituting compounds that serve as active ingredients for pharmaceuticals and agrochemicals.

Claims

1. Compound represented by formula (1): 【Chemistry 1】 (In formula (1) above, R １ R represents a C1-6 alkyl group, ２ R represents a hydrogen atom, a halogen group, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, or a 1,3-dioxolan-2-yl group. ａ (represents a C1-6 alkyl group) and Compound represented by formula (2): 【Chemistry 2】 (In formula (2) above, R ３ R represents a C1-6 alkyl group, ｂ (represents a C1-6 alkyl group) and The chemical reaction of a Lewis acid and a base in the presence of a Lewis acid and a base. Compounds represented by formula (3), including: 【Transformation 3】 (In the formula (3), R １ , R 2 , R ３ , and R ｂ represent the same ones as those in the formula (1) and the formula (2)), a production method.

2. The Lewis acid is a Ti compound represented by formula (4): 【Chemistry 4】 (In formula (4) above, X represents a halogeno group, and R ｃ The manufacturing method according to claim 1, wherein is a C1-6 alkyl group, m is an integer from 0 to 4, n is an integer from 0 to 4, and m + n = 4.

3. Compound represented by formula (3a): 【Transformation 5】 (In the above formula (3a), R １ａ R represents a C1-6 alkyl group, ２ａ R represents a C2-6 haloalkenyl group, ３ａ R represents a C1-6 alkyl group, ｂａ (This indicates a C1-6 alkyl group).

4. Compound represented by formula (1a): 【Transformation 6】 (In formula (1a) above, R １ａ R represents a C1-6 alkyl group, ２ａ R represents a C2-6 haloalkenyl group, ａａ (This indicates a C1-6 alkyl group).

5. Formula: ClCO ２ R ａａ (In the formula, R ａａ This refers to chloroformate esters represented by C1-6 alkyl groups, Compound represented by formula (7): 【Transformation 7】 (In formula (7) above, R 1ａ R represents a C1-6 alkyl group, ２ａ (This indicates a C2-6 haloalkenyl group.) The addition step involves adding it to a mixture of diisopropylethylamine and chloroform, The compound represented by formula (7) and the chloroformate ester are reacted in the presence of the diisopropylethylamine to obtain the compound represented by formula (1a): 【Transformation 8】 (In formula (1a) above, R 1ａ R represents a C1-6 alkyl group, ２ａ R represents a C2-6 haloalkenyl group, ａａ (This indicates a C1-6 alkyl group.) A method for producing a compound represented by formula (1a), comprising a reaction step to obtain [the compound].

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