Method for producing cyanoimidazole compounds

Abstract

To provide an industrially preferable and novel method for producing cyanoimidazole based compounds.SOLUTION: A compound represented by Formula (I) or a salt thereof can be produced by reacting a compound represented by Formula (II) or a salt thereof with a chlorinating agent in the presence of a halogen-based solvent and a metal chloride.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for producing a cyanoimidazole compound useful as an antibacterial agent, that is, a compound represented by the following formula (I) or a salt thereof (hereinafter, also simply referred to as compound (I)).

[0002] [ka] [Background technology]

[0003] Cyanoimidazole compounds are known to have antibacterial activity, as disclosed in Patent Documents 1 and 2. Among them, 5-chloro-4-(3-chloro-4-methylphenyl)-1H-imidazole-2-carbonitrile (hereinafter also simply referred to as compound (Ia)), which is included in compound (I), is disclosed to have excellent antibacterial activity.

[0004] As a method for producing compound (I), a method for producing compound (Ia) is known, which is based on the production method described in Patent Document 3, as disclosed in Production Example 6 of Patent Document 1 and Patent Document 2. Specifically, as shown in the following reaction scheme A, a dehydration reduction reaction and a chlorination reaction simultaneously proceed from an imidazole compound represented by the following formula (III) (hereinafter, also simply referred to as compound (III)), to produce compound (Ia).

[0005] [ka] In addition, in the above-mentioned reaction scheme A, it is known that the starting material, compound (III), can be produced by referring to the production method described in Patent Document 4 (Patent Documents 1 and 2).

[0006] As another known production method, a 2-cyanoimidazole compound is produced from an imidazole compound in which the 2-position of the imidazole is unsubstituted, via a bromination step and a cyanation step (Patent Document 5). [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Publication No. 2021 / 246453 [Patent Document 2] International Publication No. 2021 / 246455 [Patent Document 3] Japanese Patent Application Publication No. 8-225539 [Patent Document 4] Japanese Patent Application Publication No. 8-283243 [Patent Document 5] Japanese Patent Publication No. 3-99065 Summary of the Invention [Problem to be solved by the invention]

[0008] An object of the present invention is to provide a novel, industrially advantageous process for the preparation of compound (I). [Means for solving the problem]

[0009] As a result of intensive research, the present inventors have found that compound (I) can be synthesized by the following production method using raw materials that are easily available and can be produced on an industrial scale. Then, by further examining the reaction conditions, the present invention has been completed.

[0010] That is, the present invention is as follows.

[0011] [1] Formula (I):

[0012] [ka] A method for producing a compound represented by the formula: In the presence of halogenated solvents and metal chlorides Formula (II):

[0013] [ka] or a salt thereof (hereinafter also simply referred to as compound (II)) with a chlorinating agent.

[0014] [2] A method of using compound (I) produced by the production method described in [1] as an antibacterial agent. Effect of the Invention

[0015] The present invention provides an industrially advantageous and novel process for producing compound (I), which is useful as an antibacterial agent, and further enables compound (I) to be produced simply and inexpensively on an industrial scale. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] The present invention will be described in detail below.

[0017] [Method for producing compound (I)] The method for producing compound (I) of the present invention is characterized by a step of reacting compound (II) with a chlorinating agent in the presence of a halogen-based solvent and a metal chloride (hereinafter, also referred to simply as step (a)).

[0018] The salt of the compound represented by formula (I) or formula (II) is not particularly limited as long as it is a pharma- ceutically acceptable salt, and examples thereof include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc., and organic acid salts such as acetate, propionate, tartrate, fumarate, maleate, malate, citrate, methanesulfonate, benzenesulfonate, paratoluenesulfonate, etc. Examples of basic salts include alkali metal salts such as sodium salt, potassium salt, etc., and alkaline earth metal salts such as calcium salt, magnesium salt, etc. The salts of the compounds represented by formula (I) or formula (II) can be prepared by methods known in the art or analogous methods thereto.

[0019] In addition, the chemical structural formula represented by formula (I) may have the following tautomers, and the compound (I) in the present invention may exist as any one of these tautomers or may coexist with each other (including the case where each tautomer coexists in an equilibrium state).

[0020] [ka]

[0021] Compound (II) may also have tautomers, and the compound (II) of the present invention may exist as any one of the tautomers, and may also exist as a combination of the tautomers (including the combination in an equilibrium state).

[0022] Compound (I) may absorb moisture, adsorb water, or become a hydrate by being left in the air or by being recrystallized, and compound (I) also includes such various hydrates, solvates, and polymorphic compounds. In addition, hydrates of compound (I) can be produced by methods known in the art (for example, the methods described in WO 2023 / 106320, etc.) or methods similar thereto.

[0023] Compound (II) can be produced by a method known in the art (for example, the methods described in JP-A-8-225539, JP-A-8-283243, WO 2018 / 154582, JP-A-7-309843, etc.) or a method analogous thereto, or a commercially available product can be used.

[0024] The chlorinating agent used in step (a) is not particularly limited, but for example, chlorine, N-chlorosuccinimide, sulfuryl chloride, sulfur dichloride, 1,3-dichloro-5,5-dimethylhydantoin, trichloroisocyanuric acid, etc. can be used. Among these, from the viewpoint of the yield of the compound of formula (I) obtained in step (a), 1,3-dichloro-5,5-dimethylhydantoin or trichloroisocyanuric acid is preferred, and trichloroisocyanuric acid is more preferred. The chlorinating agent used in step (a) may be one type or two or more types. The amount of the chlorinating agent used in step (a) is not particularly limited, but for example, usually 0.1 to 10 moles, preferably 0.13 to 2 moles, more preferably 0.3 to 2 moles, even more preferably 0.3 to 1.5, and particularly preferably 0.32 to 1.3 moles of the chlorinating agent can be used relative to 1 mole of compound (II). When chlorine is used as the chlorinating agent in step (a), for example, usually 0.1 to 10 moles, preferably 0.13 to 2 moles, and more preferably 1 mole of chlorine can be used relative to 1 mole of compound (II). When N-chlorosuccinimide is used as the chlorinating agent in step (a), for example, usually 0.1 to 10 moles, preferably 0.13 to 2 moles, and more preferably 0.9 moles of N-chlorosuccinimide can be used relative to 1 mole of compound (II). When sulfuryl chloride is used as the chlorinating agent in step (a), for example, usually 0.1 to 10 mol, preferably 0.13 to 2 mol, more preferably 1.3 mol of sulfuryl chloride can be used per mol of compound (II). When sulfur dichloride is used as the chlorinating agent in step (a), for example, usually 0.1 to 10 mol, preferably 0.13 to 2 mol, more preferably 1.5 to 2 mol of sulfur dichloride can be used per mol of compound (II). When 1,3-dichloro-5,5-dimethylhydantoin is used as the chlorinating agent in step (a), for example, usually 0.1 to 10 mol, preferably 0.13 to 2 mol, more preferably 0.5 to 0.75 mol of 1,3-dichloro-5,5-dimethylhydantoin can be used per mol of compound (II). When trichloroisocyanuric acid is used as the chlorinating agent in the step (a), for example, typically 0.1 to 10 mol, preferably 0.13 to 2 mol, and more preferably 0.32 to 0.4 mol of trichloroisocyanuric acid can be used per 1 mol of compound (II).

[0025] The metal chloride used in step (a) is not particularly limited, but aluminum chloride, iron chloride, zinc chloride, tin chloride, lanthanum chloride, copper chloride, and bismuth chloride can be used. Among these, aluminum chloride or iron chloride is preferred, and aluminum chloride is more preferred, from the viewpoint of the yield of the compound of formula (I) obtained in step (a). The metal chloride used in step (a) may be one type or two or more types. The amount of metal chloride used in step (a) is not particularly limited, but for example, typically 0.5 to 10 mol, preferably 0.5 to 3 mol, more preferably 1.5 to 2.5 mol, even more preferably 1.9 to 2 mol, and particularly preferably 2 mol of metal chloride can be used per mol of compound (II).

[0026] The halogenated solvent used in step (a) is not particularly limited, but examples thereof include halogenated chain hydrocarbon solvents (1,2-dichloroethane, dichloromethane, etc.), halogenated aromatic solvents (monochlorobenzene, o-dichlorobenzene, etc.), and mixed solvents thereof. Among these, from the viewpoint of the yield of compound (I) obtained in step (a), halogenated chain hydrocarbon solvents or halogenated aromatic solvents are preferred, 1,2-dichloroethane, dichloromethane, monochlorobenzene or o-dichlorobenzene are more preferred, and 1,2-dichloroethane or dichloromethane are particularly preferred. The amount of the halogenated solvent used is not particularly limited as long as the reaction of each step proceeds, but is, for example, usually 1 to 60 times (V / W), preferably 10 to 40 times (V / W), more preferably 12.5 to 40 times (V / W), even more preferably 15 to 20 times (V / W), and particularly preferably 20 times (V / W) relative to compound (II).

[0027] Regarding the reaction form of step (a), the order of addition of compound (II), chlorinating agent, metal chloride and halogen-based solvent is not particularly limited, and may be added and mixed in any order. Compound (II), chlorinating agent, metal chloride and halogen-based solvent may be added to the reaction system at once or in portions, or may be added continuously. For example, the order of addition may be such that all components are mixed at once, or some components may be added later. Specific examples of such addition include, for example, mixing compound (II) and halogen-based solvent, and adding chlorinating agent and metal chloride thereto in sequence.

[0028] The reaction temperature in step (a) is usually about −15 to 30° C., preferably about −10 to 30° C., and more preferably about 15 to 30° C. The reaction time in step (a) is usually about 1 to 168 hours, preferably about 2 to 120 hours, and more preferably about 20 to 120 hours.

[0029] In step (a), after the reaction of each step is completed, compound (I) can be obtained by carrying out post-treatments such as neutralization, extraction, distillation, removal of solvent, washing, filtration and drying. Compound (I) can be isolated by appropriately selecting one or more of these post-treatments. In addition, compound (I) may be purified by conventional methods such as column chromatography, recrystallization and repulping, if necessary. As the post-treatments and purification methods, extraction, recrystallization, filtration and washing are preferred, and a combination of these is more preferred, from the viewpoint of improving the purity of compound (I).

[0030] According to the method of the present invention, it is possible to produce a highly pure compound (I) that satisfies the standards for use as an active ingredient in pharmaceuticals or veterinary medicines.

[0031] The various components in the method of the present invention can be appropriately selected from the multiple examples and conditions described above, for example, from the examples and conditions in the normal range as well as the examples and conditions in the preferred range, and can be combined with each other.

[0032] Preferred embodiments of the present invention are listed below, but the present invention is not limited to these. [1] A method for producing compound (I), comprising reacting compound (II) with a chlorinating agent in the presence of a halogen-based solvent and a metal chloride. [2] The method according to [1], wherein the chlorinating agent is at least one selected from the group consisting of N-chlorosuccinimide, sulfuryl chloride, sulfur dichloride, 1,3-dichloro-5,5-dimethylhydantoin, and trichloroisocyanuric acid. [3] The manufacturing method according to [1] or [2], characterized in that the metal chloride is at least one selected from the group consisting of aluminum chloride, iron chloride, zinc chloride, tin chloride, lanthanum chloride, copper chloride, and bismuth chloride. [4] The method according to [1], wherein the chlorinating agent is at least one selected from the group consisting of N-chlorosuccinimide, sulfuryl chloride, sulfur dichloride, 1,3-dichloro-5,5-dimethylhydantoin, and trichloroisocyanuric acid, and the metal chloride is at least one selected from the group consisting of aluminum chloride, iron chloride, zinc chloride, tin chloride, lanthanum chloride, copper chloride, and bismuth chloride. [5] The method according to any one of [1] to [4], wherein the halogenated solvent is at least one selected from the group consisting of halogenated chain hydrocarbon solvents and halogenated aromatic solvents. [6] The method according to any one of [1] to [4], wherein the halogen-based solvent is at least one selected from the group consisting of 1,2-dichloroethane, dichloromethane, monochlorobenzene, and o-dichlorobenzene. [7] A method for using compound (I), produced by the production method according to any one of [1] to [6], as an antibacterial agent. EXAMPLES

[0033] Next, experimental examples of the present invention will be described, but the present invention is not to be construed as being limited thereto. The structure of compound (IIa) used in each of the experimental examples of the present invention is shown below. :

[0034] [ka]

[0035] The HPLC analysis conditions in this example are as follows. (1) HPLC analysis conditions for Experimental Examples 1 to 6 Equipment used: Shimadzu Corporation 20A series Column: Nacalai Tesque COSMOSIL 5C18AR-II (4.6ID x 250mm Detection: UV detector (254 nm) Column temperature: 40℃ ·Flow rate: 1.0mL / min Mobile phase: Conducted under isocratic conditions (acetonitrile / water / phosphoric acid = 2000 / 1000 / 1 (v / v / v)).

[0036] (2) HPLC analysis conditions for Experimental Examples 7 to 12 ·Equipment used: Agilent 1260 Infinity Column: SunShell C18 (2.6 μm, 2.1 × 100 mm) manufactured by Chromanik Technologies Co., Ltd. Detection: UV detector (254 nm) Column temperature: 40℃ ·Flow rate: 0.72mL / min Mobile phase: Conducted under gradient conditions (liquid A: 0.1% formic acid aqueous solution, and liquid B: acetonitrile). The gradient conditions are as follows:

[0037] [Table 1]

[0038] In this specification, room temperature means a temperature of about 15 to 30°C.

[0039] [Experimental Example 1] Synthesis of compound (Ia) A mixture of 2.0 g of compound (IIa) and 25 mL of dichloromethane was ice-cooled, 2.45 g of aluminum chloride was added, and the mixture was stirred for 10 minutes, after which 1.61 g of sulfuryl chloride was added dropwise. After the dropwise addition, the mixture was stirred at room temperature for 20 hours, and then the reaction was checked by HPLC, and compound (Ia) was produced at 63.3 area %. The reaction solution was distilled under reduced pressure to obtain a solid, 2.34 g of which was dissolved in 6.0 mL of isopropyl alcohol, and 6.0 mL of water was added to obtain a slurry. The obtained slurry was filtered and air-dried to obtain 1.65 g of compound (Ia) (purity: 78.4 area %, yield: 71.2%).

[0040] [Experimental Example 2] Synthesis of compound (Ia) A mixture of 1.0 g of compound (IIa) and 10 mL of dichloromethane was cooled on ice, 1.23 g of aluminum chloride was added, and the mixture was stirred for 10 minutes, after which 0.54 g of 1,3-dichloro-5,5-dimethylhydantoin was added. After the addition was completed, the mixture was stirred at room temperature for 20 hours, and then the reaction was checked by HPLC, and compound (Ia) was produced at 34.3 area %.

[0041] [Experimental Example 3] Synthesis of compound (Ia) A mixture of 1.0 g of compound (IIa) and 10 mL of 1,2-dichloroethane was cooled on ice, and the reaction vessel containing the mixture was shielded from light with aluminum foil. 1.23 g of aluminum chloride was added to the reaction vessel and stirred for 10 minutes, after which 0.43 g of trichloroisocyanuric acid was added. After the addition was completed, the mixture was stirred at room temperature for 20 hours, and then the reaction was checked by HPLC, and compound (Ia) was produced at 66.0 area %.

[0042] [Experimental Example 4] Synthesis of compound (Ia) A mixture of 0.5 g of compound (IIa) and 20 mL of 1,2-dichloroethane was cooled on ice, 0.61 g of aluminum chloride was added, and the mixture was stirred for 10 minutes, after which 0.47 g of sulfur dichloride was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 20 hours, and then the reaction was checked by HPLC, and compound (Ia) was produced at 66.8 area %.

[0043] [Experimental Example 5] Synthesis of compound (Ia) A mixture of 2.0 g of compound (IIa) and 40 mL of 1,2-dichloroethane was cooled on ice, 2.98 g of iron chloride (III) was added, and the mixture was stirred for 30 minutes, after which 1.42 g of sulfur dichloride was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 20 hours, and then the reaction was checked by HPLC, and compound (Ia) was produced at 57.3 area %.

[0044] [Experimental Example 6] Synthesis of compound (Ia) A mixture of 2.0 g of compound (IIa) and 20 mL of 1,2-dichloroethane was cooled on ice, 2.98 g of iron chloride (III) was added, and the mixture was stirred for 20 minutes, after which 1.36 g of 1,3-dichloro-5,5-dimethylhydantoin was added dropwise. After the dropwise addition, the mixture was stirred at room temperature for 2 hours, and then the reaction was checked by HPLC, and compound (Ia) was produced at 31.9 area %.

[0045] [Experimental Example 7] Synthesis of compound (Ia) To a mixture of 1.0 g of compound (IIa) and 20 mL of dichloromethane, 1.23 g of aluminum chloride was added at room temperature and stirred for 3 hours, and then 0.34 g of trichloroisocyanuric acid was added at the same temperature. After the addition was completed and the mixture was stirred at room temperature for 144 hours, the reaction was checked by HPLC, and compound (Ia) was produced at 66.4 area %.

[0046] [Experimental Example 8] Synthesis of compound (Ia) To a mixture of 1.0 g of compound (IIa) and 20 mL of dichloromethane, 1.23 g of aluminum chloride was added at room temperature and stirred for 3 hours, and then 0.61 g of N-chlorosuccinimide was added at the same temperature. After the addition was completed and the mixture was stirred at room temperature for 144 hours, the reaction was checked by HPLC, and compound (Ia) was produced at 40.1 area %.

[0047] [Experimental Example 9] Synthesis of compound (Ia) To a mixture of 1.0 g of compound (IIa) and 20 mL of dichloromethane, 1.23 g of aluminum chloride was added at room temperature and stirred for 3 hours, and then 0.45 g of 1,3-dichloro-5,5-dimethylhydantoin was added at the same temperature. After stirring at room temperature for 144 hours after the addition, the reaction was checked by HPLC, and compound (Ia) was produced at 58.8 area %.

[0048] [Experimental Example 10] Synthesis of compound (Ia) To a mixture of 1.0 g of compound (IIa) and 20 mL of dichloromethane, 1.23 g of aluminum chloride was added at room temperature and stirred for 3 hours, and then 2.5 mL of chlorine gas solution (13 g / 100 mL dichloromethane solution) was added dropwise at the same temperature. After the dropwise addition, the mixture was stirred at room temperature for 144 hours, and the reaction was checked by HPLC, and compound (Ia) was produced at 36.8 area %.

[0049] [Experimental Example 11] Synthesis of compound (Ia) To a mixture of 1.0 g of compound (IIa) and 20 mL of dichloromethane, 1.23 g of aluminum chloride was added at room temperature and stirred for 2 hours, and then 0.45 g of 1,3-dichloro-5,5-dimethylhydantoin was added at the same temperature. After the addition was completed and the mixture was stirred at room temperature for 120 hours, the reaction was checked by HPLC, and compound (Ia) was produced at 39.6 area %.

[0050] [Experimental Example 12] Synthesis of compound (Ia) To a mixture of 1.0 g of compound (IIa) and 20 mL of o-dichlorobenzene, 1.23 g of aluminum chloride was added at room temperature and stirred for 2 hours, and then 0.45 g of 1,3-dichloro-5,5-dimethylhydantoin was added at the same temperature. After stirring at room temperature for 120 hours after the addition, the reaction was checked by HPLC, and compound (Ia) was produced at 34.0 area %.

Claims

1. Formula (I): 【Chemistry 1】 A method for producing a compound represented by the formula: In the presence of halogenated solvents and metal chlorides Formula (II): 【Chemistry 2】 or a salt thereof with a chlorinating agent.

2. The method according to claim 1, wherein the chlorinating agent is at least one selected from the group consisting of chlorine, N-chlorosuccinimide, sulfuryl chloride, sulfur dichloride, 1,3-dichloro-5,5-dimethylhydantoin, and trichloroisocyanuric acid.

3. 2. The method according to claim 1, wherein the metal chloride is at least one selected from the group consisting of aluminum chloride, iron chloride, zinc chloride, tin chloride, lanthanum chloride, copper chloride, and bismuth chloride.

4. The method according to claim 1, wherein the chlorinating agent is at least one selected from the group consisting of chlorine, N-chlorosuccinimide, sulfuryl chloride, sulfur dichloride, 1,3-dichloro-5,5-dimethylhydantoin, and trichloroisocyanuric acid, and the metal chloride is at least one selected from the group consisting of aluminum chloride, iron chloride, zinc chloride, tin chloride, lanthanum chloride, copper chloride, and bismuth chloride.

5. 2. The method according to claim 1, wherein the halogenated solvent is at least one selected from the group consisting of halogenated chain hydrocarbon solvents and halogenated aromatic solvents.

6. The method according to any one of claims 1 to 4, wherein the halogen-based solvent is at least one selected from the group consisting of 1,2-dichloroethane, dichloromethane, monochlorobenzene, and o-dichlorobenzene.

7. A method for using the compound represented by formula (I) or a salt thereof, produced by the production method according to claim 1, as an antibacterial agent.

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