Method for producing amenamevir, compound used in that production method, and production method and use of that compound

Abstract

To provide new technical means for efficiently carrying out the mass synthesis of amenamevir.SOLUTION: A method for producing a compound represented by formula (VII) comprises a step of reacting a compound represented by formula (V) with a compound represented by formula (VI) in the presence of a base so as to obtain a compound represented by formula (VII).SELECTED DRAWING: None

Description

[Technical field]

[0001] The present disclosure relates to methods for producing amenamevir, compounds used in the methods, and methods for making and using the compounds. [Background technology]

[0002] Amenamevir (a compound represented by formula (VII)), an anti-herpes virus drug, is thought to suppress the proliferation of herpes viruses at an early stage by directly inhibiting the activity of the helicase-primase complex, which is necessary for the cleavage of double-stranded DNA and the synthesis of RNA primers, which are the early stages of varicella-zoster virus replication (Patent Documents 1 and 2). Amenamevir is used, for example, to treat shingles. [ka]

[0003] Since amenamevir is considered to have little effect on renal function, it can be used for shingles patients with reduced renal function, such as elderly people and patients with renal dysfunction. In particular, the number of shingles patients in Japan is on the rise, and there is an increasing demand for a method for industrially producing amenamevir.

[0004] Patent Document 3 discloses a method for producing amenamevir in four steps by reacting ethyl bromoacetate as a starting material with 2,6-dimethylaniline, tetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide, and [4-(1,2,4-oxadiazol-3-yl)]aniline. [ka]

[0005] The manufacturing method disclosed in Patent Document 3 uses ethyl bromoacetate as a starting material, and therefore includes a deprotection step of the ethyl ester. In addition, in the final condensation reaction of the acid amide bond, it is necessary to use expensive 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC) as a carbodiimide condensing agent in order to increase the reactivity of the aniline having an electron-withdrawing substituent. The need for a deprotection step and / or the need for expensive reagents makes it unsuitable for mass synthesis of amenamevir.

[0006] In addition, Patent Document 4 discloses a method for producing amenamevir that utilizes the Ugi reaction to perform multi-step reactions in one pot (Patent Document 4). The Ugi reaction is generally considered to be a fast reaction with a good yield (Non-Patent Document 1). [ka]

[0007] The production method disclosed in Patent Document 4 is also not efficient in terms of reaction time, etc., and is not suitable for mass synthesis of amenamevir. In addition, Patent Document 4 shows the spectral data of the produced amenamevir, but does not disclose the purity or yield. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] Patent No. 3623228 [Patent Document 2] Patent No. 4549974 [Patent Document 3] Patent No. 4832093 [Patent Document 4] International Publication No. 2020 / 038812 [Non-patent literature]

[0009] [Non-Patent Document 1] ChemicalReviews,2006,106,17-89 Summary of the Invention

[0010] One objective of the present disclosure is to provide a new technical means for efficiently carrying out the large-scale synthesis of amenamevir.

[0011] As a result of intensive research, the present inventors have found that by using a specific oxadiazole derivative as a production raw material, it is possible to efficiently synthesize amenamevir on a large scale. The present disclosure is based on this finding.

[0012] According to one embodiment of the present disclosure, Formula (VII): [ka] A method for producing a compound represented by the formula: Formula (V): [ka] and compounds represented by formula (VI): [ka] (wherein LG is a leaving group). in the presence of a base to obtain a compound represented by formula (VII). A method is provided, comprising:

[0013] According to one embodiment of the present disclosure, there is provided a method for producing a compound represented by formula (VII), comprising the steps of: Formula (III): [ka] (wherein X is a halogen) and 2,6-dimethylaniline in the presence of a base to obtain the compound represented by formula (V).

[0014] According to one embodiment of the present disclosure, Formula (V): [ka] The compound is represented by the formula:

[0015] According to one embodiment of the present disclosure, Formula (III): [ka] (wherein X is a halogen) The compound is represented by the formula:

[0016] According to one embodiment of the present disclosure, Formula (VII): [ka] The present invention provides a use of a compound according to formula (III) or formula (V) for the preparation of a compound represented by the formula:

[0017] The present disclosure is advantageous in efficiently carrying out the large-scale synthesis of amenamevir. According to the present disclosure, a series of intermediate compounds can be obtained as crystals or solids, which is particularly advantageous in efficiently carrying out a synthesis reaction with simple post-treatment.

[0018] According to one embodiment of the present disclosure, amenamevir (a compound represented by formula (VII)) can be efficiently produced via a compound represented by formula (III) and / or a compound represented by formula (V). Each reaction will be described in detail below.

[0019] [ka]

[0020] [Production of the compound represented by formula (III)] According to one embodiment of the present disclosure, a step (also referred to as "Step A" in the present disclosure) of reacting a compound represented by formula (I) ([4-(1,2,4-oxadiazol-3-yl)]aniline) with a compound represented by formula (II) (α-halogenoacetic acid halogenide) (wherein X and Y are each independently halogen) to obtain a compound represented by formula (III) (N-halogenoacetyl-[4-(1,2,4-oxadiazol-3-yl)]aniline) (wherein X is halogen) is carried out. Thus, according to one embodiment of the present disclosure, the method for producing the compound represented by formula (VII) above includes a step of obtaining a compound represented by formula (V) above by Step A. Step A typically includes an acid amidation reaction.

[0021] [ka]

[0022] The compound of formula (I) used in step A: [ka] The compound represented by formula (I), [4-(1,2,4-oxadiazol-3-yl)]aniline, may be synthesized by a known method (e.g., the method described in Patent Document 4 and JP-A-49-127973) or may be commercially available (e.g., available from FUJIFILM Wako Pure Chemical Industries, Ltd.). The amount of the compound represented by formula (I) used may be determined in consideration of the amount of the compound represented by formula (II) used, which will be described later.

[0023] The compound of formula (II) used in step A: [ka] (wherein X and Y are each independently a halogen). The compound represented by the formula (II) is an α-halogenoacetic acid halogenide. X and Y in the formula (II) may be any halogen, and may be the same or different. Examples of halogen include fluorine, chlorine, bromine, and iodine. When X and Y are different halogens, examples of the halogen combination (X / Y) include fluorine / iodine, chlorine / bromine, chlorine / iodine, bromine / chlorine, bromine / iodine, iodine / chlorine, and iodine / bromine. Specific examples of the compound represented by the formula (II) include, but are not limited to, chloroacetyl chloride, bromoacetyl chloride, bromoacetyl bromide, and iodoacetyl chloride.

[0024] The amount of the compound represented by formula (II) used in step A is not particularly limited as long as the reaction with the compound represented by formula (I) proceeds, and can be appropriately adjusted by a person skilled in the art. The amount of the compound represented by formula (II) used in step A may be, for example, about 0.1 to about 10 mol, preferably about 0.3 to about 5 mol, and more preferably about 0.5 to about 2 mol, based on 1 mol of the compound represented by formula (I).

[0025] Step A may be performed in the presence of a solvent or in the absence of a solvent. When step A is performed in the presence of a solvent, the solvent used is not particularly limited as long as the acid amidation reaction can proceed, and may be a polar solvent or a solvent with low polarity (including a non-polar solvent). In this case, for example, the solvent may be tetrahydrofuran (THF), diethyl ether, dimethoxyethane, dioxane, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dichloromethane, chloroform, 1,2-dichloroethane, toluene, hexane, acetone, or other solvents that can be used in the art, or a mixed solvent of two or more of these. In this case, the amount of the solvent used is not particularly limited as long as the reaction proceeds, and a person skilled in the art may appropriately adjust the amount of the compound represented by formula (I) and / or the compound represented by formula (I) in consideration of the amount of the compound.

[0026] The reaction temperature in step A is not particularly limited as long as the acid amidation reaction can proceed. In one embodiment of the present disclosure, the reaction temperature in step A may be, for example, about -78 to about 100°C, preferably about -40 to about 70°C, and more preferably about 0 to about 50°C. Such a reaction temperature may be advantageous in terms of improving the yield, suppressing by-products, and / or economic efficiency.

[0027] The reaction time of step A is not particularly limited as long as the compound represented by formula (III) can be obtained. In one embodiment of the present disclosure, the reaction time may be, for example, about 0.5 to about 48 hours, preferably about 1 to about 24 hours, more preferably about 1 to about 10 hours. Such a reaction time may be advantageous in terms of improving the yield, suppressing by-products, and economic efficiency.

[0028] In step A, an acid or a base may or may not be present. When an acid or a base is present in step A, an acid that can be used in the art (e.g., inorganic acids such as hydrochloric acid and nitric acid; organic acids such as formic acid, acetic acid, citric acid, and paratoluenesulfonic acid; combinations of two or more of these) or a base (e.g., inorganic bases such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, and cesium carbonate; organic bases such as sodium acetate, potassium acetate, triethylamine, diisopropylethylamine, and pyridine; combinations of two or more of these) may be used. When an acid or a base is present in step A, the amount of the acid or base used is not particularly limited, and may be, for example, about 0.1 to about 10 mol, preferably about 0.3 to about 8 mol, and more preferably about 0.6 to about 4 mol based on 1 mol of the compound represented by formula (I). When an acid or a base is present in step A, the amount of the acid or base used may be, for example, about 0.1 to about 10 mol, preferably about 0.3 to about 8 mol, and more preferably about 0.6 to about 4 mol, based on 1 mol of the compound represented by formula (II).

[0029] X (halogen) in the compound represented by formula (III) obtained in step A may be various depending on X (halogen) in the compound represented by formula (II) used, and examples thereof include fluorine, chlorine, bromine, and iodine. In one embodiment in which X in the compound represented by formula (III) is a halogen other than iodine, X (excluding iodine) in the compound represented by formula (III) may be substituted with iodine by an iodide salt.

[0030] [ka]

[0031] Examples of the iodide salt used in this case include lithium iodide, sodium iodide, potassium iodide, magnesium iodide, calcium iodide, and silver iodide. The amount of the iodide salt used in this case can be appropriately adjusted by a person skilled in the art, taking into consideration, for example, the amount of the compound represented by formula (III) (where X is not iodine), and may be, for example, about 0.1 to about 10 mol, preferably about 0.3 to about 5 mol, and more preferably about 0.5 to about 3 mol, based on 1 mol of the compound represented by formula (III) (where X is not iodine). The iodide salt may be mixed with the compound represented by formula (I) and the compound represented by formula (II) (where X is not iodine), or may be mixed after the compound represented by formula (III) (where X is not iodine) is obtained. When the iodide salt is mixed after the compound represented by formula (III) (wherein X is not iodine) is obtained, the solvent, reaction time, reaction temperature, etc. used can be appropriately adjusted by a person skilled in the art, and may be, for example, the same as those described above in step A.

[0032] The compound represented by formula (III) obtained in step A may be purified, crystallized, or solidified by any method. For example, the compound represented by formula (III) may be obtained as a crystal or solid by removing insoluble matters remaining in the reaction system by filtration or the like, adding a desired solvent (e.g., water) to the reaction system, and adjusting the temperature to a desired temperature (e.g., about -78 to about 20°C, preferably about -20 to about 15°C, more preferably about -5 to about 10°C). In this way, the compound represented by formula (III) can be obtained as a crystal or solid, which is advantageous in that the compound represented by formula (VII) and / or its intermediate compound (e.g., the compound represented by formula (V) described later) can be produced with high purity. In addition, the compound represented by formula (III) can be easily obtained as a crystal or solid using a solvent such as water, which is particularly advantageous in carrying out a synthesis reaction efficiently by simple post-treatment in industrially synthesizing a large amount of the compound represented by formula (VII) and / or its intermediate compound (e.g., the compound represented by formula (V) described later).

[0033] [Production of the compound represented by formula (V)] According to one embodiment of the present disclosure, a step (also referred to as "Step B" in the present disclosure) is carried out in which a compound represented by formula (III) (N-halogenoacetyl-[4-(1,2,4-oxadiazol-3-yl)]aniline) (wherein X is halogen) and a compound represented by formula (IV) (2,6-dimethylaniline) are reacted in the presence of a base to obtain a compound represented by formula (V) (N-(2,6-dimethylphenylamino)acetyl-[4-(1,2,4-oxadiazol-3-yl)]aniline). Thus, according to one embodiment of the present disclosure, the method for producing the compound represented by formula (VII) above includes a step of obtaining the compound represented by formula (V) above by Step B. Step B typically includes an amination reaction.

[0034] [ka]

[0035] The compound represented by formula (III) used in step B may be one obtained by step A. In this case, the compound represented by formula (III) obtained in step A may be isolated and used in step B, or may be used in step B immediately after step A without being isolated (i.e., step A and step B may be carried out in one reaction system (one-pot)). Thus, according to a preferred embodiment of the present disclosure, the method for producing the compound represented by formula (VII) above includes a step of obtaining the compound represented by formula (III) above by step A, and a step of obtaining the compound represented by formula (V) above by step B.

[0036] The 2,6-dimethylaniline (compound represented by formula (IV)) used in step B may be synthesized by a known method (for example, the method described in International Atomic Energy agency, IAEA-TECDOC-1612, 159-170, 2009) or may be commercially available (for example, available from Fujifilm Wako Pure Chemical Industries, Tokyo Chemical Industry Co., Ltd., Kanto Chemical Co., Ltd.). The amount of 2,6-dimethylaniline used in step B is not particularly limited as long as the reaction with the compound represented by formula (III) proceeds, and can be appropriately adjusted by a person skilled in the art. The amount of 2,6-dimethylaniline used in step B may be, for example, about 0.1 to about 10 mol, preferably about 0.3 to about 5 mol, more preferably about 0.5 to about 3 mol, based on 1 mol of the compound represented by formula (III).

[0037] The base used in step B is not particularly limited as long as the amination reaction can proceed. The base used in step B is not limited to these, but may be, for example, an inorganic base such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, or cesium carbonate; an organic base such as sodium acetate, potassium acetate, triethylamine, diisopropylethylamine, or pyridine; or a combination of two or more of these. The base used in step B is preferably an inorganic base or sodium acetate. The use of an inorganic base or sodium acetate in step B is advantageous in that the reaction can be carried out more efficiently. The amount of the base used in step B is not particularly limited as long as the amination reaction proceeds, and can be appropriately adjusted by a person skilled in the art. The amount of the base used in step B may be, for example, about 0.1 to about 10 mol, preferably about 0.3 to about 5 mol, and more preferably about 0.5 to about 3 mol, based on 1 mol of the compound represented by formula (III). The amount of the base used in step B may be, for example, about 0.1 to about 10 mol, preferably about 0.3 to about 5 mol, and more preferably about 0.5 to about 3 mol, based on 1 mol of the compound represented by formula (IV).

[0038] Step B is preferably carried out in the presence of a solvent. The solvent used in step B is not particularly limited as long as the amination reaction can proceed, and may be a polar solvent or a solvent with low polarity (including a non-polar solvent). The solvent used in step B is not limited to these, but examples thereof include solvents that can be used in the art, such as tetrahydrofuran (THF), diethyl ether, dimethoxyethane, dioxane, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dichloromethane, chloroform, 1,2-dichloroethane, toluene, hexane, and acetone, and mixed solvents of two or more of these. The amount of the solvent used in step B is not particularly limited as long as the amination reaction proceeds, and a person skilled in the art can appropriately adjust the amount of the solvent in consideration of the amount of the compound represented by formula (III) and / or the compound represented by formula (IV).

[0039] The reaction temperature in step B is not particularly limited as long as the amination reaction can proceed. In one embodiment of the present disclosure, the reaction temperature in step B may be, for example, about -78 to about 100°C, preferably about -20 to about 80°C, and more preferably about 0 to about 60°C. Such a reaction temperature may be advantageous in terms of improving the yield, suppressing by-products, and / or economic efficiency.

[0040] The reaction time of step B is not particularly limited as long as the compound represented by formula (V) can be obtained. In one embodiment of the present disclosure, the reaction time may be, for example, about 0.5 to about 48 hours, preferably about 1 to about 24 hours, more preferably about 1 to about 10 hours. Such a reaction time may be advantageous in terms of improving the yield, suppressing by-products, and economic efficiency.

[0041] In one embodiment where X in the compound represented by formula (III) used in step B is not iodine, step B may be carried out in the presence of an iodide salt. Examples of the iodide salt used in this case include those listed in step A. The amount of the iodide salt used in this case may be, for example, about 0.1 to about 10 mol, preferably about 0.3 to about 5 mol, and more preferably about 0.5 to about 3 mol, based on 1 mol of the compound represented by formula (III). When step B is carried out subsequent to step A without isolating the compound represented by formula (III) obtained in step A, the amount of the iodide salt used may be, for example, about 0.1 to about 10 mol, preferably about 0.3 to about 5 mol, and more preferably about 0.5 to about 3 mol, based on 1 mol of the compound represented by formula (I).

[0042] The compound represented by formula (V) obtained in step B may be purified by any method, or may be crystallized or solidified. For example, the insoluble matter remaining in the reaction system is removed by filtration or the like, a desired solvent (e.g., water) is added to the reaction system, and the desired temperature (e.g., about -78 to about 20°C, preferably about -20 to about 15°C, more preferably about -5 to about 10°C) is added to obtain the compound represented by formula (V) as a crystal or solid. In this way, the fact that the compound represented by formula (V) can be obtained as a crystal or solid is advantageous in that the compound represented by formula (VII) can be produced with high purity. In addition, the fact that the compound represented by formula (V) can be easily obtained as a crystal or solid using a solvent such as water is particularly advantageous in carrying out the synthesis reaction efficiently by simple post-treatment in industrially synthesizing the compound represented by formula (VII) on a large scale.

[0043] [Production of the compound represented by formula (VII)] According to one embodiment of the present disclosure, a compound represented by formula (V) (N-(2,6-dimethylphenylamino)acetyl-[4-(1,2,4-oxadiazol-3-yl)]aniline) and a compound represented by formula (VI) (e.g., tetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide) (LG is a leaving group) are reacted in the presence of a base to obtain a compound represented by formula (VII) (amenamevir) (also referred to as "Step C" in the present disclosure). Step C typically involves an acid amidation reaction.

[0044] [ka]

[0045] The compound represented by formula (V) used in step C may be, for example, the compound obtained in step B. In this case, the compound represented by formula (V) obtained in step B may be isolated and used in step C, or may be used in step B and then step C without being isolated (i.e., step B and step C may be carried out in one pot).

[0046] The LG (leaving group) of the compound represented by formula (VI) used in step C is not particularly limited as long as it can react with the compound represented by formula (V), and examples thereof include a hydroxy group; a halogen atom such as fluorine, chlorine, bromine, or iodine; an alkylsulfonyloxy group such as methanesulfonyloxy group or ethanesulfonyloxy group; a haloalkylsulfonyloxy group such as trifluoromethanesulfonyloxy group; an arylsulfonyloxy group such as benzenesulfonyloxy group, p-toluenesulfonyloxy group, p-nitrobenzenesulfonyloxy group, or o-nitrobenzenesulfonyloxy group; etc. The leaving group is preferably a hydroxy group or a halogen atom, more preferably a hydroxy group, chlorine, bromine, or iodine, and even more preferably a hydroxy group or chlorine.

[0047] When LG of the compound represented by formula (VI) used in step C is a hydroxy group or the like, it may be substituted with a more reactive group (e.g., a halogen atom). A person skilled in the art can appropriately carry out the method of substituting the leaving group by referring to the technical common sense in the art. For example, the leaving group can be substituted with chlorine or bromine by mixing the compound represented by formula (VI) (LG=hydroxy group), thionyl chloride, thionyl bromide, etc., and, if necessary, a base (e.g., an inorganic base such as potassium carbonate; an organic base such as pyridine) in a desired solvent (e.g., tetrahydrofuran, etc.) and reacting at a desired temperature (e.g., about 20 to about 100° C., preferably about 40 to about 60° C.) for a desired time (e.g., about 0.5 to about 12 hours, preferably about 0.5 to about 4 hours).

[0048] The amount of the compound represented by formula (VI) used in step C is not particularly limited as long as the reaction with the compound represented by formula (V) proceeds, and can be appropriately adjusted by a person skilled in the art. The amount of the compound represented by formula (VI) used in step C may be, for example, about 0.1 to about 5 mol, preferably about 0.3 to about 3 mol, and more preferably about 0.5 to about 2 mol, based on 1 mol of the compound represented by formula (V).

[0049] The base used in step C is not particularly limited as long as the acid amidation reaction can proceed. The base used in step C is not limited to these, but may be, for example, an inorganic base such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, or cesium carbonate; an organic base such as sodium acetate, potassium acetate, triethylamine, diisopropylethylamine, or pyridine; or a combination of two or more of these. The base used in step C is preferably an organic base, more preferably pyridine. The amount of the base used in step C is not particularly limited as long as the acid amidation reaction proceeds, and can be appropriately adjusted by a person skilled in the art. The amount of the base used in step C may be, for example, about 0.1 to about 15 mol, preferably about 0.5 to about 10 mol, and more preferably about 1 to about 8 mol, based on 1 mol of the compound represented by formula (V). The amount of the base used in step C may be, for example, about 0.1 to about 15 mol, preferably about 0.5 to about 10 mol, and more preferably about 1 to about 8 mol, based on 1 mol of the compound represented by formula (VI).

[0050] The solvent used in step C is not particularly limited as long as the acid amidation reaction can proceed, and may be a polar solvent or a solvent with low polarity (including a non-polar solvent). The solvent used in step C is not limited to these, but examples thereof include tetrahydrofuran (THF), diethyl ether, dimethoxyethane, dioxane, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dichloromethane, chloroform, 1,2-dichloroethane, toluene, hexane, acetone, and other solvents that can be used in the art, and mixed solvents of two or more of these. The amount of the solvent used in step C is not particularly limited as long as the reaction proceeds, and a person skilled in the art can appropriately adjust the amount of the solvent in consideration of the amount of the compound represented by formula (V) and / or the compound represented by formula (VI).

[0051] The reaction temperature in step C is not particularly limited as long as the acid amidation reaction can proceed. In one embodiment of the present disclosure, the reaction temperature in step C may be, for example, about -78 to about 100°C, preferably about -40 to about 80°C, and more preferably about 0 to about 70°C. Such a reaction temperature may be advantageous in terms of improving the yield, suppressing by-products, and / or economic efficiency.

[0052] The reaction time of step C is not particularly limited as long as the compound represented by formula (VII) can be obtained. In one embodiment of the present disclosure, the reaction time may be, for example, about 0.5 to about 48 hours, preferably about 1 to about 24 hours, more preferably about 1 to about 10 hours. Such a reaction time may be advantageous in terms of improving the yield, suppressing by-products, economic efficiency, etc.

[0053] According to a preferred embodiment of the present disclosure, the method for producing a compound represented by formula (VII) includes the step of obtaining a compound represented by formula (V) by step B, and the step of obtaining a compound represented by formula (VII) by step C.

[0054] In a more preferred embodiment of the present disclosure, the method for producing the compound represented by formula (VII) includes the steps of obtaining a compound represented by formula (III) by step A, obtaining a compound represented by formula (V) by step B, and obtaining a compound represented by formula (VII) by step C.

[0055] According to another preferred embodiment of the present disclosure, in the method for producing the compound represented by formula (VII), the step of obtaining the compound represented by formula (III) (step A) and the step of obtaining the compound represented by formula (V) (step B) are carried out in one reaction system. Carrying out step A and step B in one pot is particularly advantageous in terms of efficiently carrying out the synthesis reaction with simple post-treatment in industrially synthesizing the compound represented by formula (VII) on a large scale.

[0056] [Intermediate compound: Compound represented by formula (III)] According to another embodiment of the present disclosure, the compound of formula (III): [ka] (wherein X is a halogen) The compound represented by formula (III) can be advantageously used as a production intermediate (intermediate compound) for the compound represented by formula (V) and / or the compound represented by formula (VII), as described above.

[0057] According to another embodiment of the present disclosure, the compound of formula (III): [ka] (wherein X is a halogen) A method for producing a compound represented by the formula: Formula (I): [ka] and compounds represented by formula (II): [ka] (wherein X and Y are each independently a halogen). to obtain a compound represented by formula (III) (i.e., the above step A). A method is provided, comprising:

[0058] Those skilled in the art can easily obtain a compound represented by formula (VII): by using the compound represented by formula (III) (obtained in step A) and carrying out a method including step B, for example. [ka] It will be understood that the compound represented by formula (III) can be efficiently obtained as a crystal or solid as described above, and therefore can be advantageously used as a synthetic reagent or a synthetic intermediate for the compound represented by formula (VII).

[0059] Therefore, according to another embodiment of the present disclosure, a reagent is provided that contains the compound represented by the above formula (III). According to another preferred embodiment of the present disclosure, a reagent is provided that contains the compound represented by the above formula (III) for producing the compound represented by the above formula (VII).

[0060] According to another embodiment of the present disclosure, there is provided a use of a compound represented by the above formula (III) for the production of a compound represented by the above formula (VII).

[0061] [Intermediate compound: Compound represented by formula (V)] In another embodiment of the present disclosure, Formula (V): [ka] The compound represented by the formula (V) can be advantageously used as an intermediate for producing the compound represented by the formula (VII) as described above.

[0062] In another embodiment of the present disclosure, the compound of formula (V): [ka] A method for producing a compound represented by the formula: Formula (III): [ka] (wherein X is a halogen) and 2,6-dimethylaniline in the presence of a base to obtain a compound represented by formula (V) (i.e., the above step B). As described above, the compound represented by formula (III) can be efficiently obtained as a crystal or solid, and therefore can be advantageously used as a synthetic reagent or a production intermediate for the compound represented by formula (V) or formula (VII).

[0063] According to another preferred embodiment of the present disclosure, the method for producing the compound represented by the above formula (V) comprises the step of obtaining the compound represented by the above formula (III) by the above step A.

[0064] According to another preferred embodiment of the present disclosure, the step of obtaining the compound represented by formula (III) (step A) and the step of obtaining the compound represented by formula (V) (step B) are carried out in one reaction system. Carrying out step A and step B in one pot is particularly advantageous in carrying out the synthesis reaction efficiently with simple post-treatment in industrially synthesizing the compound represented by formula (VII) and / or its intermediate compound (e.g., the compound represented by formula (V)) on a large scale.

[0065] Those skilled in the art can easily obtain a compound represented by formula (VII): by using a compound represented by formula (V) (e.g., obtained in step B) and carrying out, for example, the method of step C above or any method (e.g., with reference to the method described in Patent Document 1): [ka] It will be appreciated that compounds of the formula:

[0066] Therefore, according to another embodiment of the present disclosure, there is provided a reagent comprising the compound represented by the above formula (V). According to another preferred embodiment of the present disclosure, there is provided a reagent comprising the compound represented by the above formula (V) for producing the compound represented by the above formula (VII).

[0067] According to another embodiment of the present disclosure, there is provided a use of a compound represented by the above formula (V) for the production of a compound represented by the above formula (VII).

[0068] According to one embodiment of the present disclosure, the following is provided. [1] Formula (VII): [ka] A method for producing a compound represented by the formula: Formula (V): [ka] and compounds represented by formula (VI): [ka] (wherein LG is a leaving group). in the presence of a base to obtain a compound represented by formula (VII). A method comprising: [2] Formula (V): [ka] A method for producing a compound represented by the formula: Formula (III): [ka] (wherein X is a halogen) and 2,6-dimethylaniline in the presence of a base to obtain a compound represented by formula (V). A method comprising: [3] The method according to [1], wherein the base is an organic base. [4] The method according to [1], which comprises the step of obtaining the compound represented by (V) by the method according to [2]. [5] Formula (III): [ka] (wherein X is a halogen) A method for producing a compound represented by the formula: Formula (I): [ka] and compounds represented by formula (II): [ka] (wherein X and Y are each independently a halogen). to obtain a compound represented by formula (III). A method comprising: The method according to [2], comprising the step of obtaining a compound represented by the above formula (III) by the method according to [6] or [5]. The method according to [1], comprising the step of obtaining a compound represented by the above formula (V) by the method according to [7] or [6]. [8] The method according to [6] or [7], wherein the step of obtaining the compound represented by formula (III) and the step of obtaining the compound represented by formula (V) are carried out in one reaction system. [9] Formula (V): [ka] A compound represented by the formula:

[10] Formula (III): [ka] (wherein X is a halogen) A compound represented by the formula: A reagent comprising the compound according to

[11] , [9] or

[10] .

[12] Formula (VII): [ka] The reagent according to

[11] for producing a compound represented by the formula:

[13] Formula (VII): [ka] Use of the compound according to [9] or

[10] for the production of a compound represented by the formula: EXAMPLES

[0069] The present disclosure will be described in more detail below with reference to examples, but the present disclosure is not limited to these examples. The following instruments were used to measure the various physical properties in the following examples. 1 H nuclear magnetic resonance spectrum ( 1 HNMR), 13 C nuclear magnetic resonance spectrum ( 13 CNMR): JNM-AL400 (manufactured by JEOL Ltd.) Internal standard: tetramethylsilane Liquid chromatography (LC): Equipment: LC-20A series (Shimadzu Corporation) / Column: YMC-Pack Pro C18 (YMC Corporation) Mass spectrometry (MS): ISQ EM (Thermo Fisher Scientific)

[0070] [Example 1: Manufacturing of Amenamevir 1] Amenamevir was prepared according to the following scheme: In the following scheme, compounds 1 to 4 correspond to the compounds represented by formula (I), formula (III), formula (V) and formula (VII), respectively. Each reaction will be explained below.

[0071] [ka]

[0072] <Step A: Production of N-iodoacetyl-[4-(1,2,4-oxadiazol-3-yl)]aniline (Compound 2a, X=I)> In a nitrogen atmosphere, 20.0 g of compound 1 and 20.5 g of triethylamine were placed in a four-neck flask, and 350 mL of tetrahydrofuran was added to dissolve. 12.0 g of chloroacetyl chloride dissolved in 50 mL of tetrahydrofuran was added dropwise to this reaction liquid at 0-10°C. After heating to 40°C and stirring for 1 hour, water was added to separate the organic phase. The solvent of the obtained organic phase was distilled off under reduced pressure, and 200 mL of 2-propanol was added to the residue to dissolve it. After cooling to 5°C, the precipitated solid was collected by filtration to obtain 18.2 g of N-chloroacetyl-[4-(1,2,4-oxadiazol-3-yl)]aniline (compound 2a, X=Cl) as a pale brownish white powder (LC purity: 99.96%, yield: 75%).

[0073] Compound 2a: mp:171℃ 1 HNMR(DMSO-d6)δ4.33(s,2H),7.82(d,2H),8.04(d,2H),9.68(s,1H),10.66(s,1H). 13 CNMR(DMSO-d6)δ43.6,119.5,121.0,128.1,141.4,165.1,166.4,167.2. m / z296[M + CH3COO] -

[0074] Next, in a nitrogen atmosphere, 10.0 g of the compound 2a (X=Cl) obtained above and 7.6 g of sodium iodide were placed in a four-neck flask, 150 mL of acetone was added, and the mixture was stirred overnight at 40°C. After removing insoluble matter by filtration, water was added and the mixture was cooled to 5°C. The precipitated solid was collected by filtration to obtain 12.5 g of the target product (compound 2b, X=I) (LC purity: 99.64%, yield: 92%) as a white powder.

[0075] Compound 2b: mp:192℃(decomposition) 1 HNMR(DMSO-d6)δ3.88(s,2H),7.79(d,2H),8.02(d,2H),9.68(s,1H),10.64(s,1H). 13 CNMR(DMSO-d6)δ1.3,119.3,120.7,128.0,141.7,166.4,167.1,167.2. m / z388[M + CH3COO] -

[0076] <Step B: Production of N-(2,6-dimethylphenylamino)acetyl-[4-(1,2,4-oxadiazol-3-yl)]aniline (Compound 3)> In a nitrogen atmosphere, 1.00 g of compound 2b (X=I), 0.37 g of sodium acetate, and 0.55 g of 2,6-dimethylaniline were placed in a four-neck flask, and 10 mL of THF was added. After stirring for 7 hours under reflux, 12 mL of 1 M hydrochloric acid and 15 mL of toluene were added and cooled to 5°C. The precipitated solid was filtered to obtain 0.98 g of the target product (compound 3) (LC purity: 99.14%, yield: 89%) as a pale yellow powder.

[0077] Compound 3: mp:157℃ 1 HNMR(DMSO-d6)δ2.29(s,6H),3.86(s,2H),4.45(t,1H),6.72(t,1H),6.94(d,2H),7.83(d,2H),8.01(d,2H),9.66(s,1H),10.36(s,1H). 13 CNMR(DMSO-d6)δ18.6,51.3,119.4,120.5,120.8,127.9,128.0,128.6,141.6,146.1,166.4,167.2,170.3. m / z323[M+H]

[0078] <Step C: Preparation of amenamevir (compound 4)> Under a nitrogen atmosphere, 82 g of tetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide was placed in a four-neck flask, and 1.5 L of THF was added. 1.65 g of pyridine and 75 g of thionyl chloride were added thereto, and the mixture was stirred at 40 to 60°C for 2 hours to obtain a carboxylic acid chloride. In addition, under a nitrogen atmosphere, 150 g of compound 3 was placed in another four-neck flask, and 1.5 L of THF and 165 g of pyridine were added and the mixture was heated to 60°C. The carboxylic acid chloride obtained above was added dropwise thereto, and the mixture was stirred at 60°C for 4 hours. 1350 mL of water and 2300 mL of ethyl acetate were added, and the THF was concentrated under reduced pressure, and the organic phase was separated and further concentrated. The precipitated solid was filtered, and 144 g of crude crystals of amenamevir was obtained as a white powder. 2.4 L of ethanol was added to 120 g of the crude crystals, and the mixture was refluxed to dissolve, and then cooled slowly to 20°C. The precipitated crystals were filtered to obtain 88 g of amenamevir (LC purity: 99.97%, yield: 74%) as a white powder.

[0079] Compound 4: mp:217℃(decomposition) 1 HNMR(DMSO-d6)δ1.84-1.92(m,2H),1.98-2.08(m,2H),2.34(s,6H),2.36-2.42(m,1H),3.00-3. 03(m,4H),4.21(s,2H),7.19-7.24(m,3H),7.79(d,2H),7.99(d,2H),9.67(s,1H),10.42(s,1H). 13 CNMR(DMSO-d6)δ18.0,27.1,36.4,48.8,53.2,119.1,120.3,128.0,128.2,129.2,135.9,140.1,142.0,166.4,166.7,167.2,173.9.

[0080] [Example 2: Manufacturing of Amenamevir 2] Amenamevir was produced by carrying out each step consecutively according to the following scheme: In the following scheme, compounds 1 to 4 correspond to the compounds represented by formula (I), formula (III), formula (V) and formula (VII), respectively. Each reaction will be explained below.

[0081] [ka]

[0082] In a nitrogen atmosphere, 102g of compound 1 and 175g of potassium carbonate were placed in a four-neck flask, 510mL of THF was added, 75g of chloroacetyl chloride was added dropwise at 0-10°C, and the mixture was stirred at room temperature for 1 hour. Next, water was added to the resulting mixture to separate the organic phase containing compound 2a. Next, 115g of 2,6-dimethylaniline, 78g of sodium acetate, and 114g of sodium iodide were added to the resulting organic phase, and the mixture was stirred under reflux for 4 hours. Water was added to the resulting mixture to separate the organic phase, and then 1M hydrochloric acid was added, and the precipitated solid was filtered, and 176g of the target product (compound 3) (LC purity: 91.04%, yield: 77%) was obtained as a pale yellow powder.

[0083] Thereafter, the same method as in Step C of Example 1 was carried out to obtain Compound 4 (amenamevir) from Compound 3.

[0084] It has been confirmed that the method of Example 2 can be used as a substantially one-pot production method for obtaining N-(2,6-dimethylphenylamino)acetyl-[4-(1,2,4-oxadiazol-3-yl)]aniline (Compound 3) from Compound 1 without the need for isolation of Compound 2.

[0085] [Example 3: Preparation of N-bromoacetyl-[4-(1,2,4-oxadiazol-3-yl)]aniline (Compound 2c)]

[0086] In a nitrogen atmosphere, 3.00 g of compound 1 and 2.06 g of potassium carbonate were placed in a four-neck flask, and 15 mL of tetrahydrofuran was added to dissolve. 4.88 g of bromoacetyl bromide was added dropwise to this reaction solution. The temperature was raised to 40°C and the mixture was stirred for 1 hour, after which water was added. The precipitated solid was collected by filtration to obtain 3.65 g of N-bromoacetyl-[4-(1,2,4-oxadiazol-3-yl)]aniline (compound 2b, X=Br) (LC purity: 99.09%, yield: 70%) as a white powder.

[0087] Compound 2c: mp:168℃(decomposition) 1 HNMR(DMSO-d6)δ4.09(s,2H),7.80(d,2H),8.03(d,2H),9.68(s,1H),10.71(s,1H). 13 CNMR(DMSO-d6)δ30.3,119.5,121.0,128.1,141.5,165.3,166.4,167.3. m / z340[M + CH3COO] -

[0088] It was confirmed that compound 4 (amenamevir) could be obtained by carrying out a method similar to that of Example 1 or Example 2 using compound 2c (X=Br) obtained above.

Claims

1. Formula (VII): 【Chemistry 1】 A method for producing a compound represented by the formula: Formula (V): 【Chemistry 2】 and compounds represented by formula (VI): 【Chemistry 3】 (Wherein LG is a leaving group.) in the presence of a base to obtain a compound represented by formula (VII). A method comprising:

2. Formula (V): 【Chemistry 4】 A method for producing a compound represented by the formula: Formula (III): 【Chemistry 5】 (wherein X is a halogen) and 2,6-dimethylaniline in the presence of a base to obtain a compound represented by formula (V). A method comprising:

3. The method of claim 1 , wherein the base is an organic base.

4. The method according to claim 1, comprising obtaining the compound represented by (V) by the method according to claim 2.

5. Formula (III): 【Chemistry 6】 (wherein X is a halogen) A method for producing a compound represented by the formula: Formula (I): 【Chemistry 7】 and compounds represented by formula (II): 【Chemistry 8】 wherein X and Y are each independently a halogen. to obtain a compound represented by formula (III). A method comprising:

6. The method according to claim 2, comprising obtaining the compound of formula (III) by the method according to claim 5.

7. The method according to claim 1, comprising obtaining the compound of formula (V) by the method according to claim 6.

8. The method according to claim 6 or 7, wherein the step of obtaining the compound represented by formula (III) and the step of obtaining the compound represented by formula (V) are carried out in one reaction system.

9. Formula (V): 【Chemistry 9】 A compound represented by the formula:

10. Formula (III): 【Chemistry 10】 (wherein X is a halogen) A compound represented by the formula:

11. A reagent comprising the compound according to claim 9 or 10.

12. Formula (VII): 【Chemistry 11】 The reagent according to claim 11 for producing a compound represented by the formula:

13. Formula (VII): 【Chemistry 12】 11. Use of a compound according to claim 9 or 10 for the preparation of a compound of the formula:

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