Methods for producing 3-phenylcyclohexenone compound and derivative thereof

Abstract

The present invention provides: a novel method for producing a 3-phenylcyclohexenone compound having a substituent at the 6-position; and a novel method for producing, by using the same, a derivative of a 3-phenylcyclohexenone compound having a substituent at the 4-position. Provided is a method for producing a compound represented by formula (3), the method comprising a step for mixing a compound represented by formula (1) [in the formula, R1, R2, R3, R4, and R5 are the same as or different from each other, and each represent a hydrogen atom or the like, R6 represents a C1-C6 chain hydrocarbon group which may be substituted with one phenyl group, R7 represents a hydrogen atom or the like, or R6 and R7 may be taken together to form –(CH2)4- or the like] or a salt thereof, a compound represented by formula (2) [in the formula, R8 represents a C1-C12 chain hydrocarbon group, and R9 represents a hydrogen atom or the like], and an alkali metal carbonate, and reacting these components in the presence of pyrrolidone to obtain a compound represented by formula (3) [in the formula, R1, R2, R3, R4, R5, R8, and R9 have the same meanings as above].

Description

Method for producing 3-phenylcyclohexenone compound and its derivatives

[0001] This patent application claims priority under the Paris Convention to and the benefit of Japanese Patent Application No. 2024-055710 (filed March 29, 2024), the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to a method for producing a 3-phenylcyclohexenone compound and its derivatives.

[0003] Patent Document 1 describes a useful 3-hydroxy-4-methylbiphenyl compound derivative that has plant disease control efficacy. As a method for producing the 3-hydroxy-4-methylbiphenyl compound derivative, for example, Patent Document 1 describes a method of reacting a 3-hydroxy-4-methylbiphenyl compound with a methyl acetate (e.g., methyl chloroacetate) having a leaving group at the 2-position, and a 3-hydroxybiphenyl compound having a substituent such as a chain hydrocarbon group at the 4-position is useful as a production intermediate. Non-Patent Document 1 also describes a method for producing a 3-hydroxybiphenyl compound using a 3-phenylcyclohexenone compound as a raw material, and the 3-phenylcyclohexenone compound is also useful as a production intermediate.

[0004] Non-Patent Document 2 describes a method for producing a 3-phenylcyclohexenone compound, but the product of the reaction to construct the 3-phenylcyclohexenone ring is inevitably substituted with an ester group at the 6-position. Therefore, in order to synthesize a 3-phenylcyclohexenone compound having a desired substituent (e.g., a chain hydrocarbon group) at the 6-position, it was necessary to remove the ester group at the 6-position by sequentially carrying out hydrolysis and decarboxylation, and then introduce the desired substituent (e.g., a chain hydrocarbon group) at the 6-position. Therefore, a new method for producing a 3-phenylcyclohexenone compound having a substituent at the 6-position was desired.

[0005] Japanese Patent Application Laid-Open No. 2001-64237

[0006] Green Chemistry, 2016, 18, 6462-6467Journal of the American Chemical Society (1953), 75, 4995-5001

[0007] An object of the present invention is to provide a novel method for producing a 3-phenylcyclohexenone compound having a substituent at the 6-position, and a novel method for producing a derivative of a 3-hydroxybiphenyl compound having a substituent at the 4-position using the same.

[0008] The present inventors have conducted extensive research to solve the above problems and have completed the present invention.

[0009] That is, the present invention is as follows: [1] Step 1: A method for producing a compound represented by formula (1) [In the formula, R 1 , R 2 , R 3 , R 4 and R 5 are the same or different and represent a C1-C12 chain hydrocarbon group optionally substituted with one or more fluorine atoms, a hydrogen atom, a halogen atom, a cyano group, or a nitro group; R 6 represents a C1-C6 chain hydrocarbon group optionally substituted with one phenyl group, R 7 represents a C1-C6 chain hydrocarbon group optionally substituted with one phenyl group, a phenyl group, or a hydrogen atom, or R 6 and R 7 may combine with each other to form —(CH2)4—, —(CH2)5—, or —(CH2)2-O—(CH2)2—. ] (hereinafter referred to as compound (1)) or a salt thereof with formula (2) [In the formula, R 8 represents a C1-C12 chain hydrocarbon group, R 9 represents a hydrogen atom or a C1-C12 chain hydrocarbon group (where R 8 and R 9 If they are different, R 8 R is better 9 is a group more bulky than the above.) A compound represented by the formula (3) (hereinafter referred to as compound (2)) is mixed with an alkali metal carbonate and reacted in the presence of pyrrolidine to obtain a compound represented by the formula (3) [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 8 and R 9 has the same meaning as above.] (hereinafter referred to as compound (3)). [2] A method for producing compound (3), comprising a step of obtaining a compound represented by the formula: 6 and R 7 and R combine to form —(CH)—, and the pyrrolidine is pyrrolidine produced from compound (1) in the reaction system. 6 and R 7 The combination of 6 and R 7 is a methyl group; 6 and R 7 is an ethyl group; 6 and R 7 is an isopropyl group; 6 and R 7 is a butyl group; 6 and R 7 is a benzyl group; 6 is an ethyl group, and R 7 is a hydrogen atom; 6 is a benzyl group, and R 7 is a hydrogen atom; 6 is a methyl group, and R 7 is a phenyl group; 6 and R 7 and R combine to form -(CH2)4-; 6 and R 7 and R together form -(CH2)5-; or R 6 and R 7 [4] The method according to [1], wherein R 6 and R 7 The combination of 6 and R 7 is a methyl group;6 and R 7 is an ethyl group; or R 6 and R 7 [5] The method according to [1], wherein R is a combination of R and R together to form —(CH2)4—. 8 is a methyl group, and R 9 [6] The method according to any one of [1] to [4], wherein R is a hydrogen atom. 1 and R 5 is a hydrogen atom, and R 2 , R 3 and R 4 [7] The method according to any one of [1] to [5], wherein R are the same or different and are a hydrogen atom or a halogen atom. 2 , R 3 and R 4 [8] In addition to step 1 according to any one of [1] to [7], step 2: oxidizing the compound (3) obtained in step 1 to obtain a compound represented by formula (6): [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 8 and R 9 has the same meaning as above.] (hereinafter referred to as compound (6)). [9] The production method according to [8], wherein step 2 includes steps 2-1 and 2-2: Step 2-1: reacting compound (3) obtained in step 1 with a compound represented by formula (4) [In the formula, R 10 represents a C1-C12 chain hydrocarbon group.] (hereinafter referred to as compound (4)) is reacted with bromine or sulfuric acid to obtain a compound represented by formula (5): [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 9 and R 10has the same meaning as above.] (hereinafter referred to as compound (5)); Step 2-2: A step of solvolyzing compound (5) obtained in step 2-1 to obtain compound (6).

[10] R 10

[11] In addition to the steps 1 and 2 described in any one of [8] to

[10] , the method for producing a compound according to [9], further comprising the steps of: step 3: reacting the compound (6) obtained in step 2 with a compound represented by formula (7) [In the formula, X 1 represents a leaving group, R 11 represents a C1-C6 chain hydrocarbon group. ] (hereinafter referred to as compound (7)) in the presence of a base to obtain a compound represented by formula (8): [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 9 and R 11 has the same meaning as above.] (hereinafter referred to as compound (8)).

[12] A method for producing compound (8), comprising a step of obtaining a compound represented by formula (11): [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 9 and R 11 has the same meaning as above.] (hereinafter referred to as compound (11)): Step 4: Reacting compound (8) obtained in step 3 with a compound represented by formula (9) [In the formula, R 12 represents a C1-C6 chain hydrocarbon group.] (hereinafter referred to as compound (9)) in the presence of a base; Step 5: reacting the compound obtained in Step 4 with a methylating agent to obtain compound (11).

[0010] According to the present invention, it is possible to efficiently produce a 3-phenylcyclohexenone compound having a substituent at the 6-position, i.e., compound (3), which can be used as a production intermediate for a 3-hydroxybiphenyl compound having a substituent at the 4-position. Furthermore, compound (6), which is a 3-hydroxybiphenyl compound having a substituent at the 4-position, and compounds (8) and (11), which are derivatives of a 3-hydroxybiphenyl compound having a substituent at the 4-position, can be efficiently produced using compound (3).

[0011] The present invention will be described in detail below.

[0012] The substituents in the present invention will be explained.

[0013] The halogen atom represents a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0014] 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.

[0015] 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, a hexyl group, a heptyl group, an octyl group, a decyl group, and a dodecyl 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, a 5-hexenyl group, a 6-heptenyl group, a 7-octenyl group, a 9-decenyl group, and an 11-dodecenyl 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, a 5-hexynyl group, a 6-heptynyl group, a 7-octynyl group, a 9-decynyl group, and an 11-dodecynyl group.

[0016] Compound (1) will be explained.

[0017] R 1 , R 2 , R 3 , R 4 or R 5 Examples of the C1-C12 chain hydrocarbon group include the chain hydrocarbon groups having 1 to 12 carbon atoms. Among these, the chain hydrocarbon groups having 1 to 6 carbon atoms are preferred, the chain hydrocarbon groups having 1 to 4 carbon atoms are more preferred, and a methyl group, an ethyl group, and a propyl group are even more preferred.

[0018] R 1 , R 2 , R 3 , R 4 or R 5Examples of the C1-C12 chain hydrocarbon group substituted with one or more fluorine atoms in the formula (I) include the above-mentioned chain hydrocarbon groups having 1 to 12 carbon atoms in which a hydrogen atom of the above-mentioned C1-C12 chain hydrocarbon group has been substituted with one or more fluorine atoms. Among these, a trifluoromethyl group, a pentafluoroethyl group, a heptafluoropropyl group, a difluoromethyl group, and a fluoromethyl group are preferred, a trifluoromethyl group, a pentafluoroethyl group, a difluoromethyl group, and a fluoromethyl group are more preferred, a trifluoromethyl group, a difluoromethyl group, and a fluoromethyl group are even more preferred, and a trifluoromethyl group is particularly preferred.

[0019] R 1 and R 5 With respect to R, a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, and a trifluoromethyl group are preferred, a hydrogen atom and a fluorine atom are more preferred, and a hydrogen atom is even more preferred. 2 , R 3 and R 4 With regard to R, a C1-C6 chain hydrocarbon group optionally substituted with one or more fluorine atoms, a hydrogen atom, and a halogen atom are preferred, a methyl group, an ethyl group, a propyl group, a trifluoromethyl group, a pentafluoroethyl group, a difluoromethyl group, a fluoromethyl group, a hydrogen atom, and a halogen atom are more preferred, a methyl group, a trifluoromethyl group, a hydrogen atom, a fluorine atom, a chlorine atom, and a bromine atom are even more preferred, and a hydrogen atom is particularly preferred. 1 , R 2 , R 3 , R 4 and R 5 The combination of R 1 , R 2 , R 3 , R 4 and R 5 is a hydrogen atom; 1 and R 5 is a hydrogen atom, and R 2 , R 3 and R 4 are the same or different and are a hydrogen atom or a halogen atom. 1 , R 2 , R 3 , R4 and R 5 is preferably a hydrogen atom.

[0020] R 6 or R 7 In the formula (I), the C1-C6 chain hydrocarbon group which may be substituted with one phenyl group means a C1-C6 chain hydrocarbon group which is substituted with one phenyl group and a C1-C6 chain hydrocarbon group. 6 and R 7 is a C1-C6 chain hydrocarbon group optionally substituted with 1 phenyl group, R 6 and R 7 may be the same or different. Examples of the C1-C6 chain hydrocarbon group substituted with one phenyl group include the above-mentioned chain hydrocarbon groups having 1 to 6 carbon atoms substituted with one phenyl group. Of these, a benzyl group is preferred. Examples of the C1-C6 chain hydrocarbon group include the above-mentioned chain hydrocarbon groups having 1 to 6 carbon atoms. Of these, the above-mentioned chain hydrocarbon groups having 1 to 4 carbon atoms are preferred, and the above-mentioned alkyl groups having 1 to 4 carbon atoms are more preferred. More specifically, the C1-C6 chain hydrocarbon group is preferably a methyl group, an ethyl group, an isopropyl group, or a butyl group, and more preferably a methyl group or an ethyl group.

[0021] R 6 and R 7 The compound (1) in which the groups are combined to form -(CH2)4- is specifically represented by the formula (1-1): [In the formula, R 1 , R 2 , R 3 , R 4 and R 5 has the same meaning as above. ] (hereinafter referred to as compound (1-1)). 6 and R 7 The compound (1) in which the groups are combined to form -(CH2)5- is specifically represented by the formula (1-2): [In the formula, R 1 , R 2 , R 3 , R 4 and R 5 has the same meaning as above.].6 and R 7 The compound (1) in which the above are combined to form -(CH2)2-O-(CH2)2- is specifically represented by the formula (1-3): [In the formula, R 1 , R 2 , R 3 , R 4 and R 5 has the same meaning as above. ].

[0022] R 6 and R 7 As a combination of, for example, R 6 and R 7 are the same or different and are C1-C6 chain hydrocarbon groups substituted with one phenyl group; R 6 is a C1-C6 chain hydrocarbon group substituted with one phenyl group, and R 7 is a C1-C6 chain hydrocarbon group; 6 is a C1-C6 chain hydrocarbon group substituted with one phenyl group, and R 7 is a phenyl group; 6 is a C1-C6 chain hydrocarbon group substituted with one phenyl group, and R 7 is a hydrogen atom; 6 and R 7 are the same or different and are a combination of C1-C6 chain hydrocarbon groups; R 6 is a C1-C6 chain hydrocarbon group, and R 7 is a phenyl group; 6 is a C1-C6 chain hydrocarbon group, and R 7 is a hydrogen atom; 6 and R 7 and R combine to form -(CH2)4-; 6 and R 7 and R are taken together to form —(CH)—; and 6 and R 7 and R are taken together to form -(CH2)2-O-(CH2)2-. 6 and R 7 More specifically, the combination of R 6 and R7 is a methyl group; 6 and R 7 is an ethyl group; 6 and R 7 is an isopropyl group; 6 and R 7 is a butyl group; 6 and R 7 is a benzyl group; 6 is an ethyl group, and R 7 is a hydrogen atom; 6 is a benzyl group, and R 7 is a hydrogen atom; 6 is a methyl group, and R 7 is a phenyl group; 6 and R 7 and R combine to form -(CH2)4-; 6 and R 7 and R are taken together to form —(CH)—; and 6 and R 7 and R are preferably combined to form —(CH)—O—(CH)—, and R 6 and R 7 is a methyl group; 6 and R 7 is an ethyl group; and R 6 and R 7 and are combined to form --(CH2)4--.

[0023] Compound (1) may be used as it is or as a salt of compound (1).

[0024] Examples of salts of compound (1) include hydrochloride, hydrobromide, sulfate, phosphate, etc., and among these, hydrochloride is preferred.

[0025] Salts of compound (1) are commercially available, known, or can be produced using known methods (for example, RSC Advances (2020), 10(32), 18583-18593, Research Journal of Chemistry and Environment (2015), 19(10), 20-24, and Bioorganic & Medicinal Chemistry Letters (2021), 36, 127780). The salts of compound (1) exist as tautomers (enol forms), and each isomer and a mixture of isomers in any ratio can be used.

[0026] Compound (1) is commercially available, publicly known, or can be produced using known methods (e.g., Synthesis (2001), (15), 2239-2246). Alternatively, compound (1) can be produced by neutralizing a salt of compound (1) with a base. A method for producing compound (1) by neutralizing a salt of compound (1) with a base will be described below. Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. Of these, sodium hydroxide is preferred. The amount of base used is usually 0.9 mol to 5 mol, preferably 1.0 mol to 1.6 mol, per mol of the salt of compound (1). The reaction is usually carried out in a solvent. Water is the preferred solvent. The reaction can also be carried out in a two-layer system by mixing a water-immiscible solvent with water. Examples of water-immiscible solvents include ethers such as diethyl ether, methyl tert-butyl ether (hereinafter referred to as MTBE), 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. The amount of solvent used is typically 1 to 20 parts by weight per part by weight of the salt of compound (1). The reaction is carried out by mixing the salt of compound (1), a base, and a solvent. The order of mixing the salt of compound (1), the base, and the solvent is not particularly limited. Examples include mixing the salt of compound (1) and the solvent and then adding the base; mixing the base and the solvent and then adding the salt of compound (1); and adding the salt of compound (1) and the base to the solvent. The reaction temperature is typically within the range of 0°C to 80°C, preferably 0°C to 60°C. The reaction time varies depending on conditions such as the reaction temperature, but is usually 0.1 to 100 hours, preferably 0.5 to 48 hours. Compound (1) can be purified by a conventional method. For example, after completion of the reaction, an organic solvent may be added to the reaction mixture as needed for extraction, and the resulting organic layer may be washed, dried, and concentrated under reduced pressure to purify compound (1).The solvent used for extraction is not particularly limited as long as it dissolves compound (1), but examples include ethers such as diethyl ether, tetrahydrofuran, MTBE, 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 of these. Compound (1) can also be further purified by column chromatography or the like. Compound (1) exists in the form of tautomers (enol forms), and each isomer and a mixture of isomers in any ratio can be used.

[0027] Compound (2) will now be described.

[0028] R 8 or R 9 In the formula, examples of the C1-C12 chain hydrocarbon group include the chain hydrocarbon groups having 1 to 12 carbon atoms. Among these, the chain hydrocarbon groups having 1 to 4 carbon atoms are preferred, with methyl and ethyl groups being more preferred, and methyl groups being even more preferred. 8 and R 9 are different, R 8 is R 9 In this specification, the Charton parameter (e.g., Journal of the American Chemical Society (1975), 97, 1552-1556) is used as an index of the bulkiness of a substituent. In this specification, for example, the bulkiness of a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, and a tert-butyl group increases in this order.

[0029] R 8 and R 9 As a combination of, for example, R 8 is a C1-C12 chain hydrocarbon group, and R 9 is a hydrogen atom; 8 is a C1-C4 chain hydrocarbon group, and R 9 is a hydrogen atom; 8is a C1-C12 chain hydrocarbon group, and R 9 is a C1-C12 chain hydrocarbon group (provided that R 8 and R 9 If they are different, R 8 R is better 9 and R 8 is a C1-C4 chain hydrocarbon group, and R 9 is a C1-C4 chain hydrocarbon group (provided that R 8 and R 9 If they are different, R 8 R is better 9 R 8 and R 9 More specifically, the combination of R 8 is a methyl group, and R 9 is preferably a hydrogen atom.

[0030] Compound (2) is commercially available, known, or can be prepared by a known method. Compound (2) exists as a tautomer (enol form), and each isomer and a mixture of isomers in any ratio can be used.

[0031] Compound (4) will now be described.

[0032] R 10 Examples of the C1-C12 chain hydrocarbon group in the formula include the above-mentioned chain hydrocarbon groups having 1 to 12 carbon atoms. Among them, a C1-C6 alkyl group is preferred, with a methyl group, an ethyl group, and a propyl group being more preferred, and a methyl group being even more preferred.

[0033] Compound (4) is commercially available, known, or can be prepared using known methods.

[0034] Compound (7) will now be described.

[0035] R 11 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.

[0036] X 1 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.

[0037] Compound (7) is commercially available, known, or can be prepared using known methods.

[0038] Compound (9) will now be described.

[0039] R 12 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.

[0040] Compound (9) is commercially available, known, or can be prepared using known methods.

[0041] Step 1 will be described. In step 1, compound (1) or a salt thereof, compound (2), and an alkali metal carbonate are mixed and reacted in the presence of pyrrolidine to obtain compound (3).

[0042] Examples of alkali metal carbonates include lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate. Of these, sodium carbonate, potassium carbonate, and mixtures of two or more thereof are preferred.

[0043] When compound (1) is used as compound (1) or a salt thereof, the amount of alkali metal carbonate used is usually 0.1 mol to 2.0 mol, preferably 0.3 mol to 1.2 mol, per 1 mol of compound (1). When a salt of compound (1) is used as compound (1) or a salt thereof, the amount of alkali metal carbonate used is usually 0.2 mol to 5 mol, preferably 0.4 mol to 3.5 mol, per 1 mol of the salt of compound (1).

[0044] The amount of pyrrolidine used is usually 0.2 mol to 2.0 mol, preferably 0.3 mol to 1.5 mol, per 1 mol of compound (1) or a salt thereof. 6 and R 7 When these are combined to form —(CH)—, that is, when compound (1) is compound (1-1), pyrrolidine is produced from compound (1-1) in the reaction system, and therefore pyrrolidine does not need to be added to the reaction system.

[0045] The amount of compound (2) used is usually 1 to 100 moles, preferably 1 to 15 moles, per mole of compound (1) or a salt thereof.

[0046] The reaction is usually carried out in a solvent. A protic solvent is preferred as the solvent. Examples of protic solvents include alcohols; water; and mixtures of two or more of these, with alcohol being more preferred. Specific examples of alcohols include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, tert-butyl alcohol, ethylene glycol, and mixtures of two or more of these. Methanol, ethanol, and 2-propanol are preferred, with methanol and ethanol being more preferred. A mixture of the protic solvent and an aprotic 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; ethers such as diisopropyl ether and MTBE; and mixtures of two or more of these. The reaction can also be carried out in a two-layer system by mixing a water-immiscible solvent with water. Examples of water-immiscible solvents include hydrocarbons such as heptane, toluene, xylene, and ethylbenzene; halogenated hydrocarbons such as monochlorobenzene; nitriles such as benzonitrile; ketones such as ethyl methyl ketone; ethers such as diisopropyl ether and MTBE; alcohols such as 1-butanol; and mixtures of two or more of these.

[0047] The amount of the solvent used is usually 2 to 10 parts by weight per part by weight of the compound (1).

[0048] 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.

[0049] 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 (1).

[0050] The reaction is carried out by mixing compound (1) or a salt thereof, compound (2), pyrrolidine, a solvent, and an alkali metal carbonate. As described above, when compound (1) is compound (1-1), pyrrolidine is generated in the reaction system, so there is no need to mix pyrrolidine. That is, by mixing compound (1-1) or a salt thereof, compound (2), a solvent, and an alkali metal carbonate, the reaction can be carried out in the presence of pyrrolidine. However, even when compound (1) is compound (1-1), pyrrolidine may be mixed and the reaction may be carried out. That is, compound (1-1) or a salt thereof, compound (2), pyrrolidine, a solvent, and an alkali metal carbonate may be mixed and the reaction may be carried out. In mixing compound (1) or a salt thereof, compound (2), pyrrolidine, a solvent, and an alkali metal carbonate, the order of mixing is not particularly limited. For example, compound (1), compound (2), pyrrolidine, and a solvent are mixed, and then an alkali metal carbonate is added; alkali metal carbonate, compound (1), pyrrolidine, and a solvent are mixed, and then compound (2) is added; alkali metal carbonate, compound (2), pyrrolidine, and a solvent are mixed, and then compound (1) is added; alkali metal carbonate, compound (1), compound (2), and a solvent are mixed, and then pyrrolidine is added; compound (1), pyrrolidine, and a solvent are mixed, and then an alkali metal carbonate and compound (2) are added; compound (2), pyrrolidine, and a solvent are mixed, and then an alkali metal carbonate and compound (1) are added; alkali metal carbonate, pyrrolidine, and a solvent are mixed, and then an alkali metal carbonate and compound (1) are added; After mixing the compound (1) and the solvent, add compound (1) and compound (2); after mixing the compound (1), compound (2) and the solvent, add an alkali metal carbonate and pyrrolidine; after mixing the alkali metal carbonate, compound (2) and the solvent, add compound (1) and pyrrolidine; after mixing the alkali metal carbonate, compound (1) and the solvent, add compound (2) and pyrrolidine; after mixing the compound (1) and the solvent, add the alkali metal carbonate, pyrrolidine and compound (2); after mixing the compound (2) and the solvent, add the alkali metal carbonate, pyrrolidine and compound (1); after mixing the pyrrolidine and the solvent, add the alkali metal carbonate, compound (1) and compound (2); after mixing the alkali metal carbonate and the solvent, add pyrrolidine, compound (1) and compound (2);Add an alkali metal carbonate, compound (1), compound (2), and pyrrolidine to a solvent; mix compound (1-1), compound (2), and the solvent, and then add an alkali metal carbonate; mix alkali metal carbonate, compound (1-1), and the solvent, and then add compound (2); mix alkali metal carbonate, compound (2), and the solvent, and then add compound (1-1); mix compound (1-1) and the solvent, and then add an alkali metal carbonate and compound (2); mix compound (2) and the solvent, and then add an alkali metal carbonate and compound (1-1); After mixing an alkali metal carbonate and a solvent, compound (1-1) and compound (2) are added; after adding an alkali metal carbonate, compound (1-1) and compound (2) to a solvent, compound (1-1) and compound (2) are added; after mixing a salt of compound (1), compound (2), pyrrolidine and a solvent, an alkali metal carbonate is added; after mixing an alkali metal carbonate, a salt of compound (1), pyrrolidine and a solvent, compound (2) is added; after mixing an alkali metal carbonate, compound (2), pyrrolidine and a solvent, a salt of compound (1) is added; after mixing an alkali metal carbonate, compound (2), pyrrolidine and a solvent, compound (1) is added; After mixing, pyrrolidine is added; after mixing the salt of compound (1), pyrrolidine, and the solvent, an alkali metal carbonate and compound (2) are added; after mixing compound (2), pyrrolidine, and the solvent, an alkali metal carbonate and a salt of compound (1) are added; after mixing the alkali metal carbonate, pyrrolidine, and the solvent, a salt of compound (1) and compound (2) are added; after mixing the salt of compound (1), compound (2), and the solvent, an alkali metal carbonate and pyrrolidine are added; after mixing the alkali metal carbonate, compound (2), and the solvent, a salt of compound (1) and pyrrolidine are added. Add lysine; mix the alkali metal carbonate, the salt of compound (1) and the solvent, then add compound (2) and pyrrolidine; mix the salt of compound (1) and the solvent, then add the alkali metal carbonate, pyrrolidine and compound (2); mix compound (2) and the solvent, then add the alkali metal carbonate, pyrrolidine and the salt of compound (1); mix pyrrolidine and the solvent, then add the alkali metal carbonate, the salt of compound (1) and compound (2); mix the alkali metal carbonate and the solvent, then add the pyrrolidine, the salt of compound (1) and compound (2);Examples of the method include adding an alkali metal carbonate, a salt of compound (1), compound (2), and pyrrolidine to a solvent; mixing a salt of compound (1-1), compound (2), and a solvent, and then adding an alkali metal carbonate; mixing an alkali metal carbonate, a salt of compound (1-1), and a solvent, and then adding compound (2); mixing an alkali metal carbonate, compound (2), and a solvent, and then adding a salt of compound (1-1); mixing a salt of compound (1-1) and a solvent, and then adding an alkali metal carbonate and compound (2); mixing compound (2) and a solvent, and then adding an alkali metal carbonate and a salt of compound (1-1); mixing an alkali metal carbonate and a solvent, and then adding a salt of compound (1-1); Among these, compound (2), pyrrolidine, an alkali metal carbonate, and a solvent are mixed, and then compound (1) is added; a salt of compound (1), compound (2), an alkali metal carbonate, and a solvent are mixed, and then pyrrolidine is added; an alkali metal carbonate, compound (2), and a solvent are mixed, and then compound (1-1) is added;A preferred method is to mix the compound (1-1) and a salt thereof, the alkali metal carbonate, and the solvent, and then add compound (2). Compound (1) or a salt thereof, compound (2), pyrrolidine, and the alkali metal carbonate may be mixed with a portion of the solvent before use. 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), pyrrolidine (as described above, when compound (1) is compound (1-1), pyrrolidine is generated in the reaction system, so pyrrolidine does not need to be added to the reaction system), solvent, and alkali metal carbonate, may be added in their entirety at once, or in divided portions and added multiple times, or each component may be added gradually. Furthermore, two or more of the components to be added may be added simultaneously in their entirety at once, or in divided portions and added multiple times, or each component may be added simultaneously in their gradually increasing amounts. Furthermore, two or more of the components to be added may be mixed in advance and then added. The components to be mixed in advance may be mixed in their entirety or in part. Furthermore, two or more premixes of two or more components may be prepared so that the combinations of the components are different.

[0051] The reaction temperature is usually within the range of 40°C to 120°C, preferably within the range of 60°C to 100°C.

[0052] The reaction time varies depending on conditions such as the reaction temperature, but is usually 0.1 to 100 hours, preferably 1 to 48 hours.

[0053] When a salt of compound (1) is used as compound (1) or a salt thereof, it is preferable to carry out the reaction at a temperature usually within a range of 0°C to 60°C, preferably within a range of 10°C to 40°C, for usually 0.1 to 10 hours, preferably 0.5 to 2 hours, in order to neutralize the salt of compound (1) with an alkali metal carbonate in the reaction system before carrying out the reaction at the reaction temperature for the reaction time. More specifically, the reaction method may be, for example, mixing a salt of compound (1), compound (2), a solvent, an alkali metal carbonate, and pyrrolidine, followed by reacting for 0.1 to 10 hours at a temperature ranging from 0°C to 60°C, and then reacting for 0.1 to 100 hours at a temperature ranging from 60°C to 120°C; mixing a salt of compound (1), compound (2), a solvent, an alkali metal carbonate, and pyrrolidine, followed by reacting for 0.1 to 10 hours at a temperature ranging from 0°C to 60°C, and then reacting for 0.1 to 100 hours at a temperature ranging from 60°C to 100°C; mixing a salt of compound (1), compound (2), a solvent, an alkali metal carbonate, and pyrrolidine, followed by reacting for 0.5 to 2 hours at a temperature ranging from 10°C to 40°C, and then reacting for 0.1 to 100 hours at a temperature ranging from 40°C to 120°C; mixing a salt of compound (1), compound (2), a solvent, an alkali metal carbonate, and pyrrolidine, followed by The reaction is carried out at a temperature ranging from 10°C to 40°C for 0.5 to 2 hours, and then at a temperature ranging from 40°C to 100°C for 0.1 to 100 hours; the salt of compound (1), compound (2), a solvent, an alkali metal carbonate, and pyrrolidine are mixed, and then the reaction is carried out at a temperature ranging from 10°C to 40°C for 0.5 to 2 hours, and then at a temperature ranging from 60°C to 100°C for 0.1 to 100 hours; the salt of compound (1), compound (2), a solvent, and an alkali metal carbonate are mixed, and then the reaction is carried out at a temperature ranging from 10°C to 40°C for 0.5 to 2 hours, and then at a temperature ranging from 60°C to 100°C for 0.1 to 100 hours; After mixing the metal carbonate, pyrrolidine is added and the mixture is reacted at a temperature ranging from 0°C to 60°C for 0.1 to 10 hours, and then at a temperature ranging from 60°C to 120°C for 0.1 to 100 hours; after mixing the salt of compound (1), compound (2), a solvent, and an alkali metal carbonate, pyrrolidine is added and the mixture is reacted at a temperature ranging from 0°C to 60°C for 0.1 to 10 hours, and then at a temperature ranging from 60°C to 100°C for 0.1 to 100 hours;After mixing a salt of compound (1), compound (2), a solvent, and an alkali metal carbonate, pyrrolidine is added and the mixture is reacted at a temperature ranging from 10°C to 40°C for 0.5 to 2 hours, and then at a temperature ranging from 40°C to 120°C for 0.1 to 100 hours; after mixing a salt of compound (1), compound (2), a solvent, and an alkali metal carbonate, pyrrolidine is added and the mixture is reacted at a temperature ranging from 10°C to 40°C for 0.5 to 2 hours, and then at a temperature ranging from 40°C to 100°C for 0.1 to 100 hours; After mixing the solvent and the alkali metal carbonate, pyrrolidine is added and the mixture is reacted at a temperature ranging from 10°C to 40°C for 0.5 to 2 hours, and then at a temperature ranging from 60°C to 100°C for 0.1 to 100 hours; after mixing the salt of compound (1-1), compound (2), the solvent and the alkali metal carbonate, the mixture is reacted at a temperature ranging from 0°C to 60°C for 0.1 to 10 hours, and then at a temperature ranging from 60°C to 12 ... ℃ to 60°C for 0.1 to 10 hours, and then react at 60°C to 100°C for 0.1 to 100 hours; after mixing the salt of compound (1-1), compound (2), solvent and alkali metal carbonate, the mixture is reacted at 10°C to 40°C for 0.5 to 2 hours, and then reacted at 40°C to 120°C for 0.1 to 100 hours; after mixing the salt of compound (1-1), compound (2), solvent and alkali metal carbonate, the mixture is reacted at 10°C to 40°C for 0.5 to 2 hours, and then reacted at 40°C to 120°C for 0.1 to 100 hours; reacting for 0.1 to 100 hours at a temperature ranging from 0°C to 100°C; mixing a salt of compound (1-1), compound (2), a solvent, and an alkali metal carbonate, and then reacting for 0.5 to 2 hours at a temperature ranging from 10°C to 40°C, and then reacting for 0.1 to 100 hours at a temperature ranging from 60°C to 100°C; mixing a salt of compound (1-1), an alkali metal carbonate, and a solvent, and then adding compound (2), and then reacting for 0.1 to 10 hours at a temperature ranging from 0°C to 60°C, and then reacting for 0.1 to 100 hours at a temperature ranging from 60°C to 120°C;After mixing a salt of compound (1-1), an alkali metal carbonate, and a solvent, compound (2) is added and the mixture is reacted at a temperature ranging from 0°C to 60°C for 0.1 to 10 hours, and then at a temperature ranging from 60°C to 100°C for 0.1 to 100 hours; after mixing a salt of compound (1-1), an alkali metal carbonate, and a solvent, compound (2) is added and the mixture is reacted at a temperature ranging from 10°C to 40°C for 0.5 to 2 hours, and then at a temperature ranging from 40°C to 120°C for 0.1 to 100 hours; and a method in which a salt of compound (1-1), an alkali metal carbonate, and a solvent are mixed, and then compound (2) is added, and the mixture is reacted at a temperature of 10°C to 40°C for 0.5 to 2 hours, and then at a temperature of 40°C to 100°C for 0.1 to 100 hours; and a method in which a salt of compound (1-1), an alkali metal carbonate, and a solvent are mixed, and then compound (2) is added, and the mixture is reacted at a temperature of 10°C to 40°C for 0.5 to 2 hours, and then at a temperature of 60°C to 100°C for 0.1 to 100 hours. Among these, a method in which a salt of compound (1), compound (2), a solvent, an alkali metal carbonate, and pyrrolidine are mixed and then reacted at a temperature in the range of 10°C to 40°C for 0.5 to 2 hours, and then reacted at a temperature in the range of 40°C to 120°C for 0.1 to 100 hours; a method in which a salt of compound (1), compound (2), a solvent, an alkali metal carbonate, and pyrrolidine are mixed and then reacted at a temperature in the range of 10°C to 40°C for 0.5 to 2 hours, and then reacted at a temperature in the range of 40°C to 10 ... a mixture of a salt of compound (1), compound (2), a solvent, and an alkali metal carbonate, followed by addition of pyrrolidine, and a reaction at a temperature of 10°C to 40°C for 0.5 to 2 hours, followed by a reaction at a temperature of 40°C to 120°C for 0.1 to 100 hours; a mixture of a salt of compound (1), compound (2), a solvent, and an alkali metal carbonate, followed by addition of pyrrolidine, and a reaction at a temperature of 10°C to 40°C for 0.5 to 2 hours, followed by a reaction at a temperature of 40°C to 100°C for 0.1 to 100 hours;After mixing the salt of compound (1), compound (2), a solvent, and an alkali metal carbonate, pyrrolidine is added and the mixture is reacted at a temperature ranging from 10°C to 40°C for 0.5 to 2 hours, and then at a temperature ranging from 60°C to 100°C for 0.1 to 100 hours; after mixing the salt of compound (1-1), compound (2), a solvent, and an alkali metal carbonate, the mixture is reacted at a temperature ranging from 10°C to 40°C for 0.5 to 2 hours, and then at a temperature ranging from 40°C to 120°C for 0.1 to 100 hours; after mixing the salt of compound (1-1), compound (2), a solvent, and an alkali metal carbonate, the mixture is reacted at a temperature ranging from 10°C to 40°C for 0.5 to 2 hours, and then at a temperature ranging from 40°C to 100°C for 0.1 to 100 hours; after mixing the salt of compound (1-1), compound (2), a solvent, and an alkali metal carbonate, the mixture is reacted at a temperature ranging from 10°C to 40°C for 0.5 to 2 hours, and then at a temperature ranging from 40°C to 100°C for 0.1 to 100 hours; and subsequently reacting at a temperature ranging from 60°C to 100°C for 0.1 to 100 hours; mixing a salt of compound (1-1), an alkali metal carbonate, and a solvent, then adding compound (2), and reacting at a temperature ranging from 10°C to 40°C for 0.5 to 2 hours, and then reacting at a temperature ranging from 40°C to 120°C for 0.1 to 100 hours; mixing a salt of compound (1-1), an alkali metal carbonate, and a solvent, then adding compound (2), and reacting at a temperature ranging from 10°C to 40°C for 0.5 to 2 hours, and then reacting at a temperature ranging from 40°C to 100°C for 0.1 to 100 hours; and a method of mixing a salt of compound (1-1), an alkali metal carbonate, and a solvent, then adding compound (2), and reacting at a temperature ranging from 10°C to 40°C for 0.5 to 2 hours, and then reacting at a temperature ranging from 60°C to 100°C for 0.1 to 100 hours are preferred.

[0054] R 8 and R 9 are different from each other, the positional isomer of compound (3) is represented by formula (3-X) [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 8 and R 9 has the same meaning as above. ] may be produced as a by-product.

[0055] The reaction time varies depending on conditions such as the reaction temperature, but is usually 0.1 to 100 hours, preferably 1 to 48 hours.

[0056] Compound (3) 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 (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). Examples of suitable solvents include ethers such as diethyl ether, tetrahydrofuran, MTBE, 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 hydrocarbon solvents 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 MTBE; 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. Compound (3) exists as a tautomer (enol form), and compound (3) obtained in step 1 may be any tautomer or a mixture of tautomers in any ratio. After completion of the reaction, compound (3) can be subjected to step 2 without isolation.

[0057] Step 2 will now be described. In step 2, compound (3) obtained in step 1 is oxidized to obtain compound (6).

[0058] The compound (3) obtained in step 1 may be one obtained by the purification method described above in step 1, or 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 may be used. An example of a mixture containing compound (3) is the organic layer containing compound (3). Compound (3) exists in the form of tautomers (enol forms), and each tautomer and a mixture of tautomers in any ratio can be used.

[0059] Examples of the method for obtaining compound (6) by oxidizing compound (3) obtained in step 1 include a method for obtaining compound (6) in one step by reacting compound (3) obtained in step 1 with an oxidizing agent; and a method for obtaining compound (6) by a combination of steps 2-1 and 2-2, i.e., a method for obtaining compound (6) by a combination of a step (step 2-1) of reacting compound (3) obtained in step 1 with compound (4) and bromine or sulfuric acid to obtain compound (5), and a step (step 2-2) of solvolyzing compound (5) obtained in step 2-1 to obtain compound (6). Among these, the method for obtaining compound (6) by a combination of steps 2-1 and 2-2 is preferred.

[0060] A method for obtaining compound (6) in one step by reacting compound (3) obtained in step 1 with an oxidizing agent will be described. Examples of oxidizing agents include bromine, iodine, sulfuryl chloride, and 1,3-dibromo-5,5-dimethylhydantoin (hereinafter referred to as DBDMH). When the oxidizing agent is bromine, iodine, or sulfuryl chloride, the amount of the oxidizing agent used is usually 0.7 mol to 1.6 mol, preferably 0.9 mol to 1.1 mol, per mol of compound (3). When the oxidizing agent is DBDMH, the amount of the oxidizing agent used is usually 0.4 mol to 1 mol, preferably 0.5 mol to 0.7 mol, per mol of compound (3). The reaction is usually carried out in a solvent. Examples of solvents include carboxylic acids such as acetic acid, propionic acid, and butyric acid; nitriles such as acetonitrile and propionitrile; and alcohols such as methanol, ethanol, 2-propanol, and tert-butyl alcohol. The amount of solvent used is usually 1 to 20 parts by weight per part by weight of compound (3). The reaction temperature is usually within the range of 10 to 100°C, preferably within the range of 40 to 80°C. 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. When the oxidizing agent is iodine, a catalytic amount of iodine can be used in combination with dimethyl sulfoxide as a reoxidizing agent. In this case, the amount of iodine used is usually 0.01 to 0.2 moles per mole of compound (3), and the amount of dimethyl sulfoxide used is usually 2 to 10 parts by weight per part by weight of compound (3). The reaction temperature is usually within the range of 60 to 150°C, preferably within the range of 80 to 120°C. 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.

[0061] Step 2-1 will be described. In step 2-1, compound (3) obtained in step 1, compound (4), and bromine or sulfuric acid are reacted to obtain compound (5).

[0062] The amount of compound (4) used is usually 0.5 to 10 parts by weight, preferably 1 to 5 parts by weight, per part by weight of compound (3).

[0063] The sulfuric acid content is preferably 90% by weight or more and 100% by weight or less, and more preferably 96% by weight or more and 98% by weight or less.

[0064] The amount of bromine or sulfuric acid used is usually 0.6 to 3.3 moles, preferably 0.8 to 1.2 moles, per mole of compound (3).

[0065] The reaction is usually carried out in the absence of a solvent.

[0066] The reaction is carried out by mixing compound (3), compound (4), and bromine or sulfuric acid. The order of mixing compound (3), compound (4), and bromine or sulfuric acid is not particularly limited, and examples thereof include: mixing compound (3) and compound (4) and then adding bromine; mixing compound (3) and bromine and then adding compound (4); mixing compound (4) and bromine and then adding compound (3); adding compound (4) and bromine to compound (3); adding compound (3) and bromine to compound (4); adding compound (3) and compound (4) to bromine; mixing compound (3) and compound (4) and then adding sulfuric acid; mixing compound (3) and sulfuric acid and then adding compound (4); mixing compound (4) and sulfuric acid and then adding compound (3); adding compound (4) and sulfuric acid to compound (3); adding compound (3) and sulfuric acid to compound (4); adding compound (3) and compound (4) to compound (3); adding compound (4) and sulfuric acid to compound (3); adding compound (3) and sulfuric acid to compound (4); and adding compound (3) and compound (4) to sulfuric acid. Among these, a method in which sulfuric acid is added after mixing compound (3) and compound (4) is preferred. In any of the above methods, the components to be added to the reaction system, i.e., compound (3), compound (4), and bromine or sulfuric acid, may be added in their entirety at once, or in divided portions and added in multiple batches, or each component may be added gradually. Two or more of the components to be added may be added simultaneously in their entirety at once, or in divided portions and added simultaneously in multiple batches, or each component may be added gradually. Two or more of the components to be added may be premixed before addition. The premixed components may be premixed in their entirety, or a portion of each may be premixed. Two or more premixes of two or more components may be prepared so that the combinations of the components are different.Among these, a method of mixing compound (3) and compound (4) and then gradually adding sulfuric acid; and a method of mixing compound (3) and compound (4) and then gradually adding bromine are preferred, a method of mixing compound (3) and compound (4) and then dropping sulfuric acid; and a method of mixing compound (3) and compound (4) and then dropping bromine are more preferred, and a method of mixing compound (3) and compound (4) and then dropping sulfuric acid is even more preferred.

[0067] When bromine is used in the reaction, the temperature of the reaction system when bromine is added to the reaction system is usually within the range of −10° C. to 60° C., preferably within the range of 0° C. to 40° C., and the temperature of the reaction system after the addition of bromine to the reaction system is usually within the range of 0° C. to 120° C., preferably within the range of 40° C. to 80° C. When sulfuric acid is used in the reaction, the temperature of the reaction system when sulfuric acid is added to the reaction system is usually within the range of −10° C. to 80° C., preferably within the range of −5° C. to 70° C., and the temperature of the reaction system after the addition of sulfuric acid to the reaction system is usually within the range of 0° C. to 120° C., preferably within the range of 40° C. to 80° C.

[0068] 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.

[0069] 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 with water or an aqueous sodium sulfite solution after the reaction is complete, extracting with an organic solvent, and then washing, drying, and concentrating the resulting organic layer under reduced pressure. The solvent used for extraction is not particularly limited as long as it dissolves compound (5). Examples of suitable solvents include ethers such as diethyl ether, tetrahydrofuran, MTBE, 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 thereof. Compound (5) can also be further purified by column chromatography or the like. After the reaction is complete, compound (5) can also be subjected to Step 2-2 without isolation.

[0070] Step 2-2 will be explained below. In step 2-2, compound (5) obtained in step 2-1 is solvolyzed to give compound (6).

[0071] The compound (5) obtained in step 2-1 may be the one obtained by the purification in step 2-1, or may be a mixture containing compound (5) obtained by performing a post-treatment such as extraction on the reaction mixture after the completion of the reaction in step 2-1. Examples of the mixture containing compound (5) include the organic layer containing compound (5). Alternatively, the reaction mixture containing compound (5) obtained in step 2-1 may be used as is. It is particularly preferable to use the reaction mixture containing compound (5) obtained in step 2-1 as is. In this case, steps 2-1 and 2-2 can be carried out in one pot.

[0072] A protic solvent can be used for the solvolysis of compound (5). Examples of the protic solvent include aqueous amine solutions such as aqueous ammonia, aqueous methylamine, aqueous dimethylamine, and aqueous ethylamine; amines such as diethylamine; alcohols such as methanol, ethanol, 2-propanol, and ethylene glycol; water; and mixtures of two or more thereof. Alcohols, water, and mixtures thereof are preferred, and alcohols are more preferred. Specific examples of alcohols include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, ethylene glycol, and mixtures of two or more thereof. Methanol and ethanol are preferred.

[0073] The amount of the protic solvent used in the solvolysis is usually 0.2 to 10 parts by weight, preferably 0.5 to 4 parts by weight, relative to 1 part by weight of compound (5). When the reaction mixture containing compound (5) obtained in step 2-1 is used as compound (5) as is, or when a mixture containing compound (5) obtained by subjecting the reaction mixture after completion of the reaction in step 2-1 to post-treatment such as extraction is used as compound (5), the amount of the protic solvent used in the solvolysis is usually 0.2 to 10 parts by weight, preferably 0.5 to 4 parts by weight, relative to 1 part by weight of compound (3) in step 2-1.

[0074] The reaction can be carried out using only the protic solvent as the solvent, or a mixture of the protic solvent with another solvent. Examples of the other solvent include ethers such as diethyl ether, tetrahydrofuran, MTBE, 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; aprotic polar solvents such as N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and sulfolane; and mixtures of two or more thereof. When using, as compound (5), a mixture containing compound (5) obtained by performing a post-treatment such as extraction on the reaction mixture after completion of the reaction in step 2-1, a mixture of the solvent used for extraction and the protic solvent can be used as the solvent.

[0075] The amount of the other solvent used is usually 0.1 to 100 parts by weight, preferably 0.5 to 10 parts by weight, relative to 1 part by weight of compound (5). When the reaction mixture containing compound (5) obtained in step 2-1 is used as compound (5) as is, or when a mixture containing compound (5) obtained by subjecting the reaction mixture after completion of the reaction in step 2-1 to post-treatment such as extraction is used as compound (5), the amount of the other solvent used is usually 0.1 to 100 parts by weight, preferably 0.5 to 10 parts by weight, relative to 1 part by weight of compound (3) in step 2-1.

[0076] When alcohol or water is used as the protic solvent, the addition of an acid or a base may promote solvolysis. Examples of the acid include Bronsted acids and Lewis acids. Examples of Bronsted acids include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid; and organic acids such as acetic acid, propionic acid, and benzoic acid. Examples of Lewis acids include boron compounds such as boron trifluoride, boron trichloride, boron tribromide, boron trifluoride diethyl ether complex, and tris(pentafluorophenyl)borane; aluminum compounds such as aluminum chloride and aluminum bromide; titanium compounds such as titanium(IV) chloride; iron compounds such as iron(III) chloride; zinc compounds such as zinc chloride; tin compounds such as tin(IV) chloride; scandium compounds such as scandium(III) triflate; lanthanoid triflates such as lanthanum(III) triflate and ytterbium(III) triflate; and mixtures of two or more thereof. 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. When the reaction mixture containing compound (5) obtained in step 2-1 is used as compound (5) as is, in addition to hydrobromic acid generated from bromine added in step 2-1 or unreacted sulfuric acid added in step 2-1, a carboxylic acid generated from compound (4) added in step 2-1, and a carboxylic acid generated by solvolysis in step 2-2 from unreacted compound (4) added in step 2-1 are present in the reaction system. This allows solvolysis to be promoted without the addition of an acid or a base.

[0077] When the reaction is carried out by adding an acid, the amount of the acid used is usually 0.1 mol to 10 mol per mol of compound (5). When a mixture containing compound (5) obtained by subjecting the reaction mixture after completion of the reaction in step 2-1 to post-treatment such as extraction is used as compound (5), the amount of the acid used is usually 0.01 mol to 5 mol per mol of compound (3) in step 2-1. When the reaction is carried out by adding a base, the amount of the base used is usually 1 mol to 10 mol per mol of compound (5). When a mixture containing compound (5) obtained by subjecting the reaction mixture after completion of the reaction in step 2-1 to post-treatment such as extraction is used as compound (5), the amount of the base used is usually 2 mol to 20 mol per mol of compound (3) in step 2-1.

[0078] The reaction is carried out by mixing compound (5), the protic solvent, and, if necessary, the other solvent, and, if necessary, an acid or a base. As compound (5), the reaction mixture containing compound (5) obtained in step 2-1 may be used as is, or a mixture containing compound (5) obtained by subjecting the reaction mixture after completion of the reaction in step 2-1 to post-treatment such as extraction may be used. In mixing compound (5), the protic solvent, and optionally the other solvent, and optionally the acid or base, there is no particular limitation on the order of mixing. For example, the order of mixing compound (5) and the protic solvent may be: mixing compound (5) and the protic solvent, and then adding an acid; mixing compound (5) and the protic solvent, and then adding a base; mixing compound (5), the protic solvent, and the other solvent, and then adding an acid; mixing compound (5), the protic solvent, and the other solvent, and then adding a base; adding the protic solvent to compound (5); adding the protic solvent and the acid to compound (5); adding the protic solvent to compound (5); Examples of such methods include adding a protic solvent and the other solvent; adding the protic solvent, the other solvent, and an acid to compound (5); adding compound (5) to the protic solvent; adding compound (5) and an acid to the protic solvent; adding compound (5) and the other solvent to the protic solvent; adding compound (5), an acid, and the other solvent to the protic solvent; mixing the reaction mixture containing compound (5) obtained in step 2-1 and the protic solvent; adding the protic solvent to the reaction mixture containing compound (5) obtained in step 2-1; and adding the reaction mixture containing compound (5) obtained in step 2-1 to the protic solvent. Among these, the method of adding the protic solvent to the reaction mixture containing compound (5) obtained in step 2-1; and adding the reaction mixture containing compound (5) obtained in step 2-1 to the protic solvent is preferred. The compound (5) and, if necessary, an acid or a base may be mixed in advance with the protic solvent or a part of the other solvent if necessary, before use.In any of the above methods, the components added to the reaction system, i.e., compound (5), the protic solvent, and the other solvent used as needed, as well as the acid or base used as needed, may be added in their entirety all at once, or in separate portions and added in multiple batches, or each component may be added gradually. Two or more of the components to be added may be added simultaneously in their entirety all at once, or in separate portions and added in multiple batches, or each component may be added simultaneously and gradually. Two or more of the components to be added may be premixed before addition. The premixed components may be premixed in their entirety, or a portion of each may be premixed. Two or more premixes of two or more components may be prepared so that the combinations of the components are different.

[0079] The reaction temperature is usually within the range of 30°C to 150°C, preferably within the range of 60°C to 100°C.

[0080] 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.

[0081] Compound (6) can be purified by a conventional method. For example, if a solid precipitates, the resulting solid can be filtered after the reaction is completed, and compound (6) can be purified. Alternatively, compound (6) 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, or with water, 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 (6), and 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; 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 (6) can be purified by, if necessary, adding water, a water-immiscible solvent, and a base to perform acid-base extraction, extracting compound (6) as a salt into the aqueous layer, mixing the resulting aqueous layer with an acidic aqueous solution such as dilute hydrochloric acid or dilute sulfuric acid, and then extracting with an organic solvent. The resulting organic layer is 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. 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 basic solutions include aqueous sodium hydroxide and methanolic sodium methoxide solutions.Compound (6) 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 hydrocarbon solvents 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.

[0082] Compound (6) 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 (6) obtained after post-treatment such as extraction, and the resulting solid can be collected by filtration to obtain a salt of compound (6). 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 (6) can also be used as is as compound (6) in Step 3.

[0083] Step 3 will now be described. In step 3, compound (6) obtained in step 2 is reacted with compound (7) in the presence of a base to obtain compound (8).

[0084] The compound (6) obtained in step 2 may be the one obtained by the purification in step 2, or may be a mixture containing compound (6) obtained by subjecting the reaction mixture after completion of the reaction in step 2 to post-treatment such as extraction, or may be a salt of compound (6). Examples of the mixture containing compound (6) include the organic layer containing compound (6). When a salt of compound (6) is used, the use of a base described below in the reaction of step 3 can be omitted or the amount used can be reduced.

[0085] 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, MTBE, etc.; and mixtures of two or more thereof. 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 11 OH [where R 11 has the same meaning as above.] can also be used as a solvent.

[0086] 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 11 and K.O.R. 11 [where R 11has 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 11 , K.O.R. 11 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 11 OH [where R 11 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 11 OH is added to the reaction system. 11 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.

[0087] The amount of the base used is usually 0.5 to 2 moles, preferably 0.66 to 1.5 moles, more preferably 0.8 to 1.2 moles, per mole of compound (6).

[0088] The amount of compound (7) used is usually 0.5 to 3 moles, preferably 0.66 to 2.5 moles, more preferably 0.8 to 1.8 moles, per mole of compound (6).

[0089] The amount of the solvent used is usually 1 to 20 parts by weight per part by weight of the compound (6).

[0090] The reaction is carried out by mixing compound (6), compound (7), a base, and, if necessary, a solvent.

[0091] 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.

[0092] 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.

[0093] 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 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 (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. 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 (8) can also be subjected to Step 4 without isolation.

[0094] Step 4 will now be described. In step 4, compound (8) obtained in step 3 is reacted with compound (9) in the presence of a base.

[0095] By the reaction of step 4, a compound represented by formula (10) [In the formula, R 4 has the same meaning as above. ] (hereinafter referred to as compound (10)) can be obtained.

[0096] As the compound (8) obtained in step 3, the compound obtained by the purification in step 3 may be used, or a mixture containing compound (8) obtained by subjecting the reaction mixture after completion of the reaction in step 3 to post-treatment such as extraction may be used.

[0097] 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 tert-butoxide; alkali metal amides such as sodium amide, lithium amide, lithium diisopropylamide, sodium hexamethyldisilazide and lithium hexamethyldisilazide; and mixtures of two or more thereof.

[0098] The amount of the base used is usually 1 to 10 moles per mole of compound (8).

[0099] The amount of compound (9) used is usually 1 to 10 moles per mole of compound (8).

[0100] 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.

[0101] The reaction temperature is usually within the range of 0°C to 80°C.

[0102] The reaction time is usually within the range of 1 hour to 48 hours.

[0103] Compound (10) 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 (10) can be purified. Alternatively, compound (10) 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 (10). 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 (10) can also be further purified by column chromatography, recrystallization, or the like. After completion of the reaction, compound (10) can be subjected to step 5 without isolation or without post-treatment such as extraction. Alternatively, compound (10) can be reacted with a base such as an alkali metal hydroxide to form a salt of compound (10) (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 5.

[0104] Step 5 will be described. In step 5, the compound obtained in step 4 is reacted with a methylating agent to obtain compound (11).

[0105] The compound obtained in step 4, i.e., compound (10), may be one obtained by post-treatment such as extraction or purification in step 4. Alternatively, a mixture containing compound (10) obtained by performing post-treatment such as extraction as necessary without neutralizing the reaction mixture after the completion of the reaction in step 4 may be used. Alternatively, a mixture containing compound (10) obtained by partially neutralizing the reaction mixture after the completion of the reaction in step 4 or neutralizing it until it becomes neutral may be provided to step 5. When a mixture containing compound (10) obtained by partially neutralizing the reaction mixture after the completion of the reaction in step 4 without neutralizing it is provided to step 5, compound (10) 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 5 can be omitted or the amount used can be reduced. Examples of acids used for the partial neutralization or 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.

[0106] 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.

[0107] 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.

[0108] Examples of methylating agents include CH3-X 2 A compound represented by the formula: 2 represents a leaving group. ], dimethyl sulfate, dimethyl carbonate and diazo compounds are listed, and among them, dimethyl sulfate is preferred. 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. Examples of the diazo compound include trialkylsilyldiazomethanes such as trimethylsilyldiazomethane; and diazomethane.

[0109] The amount of the methylating agent used is usually 1 mol to 5 mol per mol of compound (10). When the mixture containing compound (10) obtained in step 4 is used as compound (10), the amount of the methylating agent used is usually 1 mol to 5 mol per mol of compound (8) in step 4.

[0110] As a methylating agent, CH3-X 2When a compound represented by the formula (I), dimethyl sulfate, or dimethyl carbonate is used, the reaction is preferably carried out 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 tert-butoxide, sodium methoxide, potassium methoxide, and sodium ethoxide.

[0111] When a base is used, the amount of the base used is preferably 1 to 10 moles per mole of compound (10).

[0112] When a diazo compound is used as a methylating agent, it is preferable to use a protic solvent, such as the alcohols mentioned above.

[0113] 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, benzyltriethylammonium 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 (10).

[0114] The reaction temperature is usually within the range of -20°C to 100°C.

[0115] The reaction time is usually within the range of 1 hour to 48 hours.

[0116] Compound (11) 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 (11) can be purified. Alternatively, compound (11) 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, or with water, 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 (11). 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 (7) can also be further purified by column chromatography, recrystallization, or the like.

[0117] The reaction is carried out by mixing compound (10) and a methylating agent, and optionally a solvent, a base, and a catalyst. The order of mixing compound (10), the methylating agent, and optionally a solvent, a base, and a catalyst is not particularly limited. For example, compound (10), the solvent, and the methylating agent may be mixed simultaneously, or compound (10) 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 (10) may be added. When compound (10) or the methylating agent is added to the reaction system, compound (10) or the methylating agent may be added as a mixture with the solvent.

[0118] The present invention will be described in detail below with reference to Production Examples, Examples and Comparative Examples, but the present invention is not limited to the following Examples.

[0119] Compound (1-1-1) is a compound (1-1) in which R 1 , R 2 , R 3 , R 4 and R 5is a hydrogen atom. Compound (1-1-2) is the hydrochloride salt of compound (1-1-1). Compound (1-2-1) is the compound (1-2) in which R 1 , R 2 , R 3 , R 4 and R 5 is a hydrogen atom. Compound (1-2-2) is the hydrochloride of compound (1-2-1). Compound (1-3-1) is a compound (1-3) in which R 1 , R 2 , R 3 , R 4 and R 5 is a hydrogen atom. Compound (1-3-2) is the hydrochloride of compound (1-3-1). Compound (1-4-1) is the compound (1) in which R 1 , R 2 , R 3 , R 4 and R 5 is a hydrogen atom, and R 6 and R 7 is a methyl group. Compound (1-4-2) is the hydrochloride salt of compound (1-4-1). Compound (1-5-1) is a compound in which R 1 , R 2 , R 3 , R 4 and R 5 is a hydrogen atom, and R 6 and R 7 is an ethyl group. Compound (1-5-2) is the hydrochloride salt of compound (1-5-1). Compound (1-6-1) is a compound in which R 1 , R 2 , R 3 , R 4 and R 5 is a hydrogen atom, and R 6 and R 7 is an isopropyl group. Compound (1-6-2) is the hydrochloride salt of compound (1-6-1). Compound (1-7-1) is the compound (1) in which R 1 , R 2 , R 3 , R 4 and R 5 is a hydrogen atom, and R6 and R 7 is a butyl group. Compound (1-7-2) is the hydrochloride salt of compound (1-7-1). Compound (1-8-1) is the compound (1) in which R 1 , R 2 , R 3 , R 4 and R 5 is a hydrogen atom, and R 6 and R 7 is a benzyl group. Compound (1-8-2) is the hydrochloride salt of compound (1-8-1). Compound (1-9-1) is the compound (1) in which R 1 , R 2 , R 3 , R 4 , R 5 and R 7 is a hydrogen atom, and R 6 is an ethyl group. Compound (1-9-2) is the hydrochloride salt of compound (1-9-1). Compound (1-10-1) is the compound (1) in which R 1 , R 2 , R 3 , R 4 , R 5 and R 7 is a hydrogen atom, and R 6 is a benzyl group. Compound (1-10-2) is the hydrochloride salt of compound (1-10-1). Compound (1-11-1) is the compound (1) in which R 1 , R 2 , R 3 , R 4 and R 5 is a hydrogen atom, and R 6 is a methyl group, and R 7 is a phenyl group. Compound (1-11-2) is the hydrochloride salt of compound (1-11-1). Compound (3-1) is a compound (3) in which R 1 , R 2 , R 3 , R 4 , R 5 and R 9 is a hydrogen atom, and R 8 is a methyl group. The compound (5-1) is a positional isomer of the compound (5). 1 , R 2 , R 3 , R 4 , R 5 and R 9 is a hydrogen atom, and R 8 and R 10 is a methyl group. Compound (6-1) is a compound in which R 1 , R 2 , R 3 , R 4 , R 5 and R 9 is a hydrogen atom, and R 8 is a methyl group. Compound (8-1) is a compound in which R 1 , R 2 , R 3 , R 4 , R 5 and R 9 is a hydrogen atom, and R 8 and R 11 is a methyl group. Compound (10-1) is a compound in which R 1 , R 2 , R 3 , R 4 , R 5 and R 9 is a hydrogen atom, and R 8 and R 11 is a methyl group. Compound (11-1) is a compound in which R 1 , R 2 , R 3 , R 4 , R 5 and R 9 is a hydrogen atom, and R 8 and R 11 is a methyl group.

[0120] Compound (1-1-1)

[0121] Compound (1-1-2)

[0122] Compound (1-2-1)

[0123] Compound (1-2-2)

[0124] Compound (1-3-1)

[0125] Compound (1-3-2)

[0126] Compound (1-4-1)

[0127] Compound (1-4-2)

[0128] Compound (1-5-1)

[0129] Compound (1-5-2)

[0130] Compound (1-6-1)

[0131] Compound (1-6-2)

[0132] Compound (1-7-1)

[0133] Compound (1-7-2)

[0134] Compound (1-8-1)

[0135] Compound (1-8-2)

[0136] Compound (1-9-1)

[0137] Compound (1-9-2)

[0138] Compound (1-10-1)

[0139] Compound (1-10-2)

[0140] Compound (1-11-1)

[0141] Compound (1-11-2)

[0142] Compound (3-1)

[0143] Compound (5-1)

[0144] Compound (6-1)

[0145] Compound (8-1)

[0146] Compound (10-1)

[0147] Compound (11-1)

[0148] 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:

[0149] [Analysis Method 1] Mobile phase: Solution A: 0.1% trifluoroacetic acid aqueous solution, Solution B: acetonitrile Column: SUMIPAX (registered trademark) ODS Z-CLUE, particle size 3 μm, 4.6 mm ID × 250 mm (manufactured by Sumika Chemical Analysis Center) UV measurement wavelength: 254 nm Flow rate: 1.0 mL / min Column oven: 40°C Pump: LC-20AD (manufactured by Shimadzu Corporation) (high-pressure gradient) Gradient conditions: Solution was delivered at the concentration gradient shown in [Table LC1].

[0150]

[0151] The retention times of each compound described in the Preparation Examples, Examples, or Comparative Examples when analyzed by high performance liquid chromatography using Analytical Method 1 are shown in Table LC2.

[0152]

[0153] [Analysis Method 2] Mobile phase: Solution A: 0.1% trifluoroacetic acid aqueous solution, Solution B: acetonitrile Column: SUMIPAX (registered trademark) ODS Z-CLUE, particle size 3 μm, 4.6 mm ID × 250 mm (manufactured by Sumika Chemical Analysis Center) UV measurement wavelength: 254 nm Flow rate: 1.0 mL / min Column oven: 40°C Pump: LC-20AD (manufactured by Shimadzu Corporation) (high-pressure gradient) Gradient conditions: Solution was delivered at the concentration gradient shown in [Table LC3].

[0154]

[0155] The retention times of each compound described in the Preparation Examples, Examples, or Comparative Examples when analyzed by high performance liquid chromatography using Analytical Method 2 are shown in Table LC4.

[0156]

[0157] [Analytical Method 3] Mobile phase: Solution A: 0.1% trifluoroacetic acid aqueous solution, Solution B: acetonitrile Column: Shim-pack (registered trademark) XR-ODSII, particle size 2.2 μm, 3.0 mm ID × 75 mm (Shimadzu Corporation) UV measurement wavelength: 254 nm Flow rate: 1.0 mL / min Column oven: 40°C Pump: 2 LC-40AD (Shimadzu Corporation) (high-pressure gradient) Gradient conditions: Solution was delivered at the concentration gradient shown in [Table LC5].

[0158]

[0159] The retention times of each compound described in the Preparation Examples, Examples, or Comparative Examples when analyzed by high performance liquid chromatography using Analytical Method 3 are shown in Table LC6.

[0160]

[0161] [Analytical Method 4] 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 (manufactured by Sumika Chemical Analysis Center) UV measurement wavelength: 238 nm Flow rate: 1.0 mL / min Column oven: 30°C Pump: LC-20AD (manufactured by Shimadzu Corporation) x 2 (high-pressure gradient) Gradient conditions: Solution was delivered at the concentration gradient shown in [Table LC7].

[0162]

[0163] Table LC8 shows the retention times of each compound described in the Examples when analyzed by high performance liquid chromatography using Analytical Method 4. The sodium salt of compound (10-1) is detected as compound (10-1).

[0164]

[0165] In the following examples, unless otherwise specified, the reaction temperature refers to the external temperature of the reaction vessel. Furthermore, the area percentage refers to the ratio of the area of ​​a certain component to the total area of ​​peaks obtained when analyzed using high performance liquid chromatography.

[0166] Production Example 1: Production of Compound (1-1-2) To a mixture of 26.0 g of 35 wt % hydrochloric acid and 80 mL of ethanol, 15.0 g of pyrrolidine was gradually added at 0°C, and then 20.0 g of acetophenone and 9.10 g of paraformaldehyde were added successively at 0°C. The resulting mixture was stirred at 100°C for 16 hours. After cooling to room temperature, the resulting reaction mixture was concentrated under reduced pressure, and 50 mL of 2-propanol was added to the resulting concentrated residue and stirred. The precipitated solid was collected by filtration and washed with 50 mL of acetone at 5°C. The resulting solid was dried under reduced pressure to obtain 26.0 g of Compound (1-1-2). 1 The H-NMR values ​​are shown below. 1H-NMR (DMSO-d6) δ: 11.06(1H, br s), 7.99-8.01 (2H, m), 7.67-7.71 (1H, m), 7.56-7.59 (2H, m), 3.44-3.66 (6H, m), 3.00-3.08 (2H, m), 1.81-2.05 (4H, m).

[0167] Production Example 2: Production of Compound (1-3-2) To a mixture of 26.0 g of 35 wt % hydrochloric acid and 80 mL of ethanol, 18.4 g of morpholine was gradually added at 0°C, and then 20.0 g of acetophenone and 9.10 g of paraformaldehyde were added successively at 0°C. The resulting mixture was stirred at 100°C for 16 hours. After cooling to room temperature, the resulting reaction mixture was concentrated under reduced pressure, and 50 mL of 2-propanol was added to the resulting concentrated residue and stirred. The precipitated solid was collected by filtration and washed with 50 mL of acetone at 5°C. The resulting solid was dried under reduced pressure to obtain 28.0 g of Compound (1-3-2). 1 The H-NMR values ​​are shown below. 1 H-NMR (DMSO-d6) δ: 13.26(1H, br s), 7.99-8.02 (2H, m), 7.60-7.64 (1H, m), 7.47-7.51 (2H, m), 4.24-4.31 (2H, m), 3.98-4.01 (2H, m), 3.80-3.90 (2H, m), 3,50-3.52 (2H, m), 3.41-3.44 (2H, m), 2.96-2.99 (2H, m).

[0168] Production Example 3: Production of Compound (1-2-2) To a mixture of 26.0 g of 35 wt % hydrochloric acid and 80 mL of ethanol, 18.0 g of piperidine was gradually added at 0°C, and then 20.0 g of acetophenone and 9.1 g of paraformaldehyde were added successively at 0°C. The resulting mixture was stirred at 100°C for 16 hours. After cooling to room temperature, the resulting reaction mixture was concentrated under reduced pressure, and 50 mL of 2-propanol was added to the resulting concentrated residue and stirred. The precipitated solid was collected by filtration and washed with 50 mL of acetone at 5°C. The resulting solid was dried under reduced pressure to obtain 30.0 g of Compound (1-2-2). 1The H-NMR values ​​are shown below. 1 H-NMR (DMSO-d6) δ: 11.77(1H, br s), 8.01-8.03 (2H, m), 7.67-7.71 (1H, m), 7.55-7.59 (2H, m), 3.69-3.72(2H, m), 3.46-3.49(2H, m), 3.34-3.39(2H, m), 2.87-2.96(2H, m), 1.69-1.87(5H, m), 1.34-1.44(1H, m).

[0169] Production Example 4: Production of Compound (1-5-2) To a mixture of 130 g of 35 wt% hydrochloric acid and 300 mL of ethanol, 54.8 g of diethylamine was gradually added at 0°C, and then 100 g of acetophenone and 44.0 g of paraformaldehyde were added sequentially at 0°C. The resulting mixture was stirred at 100°C for 16 hours. To the resulting mixture, 35.0 g of acetophenone and 8.70 g of paraformaldehyde were added sequentially, and the resulting mixture was stirred at 100°C for 12 hours. After cooling to room temperature, the resulting reaction mixture was concentrated under reduced pressure, and 500 mL of diethyl ether was added to the resulting concentrated residue and stirred. The precipitated solid was collected by filtration and washed with 100 mL of diethyl ether at 5°C. The resulting solid was dried under reduced pressure to obtain 170 g of compound (1-5-2). 1 The H-NMR values ​​are shown below. 1 H-NMR (DMSO-d6) δ: 10.55(1H, br s), 8.01-8.04 (2H, m), 7.67-7.70 (1H, m), 7.56-7.59 (2H, m), 3.61-3.72(2H, m), 3.36-3.41(2H, m), 3.14-3.21(4H, m), 1.19-1.26(6H, m).

[0170] Production Example 5: Production of Compound (1-8-2) To a mixture of 117 g of 35 wt% hydrochloric acid and 340 mL of ethanol, 133 g of dibenzylamine was gradually added at 0°C, and then 90.0 g of acetophenone and 40.0 g of paraformaldehyde were added successively at 0°C. The resulting mixture was stirred at 100°C for 16 hours. After cooling to room temperature, the resulting reaction mixture was concentrated under reduced pressure, and 300 mL of 2-propanol was added to the resulting concentrated residue and stirred. The precipitated solid was collected by filtration and washed with 50 mL of acetone at 5°C. The resulting solid was dried under reduced pressure to obtain 131 g of compound (1-8-2). 1 The H-NMR values ​​are shown below. 1 H-NMR (DMSO-d6) δ: 11.46(1H, br s), 7.98-7.96 (2H, m), 7.67-7.71 (5H, m), 7.54-7.58(2H, m), 7.45-7.46(6H, m), 4.33-4.44(4H, m), 3.78-3.81(2H, m), 3.29-3.33(2H, m).

[0171] Production Example 6: Production of Compound (1-7-2) To a mixture of 130 g of 35 wt% hydrochloric acid and 400 mL of ethanol, 137 g of dibutylamine was gradually added at 0°C, and then 100 g of acetophenone and 43.9 g of paraformaldehyde were added sequentially at 0°C. The resulting mixture was stirred at 100°C for 16 hours. To the resulting mixture, 75.0 g of acetophenone and 26.0 g of paraformaldehyde were added sequentially, and the resulting mixture was stirred at 100°C for 16 hours. To the resulting mixture, 49.0 g of acetophenone and 9.00 g of paraformaldehyde were added sequentially, and the resulting mixture was stirred at 100°C for 16 hours. To the resulting mixture, 19.0 g of acetophenone and 2.80 g of paraformaldehyde were added sequentially, and the resulting mixture was stirred at 100°C for 16 hours. After cooling to room temperature, the resulting reaction mixture was concentrated under reduced pressure, and 1500 mL of diethyl ether was added to the resulting concentrated residue and stirred. The precipitated solid was collected by filtration and washed with 500 mL of diethyl ether at 5°C. The resulting solid was dried under reduced pressure to obtain 200 g of compound (1-7-2). 1The H-NMR values ​​are shown below. 1 H-NMR (DMSO-d6) δ: 10.38(1H, br s), 8.02-8.04 (2H, m), 7.67-7.71 (1H, m), 7.56-7.60 (2H, m), 3.62-3.66 (2H, m), 3.40-3.43 (2H, m), 3.06-3.12 (4H, m), 1.63-1.71 (4H, m), 1.31-1.36 (4H, m), 0.89-0.94 (6H, m).

[0172] Production Example 7: Production of Compound (1-6-2) To a mixture of 1.00 g of acetophenone and 2 mL of ethyl acetate, 0.90 g of diisopropylamine was added, and then 8 mL of chloromethyl methyl ether was gradually added at 0°C, followed by stirring at 0°C for 2 hours. The resulting mixture was stirred at 55°C for an additional 16 hours. After cooling to room temperature, the resulting reaction mixture was concentrated under reduced pressure, and 3 mL of diethyl ether was added to the resulting concentrated residue, followed by gradually adding 2 mL of a 4N hydrogen chloride-ethyl acetate solution at 0°C, followed by stirring at room temperature for 3 hours. The resulting reaction mixture was concentrated under reduced pressure, and 3 mL of diethyl ether was added and stirred. The precipitated solid was collected by filtration and washed with diethyl ether at 5°C. The resulting solid was dried under reduced pressure to obtain 400 mg of compound (1-6-2). 1 The H-NMR values ​​are shown below. 1 H-NMR (DMSO-d6) δ: 9.55(1H, br s), 7.98-8.01 (2H, m), 7.67-7.71 (1H, m), 7.67-7.71 (2H, m), 3.65-3.75 (4H, m), 3.44-3.46 (2H, m), 1.22-1.36 (12H, m).

[0173] Production Example 8: Production of Compound (1-10-2) To a mixture of 130 g of 35 wt% aqueous hydrochloric acid and 400 mL of ethanol, 100 g of benzylamine was gradually added at 0°C, and then 100 g of acetophenone and 43.9 g of paraformaldehyde were added sequentially at 0°C. The resulting mixture was stirred at 100°C for 16 hours. After cooling to room temperature, the resulting reaction mixture was concentrated under reduced pressure, and the resulting concentrated residue was purified by silica gel column chromatography (solvent system: methanol / ethyl acetate = 3 / 17 (volume ratio)) to obtain a fraction containing compound (1-10-2). The resulting fraction was concentrated, and 500 mL of diethyl ether was added at room temperature and stirred. The precipitated solid was collected by filtration and washed with 500 mL of diethyl ether at 5°C. The resulting solid was dried under reduced pressure to obtain 45 g of compound (1-10-2). 1 The H-NMR values ​​are shown below. 1 H-NMR (DMSO-d6) δ: 9.29(2H, br s), 7.96-7.98 (2H, m), 7.67-7.71 (1H, m), 7.55-7.59 (4H, m), 7.40-7.48 (3H, m), 4.22 (2H, s), 3.53-3.57 (2H, m), 3.25-3.28 (2H, m).

[0174] Production Example 9: Production of Compound (1-9-2) To a mixture of 150 g of acetophenone and 1.0 L of ethanol, 118 g of ethylamine hydrochloride, 52.0 g of paraformaldehyde, and 9.3 mL of 35 wt % hydrochloric acid were added sequentially at room temperature. The resulting mixture was stirred at 80°C for 16 hours in an autoclave. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and 500 mL of 2-propanol was added to the resulting concentrated residue and stirred. The precipitated solid was collected by filtration and washed with 50 mL of acetone at 5°C. The resulting solid was dried under reduced pressure to obtain 67.0 g of a concentrated residue. 62.0 g of the resulting concentrated residue was added to 124 mL of ethanol, and 19.8 g of acetophenone and 7.01 g of paraformaldehyde were added sequentially to the resulting mixture at 0°C, and the resulting mixture was stirred at 100°C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and 124 mL of 2-propanol was added to the obtained concentrated residue at room temperature and stirred. The precipitated solid was collected by filtration and washed with 50 mL of acetone at 5°C. The obtained solid was dried under reduced pressure to obtain 132 g of compound (1-9-2). 1 The H-NMR values ​​are shown below. 1 H-NMR (DMSO-d6) δ: 9.18(2H, br s), 7.97-7.99 (2H, m), 7.67-7.71 (1H, m), 7.55-7.59 (2H, m), 3.54-3.57 (2H, m), 3.20-3.30 (2H, m), 2.97-3.00 (2H, m), 1.21-1.25 (3H, m).

[0175] Production Example 10: Production of Compound (1-11-2) A mixture of 140 g of compound (1-4-2), 125 g of N-methylaniline, and 1,050 mL of an ethanol / water solution (2 / 1 by volume) was stirred at 100°C for 72 hours. 6.5 g of compound (1-4-2) was added to the resulting mixture, and the mixture was stirred at 80°C for 24 hours. After allowing to cool to room temperature, the resulting reaction mixture was concentrated under reduced pressure, and the resulting concentrated residue was dissolved in 500 mL of water. A saturated aqueous potassium carbonate solution was added to the resulting mixture, and the pH of the mixture was adjusted to approximately 9. 500 mL of ethyl acetate was added to the resulting mixture, and after stirring, the mixture was allowed to stand and separated. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a concentrated residue. This concentrated residue was purified by column chromatography (ethyl acetate / petroleum ether (1 / 19 by volume) solvent system) to obtain 60 g of compound (1-11-1). The obtained compound (1-11-1) was dissolved in 500 mL of diethyl ether, and 60 mL of a 4N hydrogen chloride-ethyl acetate solution was added to the obtained mixture and stirred for 16 hours. The obtained mixture was concentrated under reduced pressure, and 500 mL of diethyl ether was added to the obtained concentrated residue at room temperature and stirred. The obtained solid was collected by filtration and dried under reduced pressure to obtain 49 g of compound (1-11-2). 1 The H-NMR values ​​are shown below. 1 H-NMR (DMSO-d6) δ: 7.63-7.67 (5H, m), 7.32-7.57 (5H, m), 3.84-3.88 (2H, m), 3.44 (2H, br s), 3.15 (3H, br s).

[0176] Production Example 11: Production of Compound (1-1-1) To a mixture of 1.20 g of compound (1-1-2), 3.0 g of ethyl acetate, and 3.0 g of water, 0.46 g of a 48 wt % aqueous sodium hydroxide solution was added dropwise at room temperature, and the mixture was stirred at the same temperature for 1 hour. The resulting mixture was allowed to stand and then separated. The resulting organic layer was concentrated under reduced pressure to obtain 0.86 g of compound (1-1-1). When analyzed by high performance liquid chromatography according to analytical method 3, the area percentage of compound (1-1-1) was 98%.

[0177] Production Example 12: Production of Compound (1-2-1) To a mixture of 5.0 g of compound (1-2-2), 15.0 g of ethyl acetate, and 15.0 g of water, 4.10 g of a 27 wt % aqueous sodium hydroxide solution was added dropwise at room temperature, and the mixture was stirred at the same temperature for 1 hour. The resulting mixture was allowed to stand and the layers were separated. The resulting organic layer was concentrated under reduced pressure to obtain 4.0 g of compound (1-2-1). When analyzed by high performance liquid chromatography according to analytical method 3, the area percentage of compound (1-2-1) was 99%.

[0178] Production Example 13: Production of Compound (1-3-1) To a mixture of 1.29 g of compound (1-3-2), 3.0 g of ethyl acetate, and 3.0 g of water, 0.46 g of a 48 wt % aqueous sodium hydroxide solution was added dropwise at room temperature, and the mixture was stirred at the same temperature for 1 hour. The resulting mixture was allowed to stand and the layers were separated. The resulting organic layer was concentrated under reduced pressure to obtain 0.91 g of compound (1-3-1). When analyzed by high performance liquid chromatography according to analytical method 3, the area percentage of compound (1-3-1) was 97%.

[0179] Production Example 14: Production of Compound (1-4-1) To a mixture of 1.07 g of compound (1-4-2), 3.0 g of ethyl acetate, and 3.0 g of water, 0.46 g of a 48 wt % aqueous sodium hydroxide solution was added dropwise at room temperature, and the mixture was stirred at the same temperature for 1 hour. The resulting mixture was allowed to stand and the layers were separated. The resulting organic layer was concentrated under reduced pressure to obtain 0.65 g of compound (1-4-1). When analyzed by high performance liquid chromatography according to analytical method 3, the area percentage of compound (1-4-1) was 98%.

[0180] Production Example 15: Production of Compound (1-5-1) To a mixture of 5.0 g of compound (1-5-2), 15.0 g of ethyl acetate, and 15.0 g of water, 4.3 g of a 27 wt % aqueous sodium hydroxide solution was added dropwise at room temperature, and the mixture was stirred at the same temperature for 1 hour. The resulting mixture was allowed to stand and the layers were separated. The resulting organic layer was concentrated under reduced pressure to obtain 3.5 g of compound (1-5-1). When analyzed by high performance liquid chromatography according to analytical method 3, the area percentage of compound (1-5-1) was 97%.

[0181] Production Example 16: Production of Compound (1-7-1) To a mixture of 5.0 g of compound (1-7-2), 15.0 g of ethyl acetate, and 15.0 g of water, 3.5 g of a 27 wt % aqueous sodium hydroxide solution was added dropwise at room temperature, and the mixture was stirred at the same temperature for 1 hour. The resulting mixture was allowed to stand and the layers were separated. The resulting organic layer was concentrated under reduced pressure to obtain 4.0 g of compound (1-7-1). When analyzed by high performance liquid chromatography according to analytical method 3, the area percentage of compound (1-7-1) was 98%.

[0182] Example 1-1 (Example of Step 1) 0.50 g of compound (1-1-2), 0.75 g of 2-butanone, 0.43 g of potassium carbonate, and 2.5 g of ethanol were mixed and stirred at room temperature for 1 hour, and then stirred for 24 hours at 80° C. The resulting mixture was analyzed by high performance liquid chromatography according to analytical methods 1 and 2. Analysis method 1 revealed that the yield of compound (3-1) was 62%, and analysis method 2 revealed that the sum of the area percentage of compound (3-1) and the area percentage of compound (3-2) was 87%.

[0183] Example 1-2 (Example of Step 1) 0.50 g of compound (1-1-2), 1.50 g of 2-butanone, 0.86 g of potassium carbonate, and 2.5 g of ethanol were mixed and stirred at room temperature for 1 hour, and then stirred for 24 hours at 80° C. The resulting mixture was analyzed by high performance liquid chromatography according to analytical method 2, and the sum of the area percentage of compound (3-1) and the area percentage of compound (3-2) was found to be 85%.

[0184] Comparative Example 1-A 0.12 g of compound (1-1-1), 0.18 g of 2-butanone, and 0.36 g of ethanol were mixed and stirred for 8 hours at 80° C. The resulting mixture was analyzed by high performance liquid chromatography according to analytical method 3, and the sum of the area percentage of compound (3-1) and the area percentage of compound (3-2) was found to be 11%.

[0185] Comparative Example 1-B 0.12 g of compound (1-1-1), 0.18 g of 2-butanone, 0.10 g of triethylamine, and 0.36 g of ethanol were mixed and stirred for 8 hours at 80° C. The resulting mixture was analyzed by high performance liquid chromatography according to analytical method 3, and the sum of the area percentage of compound (3-1) and the area percentage of compound (3-2) was found to be 24%.

[0186] Comparative Example 1-C 0.12 g of compound (1-1-1), 0.18 g of 2-butanone, 0.11 g of tripotassium phosphate, and 0.36 g of ethanol were mixed and stirred for 8 hours at 80° C. The resulting mixture was analyzed by high performance liquid chromatography according to analytical method 3, and the sum of the area percentage of compound (3-1) and the area percentage of compound (3-2) was found to be 31%.

[0187] Comparative Example 1-D 0.12 g of compound (1-1-1), 0.18 g of 2-butanone, 0.051 g of potassium tert-butoxide, and 0.36 g of ethanol were mixed and stirred for 8 hours at 80° C. The resulting mixture was analyzed by high performance liquid chromatography according to analytical method 3, and the sum of the area percentage of compound (3-1) and the area percentage of compound (3-2) was found to be 6%.

[0188] Example 1-3 (Example of Step 1) 0.12 g of compound (1-1-1), 0.18 g of 2-butanone, 0.035 g of potassium carbonate, and 0.36 g of ethanol were mixed and stirred for 8 hours at 80° C. The resulting mixture was analyzed by high performance liquid chromatography according to analytical method 3, and the sum of the area percentage of compound (3-1) and the area percentage of compound (3-2) was found to be 73%.

[0189] Example 1-4 (Example of Step 1) 0.50 g of compound (1-4-2), 0.84 g of 2-butanone, 0.49 g of potassium carbonate, 2.5 g of ethanol, and 0.083 g of pyrrolidine were mixed and stirred at room temperature for 1 hour, and then stirred for 14 hours at 80° C. The resulting mixture was analyzed by high performance liquid chromatography according to analytical methods 1 and 2. As a result, according to analytical method 1, the yield of compound (3-1) was 67%, and according to analytical method 2, the sum of the area percentages of compound (3-1) and compound (3-2) was 89%.

[0190] Example 1-5 (Example of Step 1) 0.50 g of compound (1-5-2), 0.75 g of 2-butanone, 0.43 g of potassium carbonate, 2.5 g of ethanol, and 0.074 g of pyrrolidine were mixed and stirred at room temperature for 1 hour, and then stirred for 14 hours at 80° C. The resulting mixture was analyzed by high performance liquid chromatography according to analytical methods 1 and 2. Analysis method 1 showed that the yield of compound (3-1) was 59%, and analysis method 2 showed that the sum of the area percentage of compound (3-1) and the area percentage of compound (3-2) was 82%.

[0191] Example 1-6 (Example of Step 1) 0.50 g of compound (1-4-2), 0.34 g of 2-butanone, 0.49 g of potassium carbonate, 2.5 g of ethanol, and 0.083 g of pyrrolidine were mixed and stirred at room temperature for 1 hour, and then stirred for 24 hours at 80° C. The resulting mixture was analyzed by high performance liquid chromatography according to analytical methods 1 and 2. As a result, according to analytical method 1, the yield of compound (3-1) was 57%, and according to analytical method 2, the sum of the area percentage of compound (3-1) and the area percentage of compound (3-2) was 79%.

[0192] Example 1-7 (Example of Step 1) 0.50 g of compound (1-4-2), 0.84 g of 2-butanone, 0.37 g of sodium carbonate, 1.5 g of ethanol, and 0.083 g of pyrrolidine were mixed and stirred at room temperature for 1 hour, and then stirred for 24 hours at 80° C. The resulting mixture was analyzed by high performance liquid chromatography according to analytical methods 1 and 2. As a result, according to analytical method 1, the yield of compound (3-1) was 60%, and according to analytical method 2, the sum of the area percentages of compound (3-1) and compound (3-2) was 75%.

[0193] Comparative Example 1-E (Comparison with Example 1-7) 0.50 g of compound (1-4-2), 0.84 g of 2-butanone, 1.5 g of ethanol, and 0.083 g of pyrrolidine were mixed and stirred at room temperature for 1 hour, and then stirred for 24 hours at 80° C. The resulting mixture was analyzed by high performance liquid chromatography according to analytical methods 1 and 2. Analysis method 1 showed that the yield of compound (3-1) was 20%, and analysis method 2 showed that the sum of the area percentage of compound (3-1) and the area percentage of compound (3-2) was 18%.

[0194] Comparative Example 1-F (Comparison with Example 1-7) 0.50 g of compound (1-4-2), 0.84 g of 2-butanone, 0.47 g of triethylamine, 1.5 g of ethanol, and 0.083 g of pyrrolidine were mixed and stirred at room temperature for 1 hour, and then stirred at 80° C. for 24 hours. The resulting mixture was analyzed by high performance liquid chromatography according to analytical methods 1 and 2. Analysis method 1 showed that the yield of compound (3-1) was 30%, and analysis method 2 showed that the sum of the area percentage of compound (3-1) and the area percentage of compound (3-2) was 28%.

[0195] Comparative Example 1-G (Comparison with Example 1-7) 0.50 g of compound (1-4-2), 0.84 g of 2-butanone, 0.37 g of pyridine, 1.5 g of ethanol, and 0.083 g of pyrrolidine were mixed and stirred at room temperature for 1 hour, and then stirred for 24 hours at 80° C. The resulting mixture was analyzed by high performance liquid chromatography according to analytical methods 1 and 2. As a result of analytical method 1, the yield of compound (3-1) was 20%, and as a result of analytical method 2, the sum of the area percentages of compound (3-1) and compound (3-2) was 18%.

[0196] Comparative Example 1-H (Comparison with Example 1-7) 0.50 g of compound (1-4-2), 0.84 g of 2-butanone, 0.39 g of potassium tert-butoxide, 1.5 g of ethanol, and 0.083 g of pyrrolidine were mixed and stirred at room temperature for 1 hour, and then stirred at 80° C. for 24 hours. The resulting mixture was analyzed by high performance liquid chromatography according to analytical methods 1 and 2. Analysis method 1 showed that the yield of compound (3-1) was 5%, and analysis method 2 showed that the sum of the area percentage of compound (3-1) and the area percentage of compound (3-2) was 8%.

[0197] Example 1-8 (Example of Step 1) 0.50 g of compound (1-4-2), 0.84 g of 2-butanone, 0.97 g of potassium carbonate, 1.5 g of ethanol, and 0.083 g of pyrrolidine were mixed and stirred at room temperature for 1 hour, and then stirred for 24 hours at 80° C. The resulting mixture was analyzed by high performance liquid chromatography according to analytical methods 1 and 2. As a result, according to analytical method 1, the yield of compound (3-1) was 62%, and according to analytical method 2, the sum of the area percentage of compound (3-1) and the area percentage of compound (3-2) was 86%.

[0198] Example 1-9 (Example of Step 1) 0.50 g of compound (1-4-2), 0.84 g of 2-butanone, 0.32 g of potassium carbonate, 1.5 g of ethanol, and 0.083 g of pyrrolidine were mixed and stirred at room temperature for 1 hour, and then stirred for 24 hours at 80° C. The resulting mixture was analyzed by high performance liquid chromatography according to analytical methods 1 and 2. Analysis method 1 showed that the yield of compound (3-1) was 67%, and analysis method 2 showed that the sum of the area percentage of compound (3-1) and the area percentage of compound (3-2) was 88%.

[0199] Example 1-10 (Example of Step 1) 0.50 g of compound (1-4-2), 0.84 g of 2-butanone, 0.49 g of potassium carbonate, 1.5 g of 2-propanol, and 0.083 g of pyrrolidine were mixed and stirred at room temperature for 1 hour, and then stirred at 80° C. for 24 hours. The resulting mixture was analyzed by high performance liquid chromatography according to analytical methods 1 and 2. Analytical method 1 revealed that the yield of compound (3-1) was 67%, and analytical method 2 revealed that the sum of the area percentages of compound (3-1) and compound (3-2) was 90%.

[0200] Example 1-11 (Example of Step 1) 0.50 g of compound (1-4-2), 1.7 g of 2-butanone, 0.97 g of potassium carbonate, 5.0 g of ethanol, and 0.17 g of pyrrolidine were mixed and stirred at room temperature for 1 hour, and then stirred for 24 hours at 80° C. The resulting mixture was analyzed by high performance liquid chromatography according to analytical method 2, and the sum of the area percentage of compound (3-1) and the area percentage of compound (3-2) was found to be 83%.

[0201] Example 1-12 (Example of Step 1) 0.50 g of compound (1-5-2), 1.5 g of 2-butanone, 0.86 g of potassium carbonate, 2.5 g of ethanol, and 0.15 g of pyrrolidine were mixed and stirred at room temperature for 1 hour, and then stirred for 24 hours at 80° C. The resulting mixture was analyzed by high performance liquid chromatography according to analytical method 2, and the sum of the area percentage of compound (3-1) and the area percentage of compound (3-2) was found to be 88%.

[0202] Example 1-13 (Example of Step 1) 0.50 g of compound (1-3-2), 1.4 g of 2-butanone, 0.81 g of potassium carbonate, 2.5 g of ethanol, and 0.14 g of pyrrolidine were mixed and stirred at room temperature for 1 hour, and then stirred for 24 hours at 80° C. The resulting mixture was analyzed by high performance liquid chromatography according to analytical method 2, and the sum of the area percentage of compound (3-1) and the area percentage of compound (3-2) was found to be 88%.

[0203] Example 1-14 (Example of Step 1) 0.27 g of compound (1-4-1), 0.54 g of 2-butanone, 0.079 g of potassium carbonate, 0.80 g of ethanol, and 0.053 g of pyrrolidine were mixed and stirred for 8 hours at 80° C. The resulting mixture was analyzed by high performance liquid chromatography according to analytical method 3, and the sum of the area percentage of compound (3-1) and the area percentage of compound (3-2) was found to be 74%.

[0204] Comparative Example 1-I (Comparison with Example 1-14) 0.27 g of compound (1-4-1), 0.54 g of 2-butanone, 0.079 g of potassium carbonate, and 0.80 g of ethanol were mixed and stirred for 8 hours at 80° C. The resulting mixture was analyzed by high performance liquid chromatography according to analytical method 3, and the sum of the area percentage of compound (3-1) and the area percentage of compound (3-2) was found to be 10%.

[0205] Example 1-15 (Example of Step 1) 0.27 g of compound (1-4-1), 0.54 g of 2-butanone, 0.079 g of potassium carbonate, 0.80 g of ethanol, and 0.11 g of pyrrolidine were mixed and stirred for 8 hours at 80° C. The resulting mixture was analyzed by high performance liquid chromatography according to analytical method 3, and the sum of the area percentage of compound (3-1) and the area percentage of compound (3-2) was found to be 73%.

[0206] Example 1-16 (Example of Step 1) 0.39 g of compound (1-7-1), 0.54 g of 2-butanone, 0.079 g of potassium carbonate, 1.2 g of ethanol, and 0.11 g of pyrrolidine were mixed and stirred for 8 hours at 80° C. The resulting mixture was analyzed by high performance liquid chromatography according to analytical method 3, and the sum of the area percentage of compound (3-1) and the area percentage of compound (3-2) was found to be 69%.

[0207] Example 1-17 (Example of Step 1) 0.31 g of compound (1-5-1), 0.54 g of 2-butanone, 0.079 g of potassium carbonate, 0.92 g of ethanol, and 0.11 g of pyrrolidine were mixed and stirred for 8 hours at 80° C. The resulting mixture was analyzed by high performance liquid chromatography according to analytical method 3, and the sum of the area percentage of compound (3-1) and the area percentage of compound (3-2) was found to be 70%.

[0208] Example 1-18 (Example of Step 1) 1.0 g of compound (1-2-2), 1.4 g of 2-butanone, 0.82 g of potassium carbonate, 4.0 g of methanol, and 0.14 g of pyrrolidine were mixed and stirred at room temperature for 1 hour, and then stirred for 16 hours under reflux conditions at an external temperature of 80° C. The resulting mixture was analyzed by high performance liquid chromatography according to analytical method 3, and the sum of the area percentage of compound (3-1) and the area percentage of compound (3-2) was found to be 68%.

[0209] Example 1-19 (Example of Step 1) 1.0 g of compound (1-7-2), 1.2 g of 2-butanone, 0.70 g of potassium carbonate, 4.0 g of methanol, and 0.12 g of pyrrolidine were mixed and stirred at room temperature for 1 hour, and then stirred for 16 hours under reflux conditions at an external temperature of 80° C. The resulting mixture was analyzed by high performance liquid chromatography according to analytical method 3, and the sum of the area percentage of compound (3-1) and the area percentage of compound (3-2) was found to be 67%.

[0210] Example 1-20 (Example of Step 1) 1.0 g of compound (1-5-2), 1.5 g of 2-butanone, 0.86 g of potassium carbonate, 4.0 g of methanol, and 0.15 g of pyrrolidine were mixed and stirred at room temperature for 1 hour, and then stirred for 16 hours under reflux conditions at an external temperature of 80° C. The resulting mixture was analyzed by high performance liquid chromatography according to analytical method 3, and the sum of the area percentage of compound (3-1) and the area percentage of compound (3-2) was found to be 77%.

[0211] Example 1-21 (Example of Step 1) 1.0 g of compound (1-8-2), 0.99 g of 2-butanone, 0.57 g of potassium carbonate, 4.0 g of methanol, and 0.097 g of pyrrolidine were mixed and stirred at room temperature for 1 hour, and then stirred for 16 hours under reflux conditions at an external temperature of 80° C. The resulting mixture was analyzed by high performance liquid chromatography according to analytical method 3, and the sum of the area percentage of compound (3-1) and the area percentage of compound (3-2) was found to be 68%.

[0212] Example 1-22 (Example of Step 1) 100 g of compound (1-1-2), 144 g of 2-butanone, and 138 g of potassium carbonate were added to 300 mL of ethanol, and the mixture was stirred at room temperature for 2 hours and then at 80°C for 16 hours. After cooling to room temperature, the reaction mixture was filtered, and the obtained filtrate was concentrated under reduced pressure. 500 mL of water and 500 mL of chloroform were added sequentially to the obtained concentrated residue, and the mixture was stirred, then allowed to stand, and the layers were separated. The obtained organic layer was washed with 500 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained concentrated residue was purified by column chromatography (solvent system: ethyl acetate / petroleum ether = 1 / 19 (volume ratio)) to obtain 80 g of a mixture of compound (3-1) and compound (3-2) ( 1 The molar ratio determined by H-NMR: Compound (3-1) / Compound (3-2) was >7.7 / 1) was obtained. 100 mL of 2-propanol was added to the obtained mixture, and after stirring at room temperature, the solid was collected by filtration. The obtained solid was dried under reduced pressure to obtain 59.4 g of Compound (3-1). The yield of Compound (3-1) was 48% based on Compound (1-1-2). 1 The H-NMR values ​​are shown below. 1H-NMR (CDCl3) δ: 7.51-7.54 (2H, m), 7.37-7.42 (3H, m), 6.40 (1H, s), 2.77-2.81 (2H, m), 2.39-2.47 (1H, m), 2.18-2.25 (1H, m), 1.83-1.89 (1H, m), 1.20-1.22 (3H, m).

[0213] Example 1-23 (Example of Step 1-1) 10 g of compound (1-1-2), 50 g of water, 7.4 g of 27 wt % aqueous sodium hydroxide solution, and 20 g of xylene were mixed and stirred at room temperature for 30 minutes. After standing, the separated organic layer was washed with 10 g of 9 wt % aqueous sodium sulfate solution, yielding 27.6 g of a xylene solution of compound (1-1-1). When the resulting solution was analyzed by high-performance liquid chromatography according to analytical method 3, the area percentage of compound (1-1-1) was found to be 99%. To a mixture of 15 g of 2-butanone, 2.9 g of potassium carbonate, and 26 g of methanol at 80°C, 25 g of the xylene solution was added dropwise over 8 hours using a syringe pump. The resulting mixture was stirred at 80°C for an additional 6 hours. When the resulting mixture was analyzed by high-performance liquid chromatography according to analytical method 3, the sum of the area percentage of compound (3-1) and the area percentage of compound (3-2) was found to be 75%. After allowing to cool to room temperature, 17 g of xylene, 17 g of water, and 8.8 g of 35 wt % hydrochloric acid were added successively to the obtained reaction mixture, and the mixture was stirred, allowed to stand, and then separated. The obtained organic layer was washed with 8.6 g of water, and the obtained organic layer was concentrated under reduced pressure to obtain 6.0 g ( 1 The molar ratio determined by H-NMR: compound (3-1) / compound (3-2) was >5 / 1) was obtained. 1.5 g of the obtained mixture was dissolved in a mixture of 1.0 g of MTBE and 2.0 g of n-heptane at 50°C, and then cooled to 10°C at a rate of -10°C / hour. The obtained solid was collected by filtration and dried under reduced pressure to obtain 0.83 g of compound (3-1). Analysis by high performance liquid chromatography according to analytical method 3 revealed that the yield of compound (3-1) was 47% based on compound (1-1-2), and the content of compound (3-1) obtained was 98% by weight.

[0214] Example 1-24 (Example of Step 1-1) 3.0 g of pyrrolidine was added at room temperature to a mixture of 10 g of compound (1-4-2), 30 g of 2-butanone, 17 g of potassium carbonate, and 50 g of ethanol. The resulting mixture was stirred at room temperature for 1 hour and then at 80°C for 13 hours. When the resulting mixture was analyzed by high performance liquid chromatography according to analytical method 2, the sum of the area percentage of compound (3-1) and the area percentage of compound (3-2) was found to be 73%. After cooling to room temperature, the resulting reaction mixture was filtered, and the resulting filtrate was concentrated under reduced pressure. 20 g of water and 40 g of MTBE were added sequentially to the resulting concentrated residue at room temperature, and the mixture was stirred at the same temperature, allowed to stand, and then the layers were separated. The resulting organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting concentrated residue was purified by column chromatography (solvent system: ethyl acetate / hexane = 1 / 19 (volume ratio)) to obtain 6.6 g of a mixture of compound (3-1) and compound (3-2) ( 1 The molar ratio of compound (3-1) / compound (3-2) determined by H-NMR was >3.6 / 1. 40 g of hexane was added to the resulting mixture, and the mixture was stirred at room temperature. The resulting solid was collected by filtration and dried under reduced pressure to obtain 5.0 g of compound (3-1). Analysis by high-performance liquid chromatography according to analytical method 2 revealed that the yield of compound (3-1) was 51% based on compound (1-4-2), and the content of compound (3-1) obtained was 89% by weight.

[0215] Example 1-25 (Example of Step 1-1) 5.0 g of compound (1-4-2), 7.5 g of 2-butanone, 4.3 g of potassium carbonate, and 0.74 g of pyrrolidine were added sequentially to 25 g of ethanol at room temperature. The resulting mixture was stirred at room temperature for 1 hour and then at 80°C for 13 hours. When the resulting mixture was analyzed by high performance liquid chromatography according to analytical method 2, the sum of the area percentage of compound (3-1) and the area percentage of compound (3-2) was 89%. After cooling to room temperature, the resulting reaction mixture was filtered, and the resulting filtrate was concentrated under reduced pressure. 10 g of water and 20 g of MTBE were added sequentially to the resulting concentrated residue at room temperature, and the mixture was stirred at the same temperature, allowed to stand, and then separated. The resulting organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 3.86 g ( 1The molar ratio of compound (3-1) / compound (3-2) determined by H-NMR was >3.6 / 1. 20 g of hexane was added to the resulting mixture at room temperature, and the mixture was stirred at the same temperature. The resulting solid was collected by filtration and dried under reduced pressure to obtain 3.6 g of compound (3-1). Analysis by high-performance liquid chromatography according to analytical method 2 revealed that the yield of compound (3-1) was 52% based on compound (1-4-2), and the content of compound (3-1) obtained was 80% by weight.

[0216] Example 2-1-1 (Example of Step 2-1) 0.075 g of compound (3-1), 0.22 g of acetic anhydride, and 0.064 g of bromine were mixed at room temperature, stirred at the same temperature for 2 hours, and then stirred for 2 hours at 60° C. The resulting mixture was analyzed by high performance liquid chromatography according to analytical method 3, and the area percentage of compound (5-1) was found to be 89%.

[0217] Example 2-1-2 (Example of Step 2-1) 0.075 g of compound (3-1), 0.22 g of acetic anhydride, and 0.040 g of 98 wt % sulfuric acid were mixed at room temperature, stirred at the same temperature for 2 hours, and then stirred for 2 hours at 60° C. The resulting mixture was analyzed by high performance liquid chromatography according to analytical method 3, and the area percentage of compound (5-1) was found to be 99%.

[0218] Example 2-1-3 (Example of Step 2-1) 0.075 g of compound (3-1), 0.15 g of acetic anhydride, and 0.044 g of 98% by weight sulfuric acid were mixed at room temperature, stirred at the same temperature for 2 hours, and then stirred for 2 hours at 60° C. The resulting mixture was analyzed by high performance liquid chromatography according to analytical method 3, and the area percentage of compound (5-1) was found to be 99%.

[0219] Example 2-1-4 (Example of Step 2-1) 0.075 g of compound (3-1), 0.22 g of acetic anhydride, and 0.044 g of 98% by weight sulfuric acid were mixed at 0° C., stirred at 0° C. for 1 hour, further stirred at room temperature for 1 hour, and then further stirred at 60° C. for 2 hours. When the resulting mixture was analyzed by high performance liquid chromatography according to analytical method 3, the area percentage of compound (5-1) was found to be 99%.

[0220] Example 2-1-5 (Example of Step 2-1) 0.075 g of compound (3-1), 0.22 g of acetic anhydride, and 0.040 g of 98% by weight sulfuric acid were mixed at 60° C., and then stirred for 3 hours at 60° C. The resulting mixture was analyzed by high performance liquid chromatography according to analytical method 3, and the area percentage of compound (5-1) was found to be 98%.

[0221] Example 2-2-1 (Example of carrying out step 2-1 and step 2-2 in one pot) To the reaction mixture obtained in Example 2-1-1, 0.22 g of ethanol was added at 60°C, and the mixture was stirred at the same temperature for 2 hours. When the resulting mixture was analyzed by high performance liquid chromatography according to analytical method 3, the area percentage of compound (6-1) was found to be 87%.

[0222] Example 2-2-2 (Example in which Steps 2-1 and 2-2 are carried out in one pot) 10 g of compound (3-1) was added to 20 g of acetic anhydride, and 6.5 g of 98 wt % sulfuric acid was added dropwise to the resulting mixture at 30°C over 1 hour. The mixture was then stirred at 30°C for 3 hours and further stirred at 60°C for 1 hour. When the resulting mixture was analyzed by high performance liquid chromatography according to analytical method 3, the area percentage of compound (5-1) was found to be 96%. 10 g of methanol was added to the resulting mixture at 60°C, and the mixture was stirred at 80°C for 8 hours. After allowing to cool to room temperature, 10 g of xylene and 10 g of water were added successively to the resulting mixture, and after stirring, the mixture was allowed to stand and then separated. The resulting organic layer was concentrated under reduced pressure to obtain 10.5 g of compound (6-1). Analysis by high performance liquid chromatography according to analytical method 4 revealed that the yield of compound (6-1) was quantitative based on compound (3-1), and the content of compound (6-1) obtained was 95% by weight.

[0223] Example 2-3-1 (Example in which step 1, step 2-1, and step 2-2 are carried out consecutively) 20 g of compound (1-4-2), 33.7 g of 2-butanone, 19.4 g of potassium carbonate, and 3.3 g of pyrrolidine were added sequentially to 80 g of methanol at room temperature. The resulting mixture was stirred at room temperature for 1 hour and then stirred under reflux conditions at an external temperature of 80°C for 24 hours. When the resulting mixture was analyzed by high performance liquid chromatography according to analytical method 3, the sum of the area percentage of compound (3-1) and the area percentage of compound (3-2) was 76%. After cooling to room temperature, the mixture was concentrated under reduced pressure, and 80 g of MTBE and 40 g of water were added sequentially. The mixture was stirred at room temperature, allowed to stand, and then separated. The resulting organic layer was concentrated under reduced pressure to obtain 16.8 g of a concentrated residue containing compound (3-1). 15 g of the resulting concentrated residue was added to 30 g of acetic anhydride at room temperature, and 8.2 g of 98 wt % sulfuric acid was added dropwise to the resulting mixture at 30°C over 1 hour. The resulting mixture was stirred at 30°C for 3 hours and then at 60°C for 2 hours. 15 g of methanol was added to the resulting mixture at the same temperature, and the mixture was stirred at 80°C for 8 hours. After cooling to room temperature, 30 g of xylene and 30 g of water were added sequentially to the resulting mixture, and the mixture was stirred at the same temperature, allowed to stand, and then separated. The resulting organic layer was concentrated under reduced pressure to obtain 14.4 g of compound (6-1). Analysis by high-performance liquid chromatography according to analytical method 4 revealed that the yield of compound (6-1) was 56% based on compound (1-4-2), and the content of compound (6-1) obtained was 60 wt %.

[0224] Example 2-3-2 (Example in which Step 1-1, Step 2-1, and Step 2-2 are Successively Carried Out) 25 g of compound (1-5-2), 37.3 g of 2-butanone, 21.4 g of potassium carbonate, and 3.7 g of pyrrolidine were added sequentially to 100 g of methanol at room temperature. The resulting mixture was stirred at room temperature for 1 hour and then stirred for 24 hours under reflux conditions at an external temperature of 80°C. When the resulting mixture was analyzed by high performance liquid chromatography according to analytical method 3, the sum of the area percentage of compound (3-1) and the area percentage of compound (3-2) was 79%. After cooling to room temperature, the resulting reaction mixture was concentrated under reduced pressure, and 100 g of MTBE and 50 g of water were added sequentially. The mixture was stirred at room temperature, allowed to stand, and then separated. The resulting organic layer was concentrated under reduced pressure to obtain 18.4 g of a concentrated residue containing compound (3-1). 15 g of the resulting concentrated residue was added to 30 g of acetic anhydride, and 9.1 g of 98 wt % sulfuric acid was added dropwise to the resulting mixture at 30°C over 1 hour. The resulting mixture was stirred at 30°C for 3 hours and then at 60°C for 2 hours. 15 g of methanol was added to the resulting mixture at the same temperature, and the mixture was stirred at 80°C for 8 hours. After cooling to room temperature, 15 g of xylene and 15 g of water were added sequentially to the resulting reaction mixture, and the mixture was stirred at the same temperature, allowed to stand, and then separated. The resulting organic layer was concentrated under reduced pressure to obtain 13.8 g of compound (6-1). Analysis by high-performance liquid chromatography according to analytical method 4 revealed that the yield of compound (6-1) was 61% based on compound (1-5-2), and the content of compound (6-1) obtained was 68 wt %.

[0225] Example 2-4-1 (Example of Step 2 Not Including Steps 2-1 and 2-2) 0.075 g of compound (3-1), 0.22 g of dimethyl sulfoxide, and 0.010 g of iodine were mixed and stirred at room temperature for 2 hours, further stirred at 60° C. for 2 hours, and further stirred at 100° C. for 2 hours. When the resulting mixture was analyzed by high performance liquid chromatography according to analytical method 3, the area percentage of compound (6-1) was found to be 73%.

[0226] Example 2-4-2 (Example of Step 2 Not Including Steps 2-1 and 2-2) 0.075 g of compound (3-1), 0.220 g of acetic acid, and 0.064 g of bromine were mixed and stirred at room temperature for 2 hours, and then stirred at 60° C. for a further 2 hours. When the resulting mixture was analyzed by high performance liquid chromatography according to analytical method 3, the area percentage of compound (6-1) was found to be 69%.

[0227] Example 2-4-3 (Example of Step 2 Not Including Steps 2-1 and 2-2) 0.075 g of compound (3-1), 0.22 g of acetic acid, and 0.069 g of DBDMH were mixed and stirred at room temperature for 2 hours, and then stirred at 60° C. for a further 2 hours. When the resulting mixture was analyzed by high performance liquid chromatography according to analytical method 3, the area percentage of compound (6-1) was found to be 69%.

[0228] Example 2-4-4 (Example of Step 2 Not Including Steps 2-1 and 2-2) 0.075 g of compound (3-1), 0.22 g of tert-butyl alcohol, and 0.064 g of bromine were mixed and stirred at room temperature for 2 hours, and then stirred at 60° C. for a further 2 hours. When the resulting mixture was analyzed by high performance liquid chromatography according to analytical method 3, the area percentage of compound (6-1) was found to be 78%.

[0229] Example 2-4-5 (Example of Step 2 Not Including Step 2-1 and Step 2-2) 0.075 g of compound (3-1), 0.22 g of acetic acid, and 0.054 g of sulfuryl chloride were mixed and stirred at room temperature for 2 hours, and then stirred for another 2 hours at 60° C. The resulting mixture was analyzed by high performance liquid chromatography according to analytical method 3, and the area percentage of compound (6-1) was found to be 58%.

[0230] Example 3-1 (Example of Step 3) To a mixture of 45.8 g of compound (6-1), 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 further 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 (8-1) was isolated as a solid.

[0231] Example 4-1 (Example of Step 4) 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 (8-1), 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, and the mixture was stirred 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 (10-1) was 91% based on compound (8-1) according to Analysis Method 4.

[0232] To 4.47 g of the aqueous layer obtained in Example 4-1, 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. The resulting mixture was analyzed by high performance liquid chromatography, and the yield of compound (11-1) was found to be 93% based on the sodium salt of compound (10-1) according to Analysis Method 4.

[0233] According to the present invention, it is possible to efficiently produce a 3-phenylcyclohexenone compound having a substituent at the 6-position, i.e., compound (3), which can be used as a production intermediate for a 3-hydroxybiphenyl compound having a substituent at the 4-position. Furthermore, compound (6), which is a 3-hydroxybiphenyl compound having a substituent at the 4-position, and compounds (8) and (11), which are derivatives of a 3-hydroxybiphenyl compound having a substituent at the 4-position, can be efficiently produced using compound (3).

Claims

1. Process 1: Formula (1) [In the formula, R 1 , R 2 , R 3 , R 4 and R 5 are the same or different and represent a C1-C12 chain hydrocarbon group optionally substituted with one or more fluorine atoms, a hydrogen atom, a halogen atom, a cyano group, or a nitro group; R 6 represents a C1-C6 chain hydrocarbon group optionally substituted with one phenyl group, R 7 represents a C1-C6 chain hydrocarbon group optionally substituted with one phenyl group, a phenyl group, or a hydrogen atom, or R 6 and R 7 may be taken together to form —(CH2)4—, —(CH2)5—, or —(CH2)2-O—(CH2)2—.] or a salt thereof with a compound represented by formula (2) [In the formula, R 8 represents a C1-C12 chain hydrocarbon group, R 9 represents a hydrogen atom or a C1-C12 chain hydrocarbon group (where R 8 and R 9 If they are different, R 8 R is better 9 is a bulkier group than the above). ] and an alkali metal carbonate are mixed and reacted in the presence of pyrrolidine to obtain a compound represented by the formula (3): [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 8 and R 9 has the same meaning as defined above.].

2. R 6 and R 7 and (b) combine to form -(CH2)4-, and the pyrrolidine is pyrrolidine produced from the compound represented by formula (1) in the reaction system.

3. R 6 and R 7 The combination of 6 and R 7 is a methyl group; 6 and R 7 is an ethyl group; 6 and R 7 is an isopropyl group; 6 and R 7 is a butyl group; 6 and R 7 is a benzyl group; 6 is an ethyl group, and R 7 is a hydrogen atom; 6 is a benzyl group, and R 7 is a hydrogen atom; 6 is a methyl group, and R 7 is a phenyl group; 6 and R 7 and R combine to form -(CH2)4-; 6 and R 7 and R together form -(CH2)5-; or R 6 and R 7 and (II) are taken together to form -(CH2)2-O-(CH2)2-.

4. R 6 and R 7 The combination of 6 and R 7 is a methyl group; 6 and R 7 is an ethyl group; or R 6 and R 7 and are combined to form -(CH2)4-.

5. R 8 is a methyl group, and R 9 The method according to any one of claims 1 to 4, wherein is a hydrogen atom.

6. R 1 and R 5 is a hydrogen atom, and R 2 , R 3 and R 4 and are the same or different and are a hydrogen atom or a halogen atom.

7. R 2 , R 3 and R 4 The method according to claim 6, wherein is a hydrogen atom.

8. In addition to step 1 according to any one of claims 1 to 7, step 2: oxidizing the compound represented by formula (3) obtained in step 1 to obtain a compound represented by formula (6) [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 8 and R 9 has the same meaning as defined above.].

9. The method of claim 8, wherein step 2 comprises steps 2-1 and 2-2: Step 2-1: reacting the compound represented by formula (3) obtained in step 1 with a compound represented by formula (4) [In the formula, R 10 represents a C1-C12 chain hydrocarbon group.] is reacted with bromine or sulfuric acid to obtain a compound represented by formula (5): [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 9 and R 10 has the same meaning as above.] Step 2-2: A step of solvolyzing the compound represented by formula (5) obtained in step 2-1 to obtain a compound represented by formula (6).

10. R 10 The method according to claim 9, wherein is a methyl group.

11. In addition to steps 1 and 2 according to any one of claims 8 to 10, step 3: reacting the compound represented by formula (6) obtained in step 2 with a compound represented by formula (7) [In the formula, X 1 represents a leaving group, R 11 represents a C1-C6 chain hydrocarbon group. ] in the presence of a base to obtain a compound represented by formula (8): [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 9 and R 11 has the same meaning as defined above.].

12. A compound represented by formula (11), which includes steps 4 and 5 in addition to steps 1, 2 and 3 as set forth in claim 11. [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 9 and R 11 has the same meaning as above.]: Step 4: Reacting the compound of formula (8) obtained in step 3 with a compound of formula (9): [In the formula, R 12 represents a C1-C6 chain hydrocarbon group.] in the presence of a base; Step 5: reacting the compound obtained in Step 4 with a methylating agent to obtain a compound represented by formula (11).

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