Method for producing 3-hydroxybiphenyl compound and derivative thereof

Abstract

The present invention provides a new method for producing a 3-hydroxybiphenyl compound and a new method for producing a derivative of a 3-hydroxybiphenyl compound using the same. Specifically, the present invention provides a method for producing a compound represented by formula (3), the method comprising a step for obtaining the compound represented by formula (3) by reacting, in a solvent and under the presence of a base, a compound represented by formula (1) [in the formula, R1 and R2 may be the same or different from each other and each represent a C1-C6 chain hydrocarbon group, or may form -(CH2)a- or -(CH2)2-O-(CH2)2- through binding between R1 and R2, and a represents 4 or 5] or a salt thereof with a compound represented by formula (2) [in the formula, R3 represents a C1-C6 chain hydrocarbon group, a chlorine atom, or a hydrogen atom, and X1 represents a chlorine atom, a bromine atom, or an iodine atom].

Description

Method for producing 3-hydroxybiphenyl compounds and derivatives thereof

[0001] This patent application claims priority under the Paris Convention to and the benefit of Japanese Patent Application No. 2024-020909 (filed February 15, 2024), the entire contents of which are incorporated herein by reference. The present invention relates to a method for producing a 3-hydroxybiphenyl compound and a derivative thereof.

[0002] Patent Document 1 describes useful derivatives of 3-hydroxybiphenyl compounds that have plant disease control effects.

[0003] Patent Document 2 describes a method for producing a 3-hydroxybiphenyl compound.

[0004] Japanese Patent Application Laid-Open No. 2001-64237 International Publication No. 02 / 18311

[0005] However, the method described in Patent Document 2 involves introducing a substituent onto the phenol ring by alkylation in the final step, and from the viewpoints of the regioselectivity and yield of the alkylation, it is difficult to obtain a compound represented by the formula (3) (hereinafter referred to as compound (3)). An object of the present invention is to provide a novel process for producing a 3-hydroxybiphenyl compound, and a novel process for producing a derivative of a 3-hydroxybiphenyl compound using the same.

[0006] The present inventors have conducted extensive research to solve the above problems and have completed the present invention.

[0007] That is, the present invention is as follows: [1] Step 1: A compound represented by formula (1) [In the formula, R 1 and R 2 are the same or different and represent a C1-C6 chain hydrocarbon group, or R 1 and R 2 Together, these form -(CH2) a-, or -(CH2)2-O-(CH2)2-, and a represents 4 or 5.] (hereinafter referred to as compound (1)) or a salt thereof with formula (2) [In the formula, R 3 represents a C1-C6 chain hydrocarbon group, a chlorine atom, or a hydrogen atom; X 1 represents a chlorine atom, a bromine atom, or an iodine atom.] (hereinafter referred to as compound (2)) in the presence of a base in a solvent to obtain compound (3). [2] A method for producing compound (3), comprising the steps of: 1 and R 2 are the same or different and are a methyl group or an ethyl group. [3] The production method according to [1] or [2], wherein the base is a trialkylamine or an alkali metal carbonate. [4] The production method according to any of [1] to [3], wherein the compound (1) or a salt thereof is the hydrochloride of compound (1). [5] The production method according to any of [1] to [4], wherein the solvent is a solvent containing at least one selected from the group consisting of water and alcohol. [6] The production method according to [5], wherein the solvent is a solvent containing 0.50 parts by weight or more and 50 parts by weight or less of water and 0.050 parts by weight or more and 10 parts by weight or less of alcohol per part by weight of compound (2). [7] In addition to step 1 according to any of [1] to [6], step 2: reacting compound (3) obtained in step 1 with a compound represented by formula (4) [In the formula, X 2 represents a leaving group, R 4 represents a C1-C6 chain hydrocarbon group. ] in the presence of a base to give a compound represented by the formula (5) [In the formula, R 4 has the same meaning as above.] (hereinafter referred to as compound (5)). [8] In addition to steps 1 and 2 described in [7], step 3: reacting compound (5) obtained in step 2 with a compound represented by formula (6): [In the formula, R 5represents a C1-C6 chain hydrocarbon group. ] (hereinafter referred to as compound (6)) in the presence of a base; and step 4: reacting the compound obtained in step 3 with a methylating agent to obtain a compound represented by formula (7): [In the formula, R 4 has the same meaning as defined in [7].] (hereinafter referred to as compound (7)).

[0008] According to the present invention, compound (3) can be efficiently produced, and compound (5) and compound (7) can be efficiently produced using compound (3).

[0009] The present invention will be described in detail below.

[0010] The substituents in the present invention will be explained.

[0011] In this specification, the notation "CX-CY" means that the number of carbon atoms is X to Y. For example, the notation "C1-C6" means that the number of carbon atoms is 1 to 6.

[0012] The chain hydrocarbon group represents an alkyl group, an alkenyl group, or an alkynyl group. Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a 1,1-dimethylpropyl group, a 2,2-dimethylpropyl group, a 1-ethylpropyl group, a butyl group, a sec-butyl group, a tert-butyl group, a pentyl group, and a hexyl group. Examples of the alkenyl group include a vinyl group, a 1-propenyl group, a 2-propenyl group, a 1-methyl-1-propenyl group, a 1-methyl-2-propenyl group, a 1,2-dimethyl-1-propenyl group, a 1-ethyl-2-propenyl group, a 3-butenyl group, a 4-pentenyl group, and a 5-hexenyl group. Examples of the alkynyl group include an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-methyl-2-propynyl group, a 1,1-dimethyl-2-propynyl group, a 1-ethyl-2-propynyl group, a 2-butynyl group, a 4-pentynyl group, and a 5-hexynyl group.

[0013] Compound (1) will be explained.

[0014] R 1 or R 2 Examples of the C1-C6 chain hydrocarbon group include the aforementioned chain hydrocarbon groups having 1 to 6 carbon atoms. Among these, the aforementioned chain hydrocarbon groups having 1 to 4 carbon atoms are preferred, with methyl and ethyl groups being more preferred.

[0015] R 1 and R 2 Together, these form -(CH2) a Specifically, when a is 4, the compound (1) forming - is represented by the formula (1-1): When a is 5, the compound is represented by the formula (1-2) R 1 and R 2 The compound (1) in which the above are combined to form —(CH)—O—(CH)— is specifically represented by the formula (1-3): The compound represented by the formula:

[0016] Compound (1) may be used as it is or as a salt of compound (1).

[0017] Examples of salts of compound (1) include hydrochloride, hydrobromide, sulfate, phosphate, etc., and among these, hydrochloride is preferred.

[0018] Compound (1) is commercially available, known, or can be prepared by known methods (e.g., Synthesis (2001), (15), 2239-2246). Compound (1) exists as a tautomer (enol form), and each isomer and a mixture of isomers in any ratio can be used.

[0019] Salts of compound (1) are commercially available, known, or can be prepared using known methods (e.g., RSC Advances (2020), 10(32), 18583-18593). The salts of compound (1) exist as tautomers (enol forms), and each isomer and a mixture of isomers in any ratio can be used.

[0020] Compound (2) will now be described.

[0021] R 3 Examples of the C1-C6 chain hydrocarbon group include the aforementioned chain hydrocarbon groups having 1 to 6 carbon atoms. Among these, the aforementioned chain hydrocarbon groups having 1 to 4 carbon atoms are preferred, with methyl and ethyl groups being more preferred.

[0022] R 3 is preferably a hydrogen atom, a chlorine atom, a methyl group, or an ethyl group, more preferably a hydrogen atom.

[0023] Compound (2) is represented by formula (2-1) [In the formula, X 1 has the same meaning as above. ] (hereinafter referred to as compound (2-1)) and the corresponding compound represented by formula (2-2) [In the formula, R 3have the same meanings as above. ] (hereinafter referred to as compound (2-2)). The reaction for producing compound (2) from compound (2-1) and compound (2-2) is usually carried out in a solvent. Examples of the solvent include hydrocarbons such as heptane, toluene, xylene, and ethylbenzene; halogenated hydrocarbons such as monochlorobenzene; nitriles such as acetonitrile and benzonitrile; ketones such as ethyl methyl ketone; ethers such as diisopropyl ether and methyl tert-butyl ether; alcohols such as methanol, ethanol, 2-propanol, tert-butyl alcohol, and ethylene glycol; and mixtures of two or more thereof. The amount of compound (2-2) used is usually 1 to 10 moles per mole of compound (2-1). In mixing the compound (2-1) and the compound (2-2), and the solvent used as needed, the order of mixing is not particularly limited, and can be carried out by, for example, mixing the compound (2-1) and the solvent and then adding the compound (2-2); mixing the compound (2-2) and the solvent and then adding the compound (2-1); adding the compound (2-1) and the compound (2-2) to the solvent, or the like. In mixing the compound (2-1) and the compound (2-2), and the solvent used as needed, the entire amount of each component, i.e., the compound (2-1) and the compound (2-2), and the solvent used as needed, may be added at once, or each component may be divided and added in multiple portions, or each component may be added dropwise. Furthermore, of the components to be added, two or more components may be added simultaneously in their entirety at once, or two or more components may be added simultaneously in their respective portions and added in multiple portions, or two or more components may be added simultaneously in their respective dropwise portions. Furthermore, two or more of the components to be added may be mixed in advance before being added. The components to be mixed in advance may be mixed in their entirety or in part. Two or more premixes of two or more components may be prepared so that the combinations of the components are different. The reaction temperature is usually within the range of 0°C to 80°C. The reaction time is usually within the range of 1 hour to 48 hours.Compound (2-1) is commercially available, known, or can be prepared using known methods (e.g., WO 2009 / 016460). Compound (2-2) is commercially available.

[0024] Compound (2) can also be prepared in the reaction system and then used. That is, a reaction mixture containing compound (2) obtained by reacting compound (2-1) with compound (2-2) can be used as compound (2) in step 1.

[0025] Compound (4) will now be described.

[0026] R 4 Examples of the C1-C6 chain hydrocarbon group in the formula include the aforementioned chain hydrocarbon groups having 1 to 6 carbon atoms. Among these, the aforementioned chain hydrocarbon groups having 1 to 3 carbon atoms are preferred, with a methyl group and an ethyl group being more preferred, and a methyl group being even more preferred.

[0027] X 2 Examples of the leaving group represented by the formula (I) include a chlorine atom, a bromine atom, an iodine atom, a p-toluenesulfonyloxy group, a methanesulfonyloxy group, and a trifluoromethanesulfonyloxy group. Among these, a chlorine atom, a bromine atom, and an iodine atom are preferred, and a chlorine atom is more preferred.

[0028] Compound (4) is commercially available, known, or can be prepared using known methods.

[0029] Compound (6) will now be described.

[0030] R 5 Examples of the C1-C6 chain hydrocarbon group in the formula (I) include the aforementioned chain hydrocarbon groups having 1 to 6 carbon atoms. Among these, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a pentyl group, and a hexyl group are preferred, and a methyl group is more preferred.

[0031] Compound (6) is commercially available, known, or can be prepared using known methods.

[0032] Step 1 will be described below. In step 1, compound (1) or a salt thereof is reacted with compound (2) in the presence of a base and a solvent to give compound (3).

[0033] Examples of the base include inorganic bases, alkali metal alkoxides, organic bases, and mixtures of two or more thereof. Examples of the inorganic base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide; alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate; and alkali metal phosphates such as trisodium phosphate and tripotassium phosphate. Examples of the alkali metal alkoxide include sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, and potassium tert-butoxide. Examples of the organic base include trialkylamines such as trimethylamine, triethylamine, tripentylamine, tributylamine, tripentylamine, trihexylamine, and N,N-diisopropylethylamine; N,N,N',N'-tetramethylethane-1,2-diamine; guanidine, and diazabicycloundecene. The trialkylamine is an amine having three alkyl groups bonded to a nitrogen atom, and the three alkyl groups are, for example, independently selected from the alkyl groups having 1 to 6 carbon atoms, and may be the same or different. Among these, the base is preferably an inorganic base, an organic base, or a mixture of two or more thereof, more preferably an alkali metal carbonate, an alkali metal phosphate, an organic base, or a mixture of two or more thereof, still more preferably an alkali metal carbonate, a trialkylamine, or a mixture of two or more thereof, particularly preferably an alkali metal carbonate, a tri(C1-C6 alkyl)amine, or a mixture of two or more thereof, and most preferably a tri(C1-C6 alkyl)amine.More specifically, the base is preferably sodium carbonate, potassium carbonate, cesium carbonate, trimethylamine, triethylamine, tripropylamine, tributylamine, tripentylamine, trihexylamine, N,N-diisopropylethylamine, N,N,N',N'-tetramethylethane-1,2-diamine, or a mixture of two or more thereof; more preferably sodium carbonate, trimethylamine, triethylamine, tripropylamine, tributylamine, tripentylamine, trihexylamine, N,N-diisopropylethylamine, or a mixture of two or more thereof; even more preferably sodium carbonate, triethylamine, tripropylamine, tributylamine, N,N-diisopropylethylamine, or a mixture of two or more thereof; particularly preferably triethylamine and N,N-diisopropylethylamine; and most preferably triethylamine. The base may be an anhydride, a hydrate, or a solution, and commercially available bases can be used as they are. Examples of the base solution include an aqueous solution of sodium hydroxide and a methanol solution of sodium methoxide.

[0034] When compound (1) is used as compound (1) or a salt thereof, the amount of the base used is usually 0.10 mol to 5.0 mol, preferably 0.10 mol to 2.0 mol, more preferably 0.10 mol to 1.5 mol, and even more preferably 0.20 mol to 1.20 mol, relative to 1 mol of compound (1). When a salt of compound (1) is used as compound (1) or a salt thereof, the amount of the base used is usually 1.1 mol to 6.0 mol, preferably 1.1 mol to 3.0 mol, more preferably 1.1 mol to 2.5 mol, and even more preferably 1.2 mol to 2.2 mol, relative to 1 mol of the salt of compound (1).

[0035] The amount of compound (1) or a salt thereof used is usually 0.50 to 5.0 moles, preferably 0.80 to 4.0 moles, more preferably 0.80 to 3.0 moles, per mole of compound (2).

[0036] The reaction is carried out in a solvent. A protic solvent is preferred as the solvent. Examples of protic solvents include alcohols such as methanol, ethanol, 2-propanol, tert-butyl alcohol, and ethylene glycol; water; and mixtures of two or more thereof, with a mixture of alcohol and water being more preferred. Specific examples of mixtures of alcohol and water include mixtures of ethanol and water, 2-propanol and water, tert-butyl alcohol and water, and ethylene glycol and water, with a mixture of ethylene glycol and water being preferred. A mixture of an aprotic solvent with the protic solvent can also be used as the solvent. Examples of aprotic solvents include hydrocarbons such as heptane, toluene, xylene, and ethylbenzene; halogenated hydrocarbons such as monochlorobenzene; nitriles such as acetonitrile and benzonitrile; ketones such as ethyl methyl ketone; ethers such as diisopropyl ether and methyl tert-butyl ether; and mixtures of two or more thereof. The reaction can also be carried out in a two-phase system using water as the protic solvent and a water-immiscible solvent as the aprotic solvent. However, since the yield of compound (3) usually decreases with an increase in the amount of the aprotic solvent used, the amount of the aprotic solvent used is preferably 0.6 parts by weight or less per part by weight of the protic solvent, and more preferably 0 part by weight, i.e., no aprotic solvent is used.

[0037] The amount of the solvent used is usually 0.55 to 60 parts by weight per part by weight of compound (2). When a mixture of alcohol and water is used as the solvent, it is usually a mixture of 0.50 to 50 parts by weight of water and 0.050 to 10 parts by weight of alcohol per part by weight of compound (2), preferably a mixture of 1.0 to 15 parts by weight of water and 0.10 to 5.0 parts by weight of alcohol per part by weight of compound (2), and more preferably a mixture of 2.0 to 10 parts by weight of water and 1.0 to 5.0 parts by weight of alcohol per part by weight of compound (2).

[0038] The reaction can also be carried out in the presence of a phase transfer catalyst, such as a quaternary ammonium salt, such as tetrabutylammonium chloride, tetrabutylammonium bromide, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide, benzyltriethylammonium chloride, or benzyltriethylammonium bromide.

[0039] When the reaction is carried out in the presence of a phase transfer catalyst, the amount of the phase transfer catalyst used is usually 0.005 to 0.2 moles per mole of compound (2).

[0040] The reaction is carried out by mixing compound (1) or a salt thereof, compound (2), a base, and a solvent. In mixing compound (1) or a salt thereof, compound (2), a base, and a solvent, the order of mixing is not particularly limited, and examples include mixing compound (1), compound (2), and a solvent, and then adding the base; mixing compound (1), a base, and a solvent, and then adding compound (2); mixing compound (2), a base, and a solvent, and then adding compound (1); mixing compound (1) and a solvent, and then adding compound (2) and the base; mixing compound (2) and a solvent, and then adding compound (1) and the base; mixing the base and a solvent, and then adding compound (1) and compound (2); adding compound (1), compound (2), to a solvent. The reaction can be carried out by methods such as: mixing a salt of compound (1), compound (2), and a solvent, followed by adding a base; mixing a salt of compound (1), a base, and a solvent, followed by adding compound (2); mixing compound (2), a base, and a solvent, followed by adding a salt of compound (1); mixing a salt of compound (1) and a solvent, followed by adding compound (2) and a base; mixing compound (2) and a solvent, followed by adding a salt of compound (1); mixing a salt of compound (1) and a solvent, followed by adding compound (2); mixing a base and a solvent, followed by adding a salt of compound (1) and compound (2); adding a salt of compound (1), compound (2), and a base to a solvent. Among these, the methods of mixing compound (1), compound (2), and a solvent, followed by adding a base, and mixing a salt of compound (1), compound (2), and a solvent, followed by adding a base, are preferred. In any of the above methods, the components to be added to the reaction system, i.e., compound (1) or a salt thereof, compound (2), base, and solvent, may be added all at once, or each component may be divided and added in multiple batches, or each component may be added gradually. Furthermore, of the components to be added, two or more components may be added simultaneously in their entirety all at once, or two or more components may be added simultaneously in their divided and added in multiple batches, or two or more components may be added simultaneously in their gradually increasing amounts. Furthermore, two or more components to be added may be mixed in advance before being added. The components to be mixed in advance may be mixed in their entirety in advance, or only a portion of them may be mixed in advance.Alternatively, two or more mixtures of two or more components may be prepared in advance so that the combinations of the components are different. In any of the above methods, a reaction mixture obtained by mixing compound (2-1) and compound (2-2), and optionally a solvent, may be used instead of compound (2).

[0041] The reaction temperature is usually within the range of 25°C to 140°C, preferably within the range of 60°C to 120°C, and more preferably within the range of 70°C to 100°C.

[0042] The reaction time varies depending on conditions such as the reaction temperature, but is usually 0.1 to 100 hours, preferably 1 to 24 hours.

[0043] Compound (3) can be purified by a conventional method. For example, if a solid precipitates, the resulting solid can be collected by filtration after the reaction is complete, and compound (3) can be purified. Alternatively, for example, after the reaction is complete, the reaction mixture can be mixed with water or an acidic aqueous solution such as dilute hydrochloric acid or dilute sulfuric acid, extracted with an organic solvent, and the resulting organic layer can be washed, dried, and concentrated under reduced pressure to purify compound (3). The solvent used for extraction is not particularly limited as long as it dissolves compound (3), and examples thereof include ethers such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, and cyclopentyl methyl ether; hydrocarbons such as pentane, hexane, heptane, octane, benzene, toluene, xylene, ethylbenzene, mesitylene, cyclohexane, and cyclopentane; halogenated hydrocarbons such as monochlorobenzene; ketones such as ethyl methyl ketone; and mixtures of two or more of these. Alternatively, for example, after the completion of the reaction, compound (3) can be purified by acid-base extraction, optionally with the addition of water, a water-immiscible solvent, and a base, to extract compound (3) as a salt into the aqueous layer. The resulting aqueous layer is then mixed with an acidic aqueous solution such as dilute hydrochloric acid or dilute sulfuric acid, followed by organic solvent extraction. The resulting organic layer is then washed, dried, and concentrated under reduced pressure. Examples of water-immiscible solvents include ethers such as diethyl ether, methyl tert-butyl ether, and cyclopentyl methyl ether; hydrocarbons such as pentane, hexane, heptane, octane, benzene, toluene, xylene, ethylbenzene, mesitylene, cyclohexane, and cyclopentane; halogenated hydrocarbons such as monochlorobenzene; and mixtures of two or more thereof. Compound (3) can also be further purified by column chromatography, recrystallization, or the like.Examples of solvents that can be used for recrystallization include solvents containing at least one selected from the group consisting of aromatic hydrocarbons such as toluene, xylene, and ethylbenzene; aliphatic hydrocarbons such as hexane and heptane; halogenated hydrocarbons such as monochlorobenzene; nitriles such as acetonitrile and benzonitrile; ketones such as ethyl methyl ketone and acetone; ethers such as 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, and methyl tert-butyl ether; esters such as ethyl acetate and butyl acetate; alcohols such as methanol and ethanol; water; and aprotic polar solvents such as N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and sulfolane. Among these, a mixed solvent of at least one selected from the group consisting of aromatic hydrocarbons, halogenated hydrocarbons, nitriles, ketones, ethers, esters, and aprotic polar solvents with at least one selected from the group consisting of aliphatic hydrocarbons, alcohols, and water is preferred.

[0044] Compound (3) can also be purified as a salt. Examples of salts include alkali metal salts and alkaline earth metal salts. A base can be added to the organic layer containing compound (3) obtained after post-treatment such as extraction, and the resulting solid can be collected by filtration to obtain a salt of compound (3). Examples of bases include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, and potassium ethoxide; and alkaline earth metal hydroxides such as calcium hydroxide. The base may be an anhydride, a hydrate, or a solution, and commercially available bases can be used as is. Examples of base solutions include an aqueous solution of sodium hydroxide and a methanol solution of sodium methoxide. The purified salt of compound (3) can also be used as is as compound (3) in Step 2.

[0045] Step 2 will now be described. In step 2, compound (3) obtained in step 1 is reacted with compound (4) in the presence of a base to obtain compound (5).

[0046] The compound (3) obtained in step 1 may be the one obtained by the purification in step 1, or may be a mixture containing compound (3) obtained by subjecting the reaction mixture after completion of the reaction in step 1 to post-treatment such as extraction, or may be a salt of compound (3). Examples of the mixture containing compound (3) include the organic layer containing compound (3). When a salt of compound (3) is used, the use of a base described below in the reaction of step 2 can be omitted or the amount used can be reduced.

[0047] The reaction is usually carried out in a solvent. Examples of the solvent include hydrocarbons such as heptane, toluene, xylene, ethylbenzene, etc.; halogenated hydrocarbons such as monochlorobenzene, etc.; nitriles such as acetonitrile, benzonitrile, etc.; ketones such as ethyl methyl ketone, etc.; ethers such as diisopropyl ether, methyl tert-butyl ether, etc.; and mixtures of two or more thereof. Among these, hydrocarbons such as heptane, toluene, xylene, ethylbenzene, etc.; halogenated hydrocarbons such as monochlorobenzene, etc.; and mixtures of two or more thereof are more preferred, and xylene, ethylbenzene, and mixtures thereof are particularly preferred. In addition to the above solvent, a solvent containing the above solvent and R 4 OH [where R 4 has the same meaning as above.] can also be used as a solvent.

[0048] Examples of the base include inorganic bases, alkali metal alkoxides, organic bases, and mixtures of two or more thereof. Examples of the inorganic base include alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate; and alkali metal phosphates such as trisodium phosphate and tripotassium phosphate. Examples of the alkali metal alkoxide include NaOR 4 and K.O.R. 4 [where R 4has the same meaning as above. ]. Examples of organic bases include triethylamine and diazabicycloundecene. Among them, alkali metal carbonates, alkali metal phosphates, alkali metal alkoxides, and mixtures of two or more thereof are preferred. More specifically, examples of bases include lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, NaOR 4 , K.O.R. 4 and mixtures of two or more thereof are more preferred. The base may be an anhydride, a hydrate, or a solution, and commercially available products can be used as they are. An example of a base solution is a methanol solution of sodium methoxide. When an alkali metal alkoxide is used as the base, an alcohol, i.e., R 4 OH [where R 4 In the case where the alkali metal alkoxide is used as an alcohol solution, the alcohol that is the solvent of the alkali metal alkoxide alcohol solution, i.e., R 4 OH is added to the reaction system. 4 The reaction may be carried out while distilling off the solvent (OH) by heating the reaction mixture under normal pressure or reduced pressure to a temperature equal to or higher than the boiling point of the solvent in the reaction mixture, which may allow the reaction to proceed more efficiently.

[0049] The amount of the base used is usually 0.50 to 2.0 moles, preferably 0.66 to 1.5 moles, more preferably 0.80 to 1.2 moles, per mole of compound (3).

[0050] The amount of compound (4) used is usually 0.50 to 3.0 moles, preferably 0.66 to 2.5 moles, more preferably 0.80 to 1.8 moles, per mole of compound (3).

[0051] The amount of the solvent used is usually 1 to 20 parts by weight per part by weight of the compound (3).

[0052] The reaction is carried out by mixing compound (3), compound (4), a base, and, if necessary, a solvent.

[0053] The reaction temperature is usually within the range of -20°C to 140°C, preferably within the range of 0°C to 120°C, more preferably within the range of 60°C to 100°C.

[0054] The reaction time varies depending on conditions such as the reaction temperature, but is usually 0.1 to 100 hours, preferably 1 to 24 hours.

[0055] Compound (5) can be purified by conventional methods. For example, if a solid precipitates, the resulting solid can be filtered after the reaction is complete, and compound (5) can be purified. Alternatively, compound (5) can be purified by, for example, mixing the reaction mixture after the reaction with water or an acidic aqueous solution such as dilute hydrochloric acid or dilute sulfuric acid, extracting with an organic solvent, and then washing, drying, and concentrating under reduced pressure. The solvent used for extraction is not particularly limited as long as it dissolves compound (5). Examples of the solvent include ethers such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, and cyclopentyl methyl ether; hydrocarbons such as pentane, hexane, heptane, octane, benzene, toluene, xylene, ethylbenzene, mesitylene, cyclohexane, and cyclopentane; ketones such as ethyl methyl ketone; halogenated hydrocarbons such as monochlorobenzene; and mixtures of two or more of these. Compound (5) can also be further purified by column chromatography, recrystallization, or the like. Examples of solvents that can be used for recrystallization include at least one solvent selected from the group consisting of aromatic hydrocarbons such as toluene, xylene, and ethylbenzene; aliphatic hydrocarbons such as hexane and heptane; halogenated hydrocarbons such as monochlorobenzene; nitriles such as acetonitrile and benzonitrile; ketones such as ethyl methyl ketone and acetone; ethers such as 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, and methyl tert-butyl ether; esters such as ethyl acetate and butyl acetate; alcohols such as methanol and ethanol; water; and aprotic polar solvents such as N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and sulfolane. Among these, a mixed solvent of at least one solvent selected from the group consisting of aromatic hydrocarbons, halogenated hydrocarbons, nitriles, ketones, ethers, esters, and aprotic polar solvents with at least one solvent selected from the group consisting of aliphatic hydrocarbons, alcohols, and water is preferred. After completion of the reaction, compound (5) can also be subjected to Step 3 without isolation.

[0056] Step 3 will now be described. In step 3, compound (5) obtained in step 2 is reacted with compound (6) in the presence of a base.

[0057] By the reaction of step 3, a compound represented by formula (8) [In the formula, R 4 has the same meaning as above. ] (hereinafter referred to as compound (8)) can be obtained.

[0058] As the compound (5) obtained in step 2, the compound obtained by the purification in step 2 may be used, or a mixture containing compound (5) obtained by subjecting the reaction mixture after completion of the reaction in step 2 to post-treatment such as extraction may be used.

[0059] Examples of the base include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide and potassium t-butoxide; alkali metal amides such as sodium amide, lithium amide, lithium diisopropylamide, sodium hexamethyldisilazide and lithium hexamethyldisilazide; and mixtures of two or more thereof.

[0060] The amount of the base used is usually 1 to 10 moles per mole of compound (5).

[0061] The amount of compound (6) used is usually 1 to 10 moles per mole of compound (5).

[0062] The reaction is usually carried out in a solvent. Examples of the solvent include ethers such as 1,4-dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, and methyl tert-butyl ether; aliphatic hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as toluene, xylene, and ethylbenzene; halogenated hydrocarbons such as monochlorobenzene; organic bases such as pyridine, triethylamine, and N,N-dimethylaniline; nitriles such as acetonitrile; aprotic polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethyl-2-imidazolidinone, and sulfolane; and mixtures of two or more thereof.

[0063] The reaction temperature is usually within the range of 0°C to 80°C.

[0064] The reaction time is usually within the range of 1 hour to 48 hours.

[0065] Compound (8) can be purified by conventional methods. For example, if a solid precipitates, the resulting solid can be filtered after the reaction is complete, and compound (8) can be purified. Alternatively, compound (8) can be purified by, for example, mixing the reaction mixture after the reaction with an acidic aqueous solution such as dilute hydrochloric acid or dilute sulfuric acid, extracting with an organic solvent, and then washing, drying, and concentrating under reduced pressure. The solvent used for extraction is not particularly limited as long as it dissolves compound (8). Examples of suitable solvents include ethers such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, and cyclopentyl methyl ether; hydrocarbons such as pentane, hexane, heptane, octane, benzene, toluene, xylene, ethylbenzene, mesitylene, cyclohexane, and cyclopentane; ketones such as ethyl methyl ketone; halogenated hydrocarbons such as monochlorobenzene; and mixtures of two or more of these. Compound (8) can also be further purified by column chromatography, recrystallization, or the like. After completion of the reaction, compound (8) can be subjected to step 4 without isolation, or without post-treatment such as extraction. Alternatively, compound (8) can be reacted with a base such as an alkali metal hydroxide to form a salt of compound (8) (e.g., an alkali metal salt such as a sodium salt), which can then be dissolved in a protic solvent such as water and subjected to step 4.

[0066] Step 4 will be described. In step 4, the compound obtained in step 3 is reacted with a methylating agent to obtain compound (7).

[0067] The compound obtained in step 3, i.e., compound (8), may be one obtained by post-treatment such as extraction or purification in step 3, or a mixture containing compound (8) obtained by performing post-treatment such as extraction as necessary without neutralizing the reaction mixture after the completion of the reaction in step 3 may be used, or a mixture containing compound (8) obtained by partially or completely neutralizing the reaction mixture after the completion of the reaction in step 3 may be provided to step 4. When a mixture containing compound (8) obtained by partially or without neutralizing the reaction mixture after the completion of the reaction in step 3 is provided to step 4, compound (8) forms an alkali metal salt such as a lithium salt, a sodium salt, or a potassium salt, and therefore the use of a base described below that can be used together with a methylating agent such as dimethyl sulfate in the reaction in step 4 can be omitted or the amount used can be reduced. Examples of acids used in the partial or complete neutralization include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid; and organic acids such as acetic acid, propionic acid, and benzoic acid.

[0068] The reaction is usually carried out in a solvent. Examples of the solvent that can be used include at least one selected from the group consisting of aromatic hydrocarbons, aliphatic hydrocarbons, halogenated hydrocarbons, ethers, ketones, esters, alcohols, water, nitriles, and aprotic polar solvents. Such a solvent may be one selected from the group consisting of aromatic hydrocarbons, aliphatic hydrocarbons, halogenated hydrocarbons, ethers, ketones, esters, alcohols, water, nitriles, and aprotic polar solvents, a mixed solvent of two or more selected from the group consisting of aromatic hydrocarbons, aliphatic hydrocarbons, halogenated hydrocarbons, ethers, ketones, esters, alcohols, water, nitriles, and aprotic polar solvents, or a mixed solvent of at least one selected from the group consisting of aromatic hydrocarbons, aliphatic hydrocarbons, halogenated hydrocarbons, ethers, ketones, esters, alcohols, water, nitriles, and aprotic polar solvents with a compound other than these.

[0069] Examples of aromatic hydrocarbons include toluene, xylene, and ethylbenzene. Examples of aliphatic hydrocarbons include hexane and heptane. Examples of halogenated hydrocarbons include monochlorobenzene. Examples of ethers include 1,4-dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, and methyl tert-butyl ether. Examples of ketones include acetone and ethyl methyl ketone. Examples of esters include butyl acetate and ethyl acetate. Examples of alcohols include methanol and ethanol. Examples of nitriles include acetonitrile and benzonitrile. Examples of aprotic polar solvents include N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and sulfolane.

[0070] Examples of methylating agents include CH3-X 3 A compound represented by the formula: 3 represents a leaving group. ], dimethyl sulfate, dimethyl carbonate and diazo compounds are listed, and among them, dimethyl sulfate is preferred. 3 Examples of the leaving group represented by the formula (I) include a chlorine atom, a bromine atom, an iodine atom, a p-toluenesulfonyloxy group, a methanesulfonyloxy group, and a trifluoromethanesulfonyloxy group. Examples of the diazo compound include trialkylsilyldiazomethanes such as trimethylsilyldiazomethane; and diazomethane.

[0071] The amount of the methylating agent used is usually 1 mol to 5 mol per mol of compound (8). When the mixture containing compound (8) obtained in step 3 is used as compound (8), the amount of the methylating agent used is usually 1 mol to 5 mol per mol of compound (5) in step 3.

[0072] As a methylating agent, CH3-X 3When a compound represented by the formula (I), dimethyl sulfate, or dimethyl carbonate is used, it is preferable to carry out the reaction in the presence of a base. Examples of the base include inorganic bases, alkali metal alkoxides, and mixtures of two or more thereof. Examples of the inorganic base include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, and sodium hydride. Examples of the alkali metal alkoxide include potassium t-butoxide, sodium methoxide, potassium methoxide, and sodium ethoxide.

[0073] When a base is used, the amount of the base used is preferably 1 to 10 moles per mole of compound (8).

[0074] When a diazo compound is used as a methylating agent, it is preferable to use a protic solvent, such as the alcohols mentioned above.

[0075] The reaction may be carried out in the presence of a catalyst. Examples of the catalyst include quaternary ammonium salts such as tetrabutylammonium chloride, tetrabutylammonium bromide, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide, benzyltriethylammonium chloride, and benzyltriethylammonium bromide. When a catalyst is used, the amount of the catalyst used is usually 0.005 mol to 0.2 mol per 1 mol of compound (8).

[0076] The reaction temperature is usually within the range of -20°C to 100°C.

[0077] The reaction time is usually within the range of 1 hour to 48 hours.

[0078] Compound (7) can be purified by conventional methods. For example, if a solid precipitates, the resulting solid can be filtered after the reaction is complete, and compound (7) can be purified. Alternatively, compound (7) can be purified by, for example, mixing the reaction mixture after the reaction with water or an acidic aqueous solution such as dilute hydrochloric acid or dilute sulfuric acid, extracting with an organic solvent, and then washing, drying, and concentrating under reduced pressure. The solvent used for extraction is not particularly limited as long as it dissolves compound (7). Examples of suitable solvents include ethers such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, and cyclopentyl methyl ether; hydrocarbons such as pentane, hexane, heptane, octane, benzene, toluene, xylene, ethylbenzene, mesitylene, cyclohexane, and cyclopentane; ketones such as ethyl methyl ketone; halogenated hydrocarbons such as monochlorobenzene; and mixtures of two or more of these. Compound (7) can also be further purified by column chromatography, recrystallization, or the like.

[0079] The reaction is carried out by mixing compound (8) and a methylating agent, and optionally a solvent, a base, and a catalyst. The order of mixing compound (8), the methylating agent, and optionally a solvent, a base, and a catalyst is not particularly limited. For example, compound (8), the solvent, and the methylating agent may be mixed simultaneously, or compound (8) and the solvent may be mixed and then the methylating agent may be added, or the methylating agent and the solvent may be mixed and then compound (8) may be added. When compound (8) or the methylating agent is added to the reaction system, compound (8) or the methylating agent may be added as a mixture with the solvent.

[0080] The present invention will be described in detail below with reference to Reference Production Examples and Examples, but the present invention is not limited to the following Examples.

[0081] Compound (1-4) is compound (1) wherein R 1 and R 2 is a methyl group. Compound (1-5) is the hydrochloride of compound (1-4). Compound (2-3) is a compound in which R 3 is a hydrogen atom, and X 1Compound (5-1) is a compound in which R 4 is a methyl group. Compound (8-1) is a compound in which R 4 is a methyl group. Compound (7-1) is a compound in which R 4 is a methyl group.

[0082] Compound (1-4)

[0083] Compound (1-5)

[0084] Compound (2-3)

[0085] Compound (5-1)

[0086] Compound (8-1)

[0087] Compound (7-1)

[0088] In the following examples, unless otherwise specified, quantitative analysis was performed using high-performance liquid chromatography. The yield of the target product was calculated from the peak area of ​​the target product using the absolute calibration curve method. The analytical conditions were as follows. [High-performance liquid chromatography analytical conditions] Mobile phase: Solution A: 5 mM ammonium carbonate aqueous solution, Solution B: acetonitrile Column: SUMIPAX (registered trademark) ODS Z-CLUE, particle size 3 μm, 4.6 mm ID × 100 mm UV measurement wavelength: 238 nm Flow rate: 1.0 mL / min Column oven: 30°C Pump: 2 LC-20AD (Shimadzu Corporation) (high-pressure gradient) Gradient conditions: Solution was delivered at the concentration gradient shown in [Table LC1].

[0089]

[0090] The retention times of the compounds described in the Examples when analyzed by high performance liquid chromatography are shown in Table LC2.

[0091]

[0092] In the following examples, unless otherwise specified, the reaction temperature refers to the external temperature of the reaction vessel.

[0093] Reference Production Example 1 (Production of Compound (2-3)) 44.59 g of pyridine, 50.01 g of 3-chlorobutan-2-one, and 150.10 g of 2-methyltetrahydrofuran were mixed and stirred under heating and reflux for 24 hours. The resulting mixture was allowed to cool to room temperature. The precipitated solid was collected by filtration and dried to obtain 49.04 g of compound (2-3). The physical properties of compound (2-3) are shown below. Compound (2-3): 1 H-NMR (DMSO-D6) δ: 9.07-9.03 (2H, m), 8.71-8.66 (1H, m), 8.25-8.19 (2H, m), 6.10 (1H, q), 2.37 (3H, s), 1.96 (3H, d).

[0094] Example 1-1 (Example of Step 1) 501.3 mg of compound (2-3), 1.72 g of compound (1-5), 1.17 g of triethylamine, 1.2 mL of ethylene glycol, and 1.8 mL of water were mixed and stirred for 2 hours at 80° C. The resulting mixture was analyzed by high performance liquid chromatography, and it was confirmed that compound (3) was produced in a yield of 83% based on compound (2-3).

[0095] Example 1-2 (Example of Step 1) 503.2 mg of compound (2-3), 1.73 g of compound (1-5), 1.15 g of triethylamine, 1.2 mL of ethylene glycol, and 1.8 mL of water were mixed and stirred for 2 hours at 60° C. The resulting mixture was analyzed by high performance liquid chromatography, and it was confirmed that compound (3) was produced in a yield of 73% based on compound (2-3).

[0096] Example 1-3 (Example of Step 1) 500.9 mg of compound (2-3), 0.69 g of compound (1-5), 0.41 g of triethylamine, 1.2 mL of ethylene glycol, and 3.6 mL of water were mixed and stirred for 2 hours at 80° C. The resulting mixture was analyzed by high performance liquid chromatography, and it was confirmed that compound (3) was produced in a yield of 77% based on compound (2-3).

[0097] Example 1-4 (Example of Step 1) 499.0 mg of compound (2-3), 1.15 g of compound (1-5), 1.18 g of triethylamine, 2.3 mL of ethylene glycol, and 1.8 mL of water were mixed and stirred for 2 hours at 80° C. The resulting mixture was analyzed by high performance liquid chromatography, and it was confirmed that compound (3) was produced in a yield of 80% based on compound (2-3).

[0098] Example 1-5 (Example of Step 1) 502.7 mg of compound (2-3), 0.69 g of compound (1-5), 0.53 g of N,N-diisopropylethylamine, 1.2 mL of ethylene glycol, and 1.8 mL of water were mixed and stirred for 2 hours at 80° C. The resulting mixture was analyzed by high performance liquid chromatography, and it was confirmed that compound (3) was produced in a yield of 73% based on compound (2-3).

[0099] Example 1-6 (Example of Step 1) 504.2 mg of compound (2-3), 0.69 g of compound (1-5), 0.41 g of triethylamine, 1.2 mL of tert-butyl alcohol, and 1.8 mL of water were mixed and stirred for 2 hours at 80° C. The resulting mixture was analyzed by high performance liquid chromatography, and it was confirmed that compound (3) was produced in a yield of 81% based on compound (2-3).

[0100] Example 1-7 (Example of Step 1) 504.0 mg of compound (2-3), 0.69 g of compound (1-5), 0.52 g of N,N-diisopropylethylamine, 1.2 mL of 2-propanol, and 1.8 mL of water were mixed and stirred for 2 hours at 80° C. The resulting mixture was analyzed by high-performance liquid chromatography, and it was confirmed that compound (3) was produced in a yield of 72% based on compound (2-3).

[0101] Example 1-8 (Example of Step 1) 502.3 mg of compound (2-3), 0.69 g of compound (1-5), 0.41 g of triethylamine, 1.2 mL of ethylene glycol, and 1.8 mL of water were mixed and stirred for 2 hours at 80° C. The resulting mixture was analyzed by high performance liquid chromatography, and it was confirmed that compound (3) was produced in a yield of 75% based on compound (2-3).

[0102] Example 1-9 (Example of Step 1) 495.5 mg of compound (2-3), 0.69 g of compound (1-5), 0.41 g of triethylamine, 1.2 mL of ethanol, and 1.8 mL of water were mixed and stirred for 2 hours at 80° C. The resulting mixture was analyzed by high performance liquid chromatography, and it was confirmed that compound (3) was produced in a yield of 73% based on compound (2-3).

[0103] Example 1-10 (Example of Step 1) 499.7 mg of compound (2-3), 0.69 g of compound (1-5), 0.47 g of N,N,N',N'-tetramethylethane-1,2-diamine, 1.3 mL of ethylene glycol, and 1.8 mL of water were mixed and stirred for 2 hours at 80° C. The resulting mixture was analyzed by high performance liquid chromatography, and it was confirmed that compound (3) was produced in a yield of 71% based on compound (2-3).

[0104] Example 1-11 (Example of Step 1) 500.5 mg of compound (2-3), 1.15 g of compound (1-5), 1.18 g of triethylamine, and 3.1 mL of ethylene glycol were mixed and stirred for 2 hours at 80° C. The resulting mixture was analyzed by high performance liquid chromatography, and it was confirmed that compound (3) was produced in a yield of 64% based on compound (2-3).

[0105] Example 1-12 (Example of Step 1) 3 mL of ethylene glycol, 3.70 g of pyridine, and 4.99 g of 3-chlorobutan-2-one were mixed and stirred at 80°C for 5.5 hours. At the same temperature, 10 mL of xylene, 5.00 g of compound (1-5), 18 mL of water, 0.7539 g of tetrabutylammonium bromide, and 10.22 g of triethylamine were sequentially added to the resulting mixture, and the mixture was stirred at 80°C for 3 hours. The resulting mixture was allowed to cool to room temperature and separated. The resulting organic layer was analyzed by high-performance liquid chromatography, and it was confirmed that compound (3) was produced in a yield of 76% based on compound (1-5).

[0106] Example 1-13 (Example of Step 1) 9.60 L of ethylene glycol, 5.33 kg of pyridine, and 7.18 kg of 3-chlorobutan-2-one were mixed and stirred at 80°C for 5 hours to obtain a mixture containing compound (2-3). At the same temperature, 43.2 L of ethylene glycol and 12.0 kg of compound (1-5) were added sequentially to the mixture. A solution of 8.92 kg of sodium carbonate dissolved in 43.2 L of water was slowly added to the resulting mixture, followed by stirring at 80°C for 10 hours. The resulting mixture was allowed to cool to room temperature and added to 192 L of hydrochloric acid with a molar concentration of 1 mol / L at the same temperature. The resulting mixture was extracted twice with 180 L of methyl tert-butyl ether, and the resulting organic layers were combined. The resulting organic layer was washed with 60 L of water and then with 60 L of saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. 60 L of hexane was added to the resulting concentrated residue, and the mixture was again concentrated under reduced pressure. To the concentrated residue, 144 L of hexane was added again, and the mixture was stirred at 70°C for 10 minutes. The resulting mixture was cooled to room temperature. The transparent upper layer was separated by decantation, and the resulting upper layer was concentrated under reduced pressure. The resulting concentrated residue was cooled to 0°C to 5°C. The precipitated solid was collected by filtration, washed with 24 L of hexane, and dried under reduced pressure to obtain 7.35 kg of compound (3) as a solid (71% yield based on compound (1-5)).

[0107] Example 2-1 (Example of Step 2) To a mixture of 45.8 g of compound (3), 167.6 g of xylene, and 44.1 g of methyl chloroacetate, 73.0 g of a 28 wt % sodium methoxide methanol solution was added dropwise at 80°C, and 3.4 g of dimethyl sulfate was added and stirred for 1 hour. After cooling to 60°C, 126.5 g of water was added to the resulting mixture, which was then separated, and the resulting organic layer was concentrated under reduced pressure. Methanol and water were added to the resulting concentrated residue to precipitate a solid, and 59.7 g of compound (5-1) was isolated as a solid.

[0108] Example 3-1 (Example of Step 3) 21.91 g of sodium methoxide was suspended in 50.43 g of xylene at room temperature to obtain a suspension. A solution containing 50.1 g of compound (5-1), 150.1 g of xylene, and 23.68 g of methyl formate was added dropwise to the suspension heated to 30°C over 2 hours, followed by stirring at 30°C for 2.5 hours. The resulting mixture was cooled to 0°C, and 150.4 g of water, 10.14 g of 35 wt% hydrochloric acid, and 1.11 g of a 27 wt% aqueous sodium hydroxide solution were added sequentially. The mixture was stirred, then allowed to stand, and the mixture was allowed to separate. The aqueous layer was removed to obtain 250.5 g of an aqueous layer. The resulting aqueous layer was analyzed by high-performance liquid chromatography, and the yield of the sodium salt of compound (8-1) was 91% based on compound (5-1).

[0109] To 4.47 g of the aqueous layer obtained in Example 3-1, 3.91 g of benzonitrile, 0.04 g of tetrabutylammonium bromide, 0.11 g of a 27 wt % aqueous sodium hydroxide solution, and 0.62 g of dimethyl sulfate were added successively at room temperature, and the mixture was stirred for 2 hours at 40° C. When the resulting mixture was analyzed by high performance liquid chromatography, the yield of compound (7-1) was 93% based on the sodium salt of compound (8-1).

[0110] According to the present invention, compound (3) can be efficiently produced, and compound (5) and compound (7) can be efficiently produced using compound (3).

Claims

1. Process 1: Formula (1) [In the formula, R 1 and R 2 are the same or different and represent a C1-C6 chain hydrocarbon group, or R 1 and R 2 Together, these form -(CH2) a -, or -(CH2)2-O-(CH2)2-, and a represents 4 or 5.] with a compound represented by formula (2) [In the formula, R 3 represents a C1-C6 chain hydrocarbon group, a chlorine atom, or a hydrogen atom; X 1 represents a chlorine atom, a bromine atom, or an iodine atom.] in the presence of a base in a solvent to obtain a compound represented by formula (3): A method for producing a compound represented by formula (3), comprising the step of obtaining a compound represented by formula (3):

2. R 1 and R 2 The method according to claim 1, wherein each of the groups is the same or different and is a methyl group or an ethyl group.

3. The process according to claim 1 or 2, wherein the base is a trialkylamine or an alkali metal carbonate.

4. The method according to any one of claims 1 to 3, wherein the compound represented by formula (1) or a salt thereof is the hydrochloride of the compound represented by formula (1).

5. The method according to any one of claims 1 to 4, wherein the solvent contains at least one selected from the group consisting of water and alcohol.

6. The method according to claim 5, wherein the solvent contains 0.50 to 50 parts by weight of water and 0.050 to 10 parts by weight of alcohol per 1 part by weight of the compound represented by formula (2).

7. In addition to step 1 according to any one of claims 1 to 6, step 2: reacting the compound represented by formula (3) obtained in step 1 with the compound represented by formula (4) [In the formula, X 2 represents a leaving group, R 4 represents a C1-C6 chain hydrocarbon group. ] in the presence of a base to obtain a compound represented by formula (5): [In the formula, R 4 has the same meaning as defined above.].

8. In addition to steps 1 and 2 as claimed in claim 7, step 3: reacting the compound represented by formula (5) obtained in step 2 with the compound represented by formula (6) [In the formula, R 5 represents a C1-C6 chain hydrocarbon group. ] in the presence of a base; and Step 4: reacting the compound obtained in Step 3 with a methylating agent to form a compound represented by formula (7): [In the formula, R 4 has the same meaning as defined in claim 7. A method for producing a compound represented by formula (7), comprising the step of obtaining a compound represented by formula (7):