Method for producing 2-ethylsulfonyl-1-heteroarylethanone compound

Abstract

Provided is a method for producing a 2-(ethanesulfonyl)-1-heteroarylethan-1-one compound, the method including chemically reacting an alkyl magnesium halide with (methanesulfonyl)ethane to obtain an (ethanesulfonyl)methyl magnesium halide, and chemically reacting a heteroaryl carboxylic acid ester compound, such as a substituted or unsubstituted 5- to 6-membered heteroaryl carboxylic acid alkyl ester or a substituted or unsubstituted fused bicyclic 9-membered heteroaryl carboxylic acid alkyl ester, with the (ethanesulfonyl)methyl magnesium halide.

Description

Method for producing 2-ethylsulfonyl-1-heteroarylethanone compounds

[0001] The present invention relates to a novel method for producing 2-ethylsulfonyl-1-heteroarylethanone compounds. This application claims priority to Japanese Patent Application No. 2023-119877, filed on July 24, 2023, the contents of which are incorporated herein by reference.

[0002] Heterocyclic building blocks are an important group of structural fragments used in the organic synthesis of compounds that serve as active ingredients for pharmaceuticals, agrochemicals, etc. 2-(ethanesulfonyl)-1-heteroarylethan-1-one compounds are known as heterocyclic building blocks.

[0003] For example, Patent Document 1 discloses that 1-{5-[(1Z)-2-chloro-3,3,3-trifluoropropan-1-en-1-yl]-1-methyl-1H-imidazol-2-yl}-2-(ethanesulfonyl)ethan-1-one (English name: 1-{5-[(1Z)-2-chloro-3,3,3-trifluoroprop-1-en-1-yl]-1-methyl-1H-imidazol-2-yl}-2-(ethanesulfonyl)ethan-1-one; Formula (A)) was produced by the following steps. In the formula, Et represents an ethyl group.

[0004]

[0005] Patent Document 2 discloses that triethylamine is added dropwise to a mixture of magnesium chloride and tetrahydrofuran, a mixture of 1-(ethanesulfonyl)-2-propanone and tetrahydrofuran is added dropwise to the resulting mixture and stirred at 20°C, a mixture of 5-chloro-2-pyrazinecarboxylic acid chloride and toluene is added dropwise to the resulting mixture and stirred at 20°C, the resulting mixture is cooled to 0°C, a mixture of 35% hydrochloric acid and water is added dropwise thereto, and a mixture of toluene, water and tetrahydrofuran is subsequently added thereto and stirred at 20°C, the layers are separated, the resulting organic layer is washed with an aqueous sodium hydrogencarbonate solution, the organic layer is filtered to obtain a filtrate, the filtrate is evaporated to dryness to obtain a dried product, and the dried product is purified by crystallization to obtain 1-(5-chloropyrazin-2-yl)-2-(ethanesulfonyl)ethan-1-one (1-(5-chloropyrazin-2-yl)-2-(ethanesulfonyl)ethan-1-one; Formula (B)).

[0006]

[0007] Patent Document 3 discloses a method for dissolving 2,5-diiodo-1-methyl-1H-imidazole in tetrahydrofuran, cooling the solution to -70°C, adding dropwise a solution of n-butyllithium in n-hexane, and stirring at -70°C. 2-chloro-N-methoxy-N-methylacetamide is added to the resulting mixture, stirring at -70°C. The resulting solution is poured into a saturated aqueous solution of ammonium chloride, ethyl acetate is added, the mixture is stirred, and the layers are separated. The resulting organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered to obtain a filtrate. The filtrate is concentrated under reduced pressure. The resulting concentrate (containing 2-chloro-1-(5-iodo-1-methyl-1H-imidazol-2-yl)ethan-1-one) is dissolved in a mixture of N,N-dimethylformamide and tetrahydrofuran, stirring at 0°C. Sodium ethyl mercaptan is added to the solution, stirring at room temperature. The resulting solution is poured into water, ethyl acetate is added, stirring, and the layers are separated. The resulting organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered to obtain a filtrate. The resulting solution was poured into a mixture of saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium thiosulfate, and dichloromethane was added thereto and stirred. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The obtained filtrate was concentrated under reduced pressure, and the obtained concentrate was purified to obtain 2-(ethanesulfonyl)-1-(5-iodo-1-methyl-1H-imidazol-2-yl)ethan-1-one (English name: 2-(ethanesulfonyl)-1-(5-iodo-1-methyl-1H-imidazol-2-yl)ethan-1-one; formula (C)).

[0008]

[0009] International Publication No. 2023 / 090345 International Publication No. 2018 / 194077 International Publication No. 2020 / 071304

[0010] An object of the present invention is to provide a novel method for producing 2-(ethanesulfonyl)-1-heteroarylethan-1-one compounds, which are one of the heterocyclic building blocks used in the organic synthesis of compounds that serve as active ingredients of pharmaceuticals, agricultural chemicals, etc.

[0011] As a result of extensive investigations to achieve the above object, the present invention has been completed, including the following aspects.

[0012] [1] A method for producing a 2-(ethanesulfonyl)-1-heteroarylethan-1-one compound (e.g., a compound represented by formula (5)), which comprises chemically reacting (ethanesulfonyl)methyl magnesium halide (a compound represented by formula (3)) with a heteroaryl carboxylic acid ester compound (e.g., a compound represented by formula (4)).

[0013] (In formula (3), X is a halogeno group.)

[0014] (In formula (4), R ｂ is an alkyl group, and Ar is a substituted or unsubstituted heteroaryl group.

[0015] (In formula (5), Ar is the same substituted or unsubstituted heteroaryl group as Ar in formula (4).)

[0016] [2] The production method according to [1], further comprising chemically reacting (methanesulfonyl)ethane (a compound represented by formula (1)) with an alkyl magnesium halide (a compound represented by formula (2), also referred to as an alkyl Grignard reagent) to obtain the (ethanesulfonyl)methyl magnesium halide (a compound represented by formula (3)).

[0017]

[0018] (In formula (2), X is the same halogeno group as X in formula (3), and R ａ is an alkyl group.

[0019] [3] The production method according to [1] or [2], wherein the heteroaryl carboxylic acid ester compound is a substituted or unsubstituted 5- to 6-membered heteroaryl carboxylic acid alkyl ester or a substituted or unsubstituted fused bicyclic 9-membered heteroaryl carboxylic acid alkyl ester.

[0020] [4] A method for producing (ethanesulfonyl)methylmagnesium halide (a compound represented by formula (3)), which comprises chemically reacting (methanesulfonyl)ethane (a compound represented by formula (1)) with an alkylmagnesium halide (a compound represented by formula (2), also known as an alkyl Grignard reagent).

[0021] According to the production method of the present invention, (ethanesulfonyl)methyl magnesium halide (compound represented by formula (3)) and 2-(ethanesulfonyl)-1-heteroarylethan-1-one compound (e.g., compound represented by formula (5)) can be obtained in high yield. The 2-(ethanesulfonyl)-1-heteroarylethan-1-one compound is useful as a heterocyclic building block for producing the heteroarylazole compound and pesticide described in Patent Document 3.

[0022] One embodiment of the production method of the present invention is a method for producing a 2-(ethanesulfonyl)-1-heteroarylethan-1-one compound, which comprises chemically reacting (ethanesulfonyl)methylmagnesium halide with a heteroaryl carboxylic acid ester compound. Another embodiment of the production method of the present invention is a method for producing a 2-(ethanesulfonyl)-1-heteroarylethan-1-one compound, which comprises chemically reacting (methanesulfonyl)ethane with an alkylmagnesium halide to obtain (ethanesulfonyl)methylmagnesium halide, and chemically reacting the (ethanesulfonyl)methylmagnesium halide with a heteroaryl carboxylic acid ester compound.

[0023] Another embodiment of the production method of the present invention is a method for producing (ethanesulfonyl)methylmagnesium halide, which comprises chemically reacting (methanesulfonyl)ethane with an alkylmagnesium halide.

[0024] In the present invention, the term "unsubstituted" refers to only the core group. When the name of the core group alone is used without the term "substituted," it means "unsubstituted" unless otherwise specified. On the other hand, the term "substituted" means that any hydrogen atom in the core group is substituted with a group (substituent) of the same or different structure as the core group. Therefore, a "substituent" is another group bonded to the core group. There may be one substituent, or there may be two or more substituents. The two or more substituents may be the same or different. A term such as "C1-6" indicates that the core group has 1 to 6 carbon atoms, for example. This number of carbon atoms does not include the number of carbon atoms in the substituent. For example, a butyl group having an ethoxy group as a substituent is classified as a C2 alkoxy C4 alkyl group. The "substituent" is not particularly limited as long as it is chemically permissible and achieves the effects of the present invention.

[0025] Examples of groups that can serve as "substituents" include: C1-6 alkyl groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, and n-hexyl; C2-6 alkenyl groups such as vinyl, 1-propenyl, 2-propenyl (allyl), 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, and 2-methyl-2-propenyl; C2-6 alkynyl groups such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, and 1-methyl-2-propynyl;

[0026] C3-6 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups; phenyl groups; 3- to 6-membered heterocyclyl groups;

[0027] 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; 5- to 6-membered heteroaryloxy groups such as thiazolyloxy and pyridyloxy groups;

[0028] C1-6 alkoxycarbonyl groups such as a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an i-propoxycarbonyl group, an n-butoxycarbonyl group, and a t-butoxycarbonyl group;

[0029] Halogeno groups such as a fluoro group, a chloro group, a bromo group, and an iodo group; C1-6 haloalkyl groups such as a chloromethyl group, a chloroethyl group, a trifluoromethyl group, a 1,2-dichloro-n-propyl group, a 1-fluoro-n-butyl group, and a perfluoro-n-pentyl group; C1-6 haloalkoxy groups such as a trifluoromethoxy group, a 2-chloro-n-propoxy group, and a 2,3-dichlorobutoxy group;

[0030] a formylamino group; a C1-6 alkylcarbonylamino group such as an acetylamino group, a propanoylamino group, a butyrylamino group, or an i-propylcarbonylamino group; a C1-6 alkoxycarbonylamino group such as a methoxycarbonylamino group, an ethoxycarbonylamino group, an n-propoxycarbonylamino group, or an i-propoxycarbonylamino group; an unsubstituted or substituted aminocarbonyl group such as an aminocarbonyl group, a dimethylaminocarbonyl group, a phenylaminocarbonyl group, or an N-phenyl-N-methylaminocarbonyl group;

[0031] C1-6 alkylthio groups such as methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, i-butylthio, s-butylthio, and t-butylthio; C1-6 haloalkylthio groups such as trifluoromethylthio and 2,2,2-trifluoroethylthio; C1-6 alkylsulfonyl groups such as methylsulfonyl, ethylsulfonyl, and t-butylsulfonyl; C1-6 haloalkylsulfonyl groups such as trifluoromethylsulfonyl and 2,2,2-trifluoroethylsulfonyl;

[0032] Cyano group; nitro group.

[0033] In addition, any hydrogen atom in these "substituents" may be substituted with a group of a different structure. In this case, examples of the substituent include a C1-6 alkyl group, a C1-6 haloalkyl group, a C1-6 alkoxy group, a C1-6 haloalkoxy group, a halogeno group, a cyano group, and a nitro group.

[0034] Furthermore, the above-mentioned "3- to 6-membered heterocyclyl group" contains 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms as ring-constituting atoms. The heterocyclyl group may be either monocyclic or polycyclic. In a polycyclic heterocyclyl group, as long as at least one ring is a heterocycle, the remaining rings may be saturated alicyclic, unsaturated alicyclic, or aromatic. Examples of the "3- to 6-membered heterocyclyl group" include 3- to 6-membered saturated heterocyclyl groups, 5- to 6-membered heteroaryl groups, and 5- to 6-membered partially unsaturated heterocyclyl groups.

[0035] Examples of the 3- to 6-membered saturated heterocyclyl group include an aziridinyl group, an epoxy group, a pyrrolidinyl group, a tetrahydrofuranyl group, a thiazolidinyl group, a piperidyl group, a piperazinyl group, a morpholinyl group, a dioxolanyl group, and a dioxanyl group.

[0036] Examples of the 5-membered heteroaryl group include a pyrrolyl group, a furyl group, a thienyl group, an imidazolyl group, a pyrazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, a triazolyl group, an oxadiazolyl group, a thiadiazolyl group, and a tetrazolyl group.

[0037] Examples of 6-membered heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl groups. Examples of 5-membered partially unsaturated heterocyclyl groups include pyrrolinyl, dihydrofuranyl, imidazolinyl, pyrazolinyl, oxazolinyl, and isoxazolinyl groups. Examples of 6-membered partially unsaturated heterocyclyl groups include dihydropyranyl groups.

[0038] The 2-(ethanesulfonyl)-1-heteroarylethan-1-one compound obtained by one embodiment of the production method of the present invention is one of heterocyclic building blocks, and can be used in the organic synthesis of compounds that serve as active ingredients for pharmaceuticals, agricultural chemicals, etc.

[0039] The 2-(ethanesulfonyl)-1-heteroarylethan-1-one compounds include 2-(ethanesulfonyl)-1-unsubstituted heteroarylethan-1-ones and 2-(ethanesulfonyl)-1-substituted heteroarylethan-1-ones (see formula (5)).

[0040] Examples of the heteroaryl in the 2-(ethanesulfonyl)-1-heteroarylethan-1-one compound, or in the 2-(ethanesulfonyl)-1-unsubstituted heteroarylethan-1-one and 2-(ethanesulfonyl)-1-substituted heteroarylethan-1-one include substituted or unsubstituted 5- to 6-membered heteroaryl and substituted or unsubstituted fused bicyclic 9-membered heteroaryl, preferably substituted or unsubstituted 5- to 6-membered nitrogen-containing heteroaryl and substituted or unsubstituted nitrogen-containing fused bicyclic 9-membered heteroaryl.

[0041] (In formula (5), Ar is the same unsubstituted or substituted heteroaryl group as Ar in formula (4).)

[0042] The heteroaryl group in Ar is an aromatic ring containing, as a ring-constituting atom, at least one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur atoms, and a chemically acceptable number of heteroatoms. The fused bicyclic 9-membered heteroaryl group is formed by condensing one aromatic ring containing, as a ring-constituting atom, at least one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur atoms, and a chemically acceptable number of heteroatoms, with another ring. The other ring may be a saturated alicyclic ring, an unsaturated alicyclic ring, an aromatic alicyclic ring, a saturated heterocyclic ring, an unsaturated heterocyclic ring, or an aromatic heterocyclic ring.

[0043] Examples of the 5-membered heteroaryl group include a pyrrolyl group, a furyl group, a thienyl group, an imidazolyl group, a pyrazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, a triazolyl group, an oxadiazolyl group, a thiadiazolyl group, and a tetrazolyl group. Of these, an imidazolyl group is preferred.

[0044] Examples of the 6-membered heteroaryl group include a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, a triazinyl group, etc. Examples of the fused bicyclic 9-membered heteroaryl group include an indolyl group, an isoindolyl group, a benzofuranyl group, a benzothienyl group, an indazolyl group, a benzimidazolyl group, a benzoxazolyl group, a benzisoxazolyl group, a benzothiazolyl group, a benzisothiazolyl group, an imidazopyridyl group, an imidazopyridazinyl group, etc.

[0045] As the substituent on the "5- or 6-membered heteroaryl group", a halogeno group, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, a substituted or unsubstituted C2-6 alkynyl group, a hydroxyl group, a substituted or unsubstituted C1-6 alkoxy group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted C1-6 alkylthio group, a substituted or unsubstituted C1-6 alkylsulfonyl group, or a cyano group is preferable, and a substituted or unsubstituted C1-6 alkyl group or a substituted or unsubstituted alkenyl group is more preferable.

[0046] Preferred substituents on a "C1-6 alkyl group," "C2-6 alkenyl group," "C2-6 alkynyl group," "C1-6 alkoxy group," "C1-6 alkylthio group," and "C1-6 alkylsulfonyl group" are a halogeno group, a C1-6 alkoxy group, a C1-6 haloalkoxy group, and a cyano group. Preferred substituents on a "C3-6 cycloalkyl group" are a halogeno group, a C1-6 alkyl group, a C1-6 haloalkyl group, a C1-6 alkoxy group, a C1-6 haloalkoxy group, and a cyano group.

[0047] The production method of this embodiment is preferably suitable for obtaining a compound represented by formula (5a), more preferably a compound represented by formula (5b) or formula (5C). As described in Patent Document 1, the compounds represented by formula (5a), formula (5b), or formula (5c) are useful as heterocyclic building blocks for producing heteroarylazole compounds and pesticides described in Patent Document 3. The wavy line in formula (5b) represents an undefined stereo bond or a mixture of multiple stereo structures resulting from the single bond.

[0048]

[0049]

[0050]

[0051] In formula (5a), R １ is a C1-6 alkyl group. １The C1-6 alkyl group in R may be a straight chain or a branched chain. １ Examples of the C1-6 alkyl group in the formula (I) include a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, an i-propyl group, an i-butyl group, an s-butyl group, an t-butyl group, an i-pentyl group, a neopentyl group, a 2-methylbutyl group, a 2,2-dimethylpropyl group, an i-hexyl group, etc. Of these, a methyl group is preferred.

[0052] In formula (5a), R ２ is a substituted or unsubstituted C1-6 alkyl group, or a substituted or unsubstituted C2-6 alkenyl group.

[0053] R ２ The "C1-6 alkyl group" in R １ The same can be mentioned as in

[0054] R ２ Examples of the "C2-6 alkenyl group" in the above formula include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, and 5-hexenyl groups. Of these, vinyl is preferred.

[0055] R ２ As the substituent on the "C1-6 alkyl group" and "C2-6 alkenyl group" in the above, a halogeno group, a C1-6 alkoxy group, a C1-6 haloalkyl group, a C1-6 haloalkoxy group, and a cyano group are preferred, and a halogeno group and a C1-6 haloalkyl group are more preferred.

[0056] R ２Examples of the halogeno-substituted C1-6 alkyl group (sometimes referred to as a C1-6 haloalkyl group) in the above formula include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a pentafluoroethyl group, a 3,3,3-trifluoropropyl group, a 2,2,3,3,3-pentafluoropropyl group, a 1-chloro-2,2,3,3,3-pentafluoropropyl group, a 1,2,2,3,3,3-hexafluoropropyl group, a perfluoropropyl group, a 2,2,2-trifluoro-1-trifluoromethylethyl ... Examples of such groups include a chloroisopropyl group, a 4-fluorobutyl group, a 1,4,4,4-tetrafluorobutyl group, a 2,2,3,3,4,4,4-heptafluorobutyl group, a 1,2,2,3,3,4,4,4-octafluorobutyl group, a perfluorobutyl group, a 3,3,3-trifluoro-2-trifluoromethylpropyl group, a 1-chloro-2,3,3,3-tetrafluoro-2-trifluoromethylpropyl group, a 1,2,3,3,3-pentafluoro-2-trifluoromethylpropyl group, a perfluoropentyl group, and a perfluorohexyl group.

[0057] R ２ Examples of the halogeno-substituted C2-6 alkenyl group (sometimes referred to as a C2-6 haloalkenyl group) in the formula (I) 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. Of these, 2-chloro-3,3,3-trifluoro-1-propenyl group is preferred. The 2-chloro-3,3,3-trifluoro-1-propenyl group may be a mixture of E / Z stereoisomers, or may be solely Z or solely E.

[0058] The (ethanesulfonyl)methylmagnesium halide used in this embodiment is a compound represented by formula (3). (Ethanesulfonyl)methylmagnesium halide is a type of Grignard reagent. This Grignard reagent decomposes in the presence of acidic protons such as water, so (ethanesulfonyl)methylmagnesium halide is usually contained in the organic solvent used in the preparation of (ethanesulfonyl)methylmagnesium halide.

[0059] In formula (3), X is a halogeno group. Examples of the halogeno group include a fluoro group, a chloro group, a bromo group, and an iodo group. Of these, a chloro group is preferred.

[0060] (Ethanesulfonyl)methylmagnesium halide can be obtained by the same general methods used to prepare Grignard reagents, including the chemical reaction of alkyl halides with magnesium, the reaction of highly acidic hydrocarbons with other Grignard reagents, the metal-halogen exchange reaction of alkyl halides with other Grignard reagents, and the transmetallation reaction of other organometallic compounds with magnesium halides.

[0061] The preparation of (ethanesulfonyl)methylmagnesium halide is preferably carried out in an organic solvent. Examples of organic solvents include ethers such as diethyl ether, diisopropyl ether, diethylene glycol dimethyl ether, and tetrahydrofuran; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; aliphatic hydrocarbons such as pentane, hexane, cyclohexane, heptane, and octane; and aromatic hydrocarbons such as toluene and xylene. Of these, ethers such as diethyl ether and tetrahydrofuran, and halogenated hydrocarbons such as chloroform are preferred.

[0062] (Ethanesulfonyl)methylmagnesium halide can be obtained, for example, by the method for producing (ethanesulfonyl)methylmagnesium halide according to this embodiment, i.e., a method including chemically reacting (methanesulfonyl)ethane with an alkyl Grignard reagent (alkylmagnesium halide).

[0063] The (methanesulfonyl)ethane (also known as ethyl methyl sulfone or methylsulfonyluethane) used in this embodiment is a compound represented by formula (1) [CAS RN: 594-43-4]. Commercially available (methanesulfonyl)ethane may also be used.

[0064] The alkyl magnesium halide used in this embodiment is a compound represented by formula (2). The alkyl magnesium halide is called an alkyl Grignard reagent. Since the alkyl Grignard reagent decomposes in the presence of acidic protons such as water, the alkyl magnesium halide is usually contained in the organic solvent used in the preparation of (ethanesulfonyl)methyl magnesium halide.

[0065]

[0066] In formula (2), X is the same as X in formula (3), and is a halogeno group. ａ is an alkyl group. ａ is eliminated by a chemical reaction with (methanesulfonyl)ethane and removed from the system, so R ａ is not particularly limited as long as it does not inhibit the chemical reaction, but is preferably an alkyl group having 1 to 6 carbon atoms. ａ The alkyl group in R may be a straight chain or a branched chain. ａExamples of the alkyl group in the formula (I) include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, i-propyl, i-butyl, s-butyl, t-butyl, i-pentyl, neopentyl, 2-methylbutyl, 2,2-dimethylpropyl, and i-hexyl. Of these, methyl and t-butyl are preferred, with methyl being more preferred. Alkyl magnesium halides can be obtained in accordance with general methods for preparing Grignard reagents. For example, they can be obtained by a method including chemically reacting an alkyl halide with magnesium. Commercially available alkyl magnesium halides may also be used.

[0067] Specific examples of alkyl magnesium halides include methyl magnesium chloride, ethyl magnesium chloride, t-butyl magnesium chloride, methyl magnesium bromide, ethyl magnesium bromide, t-butyl magnesium bromide, methyl magnesium iodide, ethyl magnesium iodide, and t-butyl magnesium iodide.

[0068] The amount of alkylmagnesium halide used in the chemical reaction of (methanesulfonyl)ethane with an alkylmagnesium halide (hereinafter sometimes referred to as "chemical reaction I") is preferably 1.0 to 2.0 moles, more preferably 1.0 to 1.2 moles, per mole of (methanesulfonyl)ethane. The amount of organic solvent used in the chemical reaction of (methanesulfonyl)ethane with an alkylmagnesium halide is preferably 5 to 500 parts by mass per part by mass of (methanesulfonyl)ethane. During chemical reaction I, the temperature is preferably set to 0°C or higher and below the boiling point of the organic solvent used, and the pressure is preferably set to 0.1 to 1 MPa, more preferably 0.1 to 0.5 MPa, and even more preferably 0.1 MPa. The time required for chemical reaction I (average residence time in the reactor) is not particularly limited, but is, for example, 0.5 to 24 hours. Chemical reaction I is preferably carried out under an inert gas atmosphere.

[0069] The procedure for carrying out chemical reaction I, the reaction apparatus used, and the like are not limited. For example, an organic solvent and (methanesulfonyl)ethane are mixed and stirred to obtain mixture A, and mixture B of an alkyl magnesium halide and an organic solvent is added dropwise or slowly to mixture A while stirring. The organic solvents used in mixture A and mixture B may be the same or different. The reaction apparatus is not particularly limited, and vessel-type batch reactors, vessel-type flow reactors, tubular reactors, and the like, which are well known in the field of chemical engineering, can be used. After chemical reaction I is completed, the product may be purified, but it is preferable not to purify it.

[0070] The heteroaryl carboxylic acid ester compound used in this embodiment includes unsubstituted or substituted heteroaryl carboxylic acid esters (see formula (4d)).

[0071]

[0072] Ar in formula (4d) is an unsubstituted heteroaryl group or a substituted heteroaryl group. B in formula (4d) is eliminated upon chemical reaction with (ethanesulfonyl)methylmagnesium halide and is ultimately removed from the system, so it is not particularly limited as long as it does not inhibit the chemical reaction.

[0073] Preferred heteroaryl carboxylic acid ester compounds used in this embodiment include unsubstituted or substituted heteroaryl carboxylic acid alkyl esters (see formula (4)).

[0074]

[0075] In formula (4), R ｂ is an alkyl group, and Ar is an unsubstituted or substituted heteroaryl group. Ar in formula (4) is as described for Ar in formula (5). OR in formula (4) ｂ is eliminated when it reacts with (ethanesulfonyl)methylmagnesium halide and is finally removed from the system. ｂ is not particularly limited as long as it does not inhibit the chemical reaction, but is preferably an alkyl group having 1 to 6 carbon atoms. ｂThe alkyl group in R may be a straight chain or a branched chain. ｂ Examples of the alkyl group in include a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, an i-propyl group, an i-butyl group, an s-butyl group, an t-butyl group, an i-pentyl group, a neopentyl group, a 2-methylbutyl group, a 2,2-dimethylpropyl group, an i-hexyl group, etc. Of these, a methyl group or an ethyl group is preferred, and an ethyl group is more preferred.

[0076] In this embodiment, a heteroaryl carboxylic acid ester compound corresponding to the compound represented by formula (5a), formula (5b), or formula (5c) can be used (formula (4a), formula (4b), or formula (4c)). The wavy line in formula (4b) represents an undefined stereo bond or a mixture of multiple stereo structures resulting from the single bond. R in formula (4b) or formula (4c) ｂ is preferably an ethyl group.

[0077]

[0078]

[0079]

[0080] An organic solvent can be used in the chemical reaction between (ethanesulfonyl)methyl magnesium halide and a heteroaryl carboxylic acid ester compound (hereinafter sometimes referred to as Chemical Reaction II). Examples of organic solvents that can be used in Chemical Reaction II include ethers such as diethyl ether, diisopropyl ether, diethylene glycol dimethyl ether, and tetrahydrofuran; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; aliphatic hydrocarbons such as pentane, hexane, cyclohexane, heptane, and octane; and aromatic hydrocarbons such as toluene and xylene. Of these, ethers such as diethyl ether and tetrahydrofuran, or halogenated hydrocarbons such as chloroform are preferred.

[0081] The amount of (ethanesulfonyl)methylmagnesium halide used in Chemical Reaction II is preferably 1.2 to 2.0 mol, more preferably 1.4 to 1.8 mol, per mol of the heteroaryl carboxylic acid ester compound. The amount of organic solvent used in Chemical Reaction II is preferably 5 to 500 parts by mass per part by mass of the heteroaryl carboxylic acid ester compound. During Chemical Reaction II, the temperature is preferably set to 0°C or higher and 40°C or lower, more preferably 5°C or higher and 35°C or lower, and the pressure is preferably set to 0.1 to 1 MPa, more preferably 0.1 to 0.5 MPa, and even more preferably 0.1 MPa. The time required for Chemical Reaction II (average residence time in the reactor) is not particularly limited, but is, for example, 0.5 to 24 hours. Chemical Reaction II is preferably carried out under an inert gas atmosphere.

[0082] The procedure for carrying out chemical reaction II, the reaction apparatus used, and the like are not limited. For example, an organic solvent and a heteroaryl carboxylic acid ester compound are mixed and stirred to obtain mixture C, and mixture D of (ethanesulfonyl)methylmagnesium halide and an organic solvent is added dropwise or slowly to mixture C while stirring. The organic solvent used in mixture C and mixture D may be the same or different. The reaction apparatus is not particularly limited, and a tank-type batch reactor, tank-type flow reactor, tubular reactor, or the like, well known in the field of chemical engineering, can be used. After chemical reaction II is completed, the product may or may not be purified. Purification can be performed by known techniques, such as extraction, crystallization, chromatography, and the like.

[0083] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to the following examples.

[0084] Example 1: Preparation of 1-[5-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-1-methyl-1H-imidazol-2-yl]-2-(ethylsulfonyl)-ethan-1-one

[0085] [Step 1] Chemical reaction of (methanesulfonyl)ethane with methylmagnesium chloride

[0086] Reactor I was charged with (methanesulfonyl)ethane (837.8 mg, 7.7 mmol), and the pressure in reactor I was reduced and replaced with nitrogen three times. Dehydrated tetrahydrofuran (5.0 mL) was added and mixed to obtain mixture I. While stirring mixture I at room temperature, a 2.81 M solution of methylmagnesium chloride in tetrahydrofuran (2.75 mL, 7.7 mmol) was added dropwise to reactor I over 3 minutes to obtain mixture II. After the dropwise addition was completed, reactor I was heated to 50°C, and mixture II was stirred at 50°C for 4 hours. Then, reactor I was returned to room temperature to obtain a solution of (ethanesulfonyl)methylmagnesium chloride in tetrahydrofuran.

[0087] [Step 2] Chemical reaction of (ethanesulfonyl)methylmagnesium chloride with ethyl 5-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-1-methyl-1H-imidazole-2-carboxylate

[0088] Ethyl 5-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-1-methyl-1H-imidazole-2-carboxylate (1.37 g, 4.8 mmol) was charged into reactor II, and the pressure in reactor II was reduced and replaced with nitrogen three times. Dehydrated tetrahydrofuran (7.3 mL) was added and mixed to obtain mixture III. While stirring mixture III at room temperature, the tetrahydrofuran solution of (ethanesulfonyl)methylmagnesium chloride stored in reactor I was transferred dropwise to reactor II. After the addition was complete, the mixture was stirred at room temperature for 2 hours. Reactor II was cooled to 0°C, and 2N hydrochloric acid was added to terminate the chemical reaction. Extraction with ethyl acetate was performed. The organic layer contained the target compound at a relative area ratio of 97.6% based on HPLC analysis. The organic layer was concentrated and purified by silica gel chromatography to obtain the target compound (1.55 g, yield 93.4%). １ H-NMR (400MHz, CDCl ３) δ1.47 (t, 3H), 3.29 (q, 2H), 4.05 (s, 3H), 4.86 (s, 2H), 7.14 (s, 1H), 8.06 (s, 1H).

[0089] As shown in the examples, the method for producing a 2-(ethanesulfonyl)-1-heteroarylethan-1-one compound according to the present invention can produce the 2-(ethanesulfonyl)-1-heteroarylethan-1-one compound in high yield using (methanesulfonyl)ethane as a starting material.

[0090] Example 2 Chemical Reaction of (Methanesulfonyl)ethane and Methylmagnesium Chloride Reactor I was charged with (methanesulfonyl)ethane (1.06 g, 9.8 mmol), and the pressure in reactor I was reduced and replaced with nitrogen three times. Dehydrated tetrahydrofuran (6.3 mL) was added and mixed to obtain mixture I. While stirring mixture I at room temperature, a 2.81 M solution of methylmagnesium chloride in tetrahydrofuran (3.5 mL, 9.8 mmol) was added dropwise to reactor I over 3 minutes to obtain mixture II. After the dropwise addition, reactor I was heated to 50°C, and mixture II was stirred at 50°C for 2 hours. A small amount of the liquid was withdrawn from reactor I as sample a, and deuterated methanol was added to this to terminate the chemical reaction. The mixture was then stirred in reactor I at 50°C for 2 hours. A small amount of the liquid was withdrawn from reactor I as sample b, and deuterated methanol was added to this to terminate the chemical reaction. The results of the comparison of sample a and sample b were as follows: １ The degree of deuterium conversion, based on the integrated value of the peak derived from the methyl group in (methanesulfonyl)ethane by H-NMR, was 97.8% D after 2 hours and 100% D after 4 hours. That is, 97.8% of (methanesulfonyl)ethane had been converted to (ethanesulfonyl)methylmagnesium chloride after 2 hours and 100% after 4 hours.

[0091] Example 3 Chemical Reaction of (Methanesulfonyl)ethane and t-butylmagnesium chloride Reactor I was charged with (methanesulfonyl)ethane (514.0 mg, 4.7 mmol), and the pressure inside Reactor I was reduced and replaced with nitrogen three times. Reactor I was then heated to 50°C, and while stirring the (methanesulfonyl)ethane at 50°C, a 1.0 M solution of t-butylmagnesium chloride in tetrahydrofuran (4.7 mL, 4.7 mmol) was added dropwise to Reactor I over 3 minutes to obtain Mixture II. After the dropwise addition was completed, Mixture II was stirred at 50°C for 2 hours. A small amount of the liquid was withdrawn from Reactor I as Sample a, and deuterated methanol was added to this to terminate the chemical reaction. The mixture was then stirred in Reactor I at 50°C for 2 hours. A small amount of the liquid was withdrawn from Reactor I as Sample b, and deuterated methanol was added to this to terminate the chemical reaction. １ The degree of deuterium conversion, based on the integrated value of the peak derived from the methyl group in (methanesulfonyl)ethane by H-NMR, was 80.3% D after 2 hours and 82.1% D after 4 hours. That is, 80.3% of (methanesulfonyl)ethane had been converted to (ethanesulfonyl)methylmagnesium chloride after 2 hours and 82.1% after 4 hours.

[0092] [Example 4] Samples a and b were obtained in the same manner as in Example 2, except that the temperature in reactor I after the completion of the dropwise addition was changed from 50°C to 22°C. １ The degree of deuterium conversion, based on the integrated value of the peak derived from the methyl group in (methanesulfonyl)ethane by H-NMR, was 74.5% D after 2 hours and 89.7% D after 4 hours. That is, 74.5% of (methanesulfonyl)ethane had been converted to (ethanesulfonyl)methylmagnesium chloride after 2 hours and 89.7% after 4 hours.

[0093] [Example 5] Samples a and b were obtained in the same manner as in Example 2, except that the temperature in reactor I after the completion of the dropwise addition was changed from 50°C to 40°C. １The degree of deuterium conversion, based on the integrated value of the peak derived from the methyl group in (methanesulfonyl)ethane by H-NMR, was 88.6% D after 2 hours and 99.4% D after 4 hours. That is, 88.6% of (methanesulfonyl)ethane had been converted to (ethanesulfonyl)methylmagnesium chloride after 2 hours and 99.4% after 4 hours.

[0094] Example 6 Samples a and b were obtained in the same manner as in Example 4, except that the 2.81 M methylmagnesium chloride solution in tetrahydrofuran (3.5 mL, 9.8 mmol) was replaced with a 2.81 M methylmagnesium chloride solution in tetrahydrofuran (4.2 mL, 11.76 mmol). １ The degree of deuterium conversion, based on the integrated value of the peak derived from the methyl group in (methanesulfonyl)ethane by H-NMR, was 90.3% D after 2 hours and 98.3% D after 4 hours. That is, 90.3% of (methanesulfonyl)ethane had been converted to (ethanesulfonyl)methylmagnesium chloride after 2 hours and 98.3% after 4 hours.

[0095] As shown in the examples, the method for producing (ethanesulfonyl)methylmagnesium halide according to the present invention can obtain (ethanesulfonyl)methylmagnesium halide from (methanesulfonyl)ethane in high yield.

[0096] It is possible to provide a novel method for producing 2-(ethanesulfonyl)-1-heteroarylethan-1-one compounds, which are one of the heterocyclic building blocks used in the organic synthesis of compounds that serve as active ingredients for pharmaceuticals, agricultural chemicals, and the like.

Claims

1. A method for preparing 2-(ethanesulfonyl)-1-heteroarylethan-1-one compounds, comprising chemically reacting (ethanesulfonyl)methyl magnesium halide with a heteroaryl carboxylic acid ester compound.

2. The process of claim 1, further comprising chemically reacting (methanesulfonyl)ethane with an alkyl magnesium halide to obtain the (ethanesulfonyl)methyl magnesium halide.

3. The method according to claim 1 or 2, wherein the heteroaryl carboxylate compound is a substituted or unsubstituted 5- to 6-membered heteroaryl carboxylate alkyl ester or a substituted or unsubstituted fused bicyclic 9-membered heteroaryl carboxylate alkyl ester.

4. A method for producing (ethanesulfonyl)methylmagnesium halide which comprises chemically reacting (methanesulfonyl)ethane with an alkylmagnesium halide.

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