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

the combination in which R6 and R7 each represents a methyl group; the combination in which R6 and R7 each represents an ethyl group; and the combination in which R6 and R7 combine with each other to form -(CH2)4- are more preferably included.

[0023] The compound (1) may be used as itself or may be used as salts of the compound (1).

[0024] Examples of the salts of the compound include hydrochloride   salts,   hydrobromide salts,    sulfates, phosphates and the others. The hydrochloride salts are particularly preferably included.

[0026] The salts of compound (1) are commercially available, are publicly known, or may be prepared by using the known method (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 are included), The salts of compound (1) may exist as tautomer (enol form) and can be used as each isomer or isomeric mixture as any arbitrary ratios thereof.

[0026] The compound (1) is commercially available, is publicly known, or may be prepared by using the known method (for example, Synthesis (2001), (15), 2239-2246). Also, the salts of compound (1) may be neutralized with a base to obtain the compound (1). Hereinafter, the method for obtaining the compound (1) by neutralizing the salts of compound (1) with a base is explained. Examples of the base include alkali metal hydroxides such as sodium hydroxide, and alkaline earth metal hydroxides such as potassium hydroxide, and others.    The sodium hydroxide is particularly preferably included. The used amounts of the base are usually within a range of 0.9 moles to 5 moles, preferably within a range of 1.0 mole to 1.6 moles, as opposed to 1 mole of the salts of compound (1). The reaction is usually carried out in a solvent. As examples of the solvents, water is preferably included. The solvents which is immiscible to water and water are mixed and the reaction may be carried out in a bilayer system. Examples of the solvents which is immiscible to water include ethers (such as diethylether, 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 mixed solvents of two or more kinds of the solvents. The used amounts of the solvents are usually within a range of 1 part of weight to 20 parts of weight per 1 part of weight of the salts of compound (1). The reaction is carried out by mixing the salts of compound (1), the base, and the solvents. In the mixing of the salts of compound (1), the base and the solvents, the mixing order thereof is not limited unless otherwise specified, and for example, the following methods are included: after the salts of compound (1) and the solvents are mixed, the base is added; after the base and the solvents are mixed, the salts of the compound (1) are added; as well as the salts of compound (1) and the base are added. The reaction temperature in the reaction is usually within a range of 0 to 80°C, and preferably within a range of 0 to 60°C. The reaction period in the reaction may be varied depending on the reaction condition such as the reaction temperature and is usually within a range of 0.1 to 100 hours, and preferably within a range of 0.5 to 48 hours. The compound (1) may be purified according to conventional methods. For example, after the completion of the reaction, the reaction mixture is extracted by adding organic solvents to the reaction mixtures as needed, and the obtained organic layers are then washed, dried, and concentrated under reduced pressure to purify the compound (1). The solvents used for extraction may be solvents in which the compound (1) is solubilized, and examples of the solvents include ethers (such as diethylether, 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); mixed solvents of two or more kinds of the solvents. Also, the compound (1) can be further purified by a column chromatography and the like. The compound (1) may exist as tautomer (enol form) and can be used as each isomer or isomeric mixture as any arbitrary ratios thereof.

[0027] A compound (2) is explained.

[0028] Examples of the C1-C12 chain hydrocarbon group as R8 and R9 include the above-mentioned chain hydrocarbon group having 1 to 12 of carbon atoms. Among them, the abovementioned chain hydrocarbon group having 1 to 4 of carbon atoms is preferably included, a methyl group and an ethyl group are more preferably included, and a methyl group is furthermore preferably included. When R8 and R9 are different from each other, R8 represents bulkier group than R9. As the index for the bulkiness as used herein, Charton parameter (for example, Journal of the American Chemical Society (1975), 97, 1552- 1556) may be used. As used herein, for example, the bulkiness of the group is increased in the order of a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, and tert-butyl group.

[0029] Examples of the combination of R8 and R9 include a combination in which R8 represents a C1-C12 chain hydrocarbon group, and R9 represents a hydrogen atom; a combination in which R8 represents a C1-C4 chain hydrocarbon group, and R9 represents  a  hydrogen  atom;  a  combination  in  which  R8 represents  a  hydrogen  atom;  a  combination  in  which  R8 represents a C1-C4 chain hydrocarbon group, and R9 represents a hydrogen atom; a combination in which R8 represents a C1-C12 chain hydrocarbon group, and R9 represents a C1-C12 chain hydrocarbon group (with the proviso that when R8 and R9 are different from each other, R8 represents a bulkier group than R9); a combination in which R8 represents a C1-C4 chain hydrocarbon group, and R9 represents a C1-C4 chain hydrocarbon group (with the proviso that when R8 and R9 are different from each other, R8 represents a bulkier group than R9). More specific examples of the combination of R8 and R9 include a combination in which R8 represents a methyl group, and R9 represents a hydrogen atom. The compound (2) is a commercially available, is publicly known, or may be prepared according to a publicly known method. The compound (2) may exist as tautomer (enol form) and can be used as each isomer or isomeric mixture as any arbitrary ratios thereof.

[0031] A compound (4) is explained.

[0032] Examples of the C1-C12 chain hydrocarbon group as R10 group includes the above-mentioned chain hydrocarbon group having 1 to 12 of carbon atoms. Among them, a C1-C6 alkyl group is preferably included, a methyl group, an ethyl group and a propyl group are more preferably included, and a methyl group is furthermore preferably included.

[0033] The compound (4) is a commercially available, is publicly known, or may be prepared according to a publicly known method.

[0034] A compound (7) is explained.

[0035] Examples of the C1-C6 chain hydrocarbon group as R11 group include the above-mentioned chain hydrocarbon group having 1 to 6 of carbon atoms. Among them, the above mentioned chain hydrocarbon group having 1 to 3 of carbon atoms is preferably included, a methyl group and an ethyl group are more preferably included, and a methyl group is furthermore preferably included.

[0036] Examples of the leaving group represented by X1 include a chlorine atom, a bromine atom, an iodine atom, a p-toluenesulfonyl group, a methanesulfonyl group, and a trifluoromethanesulfonyl group. Among them, a chlorine atom, a bromine atom and an iodine atom are preferably included, and a chlorine atom is more preferably included.

[0037] A compound (7) is commercially available, is publicly known, or may be prepared by using the known method.

[0038] A compound (9) is explained.

[0039] Examples of C1-C6 chain hydrocarbon group as R12 group include the above-mentioned chain hydrocarbon group having 1 to 6 of carbon atom.  Among them, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a pentyl group, and a hexyl group are preferably included, and a methyl group is more preferably included.

[0040] A compound (9) is commercially available, is publicly known, or may be prepared by using the known method.

[0041] A step 1 is explained. In the step 1, the compound (1) or salts thereof, the compound (2), and an alkali metal carbonate are mixed and reacted in the presence of a pyrrolidine to obtain the compound (2).

[0042] Examples of the alkali metal carbonates include lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate.     Among them, sodium carbonate, potassium carbonate, and mixtures of two or more thereof are preferably included.

[0043] When the compound (1) is used as the compound (1) or salts thereof, the used amounts of the alkali metal carbonate are usually within the range of 0.1 moles to 20 moles, and preferably within 0.2 moles to 1.2 moles as opposed to 1 mole of the compound (1). When the salt of compound (1) is used as the compound (1) or salts thereof, the used amounts of the alkali metal carbonate are usually within the range of 0.2 moles to 5 moles, and preferably within 0.4 moles to 3.5 moles as opposed to 1 mole of the salt of compound (1). The used amounts of the pyrrolidine are usually within the range of 0.2 moles to 2.0 moles, and preferably within 0.3 moles to 1.5 moles as opposed to 1 mole of the compound (1) or the salt thereof. With the proviso that when R6 and R7 combine with each other to form -(CH2)4-, that is, the compound (1) is the compound (1-1), since pyrrolidine is formed from the compound (1-1) in the reaction system, there is no need to add the pyrrolidine into the reaction system.

[0045] The used amounts of the compound (2) are usually within a range of 1 mole to 100 moles, preferably within a range of 1 mole to 15 moles, as opposed to 1 mole of the compound (1) or salts thereof.

[0046] The reaction is usually carried out in a solvent. As examples of the solvents, polar solvents are preferably included. Examples of the protic solvents include alcohols; water; and mixed solvents of two or more kinds of the solvents. Alcohols are more preferably included. Specific examples of the alcohols include methanol, ethanol,  1- propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, tert-butyl alcohol, ethylene glycol, and mixed solvents of two or more kinds of the solvents, methanol, ethanol and 2-propanol are preferably included, and methanol and ethanol are more preferably included. A mixture of the above-mentioned protic solvents and aprotic solvents may be used as solvents. Examples of the 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 mixed solvents of two or more kinds of the solvents. The reaction may be carried out in a bilayer system by mixing the solvent which is immiscible to water and water. Examples of the solvent which is immiscible to water 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 mixed solvents of two or more kinds of the solvents.

[0047] The used amounts of solvents are usually within a range of 2 parts of weight 10 parts of weight per 1 part of weight of the compound (1).

[0048] The reaction may be carried out by adding a phasetransfer catalyst into a reaction system. Examples of the phase-transfer catalysts include quaternary ammonium salts (such as tetrabutylammonium chloride, tetrabutylammonium bromide,          benzyltrimethylammonium         chloride, benzyltrimethylammonium bromide, benzyltriethylammonium chloride, and benzyltriethylammonium bromide).

[0049] When the reaction is carried out by adding the phase transfer catalyst into a reaction system, the used amounts of the phase-transfer catalyst are usually within a range of 0.005 moles to 0.2 moles per 1 mole of the compound (1).

[0050] The reaction is carried out by mixing the compound (1) or salts thereof, the compound (2), pyrrolidine, the solvents, and the alkali metal carbonates. Here, since as above-mentioned, when the compound (1) is the compound (1-1), pyrrolidine is formed in the reaction system, there is no mixing with pyrrolidine. That is, the reaction can be carried out in the presence of pyrrolidine by mixing the compound (1-1) or salts thereof, the compound (2), the solvents and the alkali metal carbonates. With the proviso that even when the compound (1) is the compound (1 1), the reaction may be carried out by mixing pyrrolidine. That is, the reaction may be carried out by mixing the compound (1-1) or salts thereof, the compound (2), pyrrolidine, the solvents and the alkali metal carbonates. In the mixing of the compound (1) or salts thereof, the compound (2), pyrrolidine, the solvents and the alkali metal carbonates, the mixing order thereof is not limited unless otherwise specified, and for example, the following methods are included: after the compound (1), the compound (2), pyrrolidine and the solvents are mixed, the alkali metal carbonate is added; after the alkali metal carbonates, compound (1), pyrrolidine and the solvents are mixed, the compound (2)  is added; after the alkali metal carbonates, the compound (2), pyrrolidine and solvents are mixed, compound (1)  is added; after the alkali metal carbonates, the compound (1), the compound (2) and the solvents are mixed, pyrrolidine is added; after the compound (1), pyrrolidine and the solvents are mixed, the alkali metal carbonates and the compound (2) are added; after the compound (2), pyrrolidine and the solvents are mixed, the alkali metal carbonates, and compound (1) are added; after the alkali metal carbonates, pyrrolidine and the solvents are mixed, the compound (1) and the compound (2) are added; after the compound (1), the compound (2) and the solvents are mixed, the alkali metal carbonates and pyrrolidine are added; after the alkali metal carbonates, the compound (2) and the solvents are mixed, the compound (1) and pyrrolidine are added; after the alkali metal carbonates, the compound (1) and the solvents are mixed, the compound (2) and pyrrolidine are added; after the compound (1) and the solvents are mixed, the alkali metal carbonates, pyrrolidine and the compound (2) are added; after the compound (2) and the solvents are mixed, the alkali metal carbonates, pyrrolidine and the compound (1) are added; after pyrrolidine and the solvents are mixed, the alkali metal carbonates, the compound (1) and the compound (2) are added; after the alkali metal carbonates and the solvents are mixed, pyrrolidine, the compound (1) and the compound (2) are added; the alkali metal carbonates, the compound (1), the compound (2) and pyrrolidine are added to the solvents; after the compound (1-1), the compound (2) and the solvents are mixed, the alkali metal carbonates are added; after the alkali metal carbonates, the compound (11) and the solvents are mixed, the compound (2) is added; after the alkali metal carbonates, the compound (2) and the solvents are mixed, the compound (1-1) is added; after the compound (1-1) and the solvents are mixed, the alkali metal carbonates and the compound (2) are added; after the compound (2) and the solvents are mixed, the alkali metal carbonates and the compound (1-1) are added; after the alkali metal carbonates and the solvents are mixed, the compound (1-1) and the compound (2) are added; the alkali metal carbonates, the compound (1-1) and the compound (2) are added to the solvents; after the salts of compound (1), the compound (2), pyrrolidine and the solvents are mixed, the alkali metal carbonates are added; after the alkali metal carbonates, the salts of compound (1), pyrrolidine and the solvents are mixed, the compound (2) is added; after the alkali metal carbonates, the compound (2), pyrrolidine and the solvents are mixed, the salts of compound (1) are added; after the alkali metal carbonates, the salts of compound (1), the compound (2) and the solvents are mixed, pyrrolidine is added; after the salts of compound (1), pyrrolidine and the solvents are mixed, the alkali metal carbonates and the compound (2) are added; after the compound (2), pyrrolidine and the solvents are mixed, the alkali metal carbonates and the salts of compound (1) are added; after the alkali metal carbonates, pyrrolidine and the solvents are mixed, the salts of compound (1) and the compound (2) are added; after the salts of compound (1), the compound (2) and the solvents are mixed, the alkali metal carbonates and pyrrolidine are added; after the alkali metal carbonates, the compound (2) and the solvents are mixed, the salts of compound (1) and pyrrolidine are added; after the alkali metal carbonates, the salts of compound (1) and the solvents are mixed, the compound (2) and pyrrolidine are added; after the salts of compound (1) and the solvents are mixed, the alkali metal carbonates, pyrrolidine and the compound (2) are added; after the compound (2) and the solvents are mixed, the alkali metal carbonates, pyrrolidine and the salts of compound (1) are added; after pyrrolidine and the solvents are mixed, the alkali metal carbonates, the salts of compound (1) and the compound (2) are added; after the alkali metal carbonates and the solvents are mixed, pyrrolidine, the salts of compound (1) and the compound (2) are added; the alkali metal carbonates, the salts of compound (1), the compound (2) and pyrrolidine are added to the solvents; after the salts of compound (1-1), the compound (2) and the solvents are mixed, the alkali metal carbonates are added; after the alkali metal carbonates, the salts of compound (1-1) and the solvents are mixed, the compound (2) s is added; after the alkali metal carbonates, the compound (2) and the solvents are mixed, the salts of compound (1-1) is added; after the salts of compound (1-1) and the solvents are mixed, the alkali metal carbonates and the compound (2) are added; after the compound (2) and the solvents are mixed, the alkali metal carbonates and the salts of compound (1-1) are added; after the alkali metal carbonates and the solvents are mixed, the salts of compound (1-1) and the compound (2) are added; as well as the alkali metal carbonates, the salts of compound (1-1) and the compound (2) are added to the solvents. Among them, the following methods are preferably included: after the compound (2), pyrrolidine, the alkali metal carbonates and the solvents are mixed, the compound is added; after the salts of compound (1), the compound (2), the alkali metal carbonates and the solvents are mixed, pyrrolidine is added; after the alkali metal carbonates, the compound (2) and the solvents are mixed, the compound (1-1) is added; and after the salts of compound (1-1), the alkali metal carbonates and the solvents are mixed, the compound (2) is added. The compound (1) or salts thereof, the compound (2), pyrrolidine, and the alkali metal carbonates may be mixed with a part of solvents in advance, and then are used. In the above-mentioned every method, each component that is added to the reaction system, that is, the compound (1) or salts thereof, the compound (2), pyrrolidine (as the above-mentioned, when the compound (1) is the compound (11), pyrrolidine is formed in the reaction system, there is no need to add pyrrolidine into the reaction system), the solvents and the alkali metal carbonates, the whole amounts of each component may be added once respectively, or each component may be divided into a plurality of parts thereof and they may be then added portionwise, or each component may be added step by step. Also, among the components to be added, two or more of the components may be added at the same time and the whole amounts of each component may be added once respectively, or two or more of the components may be added at the same time, and each component may be divided into a plurality of parts thereof, and they may be added portionwise, or two or more of the components may be added at the same time, and each component may be added step by step respectively. Also, among the components to be added, two or more of the components may be added by mixing them in advance. With respect to each component to be mixed in advance, the whole amounts of each component may be mixed in advance respectively, or a part of the components may be mixed in advance. Also, the mixtures of two or more of the components may be prepared such that the kinds of combinations of the components may be varied.

[0050] The reaction temperature in the reaction is usually within a range of 40 to 120°C, and preferably within a range of 60 to 100°C.

[0051] The reaction period in the reaction is usually within a range of 0.1 to 100 hours, and preferably within a range of 1 to 48 hours, depending on the reaction condition such as the reaction temperature.

[0053] When the salts of compound (1) is used as the compound (1) or salts thereof, before the reaction is carried out at the above-mentioned reaction temperature for the abovementioned reaction period in the reaction, in order to neutralize the salts of compound (1) with the alkali metal carbonates in the reaction system, the reaction is preferably carried out at the temperature being usually within a range of 0 to 60°C, preferably within a range of 10 to 40°C, for the reaction period in the reaction being usually within a range of 0.1 to 10 hours, preferably within a range of 0.5 to 2 hours. Specific examples of the reaction include the following methods: after the salts of compound (1), the compound (2), the solvents, the alkali metal carbonates and pyrrolidine are mixed, the reaction is carried out at the temperature being within a range of 0 to 10°C for the reaction period in the reaction being within a range of 1 to 10 hours, and thereafter at the temperature being within a range of 60 to 120°C for the reaction period in the reaction being within a range of 0.1 to 100 hours; after the salts of compound (1), the compound (2), the solvents, the alkali metal carbonates and pyrrolidine are mixed, the reaction is carried out at the temperature being within a range of 0 to 60°C for the reaction period in the reaction being within a range of 1 to 10 hours, and thereafter at the temperature being within a range of 60 to 100°C for the reaction period in the reaction being within a range of 0.1 to 100 hours; after the salts of compound (1), the compound (2), the solvents, the alkali metal carbonates and pyrrolidine are mixed, the reaction is carried out at the temperature being within a range of 10 to 40°C for the reaction period in the reaction being within a range of 0.5 to 2 hours, and thereafter at the temperature being within a range of 40 to 120°C for the reaction period in the reaction being within a range of 0.1 to 100 hours; after the salts of compound (1), the compound (2), the solvents, the alkali metal carbonates and pyrrolidine are mixed, the reaction is carried out at the temperature being within a range of 10 to 40°C for the reaction period in the reaction being within a range of 0.5 to 2 hours, and thereafter at the temperature being within a range of 40 to 100°C for the reaction period in the reaction being within a range of 0.1 to 100 hours; after the salts of compound (1), the compound (2), the solvents, the alkali metal carbonates and pyrrolidine are mixed, the reaction is carried out at the temperature being within a range of 10 to 40°C for the reaction period in the reaction being within a range of 0.5 to 2 hours, and thereafter at the temperature being within a range of 60 to 100°C for the reaction period in the reaction being within a range of 0.1 to 100 hours; after the salts of compound (1), the compound (2), the solvents and the alkali metal carbonates are mixed, pyrrolidine is added thereto, and the reaction is carried out at the temperature being within a range of 0 to 60°C for the reaction period in the reaction being within a range of 0.1 to 10 hours, and thereafter at the temperature being within a range of 60 to 120°C for the reaction period in the reaction being within a range of 0.1 to 100 hours; after the salts of compound (1), the compound (2), the solvents and alkali metal carbonates are mixed, pyrrolidine is added thereto, and the reaction is carried out at the temperature being within a range of 0 to 60°C for the reaction period in the reaction being within a range of 1 to 10 hours, and thereafter at the temperature being within a range of 60 to 100°C for the reaction period in the reaction being within a range of 0.1 to 100 hours; after the salts of compound (1), the compound (2), the solvents and the alkali metal carbonates are mixed, pyrrolidine is added thereto, and the reaction is carried out at the temperature being within a range of 10 to 40°C for the reaction period in the reaction being within a range of 0.5 to 2 hours, and thereafter, at the temperature being within a range of 40 to 120°C for the reaction period in the reaction being within a range of 0.1 to 100 hours; after the salts of compound (1), the compound (2), the solvents and the alkali metal carbonates are mixed, pyrrolidine is added thereto, and the reaction is carried out at the temperature being within a range of 10 to 40°C for the reaction period in the reaction being within a range of 0.5 to 2 hours, and thereafter at the temperature being within a range of 40 to 100°C for the reaction period in the reaction being within a range of 0.1 to 100 hours; after the salts of compound (1), the compound (2), the solvents and the alkali metal carbonates are mixed, pyrrolidine is added thereto, and the reaction is carried out at the temperature being within a range of 10 to 40°C for the reaction period in the reaction being within a range of 0.5 to 2 hours, and thereafter at the temperature being within a range of 60 to 100°C for the reaction period in the reaction being within a range of 0.1 to 100 hours; after the salts of compound (1-1), the compound (2), the solvents and the alkali metal carbonates are mixed, the reaction is carried out at the temperature being within a range of 0 to 60°C for the reaction period in the reaction being within a range of 0.1 to 10 hours, and thereafter at the temperature being within a range of 60 to 120°C for the reaction period in the reaction being within a range of 0.1 to 100 hours; after the salts of compound (1-1), the compound (2), the solvents and the alkali metal carbonates are mixed, the reaction is carried out at the temperature being within a range of 0 to 60°C for the reaction period in the reaction being within a range of 0.1 to 10 hours, and thereafter at the temperature being within a range of 60 to 100°C for the reaction period in the reaction being within a range of 0.1 to 100 hours; after the salts of compound (1-1), the compound (2), the solvents and the alkali metal carbonates are mixed, the reaction is carried out at the temperature being within a range of 10 to 40°C for the reaction period in the reaction being within a range of 0.2 to 2 hours, and thereafter at the temperature being within a range of 40 to 120°C for the reaction period in the reaction being within a range of 0.1 to 100 hours; after the salts of compound (1-1), the compound (2), the solvents and the alkali metal carbonates are mixed, the reaction is carried out at the temperature being within a range of 10 to 40°C for the reaction period in the reaction being within a range of 0.2 to 2 hours, and thereafter at the temperature being within a range of 40 to 100°C for the reaction period in the reaction being within a range of 0.1 to 100 hours; after the salts of compound (1-1), the compound (2), the solvents and the alkali metal carbonates are mixed, the reaction is carried out at the temperature being within a range of 10 to 40°C for the reaction period in the reaction being within a range of 0.5 to 2 hours, and thereafter at the temperature being within a range of 60 to 100°C for the reaction period in the reaction being within a range of 0.1 to 100 hours; after the salts of compound (1-1), the alkali metal carbonates and the solvents are mixed, the compound (2) is added thereto, and the reaction is carried out at the temperature being within a range of 0 to 60°C for the reaction period in the reaction being within a range of 0.1 to 10 hours, and thereafter at the temperature being within a range of 60 to 120°C for the reaction period in the reaction being within a range of 0.1 to 100 hours; after the salts of compound (1-1), the alkali metal carbonates and the solvents are mixed, the compound (2) is added thereto, and the reaction is carried out at the temperature being within a range of 0 to 60°C for the reaction period in the reaction being within a range of 0.1 to 10 hours, and thereafter at the temperature being within a range of 60 to 100°C for the reaction period in the reaction being within a range of 0.1 to 100 hours; after the salts of compound (1-1), the alkali metal carbonates and the solvents are mixed, the compound (2) is added thereto, and the reaction is carried out at the temperature being within a range of 10 to 40°C for the reaction period in the reaction being within a range of 0.5 to 1 hours, and thereafter at the temperature being within a range of 40 to 120°C for the reaction period in the reaction being within a range of 0.1 to 100 hours; after the salts of compound (1-1), the alkali metal carbonates and the solvents are mixed, the compound (2) is added thereto, and the reaction is carried out at the temperature being within a range of 10 to 40°C for the reaction period in the reaction being within a range of 0.5 to 2 hours, and thereafter at the temperature being within a range of 40 to 100°C for the reaction period in the reaction being within a range of 0.1 to 100 hours; as well as after the salts of compound (1-1), the alkali metal carbonates and the solvents are mixed, the compound (2) is added thereto, and the reaction is carried out at the temperature being within a range of 10 to 40°C for the reaction period in the reaction being within a range of 0.5 to 2 hours, and thereafter, at the temperature being within a range of 60 to 100°C for the reaction period in the reaction being within a range of 0.1 to 100 hours. Among them, the following methods are preferably included: after the salts of compound (1), the compound (2), the solvents, the alkali metal carbonates and pyrrolidine are mixed, and the reaction is carried out at the temperature being within a range of 10 to 40°C for the reaction period in the reaction being within a range of 0.5 to 2 hours, and thereafter at the temperature being within a range of 40 to 120°C for the reaction period in the reaction being within a range of 0.1 to 100 hours; after the salts of compound (1), the compound (2), the solvents, the alkali metal carbonates and pyrrolidine are mixed, the reaction is carried out at the temperature being within a range of 10 to 40°C for the reaction period in the reaction being within a range of 0.5 to 2 hours, and thereafter at the temperature being within a range of 40 to 100°C for the reaction period in the reaction being within a range of 0.1 to 100 hours; after the salts of compound (1), the compound (2), the solvents, the alkali metal carbonates and pyrrolidine are mixed, the reaction is carried out at the temperature being within a range of 10 to 40°C for the reaction period in the reaction being within a range of 0.5 to 2 hours, and thereafter at the temperature being within a range of 60 to 100°C for the reaction period in the reaction being within a range of 0.1 to 100 hours; after the salts of compound (1), the compound (2), the solvents and the alkali metal carbonates are mixed, pyrrolidine is added thereto, and the reaction is carried out at the temperature being within a range of 10 to 40°C for the reaction period in the reaction being within a range of 0.5 to 2 hours, and thereafter at the temperature being within a range of 40 to 120°C for the reaction period in the reaction being within a range of 0.1 to 100 hours; after the salts of compound (1), the compound (2), the solvents and the alkali metal carbonates are mixed, pyrrolidine is added thereto, and the reaction is carried out at the temperature being within a range of 10 to 40°C for the reaction period in the reaction being within a range of 0.5 to 2 hours, and thereafter at the temperature being within a range of 40 to 100°C for the reaction period in the reaction being within a range of 0.1 to 100 hours; after the salts of compound (1), the compound (2), the solvents and the alkali metal carbonates are mixed, pyrrolidine is added thereto, and the reaction is carried out at the temperature being within a range of 10 to 40°C for the reaction period in the reaction being within a range of 0.5 to 2 hours, and thereafter at the temperature being within a range of 60 to 100 °C for the reaction period in the reaction being within a range of 0.1 to 100 hours; after the salts of compound (1-1), the compound (2), the solvents and the alkali metal carbonates are mixed, and the reaction is carried out at the temperature being within a range of 10 to 40°C for the reaction period in the reaction being within a range of 0.5 to 2 hours, and thereafter at the temperature being within a range of 40 to 120°C for the reaction period in the reaction being within a range of 0.1 to 100 hours; after the salts of compound (1 1), the compound (2), the solvents and the alkali metal carbonates are mixed, and the reaction is carried out at the temperature being within a range of 10 to 40°C for the reaction period in the reaction being within a range of 0.5 to 2 hours, and thereafter at the temperature being within a range of 40 to 100°C for the reaction period in the reaction being within a range of 0.1 to 100 hours; after the salts of compound (1-1), the compound (2), the solvents and the alkali metal carbonates are mixed, and the reaction is carried out at the temperature being within a range of 10 to 40°C for the reaction period in the reaction being within a range of 0.5 to 2 hours, and thereafter at the temperature being within a range of 60 to 100°C for the reaction period in the reaction being within a range of 0.1 to 100 hours; after the salts of compound (1-1), the alkali metal carbonates and the solvents are mixed, the compound (2) is added thereto, and the reaction is carried out at the temperature being within a range of 10 to 40°C for the reaction period in the reaction being within a range of 0.5 to 2 hours, and thereafter at the temperature being within a range of 40 to 120°C for the reaction period in the reaction being within a range of 0.1 to 100 hours; after the salts of compound (1-1), the alkali metal carbonates and the solvents are mixed, the compound (2) is added thereto, and the reaction is carried out at the temperature being within a range of 10 to 40°C for the reaction period in the reaction being within a range of 0.5 to 2 hours, and thereafter at the temperature being within a range of 40 to 100°C for the reaction period in the reaction being within a range of 0.1 to 100 hours; as well as after the salts of compound (1-1), the alkali metal carbonates and the solvents are mixed, the compound (2) is added thereto, and the reaction is carried out at the temperature being within a range of 10 to 40°C for the reaction period in the reaction being within a range of 0.5 to 2 hours, and thereafter at the temperature being within a range of 60 to 100°C for the reaction period in the reaction being within a range of 0.1 to 100 hours.

[0054] When R8 and R9 are different from each other, as the regioisomer of the compound (3), the compound of formula (3X): R4 [wherein R1, R2, R3, R4, R5, R8 and R9 are the same as defined above] is sometimes formed as a by-product.

[0055] The reaction period may be varied depending on the reaction conditions such as the reaction temperature, and is usually within a range of 0.1 to 100 hours, and preferably within a range of 1 to 48 hour(s).

[0056] The compound (3) may be purified by conventional methods. For example, when solids are precipitated out, the solids formed after the completion of the reaction are collected by filtration to purify the compound (3). Also, for example, after the completion of the reaction, the reaction mixtures are mixed with aqueous acidic solution such as diluted hydrochloric acid and diluted sulfuric acid, or water, and extracted with organic solvents, and the resulting organic layers are washed, dried and concentrated under reduced pressure to purify the compound (3). Here the solvents used for extraction may be solvents in which the compound (3) is solubilized, however, are not limited unless otherwise specified, and examples of the solvents include ethers (such as diethylether, tetrahydrofuran, MTBE, cyclopentyl methyl ether); hydrocarbons (such as pentane, hexane, heptane, octane, benzene, toluene, xylene, ethylbenzene, mesitylene, cyclohexane, and cyclopentane); halogenated hydrocarbons (such as monochlorobenzene); and mixed solvents of two or more kinds of the solvents. Also, the compound (3) can be further purified by column chromatography, recrystallization, and the like. As the solvents used for recrystallization, one or more solvents selected from the group consisting of the followings can be used: 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- methyl tetrahydrofuran, 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 them, the mixed solvents of one or more solvents selected from the group consisting of aromatic hydrocarbons, halogenated hydrocarbons, nitriles, ketones, ethers, esters and aprotic polar solvents, and one or more solvents selected from the group consisting of aliphatic hydrocarbons, alcohols and water are preferably included. The compound (3) may be existed as a tautomer (enol form), and the compound (3) obtained in the step 1 may be each tautomer or tautomer mixture as any arbitrary ratios thereof. Also, after the completion of the reaction, the compound (3) can be supplied to the step 2 without any purification.

[0057] A step 2 is explained. In the step 2, the compound (3) obtained in the step 1 is oxidized to obtain the compound (6).

[0058] As the compound (3) obtained in the step 1, the compound obtained by the above-mentioned purification in the step 1 may be used, or mixtures containing the compound (3) obtained by work-up treatments such as extraction on the reaction mixtures after the completion of the reaction of the step 1 may be used.   Examples of the mixtures containing the compound (3) include the above-mentioned organic layers containing the compound (3). The compound (3) may be existed as a tautomer (enol form), and each of the tautomer and tautomer mixture as any arbitrary ratios thereof can be used.

[0059] As a method for producing the compound (6) by oxidization of the compound (3) obtained in the step 1, for example, the following methods are included: the compound (3) obtained in the step 1 is reacted with an oxidization agent to obtain the compound (6) in one step; as well as, the step 2-1 and the step 2-2 are combined to obtain the compound (6), that is, the step in which the compound (3) obtained in the step 1, the compound (4), bromine or sulfuric acid are reacted to obtain the compound (5) (step 2-1), or the step in which the compound (5) obtained in the step 2-1 is subjected to a solvolysis to obtain the compound (6) (step 2-2) are used in combination to obtain compound (6). Among them, a method by combining the step 2-1 and the step 2-2 to obtain the compound (6) is preferably included.

[0060] The method in which the compound (3) obtained in the step 1 is reacted with an oxidizing agent to obtain the compound (6) is explained. Examples of the oxidizing agent 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 used amounts of the oxidizing agent are usually within a range of 0.7 moles to 1.6 moles, and preferably within a range of 0.9 moles to 1.1 moles, as opposed to 1 mole of the compound (3). When the oxidizing agent is DBDMH, the used amounts of the oxidizing agent are usually within a range of 0.4 to 1 mole(s), and preferably within a range of 0.5 moles to 0.7 moles, as opposed to 1 mole of the compound (3). The reaction is usually carried out in a solvent. Examples of the 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 used amounts of the solvents are usually within a range of 1 to 20 part(s) by weight, as opposed to 1 part by weight of the compound (3). The reaction temperature is usually within a range of 10 to 100 °C, and preferably within a range of 40 to 80 °C. The reaction period may be varied depending on the reaction conditions such as reaction temperature, and is usually within a range of 0.1 to 100 hours, and preferably within a range of 1 to 24 hour(s). When the oxidizing agent is iodine, a catalytic amount of iodine and dimethyl sulfoxide as a re-oxidizing agent can be used in combination. In this case, the used amounts of iodine are usually within a range of 0.01 to 0.2 moles as opposed to 1 mole of the compound (3), and the used amounts of dimethyl sulfoxide are usually within a range of 2 to 10 parts by weight as opposed to 1 part by weight of the compound (3). The reaction temperature is usually within a range of 60 to 150 °C, and preferably within a range of 80 to 120 °C. The reaction period may be varied depending on the reaction conditions such as the reaction temperature, and is usually within a range of 0.1 o 100 hours, and preferably within a range of 1 to 4 hour(s).

[0061] A step 2-1 is explained. In the step 2-1, the compound (3) obtained in the step 1, the compound (4), bromine or sulfuric acid are reacted to obtain the compound (5).

[0062] The used amounts of the compound (4) are usually within a range of 0.5 to 10 parts by weight, and preferably within a range of 1 to 5 part(s) by weights, as opposed to 1 part by weight of the compound (3).

[0063] With respect to sulfuric acid, sulfuric acid containing the contents of 90 % by weight or more and 100 % by weight or less is preferably included, and the sulfuric acid containing the contents of 96 % by weight or more and 98 % by weight or less is more preferably included.

[0064] The used amounts of bromine or sulfuric acid are usually within a range of 0.6 to 3 moles, and preferably within a range of 0.8 to 1.2 moles, as opposed to 1 mole of the compound (3).

[0065] The reaction is usually carried out under a solvent-free condition.

[0066] The reaction is carried out by mixing the compound (3), the compound (4), and bromine or sulfuric acid. In mixing of the compound (3), the compound (4), and bromine or sulfuric acid, the mixing order thereof is not limited unless otherwise specified, and for example, the following methods are included: after the compound (3) and the compound (4) are mixed, bromine is added thereto; after the compound (3) and bromine are mixed, the compound (4) is added thereto; after the compound (4) and bromine are mixed, the compound (3) is added thereto; the compound (4) and bromine are added to the compound (3); the compound (3) and bromine are added to the compound (4); the compound (3) and the compound (4) are added to bromine; after the compound (3) and the compound (4) are mixed, sulfuric acid is added thereto; after the compound (3) and sulfuric acid are mixed, the compound (4) is added thereto; after the compound (4) and sulfuric acid are mixed, the compound (3) is added thereto; the compound (4) and sulfuric acid are added to the compound (3); the compound (3) and sulfuric acid are added to the compound (4); as well as, the compound (3) and the compound (4) are added to sulfuric acid. Among them, the method in which after the compound (3) and the compound (4) are mixed, sulfuric acid is added is preferably included. In all of the above-mentioned methods, with respect to each component to be added to the reaction system, the compound (3), the compound (4), and bromine or sulfuric acid, the whole amounts of each component may be added at once respectively, or each component may be divided into a plurality of parts thereof and they may be then added portionwise, or each component may be added step by step. Also, among each component to be added, two or more of the components may be added at the same time and the whole amounts of each component may be added at once respectively, or two or more of the components may be added at the same time, and each component may be divided into a plurality of parts thereof, and they may be added portionwise, or two or more of the components may be added at the same time, and each component may be added step by step respectively. Also, among each component to be added, two or more of the components may be added at the same time and the whole amounts of each component may be added at once respectively, or two or more of the components may be added at the same time, and each component may be divided into a plurality of parts thereof, and they may be added portionwise, or two or more of the components may be added at the same time, and each component may be added step by step respectively. Also, among each component to be added, two or more of the components may be added by mixing them in advance. With respect to each component to be mixed in advance, the whole amounts of each component may be mixed in advance respectively, or a part of the components may be mixed in advance. Also, the mixtures of two or more of the components may be prepared such that the kinds of combinations of the components may be varied. Among them, the method in which after the compound (3) and the compound (4) are mixed, and sulfuric acid is added thereto step by step; as well as, the method in which after the compound (3) and the compound (4) are mixed, and bromine is added thereto step by step, are preferably included. The method in which after the compound (3) and the compound (4) are mixed, and sulfuric acid is added dropwise thereto; as well as, the method in which after the compound (3) and the compound (4) are mixed, and bromine is added dropwise thereto, are more preferably included. The method in which after the compound (3) and the compound (4) are mixed, and sulfuric acid is added dropwise thereto, is furthermore preferably included.

[0067] When bromine is used in the reaction, the reaction temperature at which bromine is added into the reaction system is usually within a range of -10 to 60  °C, and preferably within a range of 0 to 40 °C and the reaction temperature after adding bromine into the reaction system is usually within a range of 0 to 120 °C, and preferably within a range of 40 to 80 °C. When sulfuric acid is used in the reaction, the reaction temperature at which sulfuric acid is added into the reaction system is usually within a range of -10 to 80  °C, and preferably within a range of -5 to 70 °C, and the reaction temperature after adding sulfuric acid into the reaction system is within a range of 0 to 120 °C, and preferably within a range of 40 to 80 °C. The reaction period may be varied depending on the reaction conditions such as the reaction temperature, and is usually within a range of 0.1 to 100 hours, and preferably within a range of 1 to 24 hour(s).

[0069] The compound (1) may be purified according to conventional methods.    For example, when solids are precipitated out, the solids formed after the completion of the reaction are collected by filtration to purify the compound (5). Also, for example, after the completion of the reaction, the reaction mixtures are mixed with water or aqueous solution of sodium sulfite, and extracted with organic solvents, and the resulting organic layers are washed, dried and concentrated under reduced pressure to purify the compound (5). Here the solvents used for extraction may be solvents in which the compound (5) is solubilized, however, are not limited unless otherwise specified, and examples of the solvents include ethers (such as diethylether, 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 mixed solvents of two or more kinds of the solvents. Also, the compound (5) can be also further purified by column chromatography and the like. Also, after the completion of the reaction, the compound (5) can be supplied to the step 2-2 without any purification.

[0070] A step 2-2 is explained. In the step 2-2, the compound (5) obtained is subjected to solvolysis to obtain the compound (6).

[0071] As the compound (5) obtained in the step 2-1, the compound obtained by the above-mentioned purification in the step 2-1 may be used, or mixtures containing the compound (5) obtained by work-up treatments such as extraction on the reaction mixtures after the completion of the reaction of the step 2-1 may be used.    Examples of the mixtures containing the compound (5) include the above-mentioned organic layers containing the compound (5).   Also, the mixtures containing the compound (5) obtained in the step 21 may be used as itself. Among them, the reaction mixtures containing the compound (5) obtained in the step 2-1 is preferably used as itself. In this case, the step 2-1 and the step 2-2 can be carried out in one pot.

[0072] In the solvolysis of the compound (5), protic solvents can be used. Examples of the protic solvents include aqueous amine solutions (such as aqueous ammonia solution, aqueous methyl amine solution, aqueous diethyl amine solution, and aqueous ethyl amine solution); amines (such as diethyl amine); alcohols (such as methanol, ethanol, 2-propanol, and ethylene glycol); water; and mixed solvents of two or more kinds of the solvents, and alcohols, water and mixtures of them are preferably included, and alcohols are more preferably included.   Specific examples of the alcohols include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, ethylene glycol and mixed solvents of two or more kinds of the solvents, and methanol and ethanol are preferably included.

[0073] The used amounts of protic solvents used in solvolysis are usually within a range of 0.2 to 10 parts by weight, and preferably within a range of 0.5 to 4 parts by weight, as opposed to 1 part by weight of the compound (5). As the compound (5), when the reaction mixtures containing the compound (5) obtained in the step 2-1 is used as itself; and when the mixtures containing the compound (5) obtained by work-up treatments such as extraction on the reaction mixtures after the completion of the reaction of the step 2-1 is used, the used amounts of protic solvents used in solvolysis are usually within a range of 0.2 to 10 parts by weight, and @referably within a range of 0.5 to 4 parts by weight, as opposed to 1 part by weight of the compound (3).

[0074] Only the above-mentioned protic solvents may be used as a solvent, or the mixtures of the above-mentioned protic solvents and other solvents may be used as a solvent to conduct the reaction. Examples of the above-mentioned other solvents    include    ethers    (such    as    diethylether, 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);    protic   polar    solvents    (such   as   N,N- dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and sulfolane); and mixed solvents of two or more kinds of the solvents. As the compound (5), when the mixtures containing the compound (5) obtained by work-up treatments such as extraction on the reaction mixtures after the completion of the reaction of the step 2-1 is used, the mixture of the solvents used for extraction and the above-mentioned protic solvents may be used as a solvent. The used amounts of the above-mentioned other solvents are usually within a range of 0.1 to 100 parts by weight, and preferably within a range of 0.5 to 10 parts by weight, as opposed to 1 parts of weight of the compound (5). As the compound (5), the reaction mixtures containing the compound (5) obtained in the step 2-1 is used as itself; and when the mixtures containing the compound (5) obtained by work-up treatments such as extraction on the reaction mixtures after the completion of the reaction of the step 21 is used, the used amounts of the above-mentioned other solvents are usually within a range of 0.1 to 100 parts by weight, and preferably within a range of 0.5 to 10 parts by weight, as opposed to 1 part by weight of the compound (3) obtained in the step 2-1.

[0076] When alcohols or water is used as the above-mentioned protic solvent, addition of acid or base may sometimes promote solvolysis . Examples of the acid include Br0nsted acid and Lewis acid. Examples of the Br0nsted acid 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 acid include boron acids (such as boron trifluoride, boron trichloride, boron tribromide, boron trifluorodiethylether 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 mixed solvents of two or more kinds of the solvents. Examples of the base include alkali metal hydroxides (such as sodium hydroxide, potassium hydroxide); alkali metal alkoxides (such as sodium methoxide, sodium ethoxide, potassium methoxide, and potassium ethoxide); and alkali earth metal hydroxides (such as calcium hydroxide). The base may be chloride, hydroxide, or solution, and can be used a commercially available product as itself. Examples of the solution of base include aqueous solution of sodium hydroxide, and methanol solution of sodium methoxide. As the compound (5), when the reaction mixtures containing the compound (5) obtained in the step 2-1 is used as itself, in addition to a hydrobromic acid that is formed from bromine to be added in the step 2-1, or among sulfuric acid to be added in the step 2-2, a sulfuric acid remained as unreactive state, a carboxylic acid that is formed from the compound (4) to be added in the step 2-1, and among the compound (4) to be added in the step 2-1, carboxylic acid that is formed by solvolysis from the compound (4) remained as unreactive state in the step 2-2 are existed in the reaction system, the solvolysis can be promoted without adding an acid or a base.

[0077] When the reaction is carried out by adding an acid, the used amounts of the acid are usually within a range of 0.1 to 10 moles, as opposed to 1 mole of the compound (5). As the compound (5), when the reaction mixtures containing the compound (5) obtained in the step 2-1 by workup treatments such as extraction on the reaction mixtures after the completion of the reaction of the step 2-1 is used, the used amounts of the acid are usually within a range of 0.01 to 1 mole(s), as opposed to 1 mole of the compound (3) in the step 2-1. When the reaction is carried out by adding a base, the used amounts of the base are usually within a range of 1 to 10 mole(s) as opposed to 1 mole of the compound (5). As the compound (5), when the reaction mixtures containing the compound (5) obtained in the step 2-1 by work-up treatments such as extraction on the reaction mixtures after the completion of the reaction of the step 2-1 is used, the used amounts of the base are usually within a range of 2 to 20 moles, as opposed to 1 mole of the compound (3) in the step 2-1. The reaction ay be carried out by mixing the compound (5), the above-mentioned protic solvents, and if necessary, the above-mentioned other solvents, as well as, acid or base. As the compound (5), the reaction mixtures containing the compound (5) obtained in the step 2-1 may be used as itself, or as the compound (5), the mixtures containing the compound (5) obtained by work-up treatments such as extraction on the reaction mixtures after the completion of the reaction of the step 2-1 may be used. In mixing of the compound (5), the above-mentioned protic solvents, and if necessary, the above-mentioned other solvents, as well as, if necessary, acid or base, the mixing order thereof is not limited unless otherwise specified, and the following methods are included: the compound (5) and the above-mentioned protic solvents are mixed; after the compound (5) and the above-mentioned protic solvents are mixed, an acid is added thereto; after the compound (5) and the above-mentioned protic solvents are mixed, a base is added thereto; after the compound (5), the above-mentioned protic solvents, and the other solvents are mixed, an acid is added thereto; after the compound (5), the above-mentioned protic solvents, and the other solvents are mixed, a base is added thereto; the above-mentioned protic solvents are added to the compound (5); the above-mentioned protic solvents and an acid are added to the compound (5); the above-mentioned protic solvents and the above-mentioned other solvents are added to the compound (5); the abovementioned protic solvents, the above-mentioned other solvents, and an acid are added to the compound (5); the compound (5) is added to the above-mentioned protic solvents; the compound (5) and an acid are added to the above-mentioned protic solvents; the compound (5) and the above-mentioned other solvents are added to the above-mentioned protic solvents; the compound (5) and the above-mentioned other solvents are added to the above-mentioned protic solvents; the compound (5) and the above-mentioned other solvents are added to the above-mentioned protic solvents; the compound (5), an acid and the above-mentioned other solvents are added to the above-mentioned protic solvents; the reaction mixtures containing the compound (5) obtained in the step 21 and the above-mentioned protic solvents are mixed; the above-mentioned protic solvents is added to the reaction mixtures containing the compound (5); and the reaction mixtures containing the compound (5) obtained in the step 2 1 is added to the above-mentioned protic solvents. Among them, the method in which the above-mentioned protic solvents are added to the reaction mixtures containing the compound (5) obtained in the step 2-1; and the method in which the reaction mixtures containing the compound (5) obtained in the step 2-1 is added to the above-mentioned protic solvents, are preferably included. The compound (5) and, if necessary, acid or base to be used may be used by mixing with the above-mentioned protic solvents or if necessary, a part of the above-mentioned other solvents to be used in advance. In all of the above-mentioned methods, with respect to each component to be added to the reaction system, that is, the compound (5), the above-mentioned protic solvents, if necessary, the above-mentioned other solvents to be used, as well as, if necessary, acid or base to be used, the whole amounts of each component may be added at once respectively, or each component may be divided into a plurality of parts thereof and they may be then added portionwise, or each component may be added step by step. Also, among each component to be added, two or more of the components may be added at the same time and the whole amounts of each component may be added at once respectively, or two or more of the components may be added at the same time, and each component may be divided into a plurality of parts thereof, and they may be added portionwise, or two or more of the components may be added at the same time, and each component may be added step by step respectively. Also, among each component to be added, two or more of the components may be added at the same time and the whole amounts of each component may be added at once respectively, or two or more of the components may be added at the same time, and each component may be divided into a plurality of parts thereof, and they may be added portionwise, or two or more of the components may be added at the same time, and each component may be added step by step respectively. Also, among each component to be added, two or more of the components may be added by mixing them in advance. With respect to each component to be mixed in advance, the whole amounts of each component may be mixed in advance respectively, or a part of the components may be mixed in advance.  Also, the mixtures of two or more of the components may be prepared such that the kinds of combinations of the components may be varied.

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

[0080] The reaction period in the reaction is usually within a range of 0.1 to 100 hours, and preferably within a range of 1 to 24 hour(s), depending on the reaction condition such as the reaction temperature.

[0081] The compound (6) may be purified by conventional methods. For example, when solids are precipitated out, the solids formed after the completion of the reaction are collected by filtration to purify the compound (6). Also, for example, after the completion of the reaction, the reaction mixtures are mixed with aqueous acidic solution such as diluted hydrochloric acid and diluted sulfuric acid, or water, and extracted with organic solvents, and the resulting organic layers are washed, dried and concentrated under reduced pressure to purify the compound (6). Here the solvents used for extraction may be solvents in which the compound (6) is solubilized, however, are not limited unless otherwise specified, and examples of the solvents include ethers (such as diethylether, tetrahydrofuran, methyl tertbutyl 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 mixed solvents of two or more kinds of the solvents. Also, for example, after the completion of the reaction, if necessary, an extraction with acid or base is carried out with an immiscible solvent to water and a base to extract the compound (6) as salt thereof into an aqueous layer, and the resulting aqueous layer and the acidic aqueous solution (such as diluted hydrochloric acid, and diluted sulfuric acid) are mixed, and the mixtures are extracted with organic solvents and the resulting organic layer is washed, dried and concentrated under reduced pressure to purify the compound (6). Examples of the solvents which is immiscible to water include ethers (such as diethylether, 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 mixed solvents of two or more kinds of the solvents. Examples of the base include alkali metal hydroxides (such as sodium hydroxide, potassium hydroxide); alkali metal alkoxides (such as sodium methoxide, sodium ethoxide, potassium methoxide, and potassium ethoxide); and alkali earth metal hydroxides (such as calcium hydroxide). The base may be anhydride, hydrate, or solution, and can be used a commercially available product as itself.  Examples of the solution of base include aqueous solution of sodium hydroxide, and methanol solution of sodium methoxide. Also, the compound (6) can be further purified by column chromatography, recrystallization and the like. As the solvents used for recrystallization, one or more solvents selected from the group consisting of the followings can be used: 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-methyl tetrahydrofuran, 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 them, the mixed solvents of one or more solvents selected from the group consisting of aromatic hydrocarbons, halogenated hydrocarbons, nitriles, ketones, ethers, esters and aprotic polar solvents, and one or more solvents selected from the group consisting of aliphatic hydrocarbons, alcohols and water are preferably included.

[0082] The compound (6) may be also purified as its salt. Examples of the salts include alkali metal salts and alkaline earth metal salts. A base is added to an organic layer containing the compound (6) obtained by work-up treatments after extraction procedure, and the solids formed are collected by filtration to purify the salt of compound (6). Examples of the base 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 anhydride, hydrate, or solution, and can be used a commercially available product as itself.  Examples of the solution of base include aqueous solution of sodium hydroxide, and methanol solution of sodium methoxide. Also, the salts of the compound (6) purified can be used as itself for the compound (6) used in the step 3.

[0083] A step 3 is explained. In the step 3, the compound (6) obtained in the step 2 and the compound (7) are reacted in the presence of a base to obtain the compound (8).

[0084] As the compound (6) obtained in the step 2, the products obtained by the above-mentioned purification in the step 2 may be used, or mixtures containing the compound (6) that are obtained by work-up treatments such as extraction on the reaction mixtures after the completion of the reaction of the step 2 may be used, or salts of the compound (6) may be used. Examples of the mixtures of the compound (6) include the above-mentioned organic layers containing the compound (6). When the salts of the compound (6) are used, the below-mentioned use of a base may be omitted, or the used amounts thereof may be reduced in the step 3.

[0085] The reaction is usually carried out in a solvent. Examples of the solvents include hydrocarbons (such as heptane, toluene, xylene, and ethylbenzene); halogenated hydrocarbons (such as halogenated hydrocarbons); nitriles (such as acetonitrile, and benzonitrile); ketones (such as ethyl methyl ketone); ethers (such as diisopropyl ether, and MTBE); and mixed solvents of two or more kinds of the solvents, and hydrocarbons (such as heptane, toluene, xylene, and ethylbenzene); halogenated hydrocarbons (such as monochlorobenzene); and mixed solvents of two or more kinds of the solvents are more preferably included, and xylene, ethylbenzene and mixed solvents thereof are particularly preferably included. In addition to the above-mentioned solvents, mixtures of the above-mentioned solvents and R11OH [wherein R11 is the same as defined above] may be used as a solvent.

[0086] Examples of the base include inorganic bases, alkali metal alkoxides, organic bases, and mixed solvents of two or more kinds of the solvents. Examples of the inorganic bases include alkali metal carbonates (such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate); alkali metal phosphates (such as trisodium phosphate, and tripotassium phosphate). Examples of the alkali metal alkoxides include NaOR11 and KOR11 [wherein R11 is the same as defined above]. Examples of the organic bases include triethyl amine and diazabicyloundecene. Among them, examples of the base include preferably alkali metal carbonates, alkali metal phosphates, alkali metal alkoxides, and mixed solvents of two or more kinds of the solvents. Specific examples of the base include more preferably lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, NaOR11 and KOR11, and mixed solvents of two or more kinds of the solvents. The base may be anhydride, hydrate or solution, and can be used a commercially available product as itself. Examples of the solution of base include methanol solution of sodium methoxide. When the alkali metal alkoxides is used as a base, alcohols, that is, R11OH [wherein R11 is the same as above] are formed in the reaction system. Also, when the abovementioned alkali metal alkoxides are used as an alcohol solution, the alcohols corresponding to the solvent of alcohols solution of alkali metal alkoxides, that is, R11OH are added into the reaction system. The reaction may be carried out while distilling these alcohols (R11OH) off by heating the reaction mixtures at the temperature over the boiling point of the solvent of the reaction mixtures under ordinary pressure or reduced pressure, thereby the reaction may sometimes proceed more effectively.

[0087] The used amounts of the base are usually within a range of 0.5 to 2 moles, preferably within a range of 0.66 to 1.5 moles, and more preferably within a range of 0.8 to 1.2 moles, as opposed to 1 mole of the compound (6).

[0088] The used amounts of the compound (7) are usually within a range of 0.5 to 3 moles, preferably within a range of 0.66 to 1.5 moles, and more preferably within a range of 0.8 to 1.2 moles, as opposed to 1 mole of the compound (6).

[0089] The used amounts of the solvents are usually within a range of 1 part by weight, as opposed to 1 part by weight of the compound (6).

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

[0091] The reaction temperature is usually within a range of -20 to 140 °C, preferably within a range of 0 to 120 °C, and more preferably within a range of 60 to 140 °C.

[0092] The reaction period may be varied depending on the reaction conditions such as the reaction temperature, and is usually within a range of 0.1 to 100 hours, and preferably within a range of 1 to 24 hour(s).

[0093] The compound (8) can be purified according to conventional methods. For example, when solids are precipitated out, the solids formed after the completion of the reaction are collected by filtration to purify the compound (8). Also, for example, after the completion of the reaction, the reaction mixtures are mixed with aqueous acidic solution such as diluted hydrochloric acid and diluted sulfuric acid, or water, and extracted with organic solvents, and the resulting organic layers are washed, dried and concentrated under reduced pressure to purify the compound (8). Here the solvents used for extraction may be solvents in which the compound (8) is solubilized, however, are not limited unless otherwise specified, and examples of the solvents include ethers (such as diethylether, tetrahydrofuran, methyl tertbutyl 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); halogenated hydrocarbons (such as monochlorobenzene); and mixed solvents of two or more kinds of the solvents. Also, the compound (8) can be further purified by column chromatography, recrystallization, and the like. As the solvents used for recrystallization, one or more solvents selected from the group consisting of the followings can be used: 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-methyl tetrahydrofuran, 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 them, the mixed solvents of one or more solvents selected from the group consisting of aromatic hydrocarbons, halogenated hydrocarbons, nitriles, ketones, ethers, esters and aprotic polar solvents, and one or more solvents selected from the group consisting of aliphatic hydrocarbons, alcohols and water, are preferably included. Also, after the completion of the reaction, the compound (8) can be supplied to the step 4 without any purification.

[0094] A step 4 is explained. In the step 4, the compound (8) obtained in the step 3 and the compound (9) are reacted in the presence of a base.

[0095] According to the reaction of the step 4, a compound represented by a formula (10): i                         r11 " Yx° c - R4 [wherein R4 is the same as defined above] (hereinafter, referred to as Compound (10)) can be obtained.

[0096] As the compound (8) obtained in the step 3, the compound obtained by the above-mentioned purification in the step 3 may be used, or mixtures containing the compound (8) that are obtained by work-up treatments such as extraction on the reaction mixtures after the completion of the reaction of the step 3, 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 amide (such as sodium amide, lithium amide, lithium diisopropylamide, sodium hexamethyldisilazide, and lithium hexamethyldisilazide); and mixed solvents of two or more kinds of the solvents.

[0096] The used amounts of the base are usually within a range of 1 to 10 mole(s) as opposed to 1 mole of the compound (8).

[0099] The used amounts of the compound (9) are usually within a range of 1 to 10 mole(s) as opposed to 1 mole of the compound (8).

[0100] The reaction is usually carried out in a solvent. Examples of the solvents 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, triethyl amine, 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 mixed solvents of two or more kinds of the solvents.

[0101] The reaction temperature in the reaction is usually within a range of 0 to 80°C. The reaction period in the reaction is usually within a range of 1 to 48 hour(s).

[0103] The compound (10) can be purified according to conventional methods.    For example, when solids are precipitated out, the solids formed after the completion of the reaction are collected by filtration to purify the compound (10). Also, for example, after the completion of the reaction, the reaction mixtures are mixed with aqueous acidic solution such as diluted hydrochloric acid and diluted sulfuric acid, or water, and extracted with organic solvents, and the resulting organic layers are washed, dried and concentrated under reduced pressure to purify the compound (10). Here the solvents used for extraction may be solvents in which the compound (10) is solubilized, however, are not limited unless otherwise specified, and examples of the solvents    include    ethers    (such    as    diethylether, tetrahydrofuran, methyl tert-butyl ether, 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 mixed solvents of two or more kinds of the solvents. Also, the compound (10) can be further purified by column chromatography, recrystallization, and the like. Also, after the completion of the reaction, the compound (10) may be supplied to the step 5 without any purification or may be supplied to the step 5 without work-up treatments such as extraction. Also, the compound (10) is reacted with a base such as alkali metal hydroxides, and is made a salt (for example, alkali metal salts such as sodium salt) of the compound (10) and then is made a solution of the salt in protic solvents (such as water), and which may be then supplied to the step 5.

[0104] A step 5 is explained. In the step 5, the compound obtained in the step 4 and a methylating agent are reacted to obtain the compound (11).

[0105] As the compound obtained in the step 4, that is, the compound (10), the compound obtained by work-up treatments such as extraction or purification in the step 4 may be applied to the step 5, mixtures containing the compound (10) obtained in the step 4 after the completion of reaction without neutralization, if necessary, by work-up treatments such as extraction may be applied to the step 5, or mixtures containing the compound (10) obtained in the step 4 after the completion of reaction by neutralizing the reaction mixtures until a partial neutralization or a complete neutralization may be supplied to the step 5. When the mixtures containing the compound (10) that is obtained in the step 4 after the completion of reaction by neutralizing the reaction mixtures until a partial neutralization or a complete neutralization is supplied to the step 5, since the compound (10) is formed as alkali metal salts (such as lithium salt, sodium salt, and potassium salt), the below-mentioned use of a base together with a methylating agent (such as dimethyl sulfate) can be omitted, or the used amounts of the base can be reduced. Examples of the acid used for the above-mentioned partial neutralization or complete neutralization include inorganic acids (such as hydrochloric acid, and sulfuric acid, phosphoric acid) and organic acids (such as acetic acid, propionic acid, and benzoic acid).

[0106] The reaction is usually carried out in a solvent. As the solvents, for example, one or more solvents selected from the group consisting of the followings can be used: aromatic hydrocarbons, aliphatic hydrocarbons, halogenated hydrocarbons, ethers, ketones, esters, alcohols, water, nitriles and aprotic polar solvents. As the solvents, one or more solvents selected from the group consisting of aromatic hydrocarbons, aliphatic hydrocarbons, halogenated hydrocarbons, ethers, ketones, esters, alcohols, water, nitriles and aprotic polar solvents may be included, or two or more solvents selected from the group consisting of aromatic hydrocarbons, aliphatic hydrocarbons, halogenated hydrocarbons, ethers, ketones, esters, alcohols, water, nitriles and aprotic polar solvents may be included, or mixed solvents of one or more solvents selected from the group consisting of aromatic hydrocarbons, aliphatic hydrocarbons, halogenated hydrocarbons, ethers, ketones, esters, alcohols, water, nitriles and aprotic polar solvents, and the compounds other than these solvents may be included.

[0107] Examples of the aromatic hydrocarbons include toluene, xylene and ethylbenzene.    Examples of the aliphatic hydrocarbons include hexane and heptane. Examples of the halogenated   hydrocarbons    include   monochlorobenzene. Examples of the ethers include 1,4-dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, and methyl tert-butyl ether. Examples of the ketones include acetone and ethyl methyl ketone. Examples of the esters include butyl acetate and ethyl acetate. Examples of the alcohols Examples of the methanol and ethanol. Examples of the nitriles include acetonitrile and benzonitrile. Examples of the aprotic polar solvents include N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and sulfolane.

[0108] Examples of the methylating agent include a compound represented by CH3-X2 (wherein X2 represents a leaving group], dimethyl sulfate, dimethyl carbonate, and diazo compounds. Among them, dimethyl sulfate is preferably included. Examples of the leaving group represented by X2 include a chlorine atom, a bromine atom, an iodine atom, p-toluenesulfonyl   group,    methanesulfonyl   group,    and trifluoromethanesulfonyl group.    Examples of the diazo compounds include trialkylsilyldiazomethane (such as trimethylsilyldiazomethane); and diazomethane.

[0109] The used amounts of the methylating agent are usually within a range of 1 to 5 mole(s) as opposed to 1 mole of the compound (10). When mixtures containing the compound (10) obtained in the step 4 is used as the compound (10), the used amounts of the methylating agent are usually within a range of 1 to 5 mole(s) as opposed to 1 mole of the compound (8) used in the step 4. When the compound represented by CH3-X2, dimethyl sulfate or dimethyl carbonate are used as the methylating agent, the reaction is preferably carried out in the presence of a base. Examples of the base include inorganic bases, alkali metal alkoxides, and mixed solvents of two or more kinds of the solvents. Examples of the inorganic bases include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, and sodium hydride. Examples of the alkali metal alkoxides include potassium tert-butoxide, sodium methoxide, potassium methoxide, and sodium ethoxide.

[0111] When the base is used, the used amounts of the base are preferably within a range of 1 to 10 mole(s) as opposed to 1 mole of the compound (10).

[0112] When the diazo compound is used as the methylating agent, protic solvents is preferably used. Examples of the protic solvents include the above-mentioned alcohols.

[0113] The reaction may be further carried out in the presence of a catalyst. Examples of the catalyst include quaternary ammonium salts (such as tertabutylammonium chloride, tertabutylammonium     bromide,     benzyltrimethylammonium chloride,          benzyltrimethylammonium         bromide, benzyltriethylammonium             chloride,             and benzyltriethylammoniumbromide). When the catalyst is used, the used amounts of the catalyst are usually within a range of 0.0005 to 0.2 moles as opposed to 1 mole of the compound (10).

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

[0115] The reaction period is usually within a range of 1 to 48 hour(s).

[0116] The compound (11) can be purified according to conventional methods.    For example, when solids are precipitated out, the solids formed after the completion of the reaction are collected by filtration to purify the compound (11). Also, for example, after the completion of the reaction, the reaction mixtures are mixed with aqueous acidic solution such as diluted hydrochloric acid and diluted sulfuric acid, or water, and extracted with organic solvents, and the resulting organic layers are washed, dried and concentrated under reduced pressure to purify the compound (11). Here the solvents used for extraction may be solvents in which the compound (11) is solubilized, however, are not limited unless otherwise specified, and examples of the solvents    include    ethers    (such    as    diethylether, tetrahydrofuran, methyl tert-butyl ether, 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 mixed solvents of two or more kinds of the solvents. Also, the compound (11) can be further purified by column chromatography, recrystallization, and the like.

[0117] The reaction may be carried out by mixing the compound (10) and the methylating agent, as well as, if necessary, the solvents, the base and the catalyst. The mixing order of the compound (10) and the methylating agent, as well as, if necessary the followings may be used, the solvents, the base and the catalyst is not limited unless otherwise specified, for example, the following orders are included: for example, the compound (10), the solvents, and the methylating agent may be mixed at the same time; or after the compound (10) and the solvents are mixed, the methylating agent may be added thereto; after the methylating agent and the solvents are mixed, the compound (10) may be added thereto. When the compound (10) or the methylating agent is added to the reaction system, as the compound (10) or the methylating agent, they may be added as a mixture with the above-mentioned solvents. EXAMPLES

[0118] Hereinafter, the present invention is described in more detail below with Preparation Examples, Examples and Comparative Examples, but the present invention should not be construed to be limited thereto.

[0119] A Compound (1-1-1) is a Compound (1-1) wherein R1, R2, R3, R4, and R5 each represents a hydrogen atom. A Compound (1-1-2) is a hydrochloride salt of Compound (1-1-1). A Compound (1-2-1) is a Compound (1-2) wherein R1, R2, R3, R4, and R5 each represents a hydrogen atom. A Compound (1-2-2) is a hydrochloride salt of Compound (1-2-1). A Compound (13-1) is a Compound (1-3) wherein R1, R2, R3, R4, and R5 each represents a hydrogen atom.    A Compound (1-3-2) is a hydrochloride salt of Compound (1-3-1). A Compound (1-4-1) is a Compound (1) wherein R1,  R2, R3,  R4, and R5 each represents a hydrogen atom, and R6 and R7 each represents a methyl group. A Compound (1-4-2) is a hydrochloride salt of Compound (1-4-1). A Compound (1-5-1) is a Compound (1) wherein R1, R2, R3, R4, and R5 each represents a hydrogen atom, and R6 and R7 each represents an ethyl group. A Compound (15-2) is a hydrochloride salt of Compound (1-5-1). A Compound (1-6-1) is a Compound (1) wherein R1, R2, R3, R4, and R5 each represents a hydrogen atom, and R6 and R7 each represents an isopropyl group. A Compound (1-6-2) is a hydrochloride salt of Compound (1-6-1). A Compound (1-7-1) is a Compound (1) wherein R1, R2, R3, R4, and R5 each represents a hydrogen atom, and R6 and R7 each represents a butyl group. A Compound (17-2) is a hydrochloride salt of Compound (1-7-1). A Compound (1-8-1) is a Compound (1) wherein R1, R2, R3, R4, and R5 each represents a hydrogen atom, and R6 and R7 each represents a benzyl group. A Compound (1-8-2) is a hydrochloride salt of Compound (1-8-1). A Compound (1-9-1) is a Compound (1) wherein R1, R2, R3, R4, R5, and R7 each represents a hydrogen atom, and R6 represents an ethyl group. A Compound (1-9-2) is a hydrochloride salt of Compound (1-9-1). A Compound (110-1) is a Compound (1) wherein R1,  R2,  R3, R4, R5, and R7 each represents a hydrogen atom, and R6 represents a benzyl group. A Compound (1-10-2) is a hydrochloride salt of Compound (1-10-1). A Compound (1-11-1) is a Compound (1) wherein R1, R2, R3, R4, and R5 each represents a hydrogen atom, R6 represents a methyl group, and R7 represents a phenyl group. A Compound (1-11-2) is a hydrochloride salt of Compound (1-11-1). A Compound (3-1) is a Compound (3) wherein R1, R2, R3, R4, R5, and R9 each represents a hydrogen atom, and R8 represents a methyl group.    A compound represented by formula (3-2): is a regioisomer of Compound (3-1). A Compound (5-1) is a Compound (5) wherein R1 R2, R3, R4, R5, and R9 each represents a hydrogen atom, and R8 and R10 each represents a methyl group. A Compound (6-1) is a Compound (6) wherein R1, R2, R3, R4, R5, and R9 each represents a hydrogen atom, and R8 represents a methyl group. A Compound (8-1) is a Compound (8) wherein R1, R2, R3, R4, R5, and R9 each represents a hydrogen atom, and R8 and R11 each represents a methyl group. A Compound (10-1) is a Compound (10) wherein R1, R2, R3, R4, R5, and R9 each  represents a hydrogen  atom, and R8 and R11 each represents a methyl group. A Compound (11-1) is a Compound (1-1) wherein R1, R2, R3, R4, R5, and R9 each represents a hydrogen atom, and R8 and R11 each represents a methyl group.

[0120] Q Compound (1-1-1)

[0121] Q I HCI 0     (1-1-2) Compound (1-1-2) Compound (1-2-1)

[0123] 0 I HCI (1-2-2) 5    Compound (1-2-2)

[0124] 0 N (1-3-1) Compound (1-3-1)

[0125] I HCI fV^° (1'3-2) Compound (1-3-2)

[0126] Compound (1-4-1) 5

[0127] Compound (1-4-2)

[0128] 10    Compound (1-5-1)

[0129] Compound (1-5-2)

[0130] (1-6-1) 3 Compound (1-6-1)

[0131] (1-6-2) 3 Compound (1-6-2)

[0132] 10 h3c CH3 (1-7-1) Compound (1-7-1)

[0133] HCI (1-7-2) Compound (1-7-2)

[0134] (1-8-1) Compound (1-8-1) 5

[0135] HCI Compound (1-8-2)

[0136] 10    Compound (1-9-1)

[0137] Compound (1-9-2) Compound (1-10-1)

[0139] 5    Compound (1-10-2)

[0140] Compound (1-11-1)

[0141] Compound (1-11-2) (3-1) Compound (3-1)

[0143] 5    Compound (5-1)

[0144] Compound (6-1)

[0145] 10                  0 (8-1) Compound (8-1)

[0146] Compound (10-1)

[0147] 5    Compound (11-1)

[0148] In the following examples, unless otherwise indicated, a quantitative analysis is conducted using a high-performance liquid chromatography. The yield of the intended 10    product is calculated using an absolute calibration curve method from the peak area of the intended product. The analysis conditions are indicated as the below-mentioned four conditions.

[0149] 15     [Analysis method 1] Mobile phase:  A solution:  0.1  % aqueous solution of trifluoroacetic acid, B solution: acetonitrile Column: SUMIPAX (Registered trademark) ODS Z-CLUE, particle size 3pm, 4.6 mml.D. x 250 mm (manufactured by Sumika Chemical Analysis Service, Ltd.) UV measured wavelength: 254 nm Flow rate: 1.0 mL / min 5    Column oven: 40 °C Pomp: LC-20AD (manufactured by Shimadzu Corporation) two instruments (high pressure gradient) Gradient condition: delivery a solution with a concentration gradient described in [Table LC1] 10

[0150] [Table LC1] Time (min) A solution (%) B solution (%) 0 70 30 90 70 30 130 10 90 140 10 90

[0151] A retention time of each compound described in Preparation Examples, Examples or Comparative Examples when 15    an analysis was conducted using a high-performance liquid chromatography according to the analysis method 1 is indicated in [Table LC2].

[0152] Compound Retention time (min.) Compound (1-1-2) 4.49 Compound (1-4-2) 3.88 Compound (1-5-2) 5.74 Compound (3-1) 81.0 Compound (3-2) 84.8 [Analysis method 2] Mobile phase:  A solution:  0.1  % aqueous solution of trifluoroacetic acid, B solution: acetonitrile Column: SUMIPAX (Registered trademark) ODS Z-CLUE, particle size 3pm, 4.6 mml.D. x 250 mm (manufactured by Sumika Chemical Analysis Service, Ltd.) UV measured wavelength: 254 nm Flow rate: 1.0 mL / min Column oven: 40 °C Pomp: LC-20AD (manufactured by Shimadzu Corporation) two instruments (high pressure gradient) Gradient condition: delivery a solution with a concentration gradient described in [Table LC3]

[0154] [Table LC3] Time (min) A solution (%) B solution (%) 0 50 50 15 40 60 35 10 90 45 10 90

[0155] A retention time of each compound described in Preparation Examples, Examples or Comparative Examples when an analysis was conducted using a high-performance liquid chromatography according to the analysis method 2 is indicated in [Table LC4].

[0156] [Table LC4] Compound Retention time (min .) Compound (1-1-1), Compound (1-1-2) 2.95 Compound (1-4-1), Compound (1-4-2) 2.83 Compound (1-3-2) 2.86 Compound (1-5-1), Compound (1-5-2) 3.33 Compound (3-1) 13.6 Compound (3-2) 13.8

[0157] [Analysis method 3] Mobile phase:  A solution:  0.1  % aqueous solution of 5    trifluoroacetic acid, B solution: acetonitrile Column: Shim-pack (Registered trademark) XR-ODSII, particle size 2.2pm,  3.0 mml.D. x 75 mm (manufactured by Shimadzu Corporation) UV measured wavelength: 254 nm 10    Flow rate: 1.0 mL / min Column oven: 40 °C Pomp:  LC-40AD (manufactured by Shimadzu Corporation) two instruments (high pressure gradient) Gradient condition: delivery a solution with a concentration 15    gradient described in [Table LC5]

[0158] [Table LC5] Time [min .] A solution (%) B solution (%) 0 95 5 1 95 5 7 10 90 8 10 90 A retention time of each compound described in Preparation Examples, Examples or Comparative Examples when an analysis was conducted using a high-performance liquid chromatography according to the analysis method 3 is indicated in [Table LC6].

[0160] [Table LC6] Compound Retention time (min .) Compound (1-1-1), Compound (1-1-2) 2.56 Compound (1-2-1), Compound (1-2-2) 2.75 Compound (1-3-1), Compound (1-3-2) 2.22 Compound (1-4-1), Compound (1-4-2) 2.08 Compound (1-5-1), Compound (1-5-2) 2.62 Compound (1-6-2) 3.10 Compound (1-7-1), Compound (1-7-2) 3.85 Compound (1-8-2) 4.16 Compound (1-9-2) 2.29 Compound (1-10-2) 3.30 Compound (1-11-2) 3.61 Compound (3-1) 5.11 Compound (3-2) 5.12 Compound (6-1) 5.28 Compound (5-1) 5.78

[0161] 10 15 [Analysis method 4] Mobile phase: A solution: 5mM aqueous solution of ammonium carbonate, B solution: acetonitrile Column: SUMIPAX (Registered trademark) ODS Z-CLUE, particle size 3pm, 4.6 mml.D. x 100 mm (manufactured by Sumika Chemical Analysis Service, Ltd.) UV measured wavelength: 238 nm Flow rate: 1.0 mL / min Column oven: 30 °C Pomp:  LC-20AD (manufactured by Shimadzu Corporation) two instruments (high pressure gradient) Gradient condition: delivery a solution with a concentration gradient described in [Table LC7]

[0162] [Table LC7] Time [min .] A solution (%) B solution (%) 0 65 35 35 20 80 50 20 80

[0163] A retention time of each compound described in Examples when an analysis was conducted using a high-performance liquid chromatography according to the analysis method 4 is indicated in [Table LC8]. Here sodium salt of the compound (10-1) is detected as the compound (10-1).

[0164] [Table LC8] Compound Retention time (mini .) Compound (6-1) 19.11 Compound (8-1) 26.13 Compound (10-1) 3.84 Compound (11-1) 25.56

[0165] In the following Examples, unless indicated otherwise, the reaction temperature means an outside temperature of reactor. Also, an area percentage means an area ratio of a particular component as opposed to a total area of peak obtained when an analysis was conducted using a high-performance liquid chromatography.

[0166] Preparation Example 1: Preparation of compound (1-1-2) To a mixture of 35 % by weight hydrochloric acid (26.0 g) and ethanol (80 mL), pyrrolidine (15.0 g) was added gradually at 0°C, and acetophenone (20.0 g) and paraformaldehyde (9.10 g) were further added thereto at 0°C successively. The resulting mixture was stirred at 100°C for 16 hours. After the mixture was allowed to cool to room temperature, the resulting reaction mixture was concentrated under reduced pressure, and to the resulting concentrated residue, 2-propanol (50 mL) was added, and the mixture was stirred. The solids precipitated out were collected by filtration and washed with acetone (5°C,  50 mL) .    The obtained solids were dried under reduced pressure to obtain Compound (1-1-2)  (26.0 g). The 1H-NMR value of Compound (1-1-2) is indicated below. 1H-NMR (DMSO-d6) 6: 11.06(1H, br s), 7.99-8.01 (2H, m), 7.677.71  (1H, m), 7.56-7.59  (2H, m), 3.44-3.66  (6H, m), 3.003.08 (2H, m), 1.81-2.05 (4H, m).

[0167] Preparation Example 2: Preparation of Compound (1-3-2) To a mixture of 35 % by weight hydrochloric acid (26.0 g) and ethanol (80 mL), morpholine (18.4 g) was added gradually at 0°C, and acetophenone (20.0 g) and paraformaldehyde (9.10 g) were added further at 0°C successively. The resulting mixture was stirred at 100°C for 16 hours. After the mixture was allowed to cool to room temperature, the resulting reaction mixture was concentrated under reduced pressure, and to the resulting concentrated residue, 2-propanol (50 mL) was added, and the mixture was stirred. The solids precipitated out were collected by filtration and washed with acetone (5°C, 50 mL). The obtained solids were dried under reduced pressure to obtain Compound (1-3-2) (28.0 g). The 1H-NMR value of Compound (1-3-2) is indicated below. 1H-NMR (DMSO-d6) 5: 13.26(1H, br s), 7.99 — 8.02 (2H, m), 7.607.64 (1H, m), 7.47-7.51 (2H, m), 4.24-4.31 (2H, m), 3.984.01 (2H, m), 3.80-3.90 (2H, m), 3,50-3. 52 (2H, m), 3.413.44 (2H, m), 2.96-2.99 (2H, m).

[0168] Preparation Example 3: Preparation of Compound (1-2-2) To a mixture of 35 % by weight hydrochloric acid (26.0 g) and ethanol (80 mL), piperidine (18.0 g) was added gradually at 0°C, and acetophenone (20.0 g) and paraformaldehyde (9.1 g) were added further at 0°C successively. The resulting mixture was stirred at 100°C for 16 hours. After the mixture was allowed to cool to room temperature, the resulting reaction mixture was concentrated under reduced pressure, and to the resulting concentrated residue, 2-propanol (50 mL) was added, and the mixture was stirred. The solids precipitated out were collected by filtration and washed with acetone (5°C,  50 mL) .    The obtained solids were dried under reduced pressure to obtain Compound (1-2-2)  (30.0 g). The 1H-NMR value of Compound (1-2-2) is indicated below. 1H-NMR (DMSO-d6) 6: 11.77(1H, br s), 8.01-8.03 (2H, m), 7.677.71  (1H, m),  7.55-7.59  (2H, m),  3.69-3.72(2H,  m),  3.463.49(2H,  m),  3.34-3.39(2H,  m),  2.87-2.96(2H,  m),  1.691.87(5H, m), 1.34-1.44(1H, m).

[0169] Preparation Example 4: Preparation of Compound (1-5-2) To a mixture of 35 % by weight hydrochloric acid (130 g) and ethanol (300 mL), diethyl amine (54.8 g) was added gradually at 0°C, and acetophenone (100 g) and paraformaldehyde (44.0 g) were added further at 0°C successively. The resulting mixture was stirred at 100°C for 16 hours. To the resulting mixture, acetophenone (35.0 g) and paraformaldehyde (8.70 g) were further added successively, and the resulting mixture was stirred at 100°C for 12 hours. After the mixture was allowed to cool to room temperature, the resulting reaction mixture was concentrated under reduced pressure, and to the resulting concentrated residue, diethylether (500 mL) was added, and the mixture was stirred. The solids precipitated out were collected by filtration and washed with diethylether (5°C, 100 mL). The obtained solids were dried under reduced pressure to obtain Compound (1-5-2)  (170 g). The 1H-NMR value of Compound (1-5-2) is indicated below. 1H-NMR (DMSO-d6)  5:  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), 3.363.41(2H, m), 3.14-3.21(4H, m), 1.19-1.26(6H, m).

[0170] Preparation Example 5: Preparation of Compound (1-8-2) To a mixture of 35 % by weight hydrochloric acid (117 g) and ethanol (340 mL), dibenzyl amine (133 g) was added gradually at 0°C, and acetophenone (90.0 g) and paraformaldehyde (40.0 g) were added further at 0°C successively. The resulting mixture was stirred at 100°C for 16 hours. After the mixture was allowed to cool to room temperature, the resulting reaction mixture was concentrated under reduced pressure, and to the resulting concentrated residue, 2-propanol (300 mL) was added, and the mixture was stirred. The solids precipitated out were collected by filtration and washed with diethylether (5°C, 100 mL). The obtained solids were dried under reduced pressure to obtain Compound (1-8-2)  (131 g). The 1H-NMR value of Compound (1-8-2) is indicated below. 1H-NMR (DMSO-d6) 6: 11.46(1H, br s), 7.98-7.96 (2H, m), 7.677.71 (5H, m), 7.54-7.58(2H, m), 7.45-7.46(6H, m), 4.334.44(4H, m), 3.78-3.81(2H, m), 3.29-3.33(2H, m).

[0171] Preparation Example 6: Preparation of Compound (1-7-2) To a mixture of 35 % by weight hydrochloric acid (130 g) and ethanol (400 mL), dibutyl amine (137 g) was added gradually at 0°C, and acetophenone (100 g) and paraformaldehyde (43.9 g) were added further at 0°C successively. The resulting mixture was stirred at 100°C for 16 hours. To the resulting mixture, acetophenone (75.0 g) and paraformaldehyde (26.0 g) were further added successively, and the resulting mixture was stirred at 100°C for 16 hours. To the resulting mixture, acetophenone (49.0 g) and paraformaldehyde (9.00 g) were further added successively, and the resulting mixture was stirred at 100°C for 16 hours. To the resulting mixture, acetophenone (19.0 g) and paraformaldehyde (2.80 g) were further added successively, and the resulting mixture was stirred at 100°C for 16 hours. After the mixture was allowed to cool to room temperature, the resulting reaction mixture was concentrated under reduced pressure, and to the resulting concentrated residue, diethylether (1500 mL) was added, and the mixture was stirred. The solids precipitated out were collected by filtration and washed with diethylether (5°C, 500 mL). The obtained solids were dried under reduced pressure to obtain Compound (1-7-2)  (200 g). The 1H-NMR value of Compound (1-7-2) is indicated below. 1H-NMR (DMSO-d6)  5:  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] Preparation Example 7: Preparation of Compound (1-6-2) To a mixture of acetophenone (1.00 g) and ethyl acetate (2 mL), diisopropyl amine (0.90 g) was added, and thereafter, chloromethyl methyl ether (8.0 mL) was added gradually at 0°C, and the mixture was stirred at 0°C for 2 hours. The resulting mixture was stirred at 55°C for additional 16 hours. After the mixture was allowed to cool to room temperature, the resulting reaction mixture was concentrated under reduced pressure, and to the resulting concentrated residue, diethylether (3 mL) was added, and thereafter, 4N hydrogen chloride - ethyl acetate solution (2 mL) was added gradually at 0°C, and the mixture was stirred at room temperature for 3 hours.   The resulting mixture was concentrated under reduced pressure, and diethyl ether (3 mL) was added thereto, and the mixture was stirred. The solids precipitated out were   collected   by   filtration   and washed with diethylether(5°C). The obtained solids were dried under reduced pressure to obtain Compound (1-6-2)  (400 mg). The 1H-NMR value of Compound (1-6-2) is indicated below. 1H-NMR (DMSO-d6) 5: 9.55 (1H, br s), 7.98-8.01 (2H, m), 7.677.71  (1H, m), 7.67-7.71  (2H, m), 3.65-3.75  (4H, m), 3.443.46 (2H, m), 1.22-1.36 (12H, m).

[0173] Preparation Example 8: Preparation of Compound (1-10-2) To a mixture of 35 % by weight hydrochloric acid (130 g) and ethanol (400 mL), benzyl amine (100 g) was added gradually at 0°C, and acetophenone (100 g) and paraformaldehyde (43.9 g) were added further at 0°C successively. The resulting mixture was stirred at 100°C for 16 hours. After the mixture was allowed to cool to room temperature, the resulting reaction mixture was concentrated under reduced pressure, and the obtained concentrated residue was purified by silica gel column chromatography (methanol / ethyl acetate =  3 / 17 (volume ratio) solvent system) to obtain a fraction containing the compound (1-102). The obtained fraction was concentrated, and diethyl ether (500 mL) was added thereto at room temperature, and the mixture was stirred. The solids precipitated out were collected by filtration and washed with diethylether (5°C, 500 mL).   The obtained solids were dried under reduced pressure to obtain Compound (1-10-2)  (45 g). The 1H-NMR value of Compound (1-10-2) is indicated below. 1H-NMR (DMSO-d6) 5: 9.29 (2H, br s), 7.96-7.98 (2H, m), 7.677.71  (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] Preparation Example 9: Preparation of Compound (1-9-2) To a mixture of acetophenone (150 g) and ethanol (1.0 L), ethyl amine hydrochloride salt (118 g), paraformaldehyde (52.0 g), and 35 % by weight hydrochloric acid (9.3 mL) were added at room temperature successively.   The resulting mixture was stirred at 80°C in an autoclave for 16 hours. After the mixture was allowed to cool to room temperature, the resulting reaction mixture was concentrated under reduced pressure, and to the resulting concentrated residue, 2-propanol (500 mL) was added, and the mixture was stirred. The solids precipitated out were collected by filtration and washed with acetone (5°C, 50 mL). The obtained solids were dried under reduced pressure to obtain the concentrated residue (67.0 g). Among the obtained concentrated residue, a part thereof (62.0 g) was added to ethanol (124 mL), and to the resulting mixture, acetophenone (19.8 g) and paraformaldehyde (7.01 g) were added at 0°C successively, and the resulting mixture was stirred at 100°C for 16 hours. After the mixture was allowed to cool to room temperature, the reaction mixture was concentrated under reduced pressure, and to the resulting concentrated residue, 2-propanol (124 mL) was added at room temperature, and the mixture was stirred. The solids precipitated out were collected by filtration and washed with acetone (5°C,  50 mL) .    The obtained solids were dried under reduced pressure to obtain Compound (1-9-2)  (132 g). The 1H-NMR value of Compound (1-9-2) is indicated below. 1H-NMR (DMSO-d6) 5: 9.18 (2H, br s), 7.97-7.99 (2H, m), 7.677.71  (1H, m), 7.55-7.59  (2H, m), 3.54-3.57  (2H, m), 3.203.30 (2H, m), 2.97-3.00 (2H, m), 1.21-1.25 (3H, m).

[0175] Preparation Example 10: Preparation of Compound (1-11-2) A mixture of Compound (1-4-2) (140 g), N-methyl aniline (125 g), and a solution of ethanol / water = 2 / 1 (volume ratio) (1050 mL) was stirred at 100°C for 72 hours. To the resulting mixture, Compound (1-4-2) (6.5 g) was added, and the mixture was stirred at 80°C for 24 hours. After the mixture was allowed to cool to room temperature, the resulting mixture was concentrated under reduced pressure, and the resulting concentrated residue were solubilized in water (500 mL). To the resulting mixture was added saturated aqueous solution of potassium carbonate to adjust the pH of the mixture to about 9. To the resulting mixture, ethyl acetate (500 mL) was added, and after stirring the mixture, the mixture was allowed to stand and separated . The obtained organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the concentrated residue. The obtained concentrated residue was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 19 (volume ratio) solvent system) to obtain Compound (1-11-1)  (60 g). The obtained Compound (1-11-1) was solubilized in diethylether (500 mL), and to the resulting mixture, 4N-hydrogen chloride - ethyl-acetate solution (60 mL) was added, and the mixture was stirred for 16 hours. The resulting mixture was concentrated under reduced pressure, and to the obtained concentrated residue, diethyl ether (500 mL) was added at room temperature, and the mixture was stirred. The obtained solids were collected by filtration and dried under reduced pressure to obtain Compound (1-11-2)  (49 g). The 1H-NMR value of Compound (1-11-2) is indicated below. 1H-NMR (DMSO-d6)  6:  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] Preparation Example 11: Preparation of Compound (1-1-1) To a mixture of Compound (1-1-2) (1.20 g), ethyl acetate (3.0 g) and water (3.0 g), 48 % by weight aqueous solution of sodium hydroxide (0.46 g) 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 separated. The obtained organic layer was concentrated under reduced pressure to obtain Compound (1- 1-1) (0.86 g). The obtained product was analyzed using high- performance liquid chromatography according to the analysis method 3 to obtain 98 % as the area percentage of Compound (1-1-1).

[0177] Preparation Example 12: Preparation of Compound (1-2-1) To a mixture of Compound (1-2-2)  (5.0 g), ethyl acetate (15.0 g) and water (15.0 g), 27 % by weight aqueous solution of sodium hydroxide (4.10 g) 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 separated. The obtained organic layer was concentrated under reduced pressure to obtain Compound (12-1) (4.0 g). The obtained product was analyzed using high- performance liquid chromatography according to the analysis method 3 to obtain 99 % as the area percentage of Compound (1-2-1).

[0178] Preparation Example 13: Preparation of Compound (1-3-1) To a mixture of Compound (1-3-2) (1.29 g), ethyl acetate (3.0 g) and water (3.0 g), 48 % by weight aqueous solution of sodium hydroxide (0.46 g) 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 separated. The obtained organic layer was concentrated under reduced pressure to obtain Compound (13-1) (0.91 g). The obtained product was analyzed using high- performance liquid chromatography according to the analysis method 3 to obtain 97 % as the area percentage of Compound (1-3-1).

[0179] Preparation Example 14: Preparation of Compound (1-4-1) To a mixture of Compound (1-4-2) (1.07 g), ethyl acetate (5.0 g) and water (3.0 g), 48 % by weight aqueous solution of sodium hydroxide (0.46 g) 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 separated. The obtained organic layer was concentrated under reduced pressure to obtain Compound (14-1) (0.65 g). The obtained product was analyzed using high- performance liquid chromatography according to the analysis method 3 to obtain 98 % as the area percentage of Compound (1-4-1).

[0180] Preparation Example 15: Preparation of Compound (1-5-1) To a mixture of Compound (1-5-2)  (5.0 g), ethyl acetate (15.0 g) and water 15.0 g, 27 % by weight aqueous solution of sodium hydroxide (4.3 g) 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 separated. The obtained organic layer was concentrated under reduced pressure to obtain Compound (15-1) (3.5 g). The obtained product was analyzed using high- performance liquid chromatography according to the analysis method 3 to obtain 97 % as the area percentage of Compound (1-5-1).

[0181] Preparation Example 16: Preparation of Compound (1-7-1) To a mixture of Compound (1-7-2)  (5.0 g), ethyl acetate (15.0 g) and water (15.0 g), 27 % by weight aqueous solution of sodium hydroxide (3.5 g) 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 separated. The obtained organic layer was concentrated under reduced pressure to obtain Compound (17-1) (4.0 g). The obtained product was analyzed using high- performance liquid chromatography according to the analysis method 3 to obtain 98 % as the area percentage of Compound (1-7-1).

[0182] Example 1-1 (Example of step 1) Compound (1-1-2)   (0.50  g), 2-butanone (0.75 g), potassium carbonate (0.43 g), and ethanol (2.5 g) were mixed, and after stirring the mixture for 1 hour, the mixture was stirred at 80°C for 24 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 1 and the analysis method 2 to obtain 62 % as the yield of Compound (3-1) by the analysis method 1 and obtain 87 % as a total of the area percentage of Compound (3-1) and the area percentage of Compound (3-2) by the analysis method 2.

[0183] Example 1-2 (Example of step 1) Compound (1-1-2)   (0.50  g), 2-butanone (1.50 g), potassium carbonate (0.86 g), and ethanol (2.5 g) were mixed, and after stirring the mixture for 1 hour, the mixture was stirred at 80°C for 24 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 2 to obtain 85 % as a total of the area percentage of Compound (3-1) and the area percentage of Compound (3-2).

[0184] Comparative Example 1-A Compound (1-1-1)  (0.12 g), 2-butanone (0.18 g), and ethanol (0.36 g) were mixed, and the mixture was stirred at 80°C for 8 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 3 to obtain 11 % as a total of the area percentage of Compound (3-1) and the area percentage of Compound (3-2).

[0185] Comparative Example 1-B Compound (1-1-1)   (0.12  g), 2-butanone (0.18 g), triethyl amine (0.10 g), and ethanol (0.36 g) were mixed, and the mixture was stirred at 80°C for 8 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 3 to obtain 24 % as a total of the area percentage of Compound (3-1) and the area percentage of Compound (3-2).

[0186] Comparative Example 1-C Compound (1-1-1)   (0.12  g), 2-butanone (0.18 g), tripotassium phosphate (0.11 g), and ethanol (0.36 g) were mixed, and the mixture was stirred at 80°C for 8 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 3 to obtain 31 % as a total of the area percentage of Compound (3-1) and the area percentage of Compound (3-2).

[0187] Comparative Example 1-D Compound (1-1-1)   (0.12  g), 2-butanone (0.18 g), potassium tert-butoxide (0.051 g), and ethanol (0.36 g) were mixed, and the mixture was stirred at 80°C for 8 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 3 to obtain 6 % as a total of the area percentage of Compound (3-1) and the area percentage of Compound (3-2).

[0188] Example 1-3 (Example of step 1) Compound (1-1-1)   (0.12  g), 2-butanone (0.18 g), potassium carbonate (0.035 g), and ethanol (0.36 g) were mixed, and the mixture was stirred at 80°C for 8 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 3 to obtain 73 % as a total of the area percentage of Compound (3-1) and the area percentage of Compound (3-2).

[0189] Example 1-4 (Example of step 1) Compound (1-4-2)   (0.50  g), 2-butanone (0.84 g), potassium carbonate (0.49  g), ethanol (2.5  g), and pyrrolidine (0.083 g) were mixed, and the mixture was stirred at room temperature for 1 hour, and thereafter, was stirred at 80°C for 14 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 1 and the analysis method 2 to obtain 67 % as the yield of Compound (3-1) by the analysis method 1 and obtain 89 % as a total of the area percentage of Compound (3-1) and the area percentage of Compound (3-2) by the analysis method 2.

[0190] Example 1-5 (Example of step 1) Compound (1-5-2)   (0.50  g), 2-butanone (0.75 g), potassium carbonate (0.43  g), ethanol (2.5  g), and pyrrolidine (0.074 g) were mixed, and the mixture was stirred at room temperature for 1 hour, and thereafter, was stirred at 80°C for 14 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 1 and the analysis method 2 to obtain 59 % as the yield of Compound (3-1) by the analysis method 1 and obtain 82 % as a total of the area percentage of Compound (3-1) and the area percentage of Compound (3-2) by the analysis method 2.

[0191] Example 1-6 (Example of step 1) Compound (1-4-2)   (0.50  g), 2-butanone (0.34 g), potassium carbonate (0.49  g), ethanol (2.5  g), and pyrrolidine (0.083 g) were mixed, and the mixture was stirred at room temperature for 1 hour, and thereafter, was stirred at 80°C for 24 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 1 and the analysis method 2 to obtain 57 % as the yield of Compound (3-1) by the analysis method 1 and obtain 79 % as a total of the area percentage of Compound (3-1) and the area percentage of Compound (3-2) by the analysis method 2.

[0192] Example 1-7 (Example of step 1) Compound (1-4-2)   (0.50  g), 2-butanone (0.84 g), potassium carbonate (0.37  g), ethanol (1.5  g), and pyrrolidine (0.083 g) were mixed, and the mixture was stirred at room temperature for 1 hour, and thereafter, was stirred at 80°C for 24 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 1 and the analysis method 2 to obtain 60 % as the yield of Compound (3-1) by the analysis method 1 and obtain 75 % as a total of the area percentage of Compound (3-1) and the area percentage of Compound (3-2) by the analysis method 2.

[0193] Comparative Example 1-E (Comparison with Example 1-7) Compound (1-4-2) (0.50 g), 2-butanone (0.84 g), ethanol (1.5 g), and pyrrolidine (0.083 g) were mixed, and the mixture was stirred at room temperature for 1 hour, and thereafter, was stirred at 80°C for 24 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 1 and the analysis method 2 to obtain 20 % as the yield of Compound (3-1) by the analysis method 1 and obtain 18 % as a total of the area percentage of Compound (3-1) and the area percentage of Compound (3-2) by the analysis method 2.

[0194] Comparative Example 1-F (Comparison with Example 1-7) Compound (1-4-2)   (0.50  g), 2-butanone (0.84 g), triethyl amine (0.47 g), ethanol (1.5 g), and pyrrolidine (0.083 g) were mixed, and the mixture was stirred at room temperature for 1 hour, and thereafter, was stirred at 80°C for 24 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 1 and the analysis method 2 to obtain 30 % as the yield of Compound (3-1) by the analysis method 1 and obtain 28 % as a total of the area percentage of Compound (3-1) and the area percentage of Compound (3-2) by the analysis method 2.

[0195] Comparative Example 1-G (Comparison with Example 1-7) Compound (1-4-2)   (0.50  g), 2-butanone (0.84 g), pyridine (0.37 g), ethanol (1.5 g), and pyrrolidine (0.083 g) were mixed, and the mixture was stirred at room temperature for 1 hour, and thereafter, was stirred at 80°C for 24 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 1 and the analysis method 2 to obtain 20 % as the yield of Compound (3-1) by the analysis method 1 and obtain 18 % as a total of the area percentage of Compound (3-1) and the area percentage of Compound (3-2) by the analysis method 2.

[0196] Comparative Example 1-H (Comparison with Example 1-7) Compound (1-4-2)   (0.50  g), 2-butanone (0.84 g), potassium tert-butoxide (0.39  g), ethanol (1.5  g), and pyrrolidine (0.083 g) were mixed, and the mixture was stirred at room temperature for 1 hour, and thereafter, was stirred at 80°C for 24 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 1 and the analysis method 2 to obtain 5 % as the yield of Compound (3-1) by the analysis method 1 and obtain 8 % as a total of the area percentage of Compound (3-1) and the area percentage of Compound (3-2) by the analysis method 2.

[0197] Example 1-8 (Example of step 1) Compound (1-4-2)   (0.50  g), 2-butanone (0.84 g), potassium carbonate (0.97  g), ethanol (1.5  g), and pyrrolidine (0.083 g) were mixed, and the mixture was stirred at room temperature for 1 hour, and thereafter, was stirred at 80°C for 24 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 1 and the analysis method 2 to obtain 62 % as the yield of Compound (3-1) by the analysis method 1 and obtain 86 % as a total of the area percentage of Compound (3-1) and the area percentage of Compound (3-2) by the analysis method 2.

[0198] Example 1-9 (Example of step 1) Compound (1-4-2)   (0.50  g), 2-butanone (0.84 g), potassium carbonate (0.32  g), ethanol (1.5  g), and pyrrolidine (0.083 g) were mixed, and the mixture was stirred at room temperature for 1 hour, and thereafter, was stirred at 80°C for 24 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 1 and the analysis method 2 to obtain 67 % as the yield of Compound (3-1) by the analysis method 1 and obtain 88 % as a total of the area percentage of Compound (3-1) and the area percentage of Compound (3-2) by the analysis method 2.

[0199] Example 1-10 (Example of step 1) Compound (1-4-2)   (0.50  g), 2-butanone (0.84 g), potassium carbonate (0.49  g), 2-propanol (1.5  g), and pyrrolidine (0.083 g) were mixed, and the mixture was stirred at room temperature for 1 hour, and thereafter, was stirred at 80°C for 24 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 1 and the analysis method 2 to obtain 67 % as the yield of Compound (3-1) by the analysis method 1 and obtain 90 % as a total of the area percentage of Compound (3-1) and the area percentage of Compound (3-2) by the analysis method 2.

[0200] Example 1-11 (Example of step 1) Compound (1-4-2)   (0.50  g), 2-butanone (1.7 g), potassium carbonate (0.97  g), ethanol (5.0  g), and pyrrolidine (0.17 g) were mixed, and the mixture was stirred at room temperature for 1 hour, and thereafter, was stirred at 80°C for 24 hours.   The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 2 to obtain 83 % as a total of the area percentage of Compound (3-1) and the area percentage of Compound (3-2).

[0201] Example 1-12 (Example of step 1) Compound (1-5-2)   (0.50  g), 2-butanone (1.5 g), potassium carbonate (0.86  g), ethanol (2.5  g), and pyrrolidine (0.15 g) were mixed, and the mixture was stirred at room temperature for 1 hour, and thereafter, was stirred at 80°C for 24 hours.   The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 2 to obtain 88 % as a total of the area percentage of Compound (3-1) and the area percentage of Compound (3-2).

[0202] Example 1-13 (Example of step 1) Compound (1-3-2)   (0.50  g), 2-butanone (1.4 g), potassium carbonate (0.81  g), ethanol (2.5  g), and pyrrolidine (0.14 g) were mixed, and the mixture was stirred at room temperature for 1 hour, and thereafter, was stirred at 80°C for 24 hours.   The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 2 to obtain 88 % as a total of the area percentage of Compound (3-1) and the area percentage of Compound (3-2).

[0203] Example 1-14 (Example of step 1) Compound (1-4-1)   (0.27  g), 2-butanone (0.54 g), potassium carbonate (0.079  g), ethanol (0.80  g), and pyrrolidine (0.053 g) were mixed, and the mixture was stirred at 80°C for 8 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 3 to obtain 74 % as a total of the area percentage of Compound (3-1) and the area percentage of Compound (3-2).

[0204] Comparative Example 1-I (Comparison with Example 1-14) Compound (1-4-1)   (0.27  g), 2-butanone (0.54 g), potassium carbonate (0.079 g), and ethanol (0.80 g) were mixed, and the mixture was stirred at 80°C for 8 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 3 to obtain 10 % as a total of the area percentage of Compound (3-1) and the area percentage of Compound (3-2).

[0205] Example 1-15 (Example of step 1) Compound (1-4-1)   (0.27  g), 2-butanone (0.54 g), potassium carbonate (0.079  g), ethanol (0.80  g), and pyrrolidine (0.11 g) were mixed, and the mixture was stirred at 80°C for 8 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 3 to obtain 73 % as a total of the area percentage of Compound (3-1) and the area percentage of Compound (3-2).

[0206] Example 1-16 (Example of step 1) Compound (1-7-1)   (0.39  g), 2-butanone (0.54 g), potassium carbonate (0.079  g), ethanol (1.2  g), and pyrrolidine (0.11 g) were mixed, and the mixture was stirred at 80°C for 8 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 3 to obtain 69 % as a total of the area percentage of Compound (3-1) and the area percentage of Compound (3-2).

[0207] Example 1-17 (Example of step 1) Compound (1-5-1)   (0.31  g), 2-butanone (0.54 g), potassium carbonate (0.079  g), ethanol (0.92  g), and pyrrolidine (0.11 g) were mixed, and the mixture was stirred at 80°C for 8 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 3 to obtain 70 % as a total of the area percentage of Compound (3-1) and the area percentage of Compound (3-2).

[0208] Example 1-18 (Example of step 1) Compound (1-2-2) (1.0 g), 2-butanone (1.4 g), potassium carbonate (0.82 g), methanol (4.0 g), and pyrrolidine (0.14 g) were mixed, and the mixture was stirred at room temperature, and thereafter was stirred at 80°C as outside temperature under reflux for 16 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 3 to obtain 68 % as a total of the area percentage of Compound (3-1) and the area percentage of Compound (3-2).

[0209] Example 1-19 (Example of step 1) Compound (1-7-2) (1.0 g), 2-butanone (1.2 g), potassium carbonate (0.70 g), methanol (4.0 g), and pyrrolidine (0.12 g) were mixed, and the mixture was stirred at room temperature, and thereafter was stirred at 80°C as outside temperature under reflux for 16 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 3 to obtain 67 % as a total of the area percentage of Compound (3-1) and the area percentage of Compound (3-2).

[0210] Example 1-20 (Example of step 1) Compound (1-5-2) (1.0 g), 2-butanone (1.5 g), potassium carbonate (0.86 g), methanol (4.0 g), and pyrrolidine (0.15 g) were mixed, and the mixture was stirred at room temperature, and thereafter was stirred at 80°C as outside temperature under reflux for 16 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 3 to obtain 77 % as a total of the area percentage of Compound (3-1) and the area percentage of Compound (3-2).

[0211] Example 1-21 (Example of step 1) Compound (1-8-2)   (1.0  g), 2-butanone (0.99 g), potassium carbonate (0.57  g), methanol (4.0  g), and pyrrolidine (0.097 g) were mixed, and the mixture was stirred at room temperature, and thereafter was stirred at 80°C as outside temperature under reflux for 16 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 3 to obtain 68 % as a total of the area percentage of Compound (3-1) and the area percentage of Compound (3-2).

[0212] Example 1-22 (Example of step 1) Compound (1-1-2)  (100  g), 2-butanone (144  g), and potassium carbonate (138 g) were added to ethanol (300 mL), and the mixture was stirred at room temperature for 2 hours, and thereafter, was stirred at 80°C for 16 hours. After the mixture was allowed to cool to room temperature, the reaction mixture was filtered, and the obtained filtrates were concentrated under reduced pressure.    To the obtained concentrated residue, water (500 mL) and chloroform (500 mL) were added successively, and after stirring the mixture, the mixture was allowed to stand and separated. The obtained organic layer was washed with saturated aqueous solution of sodium chloride (500 mL), and thereafter, the mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained concentrated residue was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 19 (volume ratio) solvent system) to obtain a mixture of Compound (3-1) and Compound (3-2)  (80 g) (molar ratio calculated from 1H-NMR; Compound (3-1) / Compound (3-2) was > 7.7 / 1). To the resulting mixture, 2-propanol (100 mL) was added, and after stirring the mixture at room temperature, the mixture was filtered. The obtained solids were dried under reduced pressure to obtain Compound (3-1)  (59.4 g). The yield of Compound (3-1) on the basis of Compound (1-12) was 48 %. The 1H-NMR value of Compound (3-1) is indicated below. 1H-NMR (CDCI3) 6: 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) Compound (1-1-2)  (10 g), water (50 g), and 27 % by weight aqueous solution of sodium hydroxide (7.4 g), and xylene (20 g) were mixed, and the mixture was stirred at room temperature for 30 minutes. After the mixture was allowed to stand, the organic layer that was separated was washed with 9 % by weight aqueous solution of sodium sulfate (10 g) to obtain a solution of Compound (1-1-1) in xylene (27.6 g). The obtained solution was analyzed using high- performance liquid chromatography according to the analysis method 3 to obtain 99 % as the area percentage of Compound (1-1-1). To a mixture of 2-butanone (15 g), potassium carbonate (2.9 g) and methanol (26 g), the above-mentioned xylene solution (25 g) was added dropwise via syringe pump over 8 hours. The resulting mixture was further stirred at 80°C for additional 6 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 3 to obtain 75 % as a total of the area percentage of Compound (3-1) and the area percentage of Compound (3-2). After the mixture was allowed to cool to room temperature, xylene (17 g), water (17 g), and 35 % by weight hydrochloric acid (8.8 g) were added successively to the resulting mixture, and the mixture was stirred, allowed to stand and separated. The obtained organic layer was washed with water (8.6 g), and the obtained organic layer was concentrated under reduced pressure to obtain a mixture of Compound (3-1) and Compound (3-2) (6.0 g) (molar ratio calculated by 1H-NMR: Compound (3-1) / Compound (3-2) was > 5 / 1). A partial (1.5 g) of the obtained mixture was solubilized in a mixture of MTBE (1.0 g) and n-heptane (2.0 g) at 50°C, and thereafter, the mixture was cooled to 10°C with a speed of -10°C / hour. After the obtained solids were filtered, the solids were dried under reduced pressure to obtain Compound (3-1) (0.83 g). The obtained product was analyzed using high-performance liquid chromatography according to the analysis method 3, and as a result, the yield of Compound (3-1) on the basis of Compound (1-1-2) was 47 %, and the contents of the obtained Compound (3-1) was 98 % by weight.

[0214] Example 1-24 (Example of step 1-1) To a mixture of Compound (1-4-2)  (10 g), 2-butanone (30 g), potassium carbonate (17  g), and ethanol (50 g), pyrrolidine (3.0 g) was added at room temperature. The resulting mixture was stirred at room temperature for 1 hour, and thereafter, was stirred at 80°C for 13 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 2 to obtain 73 % as a total of the area percentage of Compound (3-1) and the area percentage of Compound (3-2). After the mixture was allowed to cool to room temperature, the resulting reaction mixture was filtered, and the obtained filtrates were concentrated under a reduced pressure. To the obtained concentrated residue, water (20 g) and MTBE (40 g) were added successively at room temperature, and after stirring the mixture at the same temperature, the mixture was allowed to stand and separated. The obtained organic layer was dried over anhydrous sodium sulfate and thereafter, was concentrated under reduced pressure. The obtained concentrated residue was purified by column chromatography (ethyl acetate / hexane = 1 / 19 (volume ratio) solvent system) to obtain a mixture of Compound (3- 1) and Compound (3-2)  (6.6 g) (molar ratio calculated from 1H-NMR: Compound (3-1) / Compound (3-2) was > 3.6 / 1). To the resulting mixture, hexane (40 g) was added, and after stirring the mixture at room temperature, the obtained solids were filtrated and dried under reduced pressure to obtain Compound (3-1)  (5.0 g). The obtained product was analyzed using high-performance liquid chromatography according to the analysis method 2, and as a result, the yield of Compound (3-1) on the basis of Compound (1-4-2) was 51 %, and the contents of the obtained Compound (3-1) was 89 % by weight.

[0215] Example 1-25 (Example of step 1-1) To ethanol (25 g), Compound (1-4-2) (5.0 g), 2-butanone (7.5 g), potassium carbonate (4.3 g), and pyrrolidine (0.74 g) were added successively at room temperature.    The resulting mixture was stirred at room temperature for 1 hour, and thereafter was stirred at 80°C for 13 hours.   The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 2 to obtain 89 % as a total of the area percentage of Compound (3-1) and the area percentage of Compound (3-2). After the mixture was allowed to cool to room temperature, the resulting reaction mixture was filtered, and the obtained filtrates were concentrated under a reduced pressure. To the obtained concentrated residues, water (10 g) and MTBE (20 g) were added successively at room temperature, and after stirring the mixture at the same temperature, the mixture was allowed to stand and separated. The obtained organic layer was dried over anhydrous sodium sulfate and thereafter, was concentrated under reduced pressure to obtain a mixture of Compound (3-1) and Compound (3-2)  (3.86 g) (molar ratio calculated from 1H-NMR: Compound (3-1) / Compound (3-2) was > 3.6 / 1). To the resulting mixture, hexane (20 g) was added at room temperature, and after stirring the mixture at the same temperature, the obtained solids were filtrated and dried under reduced pressure to obtain Compound (3-1)  (3.6 g). The product was analyzed using high-performance liquid chromatography according to the analysis method 2, and as a result, the yield of Compound (3-1) on the basis of the compound (1-4-2) was 52 %, and the contents of the obtained Compound (3-1) was 80 % by weight.

[0216] Example 2-1-1 (Example of step 2-1) Compound (3-1)  (0.075 g), acetic anhydride (0.22 g), and bromine (0.064 g) were mixed at room temperature, and after stirring the mixture at the same temperature for 2 hours, the mixture was stirred at 60°C for 2 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 3 to obtain 89% as the area percentage of Compound (5-1).

[0217] Example 2-1-2 (Example of step 2-1) Compound (3-1)  (0.075 g), acetic anhydride (0.22 g), and 98 % by weight of sulfuric acid (0.040 g) were mixed at room temperature, and after stirring the mixture at the same temperature for 2 hours, the mixture was stirred at 60°C for 2 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 3 to obtain 99% as the area percentage of Compound (5-1).

[0218] Example 2-1-3 (Example of step 2-1) Compound (3-1)  (0.075 g), acetic anhydride (0.15 g), and 98 % by weight of sulfuric acid (0.044 g) were mixed at room temperature, and after stirring the mixture at the same temperature for 2 hours, the mixture was stirred at 60°C for 2 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 3 to obtain 99% as the area percentage of Compound (5-1).

[0219] Example 2-1-4 (Example of step 2-1) Compound (3-1)  (0.075 g), acetic anhydride (0.22 g), and 98 % by weight of sulfuric acid (0.044 g) were mixed at 0°C, and after stirring the mixture at 0°C for 1 hour, the mixture was stirred at room temperature for 1 hour, and further stirred at 60°C for 2 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 3 to obtain 99% as the area percentage of Compound (5-1).

[0220] Example 2-1-5 (Example of step 2-1) Compound (3-1)  (0.075 g), acetic anhydride (0.22 g), and 98 % by weight of sulfuric acid (0.040 g) were mixed at 60°C, and the mixture was stirred at 60°C for 3 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 3 to obtain 98% as the area percentage of Compound (5-1).

[0221] Example 2-2-1 (Example of the case where the step 2-1 and the step 2-2 are conducted in one-pot) To the reaction mixture obtained in Example 2-1-1, ethanol (0.22 g) was added at 60°C, and the mixture was stirred at the same temperature for 2 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 3 to obtain 87% as the area percentage of Compound (6-1).

[0222] Example 2-2-2 (Example of the case where step 2-1 and step 2-2 are conducted in one-pot) Compound (3-1)  (10 g) was added to acetic anhydride (20 g), and to the resulting mixture, 98 % by weight of sulfuric acid (6.5 g) was added dropwise over 1 hour. After stirring the mixture at 30°C for 3 hours, the mixture was stirred at 60°C for 1 hour. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 3 to obtain 96% as the area percentage of Compound (5-1). To the resulting mixture, methanol (10 g) was added at 60°C, and the mixture was stirred at 80°C for 8 hours. After the mixture was allowed to cool to room temperature, to the resulting mixture, xylene (10 g) and water (10 g) were added successively, and after stirring the mixture, the mixture was allowed to stand and separated. The obtained organic layer was concentrated under reduced pressure to obtain Compound (6-1) (10.5 g). The product was analyzed using high-performance liquid chromatography according to the analysis method 4, and as a result, the yield of Compound (6-1) on the basis of Compound (3-1) was quantitative, and the contents of Compound (6-1) was 95 % by weight.

[0223] Example 2-3-1 (Example of the case where step 2-1 and step 2-2 were conducted successively) To methanol (80 g), Compound (1-4-2) (20 g), 2-butanone (33.7 g), potassium carbonate (19.4 g) and pyrrolidine (3.3 g) were added at room temperature successively.    The resulting mixture was stirred at room temperature for 1 hour, and thereafter, was stirred at 80°C as outside temperature under reflux for 24 hours.  The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 3, and as a result, a total of the area percentage of Compound (3-1) and the area percentage of Compound (3-2) was 76 %. After the mixture was allowed to cool to room temperature, the mixture was concentrated under reduced pressure, and to the mixture, MTBE (80 g) and water (40 g) were added successively, and after stirring the mixture at room temperature, the mixture was allowed to stand and separated. The obtained organic layer was concentrated under reduced pressure to obtain the concentrated residues (16.8 g) containing Compound (3-1).     The obtained concentrated residue (15 g) was added to acetic anhydride (30 g) at room temperature, and to the resulting mixture, 98 % by weight of sulfuric acid (8.2 g) was added dropwise at 30°C over 1 hour. The resulting mixture was stirred at 30°C for 3 hours, and further stirred at 60°C for 2 hours. To the resulting mixture, methanol (15 g) was added at the same temperature, and the mixture was stirred at 80°C for 8 hours.   After the mixture was allowed to cool to room temperature, to the resulting mixture, xylene (30 g) and water (30 g) were added successively, and after stirring the mixture at the same temperature, the mixture was allowed to stand and separated.    The obtained organic layer was concentrated under reduced pressure to obtain Compound (61) (14.4 g). The product was analyzed using high-performance liquid chromatography according to the analysis method 4, and as a result, the yield of Compound (6-1) on the basis of Compound (1-4-2) was 56 %, and the contents of the obtained Compound (6-1) was 60 % by weight.

[0224] Example 2-3-2 (Example of the case where step 1-1, step 2-1 and step 2-2 were conducted successively) To methanol (100 g), Compound (1-5-2) (25 g), 2-butanone (37.3 g), potassium carbonate (21.4 g), and pyrrolidine (3.7 g) were added at room temperature successively.    The resulting mixture was stirred at room temperature for 1 hour, and thereafter, stirred at 80°C as outside temperature under reflux for 24 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 3, and as a result, a total of the area percentage of Compound (3-1) and the area percentage of Compound (3-2) was 79 %. After the mixture was allowed to cool to room temperature, the resulting mixture was concentrated under reduced pressure, and to the mixture, MTBE (100 g) and water (50 g) were added successively, and after stirring the mixture at room temperature, the mixture was allowed to stand and separated. The obtained organic layer was concentrated under reduced pressure to obtain the concentrated residues (18.4 g) containing Compound (3-1). The obtained residue (15 g) was added to acetic anhydride (30 g), and to the resulting mixture, 98 % by weight of sulfuric acid (9.1 g) was added dropwise at 30°C over 1 hour. The resulting mixture was stirred at 30°C for 3 hours, and further stirred at 60°C for 2 hours. To the resulting mixture, methanol (15 g) was added at the same temperature, and the mixture was stirred at 80°C for 8 hours. After the mixture was allowed to cool to room temperature, to the resulting mixture, xylene (15 g) and water (15 g) were added successively, and after stirring the mixture at the same temperature, the mixture was allowed to stand and separated . The obtained organic layer was concentrated under reduced pressure to obtain Compound (6-1) (13.8 g). The product was analyzed using high-performance liquid chromatography according to the analysis method 4, and as a result, the yield of the compound (6-1) on the basis of Compound (1-52) was 61 %, and the contents of the obtained Compound (61) was 68 % by weight.

[0225] Example 2-4-1 (Example of step 2 not including step 2-1 and step 2-2) Compound (3-1)  (0.075 g), dimethyl sulfoxide (0.22 g), and iodine (0.010 g) were mixed, and the mixture was stirred at room temperature for 2 hours, further stirred at 60°C for 2 hours, and further stirred at 100°C for 2 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 3 to obtain 73% as the area percentage of Compound (6-1).

[0226] Example 2-4-2 (Example of step 2 not including step 2-1 and step 2-2) Compound (3-1)  (0.075 g), acetic acid (0.220 g), and bromine (0.064 g) were mixed, and the mixture was stirred at room temperature for 2 hours, and further stirred at 60°C for 2 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 3 to obtain 69% as the area percentage of Compound (6-1).

[0227] Example 2-4-3 (Example of step 2 not including step 2-1 and step 2-2) Compound (3-1)  (0.075 g), acetic acid (0.22 g), and DBDMH (0.069 g) were mixed, and the mixture was stirred at room temperature for 2 hours, and further stirred at 60°C for 2 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 3 to obtain 69% as the area percentage of Compound (6-1).

[0228] Example 2-4-4 (Example of step 2 not including step 2-1 and step 2-2) Compound (3-1)  (0.075 g), tert-butyl alcohol (0.22 g), and bromine (0.064 g) were mixed, and the mixture was stirred at room temperature for 2 hours, and further stirred at 60°C for 2 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 3 to obtain 78% as the area percentage of Compound (6-1).

[0229] Example 2-4-5 (Example of step 2 not including step 2-1 and step 2-2) Compound (3-1)  (0.075 g), acetic acid (0.22 g), and sulfuryl chloride (0.054 g) were mixed, and the mixture was stirred at room temperature for 2 hours, and further stirred at 60°C for 2 hours. The obtained mixture was analyzed using high-performance liquid chromatography according to the analysis method 3 to obtain 58% as the area percentage of Compound (6-1).

[0230] Example 3-1 (Example of step 3) To a mixture of Compound (6-1)  (45.8 g), xylene (67.6 g), and methyl chloroacetate (44.1 g), 28 % by weight of methanol solution of sodium methoxide (73.0 g) was added dropwise at 80°C, and dimethyl sulfate (3.4 g) was further added thereto, and the mixture was stirred for 1 hour. After the mixture was allowed to cool to 60°C, to the resulting mixture, water (126.5 g) was added, and the mixture was separated, and the obtained organic layer was concentrated under reduced pressure. Methanol and water were added to the obtained concentrated residue to precipitate solids out, and Compound (6-1)  (59.7 g) was isolated as a solid.

[0231] Example 4-1 (Example of step 4) Sodium methoxide (21.91 g) was suspended in xylene (50.43 g) at room temperature to obtain a suspension. To the above-mentioned suspension that was heated to 30°C, a mixed solution of Compound (8-1)  (50.1 g), xylene (150.1 g) and methyl formate (23.68 g) were added dropwise over 2 hours, and the mixture was stirred at 30°C for 2.5 hours. The resulting mixture was cooled to 0°C, and water (150.4 g), 35 % by weight of hydrochloric acid (10.14 g), and 27 % by weight of aqueous solution of sodium hydroxide (1.11 g) were added successively thereto, and the mixture was stirred, and allowed to stand and separated. An aqueous layer was pull out to obtain aqueous layer (250.5 g). The obtained aqueous layer was analyzed using high-performance liquid chromatography according to the analysis method 4, and as a result, yield of sodium salt of Compound (10-1) on the basis of Compound (6-1) was 91 %.

[0232] Example 5-1 (Example of step 5) To the aqueous layer obtained in Example 4-1 (4.47 g), benzonitrile (3.91 g), tetrabutylammonium bromide (0.04 g), 27 % by weight of aqueous solution of sodium hydroxide (0.11 g), and dimethyl sulfate (0.62 g) were added successively at room temperature, and the mixture was stirred at 40°C for 2 hours.    The obtained mixture was analyzed using high- performance liquid chromatography according to the analysis method 4, and as a result, yield of Compound (11-1) on the basis of sodium salt of Compound (10-1) was 93 %. Industrial Applicability

[0233] According    to    the    present    invention,     3- phenylcyclohexanone compound having substituent(s) at 6-position, that is, Compound (3), that can be an intermediate compound for production of 3-hydroxybiphenyl compound having substituent(s) at 4-position, can be prepared effectively. Also, using Compound (3), Compound (6) that is 3-hydroxybiphenyl compound having substituent(s) at 4-position, as well as Compound (8) and Compound (11) that are a derivative    of    3-hydroxybiphenyl    compound    having substituent(s) at 4-position can be prepared effectively.

Claims

1. A process for preparing a compound represented byformula (3)5           R4[whereinR1, R2, R3, R4, and R5 are identical to or different fromeach other and each represents a C1-C12 chain hydrocarbongroup that may be optionally substituted with one or more10    fluorine atoms, a hydrogen atom, a halogen atom, a cyanogroup, or a nitro group,R8 represents a C1-C12 chain hydrocarbon group, and R9 represents a hydrogen atom or a C1-C12 chain hydrocarbongroup (with the proviso that when R8 and R9 are different15    from each other, R8 represents a bulkier group than R9)], which comprises a step 1step 1: a step in which a compound represented by formula(1):10[whereinR1, R2, R3, R4, and R5 are the same as defined above,R6 represents a C1-C6 chain hydrocarbon group that maybe optionally substituted with one phenyl group,R7 represents a C1-C6 chain hydrocarbon group that maybe optionally substituted with one phenyl group, a phenylgroup, or a hydrogen atom, or alternatively,R6 and R7 may combine with each other to form -(CH2)4-,-(CH2)5-, or -(CH2)2-O-(CH2)2-] or salts thereof, a compound represented by formula (2):[whereinR8 and R9 are the same as defined above], andan alkali metal carbonate are mixed, and then reacted in the presence of a pyrrolidine to obtain the compound represented by formula (3)  .

2. The process according to claim 1 wherein R6 and R7combine with each other to form -(CH2)4-, and the pyrrolidine is a pyrrolidine that is formed from the compound (1) in a reaction system.

3. The process according to claim 1 whereina combination of R6 and R7 representsa combination in which R6 and R7 each represents a methyl group;a combination in which R6 and R7 each represents anethyl group;a combination in which R6 and R7 each represents anisopropyl group;a combination in which R6 and R7 each represents a butyl group;a combination in which R6 and R7 each represents a benzyl group;a combination in which R6 represents an ethyl group,and R7 represents a hydrogen atom;a combination in which R6 represents a benzyl group,and R7 represents a hydrogen atom;a combination in which R6 represents a methyl group,and R7 represents a phenyl group;a combination in which R6 and R7 combine with each otherto form -(CH2)4-;a combination in which R6 and R7 combine with each otherto form -(CH2)5-; ora combination in which R6 and R7 combine with each other to form -(CH2)2-O-(CH2)2-.

4. The process according to claim 1 whereina combination of R6 and R7 representsa combination in which R6 and R7 each represents a methyl group;a combination in which R6 and R7 each represents anethyl group; ora combination in which R6 and R7 combine with each other to form -(CH2)4-.

5. The process according to any one of claims 1 to 4 whereinR8  represents a methyl group, and R9 represents ahydrogen atom.

6. The process according to any one of claims 1 to 5 whereinR1 and R5 each represents a hydrogen atom, and R2, R3 and R4 are identical to or different from each other and each represents a hydrogen atom or a halogen atom.

7. The process according to claim 6 wherein R2, R3 and R4each represents a hydrogen atom.

8. A process for preparing a compound represented by formula (6)[wherein R1, R2, R3, R4, R5, R8 and R9 are the same as defied above], which comprises, in addition to the step 1 described in5    any one of claims 1 to 7, a step 2step 2: a step in which the compound (3) that is obtained in the step 1 is oxidized to obtain a compound represented by formula (6).

9. The process according to claim 8 wherein the step 210    comprises a step 2-1 and a step 2-2:step 2-1: a step in which the compound (3) obtained in the step 1, a compound represented by formula (4)R1° O R1°Y Y (4)O 0[wherein R10 represents a C1-C12 chain hydrocarbon group],15    andbromine or sulfuric acid are reacted to obtain a compound represented by formula (5)[wherein,  R1,  R2, R3,  R4, R5, R8, R9 and R10 are the same asdefined above];step 2-2: a step in which the compound obtained in the step2-1 is subjected to a solvolysis to obtain the compound (6).

10. The process according to claim 9 wherein R10 representsa methyl group.

11. A process for preparing a compound represented by formula (8)[wherein, R1,  R2,  R3, R4, R5, R8, R9, and R11 are the same asdefined above]which comprises, in addition to the step 1 and the step 2described in any one of claims 8 to 10, a step 3:step 3: a step in which the compound (6) obtained in thestep 2 and a compound represented by formula (7):X1,,R11 (7)0[wherein,X1 represents a leaving group, and R11 represents a C1-C6 chain hydrocarbon group] are reacted in the presence of a base to obtain a compound represented by formula (8).12.A processfor preparing a compound represented byformula (11):[wherein R1,  R2,  R3, R4,  R5, R8, R9 and R11 are the same as5    defined above], which comprises, in addition to the step 1, the step 2 and the step 3 described in claim 11, a step 4 and a step 5,step 4: a step in which the compound (8) obtained in the step 3 and a compound represented by formula (9):100 hA0,r12 (9)[wherein R12 represents a C1-C6 chain hydrocarbon group]are reacted in the presence of a base:step 5: a step in which the compound obtained in the step 4and a methylating agent are reacted to obtain the compound15     (11).