Method for producing compounds

Abstract

Provided is a method for manufacturing a compound with which yield can be improved.　This method for manufacturing a compound includes a first step for reacting a compound represented by formula (1) and a compound represented by formula (2) and obtaining a compound represented by formula (3).

Description

[Technical Field]

[0001] This invention relates to a method for producing compounds and its applications. [Background technology]

[0002] Reactive oxygen species (ROS) are generated by oxygen metabolism, which is essential for life activities. Furthermore, due to their high reactivity, excessive generation of ROS can induce tissue and cell damage, and their involvement in various diseases has been reported. For this reason, ROS scavenging agents have been developed. However, many ROS scavenging agents are unstable. For this reason, the only ROS scavenging agent that has been put into practical use and is used clinically is edaravone (5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one, trade name: Radicut, manufactured by Tanabe Mitsubishi Pharma Corporation) (Non-patent Literature 1). [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Piyanart Sommani et.al., “Effects of Edaravone on Singlet Oxygen Released From Activated Human Neutrophils”, J. Pharmacol. Sci., 2007, vol. 103, pages 117-120 [Overview of the Initiative] [Problems that the invention aims to solve]

[0004] Edaravone is a powerful radical scavenger that protects brain nerves by capturing radicals, particularly singlet oxygen, that are generated during the restoration of blood flow after acute cerebral ischemic attack or stroke. However, it is unstable in aqueous solutions and easily oxidized, so it must be stored in a reducing aqueous solution.

[0005] The inventors have found that when two substituted compounds, in which the phenyl group at the 2-position of edaravone is replaced with an alkyl group, are crosslinked with an alkenyl group, they are stabilized in aqueous solution while retaining their antioxidant activity. Furthermore, these substituted compounds can be prepared by reacting 3-methyl-3-3H-pyrazole-3-one (3-methyl-5-pyrazolone) with a bromoalkyl group. However, the reaction to obtain these substituted compounds has the problem of low yield.

[0006] Therefore, the present invention aims to provide a method for producing compounds in which the yield can be improved. [Means for solving the problem]

[0007] To achieve the above objective, the method for producing the compound of the present invention (hereinafter also referred to as the "first production method") includes a first step of reacting a compound represented by the following formula (1) with a compound represented by the following formula (2) to obtain a compound represented by the following formula (3). [ka] [In the above formula (1), R 1 This is a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxyl group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent. [ka] [In the above formula (2), R 2 This is a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxyl group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent. R 3This is a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxyl group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent. [ka]

[0008] The method for producing the compound of the present invention (hereinafter also referred to as the "second method") involves a compound represented by the following formula (4) and R 1 The first step involves reacting -I with the compound represented by the following formula (3), The aforementioned R 1 This is a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxyl group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent. [ka] [In the above formula (4), R 2 This is a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxyl group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent. [ka]

[0009] The method for producing the compound of the present invention (hereinafter also referred to as the "third method") comprises a first step of obtaining a compound represented by the following formula (3), The process includes a second step of reacting a compound represented by formula (3) below with a compound represented by formula (5) below to obtain a compound represented by formula (6) below. A method for producing a compound, wherein the first step is carried out by at least one of the method for producing the first compound and the method for producing the second compound of the present invention. [Chemical formula] [In the formula (3), R 1 is a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxy group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent, R 2 is a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxy group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent.] [Chemical formula] [In the formula (5), R 4 and R 5 may be the same or different and are each a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxy group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent, and n is an integer of 0 or more.] [Chemical formula] [In the formula (6), R 1a and R 1b may be the same or different and are each a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxy group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent, R 2a and R 2bThese may be the same or different, and each may be a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxyl group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent. n is a non-negative integer. [Effects of the Invention]

[0010] According to the present invention, a method for producing compounds in which the yield can be improved can be provided. [Brief explanation of the drawing]

[0011] [Figure 1] Figure 1 is a graph showing the LC / MS results in Example 1. [Figure 2] Figure 2 is a graph showing the LC / MS results in Example 1. [Figure 3] Figure 3 is a photograph showing the TLC results in Example 1. [Figure 4] Figure 4 is a graph showing the LC / MS results in Example 1. [Figure 5] Figure 5 is a graph showing the LC / MS results in Example 1. [Figure 6] Figure 6 is a photograph showing the TLC results in Example 1. [Figure 7] Figure 7 is a graph showing the LC / MS results in Example 1. [Figure 8] Figure 8 is a photograph showing the TLC results in Example 1. [Figure 9] Figure 9 is a graph showing the HPLC results in Example 1. [Modes for carrying out the invention]

[0012] <First manufacturing method> As described above, the method for producing the compound of the present invention includes a first step (hereinafter also referred to as "step 1A") in which a compound represented by the following formula (1) and a compound represented by the following formula (2) are reacted to obtain a compound represented by the following formula (3).

[0013] [ka]

[0014] In equation (1) above, R 1 This is a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxyl group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent.

[0015] [ka]

[0016] In equation (2) above, R 2 This is a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxyl group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent. R 3 This is a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxyl group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent.

[0017] [ka]

[0018] The compound represented by formula (1), (2), or (3) may be, for example, a salt thereof or an isomer thereof. The isomer may be, for example, a tautomer or a stereoisomer. The tautomer or stereoisomer may be, for example, all theoretically possible tautomers or stereoisomers. Furthermore, in the present invention, the stereoconfiguration of each substituent is not particularly limited. In the antioxidant of the present invention, the compound represented by formula (1), (2), or (3) may be, for example, a hydrate or solvate of the compound represented by formula (1), (2), or (3) or a salt thereof.

[0019] Furthermore, if the compound represented by formula (1), (2), or (3) has a chiral carbon atom, the compound represented by formula (1), (2), or (3) may exist, for example, as a racemate, an enantiomer of its R and S, or a mixture of R and S in any proportion. The compound represented by formula (1), (2), or (3) may have two or more chiral centers. In this case, the compound represented by formula (1), (2), or (3) may include diastereomers and mixtures thereof. If the compound represented by formula (1), (2), or (3) has a double bond in its molecule, the compound represented by formula (1), (2), or (3) may include, for example, geometric isomers of cis and trans isomers.

[0020] The following describes each substituent in each compound with examples. Unless otherwise specified, specific examples from the descriptions of other substituents can be used in the description of each substituent.

[0021] In equation (1) above, R 1 This is a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxyl group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent, preferably an alkyl group or an aryl group, and more preferably an ethyl group or a phenyl group.

[0022] Examples of the halogen atoms include fluorine atoms, chlorine atoms, bromine atoms, iodine atoms, and the like.

[0023] Examples of the alkyl group include linear, branched, or cyclic saturated or unsaturated alkyl groups having 1 to 20 or 1 to 10 carbon atoms. Specific examples of the alkyl group include, for example, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a t-butyl group, an n-pentyl group, an i-pentyl group, a t-pentyl group, an n-hexyl group, an i-hexyl group, a t-hexyl group, an n-heptyl group, an i-heptyl group, a t-heptyl group, an n-octyl group, an i-octyl group, a t-octyl group, an n-nonyl group, an i-nonyl group, a t-nonyl group, an n-decyl group, Examples include i-decyl group, t-decyl group, n-undecyl group, i-undecyl group, n-dodecyl group, i-dodecyl group, n-tridecyl group, i-tridecyl group, n-tetradecyl group, i-tetradecyl group, n-pentadecyl group, i-pentadecyl group, n-hexadecyl group, i-hexadecyl group, n-heptadecyl group, i-heptadecyl group, n-octadecyl group, i-octadecyl group, n-nonadecyl group, i-nonadecyl group, etc. The alkyl group is preferably a linear saturated alkyl group having 1 to 6 carbon atoms, and more preferably a methyl group or an ethyl group.

[0024] In the aforementioned alkoxy group (RO-), R is an alkyl group, and the explanation of alkyl groups described above can be applied.

[0025] In the hydroxyalkyl group (HOR-) mentioned above, R is an alkyl group, and the explanation of alkyl groups described above can be applied.

[0026] In the aforementioned acyl group (RCO-), R is an alkyl group, and the explanation of alkyl groups described above can be applied.

[0027] The aforementioned alkenyl group may be, for example, one or more double bonds in the alkyl group. Examples of the aforementioned alkenyl group include alkenyl groups having 2 to 20 carbon atoms, preferably 2 to 6 carbon atoms, and specific examples include vinyl group, allyl group, 1-propenyl group, 2-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 2-methylallyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 2-methyl-2-butenyl group, etc.

[0028] The alkynyl group may, for example, have one or more triple bonds in the alkyl group. Examples of the alkynyl group include alkenyl groups having 2 to 20 carbon atoms, preferably 2 to 6 carbon atoms, and specific examples include ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group, 1-pentynyl group, 2-pentynyl group, 3-pentynyl group, 4-pentynyl group, 1-methyl-3-butynyl group, etc. The alkynyl group may further have one or more double bonds, for example.

[0029] The aryl group which may have substituents may be an aryl group, or the aryl group may be substituted with substituents. The aryl group which may have substituents is, for example, an aryl group with a total of 6 to 20 carbon atoms, including the number of carbon atoms in the substituent. Specific examples include phenyl group, tolyl group, xylyl group, alkyloxyphenyl group (e.g., methoxyphenyl group, ethoxyphenyl group, etc.), hydroxyphenyl group, halogenophenyl group (e.g., fluorophenyl group, chlorophenyl group, bromophenyl group, etc.), alkylphenyl group (e.g., methylphenyl group, ethylphenyl group, propylphenyl group, etc.), cyanophenyl group, propyloxyphenyl group, 4-sulfophenyl group, etc., with phenyl group or 4-sulfophenyl group being preferred.

[0030] In equation (2) above, R 2This is a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxyl group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent, preferably an alkyl group, and more preferably a methyl group.

[0031] In equation (2) above, R 3 This is a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxyl group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent, preferably an alkyl group, and more preferably an ethyl group.

[0032] The aforementioned R 1 , R 2 , and R 3 The combinations are not particularly limited and can be any combination. For example, the R 1 , R 2 , and R 3 The combination is, for example, R 1 However, it is an alkyl group or an aryl group, R 2 However, it is an alkyl group, R 3 However, it is an alkyl group, preferably R 1 However, it is an ethyl group or a phenyl group, R 2 However, it is a methyl group, R 3 However, it is an ethyl group.

[0033] Next, the steps of the first manufacturing method of the present invention will be described with an example. In the first manufacturing method of the present invention, in step 1A, the compound represented by formula (1) and the compound represented by formula (2) are reacted to obtain the compound represented by formula (3). In step 1A, for example, the compound represented by formula (3) is obtained by a reduction reaction between the compound represented by formula (1) and the compound represented by formula (2). Specifically, in step 1A, as shown in the following reaction formula (Chemical Formula S1), the amino group (-NH2) and amine (-NH-) in the compound represented by formula (1) reduce the carbonyl group in the compound represented by formula (2) to obtain the compound represented by formula (3). [ka]

[0034] In the first A step, the molar ratio (C1:C2) of compound (C1) represented by formula (1) and compound (C2) represented by formula (2) is, for example, 1:0.1 to 10, 1:0.25 to 5, or 1:0.5 to 1.25.

[0035] Step 1A may be carried out in the presence of a base, or more specifically, in the presence of a basic substance. Examples of the base include basic inorganic salts such as calcium carbonate, potassium carbonate, and cesium carbonate; metal hydrides such as sodium hydride and calcium hydride; and amines such as triethylamine (TEA) and N,N-diisopropylethylamine (DIEA).

[0036] As the reaction solvent for step 1A, at least one solvent selected from, for example, N,N-dimethylformamide (DMF), acetonitrile, 1,4-dioxane, acetone, ethanol, chloroform, dioxane, xylene, diethyl ether, tetrahydrofuran (THF), dichloromethane (CH2Cl2), and toluene can be used. The reaction solvent may be one type, two or more types, or a mixture of two or more types. If step 1A is carried out in the presence of a base and the base can be used as the reaction solvent, the base may be used as the reaction solvent for step 1A. Examples of bases that can be used as the reaction solvent include amines such as TEA and DIEA. The reaction solvent is preferably DMF, acetonitrile, ethanol, or amines, or a mixture thereof, because it can suppress side reactions and the formation of isomers and improve the yield of the compound represented by formula (3). The amount of the reaction solvent can be, for example, 0.5 to 1000 ml or 50 to 1000 ml per 1 mole of the compound represented by formula (1).

[0037] The reaction temperature in step 1A can be appropriately adjusted depending on the compound represented by formula (1) or (2) and the reaction solvent. Specific examples of reaction temperatures include 0 to 40°C, 0 to 35°C, etc.

[0038] The first method of production of the present invention may involve purifying the compound represented by formula (3) obtained in step 1A. In this case, the first method of production of the present invention may involve, for example, recrystallization, concentration, neutralization, extraction, and / or drying of the reaction product obtained in step 1A.

[0039] According to the first manufacturing method of the present invention, the yield of the compound represented by formula (3) can be improved.

[0040] <Second manufacturing method> As described above, the method for producing the compound of the present invention involves a compound represented by the following formula (4) and R 1-The first step (hereinafter also referred to as the "first B step") involves reacting with I to obtain a compound represented by the following formula (3), and the R 1 This is a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxyl group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent.

[0041] [ka]

[0042] In equation (4) above, R 2 This is a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxyl group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent.

[0043] [ka]

[0044] The second manufacturing method of the present invention can be described by referring to the description of the first manufacturing method of the present invention.

[0045] The compound represented by formula (3) or (4) may be, for example, a salt thereof or an isomer thereof. The isomer may be, for example, a tautomer or a stereoisomer. The tautomer or stereoisomer may be, for example, all theoretically possible tautomers or stereoisomers. Furthermore, in the present invention, the stereoconfiguration of each substituent is not particularly limited. In the antioxidant of the present invention, the compound represented by formula (3) or (4) may be, for example, a hydrate or solvate of the compound represented by formula (3) or (4) or a salt thereof.

[0046] Furthermore, if the compound represented by formula (3) or (4) has a chiral carbon atom, the compound represented by formula (3) or (4) may exist, for example, as a racemate, an enantiomer of its R and S, or a mixture of R and S in any proportion. The compound represented by formula (3) or (4) may have two or more chiral centers. In this case, the compound represented by formula (3) or (4) may include diastereomers and mixtures thereof. If the compound represented by formula (3) or (4) has a double bond in its molecule, the compound represented by formula (3) or (4) may include, for example, geometric isomers of cis and trans isomers.

[0047] The following describes each substituent in each compound with examples. Unless otherwise specified, specific examples from the descriptions of other substituents can be used in the description of each substituent.

[0048] R 1 -I (iodine), the above R 1 This is a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxyl group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent, preferably an alkyl group (alkyl iodide) or an aryl group, more preferably an ethyl group (ethyl iodide) or a phenyl group (iodobenzene). The second production method of the present invention uses iodide, which, compared to the case in which bromoalkyl groups are used, provides R to the nitrogen atom at position 1 of the pyrazoline ring. 1 It is estimated that the yield will improve because the introduction efficiency of the element will be enhanced.

[0049] In equation (4) above, R 2 This is a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxyl group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent, preferably an alkyl group, and more preferably a methyl group.

[0050] The aforementioned R 1 and R 2 The combinations are not particularly limited and can be any combination. For example, the R 1 and R 2 The combination is, for example, R 1 However, it is an alkyl group or an aryl group, R 2 However, it is an alkyl group, preferably R 1 However, it is an ethyl group or a phenyl group, R 2 However, it is a methyl group.

[0051] Next, the steps of the second manufacturing method of the present invention will be described with an example. In the second manufacturing method of the present invention, in step 1B, the compound represented by formula (4) and R 1 -I is reacted to obtain the compound represented by formula (3). In step 1B, for example, the compound represented by formula (4) and R 1 -I undergoes a nucleophilic substitution reaction to obtain the compound represented by formula (3). Specifically, in step 1B, for example, the amine (-NH-) in the compound represented by formula (4) is used as a nucleophile, R 1 By acting on -I, the compound represented by formula (3) above is obtained.

[0052] In the first B step, the compound (C4) represented by formula (4) and R 1 The molar ratios (C4:CI) with -I(CI) are, for example, 1:0.1 to 100, 1:0.5 to 50, and 1:1 to 25.

[0053] In step 1B, for example, side reactions and isomer formation can be suppressed, and the yield of the compound represented by formula (3) can be improved. Therefore, it is preferable to carry out the reaction in the absence of a base, or more specifically, in a reaction system without the addition of a basic substance. The base can be described in the preceding explanation.

[0054] As the reaction solvent for step 1B, at least one solvent selected from, for example, N,N-dimethylformamide (DMF), acetonitrile, 1,4-dioxane, acetone, ethanol, chloroform, dioxane, xylene, diethyl ether, tetrahydrofuran (THF), dichloromethane (CH2Cl2), and toluene can be used. The reaction solvent may be one type, two or more types, or a mixture of two or more types. The reaction solvent is preferably DMF, acetonitrile, or a mixture thereof, for example, because it can suppress side reactions and isomer formation and improve the yield of the compound represented by formula (3). The amount of the reaction solvent is, for example, 0.5 to 1000 ml or 50 to 1000 ml per 1 mole of the compound represented by formula (4).

[0055] The reaction temperature in step 1B is determined by the compound represented by formula (3), R 1 -I and the reaction solvent can be adjusted as appropriate. The first B step is preferably carried out under heating and reflux conditions, for example, because it can improve the yield of the compound represented by formula (3). Specifically, the reaction temperature can be set as appropriate depending on the reaction solvent, for example, 20 to 100°C, preferably 50 to 100°C, 60 to 90°C, etc.

[0056] A second method of production of the present invention may involve purifying the compound represented by formula (3) obtained in step 1B. In this case, the second method of production of the present invention may involve, for example, recrystallization, concentration, neutralization, extraction, and / or drying of the reactant obtained in step 1B.

[0057] According to the second manufacturing method of the present invention, the yield of the compound represented by formula (3) can be improved.

[0058] <Third manufacturing method> As described above, the method for producing the compound of the present invention includes a first step of obtaining a compound represented by the following formula (3), and a second step of reacting the compound represented by the following formula (3) with the compound represented by the following formula (5) to obtain a compound represented by the following formula (6), wherein the first step is carried out by at least one of the first method for producing the compound of the present invention and the second method for producing the compound.

[0059] [ka]

[0060] In equation (3) above, R 1 This is a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxyl group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent. R 2 This is a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxyl group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent.

[0061] [ka]

[0062] In equation (5) above, R 4 and R 5 These may be the same or different, and each may be a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxyl group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent. n is a non-negative integer.

[0063] [ka]

[0064] In the above formula (6), R 1a and R 1b These may be the same or different, and each may be a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxyl group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent.

[0065] R 2a and R 2b These may be the same or different, and each may be a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxyl group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent. n is a non-negative integer.

[0066] The third manufacturing method of the present invention is characterized in that the first step is carried out by the first or second manufacturing method of the present invention, and other steps and conditions are not particularly limited. The third manufacturing method of the present invention can be described by referring to the descriptions of the first and second manufacturing methods of the present invention.

[0067] The compound represented by formula (3), (5), or (6) may be, for example, a salt thereof or an isomer thereof. The isomer may be, for example, a tautomer or a stereoisomer. The tautomer or stereoisomer may be, for example, all theoretically possible tautomers or stereoisomers. Furthermore, in the present invention, the stereoconfiguration of each substituent is not particularly limited. In the antioxidant of the present invention, the compound represented by formula (3), (5), or (6) may be, for example, a hydrate or solvate of the compound represented by formula (3), (5), or (6) or a salt thereof.

[0068] Furthermore, if the compound represented by formula (3), (5), or (6) has a chiral carbon atom, the compound represented by formula (3), (5), or (6) may exist, for example, as a racemate, an enantiomer of its R and S, or a mixture of R and S in any proportion. The compound represented by formula (3), (5), or (6) may have two or more chiral centers. In this case, the compound represented by formula (3), (5), or (6) may include diastereomers and mixtures thereof. If the compound represented by formula (3), (5), or (6) has a double bond in its molecule, the compound represented by formula (3), (5), or (6) may include, for example, geometric isomers of cis and trans isomers.

[0069] The following describes each substituent in each compound with examples. Unless otherwise specified, specific examples from the descriptions of other substituents can be used in the description of each substituent.

[0070] In equation (3) above, R 1 This is a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxyl group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent, preferably an alkyl group or an aryl group, and more preferably an ethyl group or a phenyl group.

[0071] R 2 This is a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxyl group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent, preferably an alkyl group, and more preferably an ethyl group.

[0072] In equation (5) above, R 4 and R 5Each of these is a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxyl group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent, preferably an alkyl group or an aryl group, and more preferably a phenyl group. 4 and R 5 They may be the same or different, but it is preferable that they be the same.

[0073] n is a non-negative integer, for example, an integer between 0 and 10, preferably an integer between 0 and 5, 0 and 3, or 1 and 3, and more preferably 0, 1, or 2.

[0074] In the above formula (6), R 1a and R 1b Each of these is a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxyl group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent, preferably an alkyl group or an aryl group, and more preferably an ethyl group or a phenyl group. 1a and R 1b They may be the same or different, but it is preferable that they be the same. 1a and R 1b For example, R 1 It is the same as this.

[0075] R 2a and R 2b Each of these is a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxyl group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent, preferably an alkyl group, and more preferably a methyl group. 2a and R 2b They may be the same or different, but it is preferable that they be the same. 2a and R 2b For example, R 2It is the same as

[0076] Said R 1 、R 2 、R 1a 、R 1b 、R 2a 、R 2b 、and the combination of n is not particularly limited and can be any combination. As a specific example, said R 1 、R 2 、R 1a 、R 1b 、R 2a 、R 2b 、and the combination of n is, for example, R 1 is an alkyl group or an aryl group, R 2 is an alkyl group, R 1a and R 1b may be the same or different and are each an alkyl group or an aryl group, R 2a and R 2b may be the same or different and are alkyl groups, and n is an integer from 0 to 5. Said R 1 、R 2 、R 1a 、R 1b 、R 2a 、R 2b 、and the combination of n is preferably that R 1 is an ethyl group or a phenyl group, R 2 is a methyl group, R 1a and R 1b may be the same or different and are each an ethyl group or a phenyl group, R 2a and R 2b may be the same or different and are methyl groups, and n is 0, 1, or 2. In this case, said R 4 and R 5 are preferably phenyl groups.

[0077] Next, the steps of the third production method of the present invention will be described with examples. In the third production method of the present invention, in the first step, the compound represented by the formula (3) is obtained. The first step can be carried out in the same manner as the first production method or the second production method of the present invention.

[0078] Next, in the second step, the compound represented by formula (3) and the compound represented by formula (5) are reacted to obtain the compound represented by formula (6). In the second step, for example, two molecules of the compound represented by formula (3) and the compound represented by formula (5) undergo a reduction reaction to obtain the compound represented by formula (6). Specifically, in the second step, for example, the amine (-NH-) in the compound represented by formula (5) undergoes a reduction reaction with the compound represented by formula (3), and the bond of the carbon atom bonded to the aniline in the compound represented by formula (5) bonds with the carbon atom at position 4 of the compound represented by formula (3). Then, in the second step, for example, the compound represented by formula (5) and another compound represented by formula (3) undergo a reduction reaction to obtain the imine (R) of the compound represented by formula (5). 4 The compound represented by formula (6) is obtained when the bond of the carbon atom (-N=C-) bonds with the carbon atom at position 4 of the compound represented by formula (3).

[0079] In the second step, the molar ratio (C3:C5) of the compound represented by formula (3) (C3) to the compound represented by formula (5) (C5) is, for example, 1:0.001 to 10, 1:0.01 to 5, or 1:0.1 to 5.

[0080] In the second step, for example, it is preferable to carry it out in the presence of a base, more specifically in the presence of a basic substance, since the yield of the compound represented by formula (6) can be improved. The base can be described in the preceding explanation.

[0081] As the reaction solvent for the second step, at least one solvent selected from, for example, N,N-dimethylformamide (DMF), acetonitrile, 1,4-dioxane, acetone, ethanol, chloroform, dioxane, xylene, diethyl ether, tetrahydrofuran (THF), dichloromethane (CH2Cl2), and toluene can be used. The reaction solvent may be one type, two or more types, or a mixture of two or more types. If the second step is carried out in the presence of a base and the base can be used as the reaction solvent, the base may be used as the reaction solvent for the second step. Examples of bases that can be used as the reaction solvent include amines such as TEA and DIEA. The reaction solvent is preferably DMF, acetonitrile, ethanol, or amines, or a mixture thereof, because it can suppress side reactions and the formation of isomers and improve the yield of the compound represented by formula (6). The amount of the reaction solvent can be, for example, 0.5 to 1000 ml or 50 to 1000 ml per 1 mole of the compound represented by formula (3).

[0082] The reaction temperature in the second step can be appropriately adjusted depending on the compound represented by formula (3), the compound represented by formula (5), and the reaction solvent. The second step is preferably carried out under heating conditions, for example, because it can improve the yield of the compound represented by formula (6). Specifically, the reaction temperature is, for example, 20 to 100°C, preferably 50 to 100°C, 60 to 90°C, etc.

[0083] A third method of production of the present invention may involve purifying the compound represented by formula (6) obtained in the second step. In this case, the second method of production of the present invention may involve, for example, recrystallization, concentration, neutralization, extraction, and / or drying of the reactant obtained in the second step.

[0084] According to the third manufacturing method of the present invention, the yield of the compound represented by formula (3) can be improved, and therefore the yield of the compound represented by formula (6) can be improved. [Examples]

[0085] Next, examples of the present invention will be described. However, the present invention is not limited to the following examples. Commercially available reagents were used according to their protocols unless otherwise specified.

[0086] [Example 1] We confirmed that the yield is improved by the manufacturing method of the present invention.

[0087] (1) First manufacturing method The first manufacturing method of the example was carried out according to Scheme 1 below. Specifically, a 50 ml ground-joint test tube was equipped with a stirrer bar, a reflux condenser, and a three-way stopcock. Next, under a nitrogen atmosphere, compound 3 (1.0006 g), which is the compound of formula (1), was added to the test tube, and then 10 ml of ethanol, triethylamine (1.857 ml, 2 eq), and compound 4 (843 μl, 1 eq), which is the compound of formula (2), were added sequentially. After the additions, the mixture was stirred overnight (18 hours) at reflux temperature (room temperature, about 25°C), and the reaction solution was concentrated to obtain an orange semi-solid. The obtained semi-solid was suspended in 20 ml of ethyl acetate, filtered, and washed again with 20 ml of ethyl acetate. This removed the triethylamine oxalate salt contained in the semi-solid. Furthermore, about 20 g of silica gel was added to the ethyl acetate solution in which the washed semi-solid was resuspended, suspended, and filtered. The obtained residue was eluted with a mixed solvent of 10% methanol / ethyl acetate (250 ml), and then concentrated using a rotary evaporator to obtain 817.4 mg of crude product (solid). The obtained solid was dispersed in approximately 2 ml of acetonitrile, and the resulting dispersion was recrystallized (reflux → 0°C) to obtain 658 mg of pale yellowish-white solid (yield 78.3%). The presence of 3-methyl-1-ethyl-5-pyrazolone, the compound of formula (3) above, in the obtained solid was confirmed by mass spectrometry under the following LC / MS conditions. The LC / MS results of the reaction solution are shown in Figure 1, the LC / MS results after recrystallization are shown in Figure 2, and the TLC data before and after recrystallization are shown in Figure 3. [ka]

[0088] (LC / MS Conditions) Instrument Shimadzu LCMS-8030 Column Phenomenex Kinetex5μ C18, 150L×2.0φ(5μm) Eluent A:10mM NH4HCO3+0.1% HCOOH / H2O B:Acetonitrile Gradient B conc 0-100 (15min) Flow rate 0.2 ml / min Column temp 40℃ Detector 1 ESI Probe voltage : +1.6kV(ESI-Positive mode), -1.6 kV(ESI-Negative mode) CDL temperature : 250℃ Block heater temp. : 200℃ Nebulizing gas flow : 1.5 l / min Drying gas pressure : 0.02Mpa Detector 2 PDA(190-800nm)

[0089] (2) The Second Manufacturing Method The second manufacturing method of the example was carried out according to Scheme 2 below. Specifically, a 50 ml ground-joint test tube was equipped with a stirrer bar and a three-way stopcock. Under a nitrogen atmosphere, compound 1 (starting material 1, 750.5 mg), which is the compound of formula (4), was suspended in 7.5 ml of acetonitrile, and EtI (iodoethyl, 1.849 ml, 3.577 g, 3 eq) was added to the test tube and heated under reflux at 72°C overnight (18 hours). After heating under reflux, the reaction solution was completely dissolved. The obtained reaction solution was concentrated using a rotary evaporator (excess EtI was removed by distillation), and 7.5 ml of water was added to the resulting light brown syrup to redissolve it. Furthermore, sodium bicarbonate (NaHCO3) powder (642 mg, 1 eq) was added in small amounts to the redissolved solution to neutralize it. Bubbles were generated during the neutralization. Furthermore, to complete the neutralization, the mixture was heated at 100°C for 10 minutes. After the heat treatment, the mixture was cooled, and chloroform was added to the resulting aqueous solution to extract 3-methyl-1-ethyl-5-pyrazolone, the compound of formula (3). In the extraction process, 10 ml of chloroform was used each time, and the process was carried out a total of 10 times. The organic layer recovered in each extraction was dried with sodium sulfate (Na2SO4), filtered, and concentrated to obtain 578.7 mg of crude product (light brown solid). The solid was dispersed in approximately 2 ml of acetonitrile and recrystallized (reflux → -20°C), yielding 355.8 mg of a white solid with a purity of 99% or higher as measured under the LC / MS conditions (yield 36.9%). The presence of 3-methyl-1-ethyl-5-pyrazolone, the compound of formula (3), in the obtained solid was confirmed by mass spectrometry under the LC / MS conditions. The LC / MS results of the reaction solution are shown in Figure 4, the LC / MS results after recrystallization are shown in Figure 5, and the TLC data before and after recrystallization are shown in Figure 6. When the reaction was carried out similarly using DMF instead of acetonitrile as the reaction solvent, the yield was 37.0%. As a comparative example, when EtBr (ethidium bromide) was used instead of EtI, the yield was 31.9%. [ka]

[0090] (3) Third manufacturing method The third manufacturing method of the example was carried out according to Scheme 3 below. Specifically, a 50 ml ground-joint test tube was equipped with a stirrer bar and a three-way stopcock. Under a nitrogen atmosphere, compound 2 (154.1 mg, 2.1 eq), which is the compound of formula (3), compound 5 (149.9 mg, 1.0 eq), which is the compound of formula (5), 1.5 ml of ethanol, and triethylamine (242 μl, 3 eq) were added to the test tube and heated at 78 °C for 1 hour. After concentrating the reaction mixture, 10 ml of water was added to redissolve it, and it was neutralized with 1N-HCl (580 μl, 1 eq). After neutralization, it was extracted with chloroform (10 ml x 4 times; in this operation, the red component was almost entirely extracted into the organic layer). The organic layer recovered in each extraction treatment was dried with sodium sulfate (Na2SO4), filtered, and concentrated to obtain 274 mg of a reddish-black crude product. 5 ml of ethyl acetate was added to the crude and suspended, then 45 ml of isopropyl ether was added and stirred for a while. After stirring, the mixture was filtered and washed again with isopropyl ether. After washing, it was vacuum dried and 147.4 mg of compound 7, the compound of formula (6), was obtained as a vermilion powder with an HPLC purity of 99.3% (yield 88.2%, based on compound 5). The presence of compound 7, the compound of formula (6), 2,4-dihydro-4-[3-(1-ethyl-5-hydroxy-3-methyl-1H-pyrazol-4-yl)-2-propen-1-ylidene]-2-ethyl-5-methyl-3H-pyrazol-3-one (compound 7), in the obtained solid was confirmed by mass spectrometry under the LC / MS conditions described above. HPLC was performed under the following HPLC conditions. The LC / MS results of the reaction solution are shown in Figure 7, the TLC results of the dispersion after the addition of ethyl acetate and isopropyl ether are shown in Figure 8, and the HPLC data of the dispersion after the addition of ethyl acetate and isopropyl ether are shown in Figure 9. The NMR results of compound 7 in the solid are as follows, and it was confirmed to be the compound described above. 1¹H-NMR (Nuclear Magnetic Resonance) (600 MHz, DMSO (dimethyl sulfoxide)-d6, AV-600 (Bruker)): δ 1.18 (t, 6H), 2.19 (s, 6H), 3.69 (q, 4H), 7.29 (d, 2H), 8.00 (t, 1H) [ka]

[0091] (HPLC conditions) Instrument Shimadzu LC-2010A HT / SPD-M20A Column Phenomenex Kinetex5μ C18, 250L×4.6φ(5μm) Eluent A:0.1% TFA / H2O B:Acetonitrile Gradient B conc 0-100 (5 min) Flow rate 1.5 ml / min Detect PDA (190-800nm) ELSD (Shimadzu ELSD-LT II) Nebulizer gas pressure: 350kPa Temperature: 50℃ Noise filter: 3 seconds. Gain: 5

[0092] From these results, it was found that the manufacturing method of the present invention can improve the yield of the compound.

[0093] Although the present invention has been described above with reference to embodiments and examples, the present invention is not limited to the above embodiments and examples. Various modifications to the configuration and details of the present invention can be made that will be understood by those skilled in the art within the scope of the present invention.

[0094] This application claims priority based on Japanese Patent Application No. 2020-128216, filed on 29 July 2020, and incorporates all of its disclosures herein.

[0095] <Note> Some or all of the above embodiments and examples may be described as follows, but are not limited to the following. (Note 1) A method for producing a compound, comprising a first step of reacting a compound represented by formula (1) with a compound represented by formula (2) to obtain a compound represented by formula (3). [In the above formula (1), R 1 This is a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxyl group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent. [In the above formula (2), R 2 This is a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxyl group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent. R 3 This is a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxyl group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent. (Note 2) R 1 A method for producing the compound described in Appendix 1, wherein the compound is an alkyl group or an aryl group. (Note 3) R 2 A method for producing the compound described in Appendix 1 or 2, wherein the compound is an alkyl group. (Note 4) R 3 A method for producing a compound described in any of the appendices 1 to 3, wherein the compound is an alkyl group. (Note 5) R 1 is an alkyl group or aryl group, R 2 is an alkyl group, R 3 A method for producing a compound described in any of the appendices 1 to 4, wherein the compound is an alkyl group. (Note 6) R 1 A method for producing the compound described in any of Appendix 1 to 5, wherein is an ethyl group or a phenyl group. (Note 7) R 2 A method for producing the compound described in any of the appendices 1 to 6, wherein the compound is a methyl group. (Note 8) R 3 A method for producing the compound described in any of the appendices 1 to 7, wherein the compound is an ethyl group. (Note 9) The compound represented by formula (4) above, and R 1 The first step involves reacting -I with the compound represented by formula (3) to obtain the compound represented by formula (3), The aforementioned R 1 A method for producing a compound, wherein is a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxyl group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent. [In the above formula (4), R 2 This is a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxyl group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent. (Note 10) R 1 A method for producing the compound described in Appendix 9, wherein the compound is an alkyl group or an aryl group. (Note 11) R 2 A method for producing the compound described in Appendix 9 or 10, wherein the compound is an alkyl group. (Note 12) R 1 is an alkyl group or aryl group, R 2 A method for producing a compound described in any of the appendices 9 to 11, wherein the compound is an alkyl group. (Note 13) R 1 A method for producing the compound described in any of appendices 9 to 12, wherein is an ethyl group or a phenyl group. (Note 14) R 2 A method for producing the compound described in any of the appendices 9 to 13, wherein the compound is a methyl group. (Note 15) A first step to obtain the compound represented by formula (3), The process includes a second step of reacting a compound represented by formula (3) with a compound represented by formula (5) to obtain a compound represented by formula (6), A method for producing a compound, wherein the first step is carried out by the method for producing a compound described in any of the appendices 1 to 14. [In the above formula (3), R 1 This is a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxyl group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent. R 2 This is a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxyl group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent. [In the above formula (5), R 4 and R 5 These may be the same or different, and each may be a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxyl group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent. n is a non-negative integer. [In the above formula (6), R 1a and R 1bThese may be the same or different, and each may be a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxyl group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent. R 2a and R 2b These may be the same or different, and each may be a hydrogen atom, a halogen atom, an alkyl group, an amino group, a cyano group, a hydroxyl group, a sulfo group, a carboxyl group, an alkoxy group, a hydroxyalkyl group, an acyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent. n is a non-negative integer. (Note 16) R 1 A method for producing the compound described in Appendix 15, wherein the compound is an alkyl group or an aryl group. (Note 17) R 2 A method for producing the compound described in Appendix 15 or 16, wherein the compound is an alkyl group. (Note 18) R 4 and R 5 A method for producing the compound described in any of Appendix 15 to 17, wherein the group is either the same or different, and each is an alkyl group or an aryl group. (Note 19) R 1 is an alkyl group or aryl group, R 2 is an alkyl group, R 1a and R 1b These may be the same or different, and each is either an alkyl group or an aryl group. R 2a and R 2b A method for producing the compound described in any of Appendix 15 to 18, wherein the alkyl group may be the same or different. (Note 20) R 1 A method for producing the compound described in any of appendices 15 to 19, wherein is an ethyl group or a phenyl group. (Note 21) R 2 A method for producing the compound described in any of the appendices 15 to 20, wherein is a methyl group. (Note 22) R 1a and R 1b These may be the same or different, and are either an ethyl group or a phenyl group, respectively. R 2a and R 2b A method for producing the compound described in any of the appendices 15 to 21, wherein is a methyl group. (Note 23) A method for producing a compound according to any one of the appendices 15 to 22, comprising carrying out the second step in the presence of a base. [Industrial applicability]

[0096] As described above, the present invention provides a method for producing compounds in which the yield can be improved. For this reason, the present invention can be suitably used in the production of a particular compound. For this reason, the present invention can be said to be extremely useful in fields such as pharmaceuticals.

Claims

1. A first step involves reacting a compound represented by formula (1) below with a compound represented by formula (2) below to obtain a compound represented by formula (3) below, and The process includes a purification step for the compound represented by the following formula (3): The first step is carried out in the presence of amines, The purification process includes an extraction step, a concentration step, and a recrystallization step. The extraction process includes washing and filtration. In the concentration step, the residue obtained after filtration is concentrated, In the recrystallization step, the crude product obtained after concentration is recrystallized. Method for producing compounds. 【Chemistry 1】 [In formula (1) above, R １ This is a hydrogen atom, an alkyl group, an amino group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent. 【Chemistry 2】 [In formula (2) above, R ２ This is a hydrogen atom, an alkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent. R ３ This is an alkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, or an aryl group which may have a substituent. 【Transformation 3】

2. R １ A method for producing the compound according to claim 1, wherein is an alkyl group or an aryl group.

3. R ２ A method for producing the compound according to claim 1 or 2, wherein is an alkyl group.

4. R ３ A method for producing the compound according to any one of claims 1 to 3, wherein is an alkyl group.

5. R １ is an alkyl group or aryl group, R ２ It is an alkyl group, R ３ The method for producing a compound according to any one of claims 1 to 4, wherein R is an alkyl group.

6. R １ A method for producing the compound according to any one of claims 1 to 5, wherein is an ethyl group or a phenyl group.

7. R ２ A method for producing the compound according to any one of claims 1 to 6, wherein is a methyl group.

8. R ３ A method for producing the compound according to any one of claims 1 to 7, wherein is an ethyl group.

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