Method for producing ketone derivative

Abstract

To provide a method for producing a new ketone derivative.SOLUTION: A method for producing a ketone derivative comprises a step of producing a ketone derivative by bringing an ester derivative or a thioester derivative into contact with a Grignard reagent at -10 to 50°C in the presence of a copper salt, wherein the copper salt is selected from CuCN and CuCl, and the amount of the copper salt used is 0.01 to 1 mol per 1 mol of the ester derivative or thioester derivative.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for producing a ketone derivative. [Background technology]

[0002] Ketone derivatives are useful compounds for use as pharmaceuticals, agricultural chemicals, chemical materials, synthetic intermediates, and the like.

[0003] Non-Patent Document 1 (BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN, VOL. 47(7), pp. 1777-1780 (1974)) states: The following formula: [ka] or a thioester derivative represented by [ka] and an ester derivative represented by the formula: The following formula: [ka] a Grignard reagent represented by to contact a compound of the formula: [ka] The present invention describes a method for producing a ketone derivative represented by the formula:

[0004] R described in Non-Patent Document 1 1 and R 2 The combinations are as follows:

[0005] [Table 1]

[0006] [Table 2] [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN,VOL.47(7),pp.1777-1780(1974) Summary of the Invention [Problem to be solved by the invention]

[0008] An object of the present invention is to provide a novel method for producing a ketone derivative. [Means for solving the problem]

[0009] A first aspect of the present invention includes the following inventions. [1A] Formula (I): [ka] [In the formula, R 1 and R 2 each independently represents an alkyl group which may have a substituent, an alkenyl group which may have a substituent, a cycloalkyl group which may have a substituent, a heterocycloalkyl group which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an arylalkyl group which may have a substituent, or an arylalkenyl group which may have a substituent. A method for producing compound (I) represented by The method comprises the steps of: (S1) In the presence of copper salts, The following formula (IIa): [ka] [In the formula, R 1 is as defined above, Y 1 represents -O- or -S-; Z 1 teeth, The following formula (P1): [ka] (wherein, (*1) represents Y 1 ) wherein the monovalent nitrogen-containing heterocyclic group optionally has a substituent.] Compound (IIa) represented by the formula: The following formula (IIb): [ka] [In the formula, R 1 is as defined above, Y 2 and Y 3 each independently represents -O- or -S-; Z 2 is expressed by the following formula (P2): [ka] (wherein, (*2) represents Y 2 ) and a partial structure (P2) represented by the following formula (P3): [ka] (wherein, (*3) represents Y 3 ) and a partial structure (P3) represented by the following formula: wherein the divalent nitrogen-containing heterocyclic group may have a substituent.] Compound (IIb) represented by and a compound (II) selected from The following formula (IIIa): [ka] [In the formula, R 2 is as defined above, and X 1 represents a halogen atom. Grignard reagent (IIIa) represented by the formula: The following formula (IIIb): [ka] [In the formula, R 2 and X 1 has the same meaning as above.] Grignard reagent (IIIb) represented by a Grignard reagent (III) selected from at a temperature of -10 to 50°C to produce compound (I), the copper salt is selected from CuCN and CuCl; The above method, wherein the amount of the copper salt used is 0.01 to 1 mole per mole of the compound (II). [2A]Z above 1 But the following group: [ka] [ka] [ka] [In the formula, X represents —O—, —S—, or —N(—CH)—.] [ka] [In the formula, X has the same meaning as defined above.] [ka] [In the formula, X has the same meaning as defined above.] [ka] [In the formula, X has the same meaning as defined above.] [ka] [In the formula, X has the same meaning as defined above.] is selected from Said Z 2 But the following group: [ka] [ka] [In the formula, X has the same meaning as defined above.] [ka] [wherein X is as defined above, t Bu represents a tert-butyl group. [ka] [In the formula, X is as defined above, and Ph represents a phenyl group.] The method according to [1A], wherein the compound is selected from the group consisting of: [3A] The method according to [1A] or [2A], wherein the amount of the Grignard reagent (III) used is 0.5 to 3 moles per mole of the compound (II). [4A] The step (S1) comprises the following steps: (S1a) preparing a first mixture containing the compound (II) and the copper salt; and (S1b) a step of contacting the first mixture with the Grignard reagent (III) to produce the compound (I). The method according to any one of [1A] to [3A], comprising: [5A] The step (S1) comprises the following steps: (S1c) preparing a second mixture containing the copper salt and the Grignard reagent (III); and (S1d) a step of contacting the second mixture with the compound (II) to produce the compound (I). The method according to any one of [1A] to [3A], comprising: [6A] The method comprises the steps of: (T1a) In the presence of a base, The following formula (IV): [ka] [In the formula, R 1 has the same meaning as above.] Compound (IV) represented by Below (Va): [ka] [In the formula, R 3 represents a hydrogen atom or an alkali metal; Y 1 and Z 1 has the same meaning as above.] A compound (Va) represented by the formula: to produce compound (IIa); or (T1b) In the presence of a base, The compound (IV), Below (Vb): [ka] [In the formula, R 3 and R 4 each independently represents a hydrogen atom or an alkali metal; Y 2 , Y 3 and Z 2 has the same meaning as above.] A compound (Vb) represented by the formula: to produce compound (IIb). The method according to any one of [1A] to [5A], further comprising: [7A] The method according to [6A], wherein the base used in the step (T1a) and the base used in the step (T1b) are each independently selected from triethylamine, diisopropylethylamine, dimethylaniline, and pyridine. [8A] The method comprises the steps of: (U1) Formula (VI): [ka] Compound (VI) represented by a chlorinating agent; The method according to [6A] or [7A], further comprising the step of producing compound (IV) by contacting [9A] The method according to [8A], wherein in the step (U1), the compound (VI) is contacted with the chlorinating agent in the presence of a catalytic amount of N,N-dimethylformamide. [10A] The method according to [8A] or [9A], wherein the chlorinating agent used in step (U1) is selected from thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus oxychloride and phosphorus pentachloride. [11A] The method comprises the steps of: (W1a) Formula (VII): [ka] [In the formula, R 2 and X 1 has the same meaning as above.] and a halide (VII) represented by magnesium or magnesium activated with a magnesium activator; optionally LiCl, to produce the Grignard reagent (IIIa) or (IIIb); or (W1b) the halide (VII), The following formula (VIII): [ka] [In the formula, i Pr represents an isopropyl group. a Grignard reagent (VIII) represented by The method according to any one of [1A] to [10A], further comprising a step of producing the Grignard reagent (IIIb) by contacting [12A] The method comprises the step (W1a), [11A]. The method according to [11A], wherein in the step (W1a), LiCl is dissolved in an organic solvent to prepare a LiCl solution, and then the halide (VII), the magnesium or magnesium activated with a magnesium activator, and the LiCl solution are brought into contact with each other to prepare the Grignard reagent (IIIb). [13A] The step (S1) comprises the following steps: (S1e) preparing a third mixture containing compound (II), magnesium or magnesium activated with a magnesium activator, and optionally LiCl; and (S1f) combining the third mixture, the copper salt, and a compound represented by the following formula (VII): [ka] [In the formula, R 2 and X 1 has the same meaning as above.] a step of producing the compound (I) by contacting the compound (I) with a halide (VII) represented by the formula: The method according to any one of [1A] to [10A], comprising: [14A] The step (S1) comprises the following steps: (S1g) The compound (II) and a compound of the following formula (VII): [ka] [In the formula, R 2 and X 1 has the same meaning as above.] and a halide (VII) represented by the formula: (S1h) Reacting the fourth mixture with the copper salt and a compound represented by the following formula (VIII): [ka] [In the formula, i Pr represents an isopropyl group. a step of producing the compound (I) by contacting the compound (I) with a Grignard reagent (VIII) represented by the formula: The method according to any one of [1A] to [10A], comprising:

[0010] The second aspect of the present invention includes the following inventions. [1B] Formula (I-1): [ka] [In the formula, n represents 1 or 2; R each independently represents an alkyl group which may have a substituent or an aryl group which may have a substituent; R 2 represents an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted arylalkyl group, or an optionally substituted arylalkenyl group. A method for producing a compound (I-1) represented by the following formula: The method comprises the steps of: (S2) Absence of copper salts, The following formula (IIa-1): [ka] [In the formula, n and R are as defined above, Y 1 represents -O- or -S-; Z 1 is expressed by the following formula (P1): [ka] (wherein, (*1) represents Y 1 ) wherein the monovalent nitrogen-containing heterocyclic group optionally has a substituent.] Compound (IIa-1) represented by the formula: The following formula (IIb-1): [ka] [In the formula, n and R are as defined above, Y 2 and Y 3 each independently represents -O- or -S-; Z 2 is expressed by the following formula (P2): [ka] (wherein, (*2) represents Y 2 ) and a partial structure (P2) represented by the following formula (P3): [ka] (wherein, (*3) represents Y 3 ) and a partial structure (P3) represented by the following formula: wherein the divalent nitrogen-containing heterocyclic group may have a substituent.] Compound (IIb-1) represented by Compound (II-1) selected from The following formula (IIIa): [ka] [In the formula, R 2 is as defined above, and X 1 represents a halogen atom. Grignard reagent (IIIa) represented by the formula: The following formula (IIIb): [ka] [In the formula, R 2 and X 1 has the same meaning as above.] Grignard reagent (IIIb) represented by a Grignard reagent (III) selected from to produce compound (I-1). [2B] The method according to [1B], wherein the amount of the Grignard reagent (III) used is 0.5 to 3 moles per mole of the compound (II-1). [3B] The method comprises the steps of: (T2a) In the presence of a base, The following formula (IV-1): [ka] [In the formula, n and R are as defined above.] Compound (IV-1) represented by Below (Va): [ka] [In the formula, R 3 represents a hydrogen atom or an alkali metal; Y 1 and Z 1 has the same meaning as above.] A compound (Va) represented by the formula: to produce compound (IIa-1); or (T2b) In the presence of a base, The compound (IV-1), Below (Vb): [ka] [In the formula, R 3 and R 4 each independently represents a hydrogen atom or an alkali metal; Y 2 , Y 3 and Z 2 has the same meaning as above.] A compound (Vb) represented by the formula: to produce compound (IIb-1). The method according to [1B] or [2B], further comprising: [4B] The method according to [3B], wherein the base is selected from triethylamine, diisopropylethylamine, dimethylaniline and pyridine. [5B] The method further comprises the steps of: (U2) Formula (VI-1) below: [ka] Compound (VI-1) represented by the formula: a chlorinating agent; The method according to [3B] or [4B], further comprising the step of producing compound (IV-1) by contacting [6B] The method according to [5B], wherein in the step (U2), the compound (VI-1) is contacted with the chlorinating agent in the presence of a catalytic amount of N,N-dimethylformamide. [7B] The method according to [5B] or [6B], wherein the chlorinating agent is selected from thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus oxychloride and phosphorus pentachloride. [8B] The method comprises the steps of: (W2a) Formula (VII): [ka] [In the formula, R 2 and X 1 has the same meaning as above.] and a halide (VII) represented by magnesium or magnesium activated with a magnesium activator; optionally LiCl, to produce the Grignard reagent (IIIa) or (IIIb); or (W2b) the halide (VII), The following formula (VIII): [ka] [In the formula, i Pr represents an isopropyl group. a Grignard reagent (VIII) represented by The method according to any one of [1B] to [7B], further comprising a step of producing the Grignard reagent (IIIb) by contacting [9B] The method comprises the step (W2a), [8B], wherein in the step (W2a), LiCl is dissolved in an organic solvent to prepare a LiCl solution, and then the halide (VII), the magnesium or magnesium activated with a magnesium activator, and the LiCl solution are brought into contact with each other to prepare the Grignard reagent (IIIb). [10B] The step (S2) comprises the following steps: (S2a) preparing a fifth mixture containing the compound (II-1), magnesium or magnesium activated with a magnesium activator, and optionally LiCl; and (S2b) combining the fifth mixture with a compound of the following formula (VII): [ka] [In the formula, R 2 and X 1 has the same meaning as above.] a step of producing the compound (I-1) by contacting the compound (VII) with a halide (VII) represented by the following formula: The method according to any one of [1B] to [7B], comprising: [11B] The step (S2) comprises the following steps: (S2c) The compound (II-1) and the compound of the following formula (VII): [ka] [In the formula, R 2 and X 1 has the same meaning as above.] and a halide (VII) represented by the formula: (S2d) combining the sixth mixture with a compound of the following formula (VIII): [ka] [In the formula, i Pr represents an isopropyl group. a step of producing the compound (I-1) by contacting the compound (I-1) with a Grignard reagent (VIII) represented by the following formula: The method according to any one of [1B] to [7B], comprising:

[0011] The third aspect of the present invention includes the following inventions. [1C] Formula (IIIb): [ka] [In the formula, R 2 represents an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted arylalkyl group, or an optionally substituted arylalkenyl group, X 1 represents a halogen atom. A method for producing a Grignard reagent (IIIb) represented by The following formula (VII): [ka] [In the formula, R 2 and X 1 has the same meaning as above.] and a halide (VII) represented by The following formula (VIII): [ka] [In the formula, i Pr represents an isopropyl group. a Grignard reagent (VIII) represented by to produce the Grignard reagent (IIIb). [Effects of the Invention]

[0012] In a first aspect of the present invention, by contacting compound (II) with Grignard reagent (III) in the presence of a catalytic amount of a copper salt selected from CuCN and CuCl at a temperature of -10 to 50°C, the regioselectivity and rate of the reaction can be increased, thereby improving the yield of the ketone derivative represented by formula (I) under mild reaction conditions that do not require low temperatures. In a second aspect of the present invention, by contacting compound (II-1) with Grignard reagent (III) in the absence of a copper salt, the yield of the ketone derivative represented by formula (I-1) can be improved under mild reaction conditions that do not require low temperatures. DETAILED DESCRIPTION OF THE INVENTION

[0013] The present invention will be described below. When two or more embodiments described herein can be combined, the combination of two or more embodiments is also encompassed in the present invention.

[0014] <Terminology> The terms used in this specification are explained below. The following explanations apply throughout this specification unless otherwise specified. The expression "value A to value B" means value A or more and value B or less unless otherwise specified.

[0015] organic solvents Examples of organic solvents include nitrile solvents such as acetonitrile and propionitrile; ether solvents such as tetrahydrofuran, 2-methyl-tetrahydrofuran, cyclopentyl methyl ether, dibutyl ether, 1,4-dioxane, tert-butyl methyl ether, diisopropyl ether, dimethoxyethane, and diglyme; ketone solvents such as acetone, methyl ethyl ketone, and diethyl ketone; ester solvents such as methyl acetate, ethyl acetate, and butyl acetate; halogenated hydrocarbon solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and chlorobenzene; aromatic hydrocarbon solvents such as toluene and xylene; and aliphatic hydrocarbon solvents such as hexane and heptane.

[0016] halogen atoms The halogen atom is selected from a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

[0017] Alkyl group The alkyl group has, for example, 1 to 50, preferably 1 to 20, more preferably 1 to 15, and even more preferably 1 to 12 (e.g., 1 to 10, 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2). The alkyl group may be linear or branched. A linear alkyl group has 1 or more carbon atoms, and a branched alkyl group has 3 or more carbon atoms.

[0018] Alkenyl group The alkenyl group has, for example, 2 to 50 carbon atoms, preferably 2 to 20 carbon atoms, more preferably 2 to 15 carbon atoms, and even more preferably 2 to 12 carbon atoms (e.g., 2 to 10, 2 to 8, 2 to 6, 2 to 5, 2 to 4, or 2 to 3 carbon atoms). The alkenyl group may be linear or branched. A linear alkenyl group has 2 or more carbon atoms, and a branched alkenyl group has 3 or more carbon atoms.

[0019] cycloalkyl group The cycloalkyl group has, for example, 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms.

[0020] Heterocycloalkyl Groups A heterocycloalkyl group is a monocyclic saturated aliphatic heterocyclic group containing, in addition to carbon atoms, one or more heteroatoms independently selected from the group consisting of oxygen, sulfur, and nitrogen atoms as ring-constituting atoms. A saturated aliphatic heterocyclic group is an aliphatic heterocyclic group whose ring is formed solely by saturated bonds. The number of heteroatoms is, for example, 1 to 4, preferably 1 to 3, and more preferably 1 or 2. The number of members of a heterocycloalkyl group is, for example, 3 to 8, preferably 4 to 7, more preferably 5 to 7, and even more preferably 5 or 6. Examples of heterocycloalkyl groups include those containing 1 to 2 oxygen atoms, those containing 1 to 2 sulfur atoms, those containing 1 to 2 oxygen atoms and 1 to 2 sulfur atoms, those containing 1 to 4 nitrogen atoms, and those containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and / or 1 to 2 oxygen atoms. Preferably, a heterocycloalkyl group contains an oxygen atom as a heteroatom. Examples of heterocycloalkyl groups include aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl (the sulfur atom on the ring may be oxidized), azepanyl, diazepanyl, oxepanyl, azocanyl, and diazocanyl groups.

[0021] In one embodiment, heterocycloalkyl groups are selected from tetrahydrofuranyl and tetrahydropyranyl groups.

[0022] In one embodiment, the heterocycloalkyl group is a tetrahydrofuranyl group.

[0023] aryl group The aryl group is, for example, a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic hydrocarbon ring group having 4 to 14 carbon atoms, preferably 6 to 14, and more preferably 6 to 10. The polycyclic group is preferably a fused ring group. Examples of the aryl group include a phenyl group and a naphthyl group.

[0024] In one embodiment, the aryl group is a phenyl group.

[0025] Heteroaryl Groups A heteroaryl group is a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic heterocyclic group containing, in addition to carbon atoms, one or more heteroatoms independently selected from the group consisting of oxygen, sulfur, and nitrogen atoms as ring-constituting atoms. The polycyclic group is preferably a fused ring group. The number of heteroatoms is, for example, 1 to 4, preferably 1 to 3, and more preferably 1 or 2. The number of members in the heteroaryl group is preferably 4 to 14, more preferably 5 to 10. Examples of heteroaryl groups include those containing 1 to 2 oxygen atoms, those containing 1 to 2 sulfur atoms, those containing 1 to 2 oxygen atoms and 1 to 2 sulfur atoms, those containing 1 to 4 nitrogen atoms, and those containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and / or 1 to 2 oxygen atoms. The heteroaryl group is preferably a monocyclic or bicyclic 4 to 10-membered, preferably 5 to 10-membered, aromatic heterocyclic group.

[0026] Examples of the monocyclic aromatic heterocyclic group include 5- to 7-membered monocyclic aromatic heterocyclic groups such as a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a thienyl group, a pyrrolyl group, a thiazolyl group, an isothiazolyl group, a pyrazolyl group, an imidazolyl group, a furyl group, an oxazolyl group, an isoxazolyl group, an oxadiazolyl group (e.g., a 1,2,4-oxadiazolyl group, a 1,3,4-oxadiazolyl group, etc.), a thiadiazolyl group (e.g., a 1,2,4-thiadiazolyl group, a 1,3,4-thiadiazolyl group, etc.), a triazolyl group (e.g., a 1,2,3-triazolyl group, a 1,2,4-triazolyl group, etc.), a tetrazolyl group, and a triazinyl group.

[0027] Examples of the fused polycyclic aromatic heterocyclic group include a benzothiophenyl group, a benzofuranyl group, a benzimidazolyl group, a benzoxazolyl group, a benzisoxazolyl group, a benzothiazolyl group, a benzisothiazolyl group, a benzotriazolyl group, an imidazopyridinyl group, a thienopyridinyl group, a furopyridinyl group, a pyrrolopyridinyl group, a pyrazolopyridinyl group, an oxazolopyridinyl group, a thiazolopyridinyl group, an imidazopyrazinyl group, an imidazopyrimidinyl group, a thienopyrimidinyl group, a furopyrimidinyl group, a pyrrolopyrimidinyl group, a pyrazolopyrimidinyl group, an oxazolo Examples of the aromatic heterocyclic group include 8- to 14-membered fused polycyclic (preferably bicyclic or tricyclic) aromatic heterocyclic groups such as a pyrimidinyl group, a thiazolopyrimidinyl group, a pyrazolotriazinyl group, a naphtho[2,3-b]thienyl group, a phenoxathiinyl group, an indolyl group, an isoindolyl group, a 1H-indazolyl group, a purinyl group, an isoquinolyl group, a quinolyl group, a phthalazinyl group, a naphthyridinyl group, a quinoxalinyl group, a quinazolinyl group, a cinnolinyl group, a carbazolyl group, an α-carbolinyl group, a phenanthridinyl group, an acridinyl group, a phenazinyl group, a phenothiazinyl group, and a phenoxazinyl group.

[0028] In one embodiment, the heteroaryl group is selected from a thienyl group, a benzothiophenyl group, a furyl group, a pyrrolyl group, an imidazolyl group, and a pyridyl group.

[0029] In one embodiment, the heteroaryl group is selected from a thienyl group and a benzothiophenyl group.

[0030] Haloalkyl, haloaryl and haloheteroaryl groups The haloalkyl group, haloaryl group, and haloheteroaryl group are alkyl groups, aryl groups, and heteroaryl groups, respectively, having one or more halogen atoms, and the alkyl groups, aryl groups, and heteroaryl groups are as described above. The number of halogen atoms in the haloalkyl group, haloaryl group, or haloheteroaryl group is, for example, 1 to 3, preferably 1 or 2, and more preferably 1.

[0031] Alkylene, arylene and heteroarylene groups An alkylene group, an arylene group, and a heteroarylene group are divalent functional groups formed by removing one hydrogen atom from an alkyl group, an aryl group, and a heteroaryl group, respectively, and the alkyl group, the aryl group, and the heteroaryl group are as described above.

[0032] Haloalkylene, haloarylene, and haloheteroarylene groups A haloalkylene group, a haloarylene group, and a haloheteroarylene group are divalent functional groups formed by removing one hydrogen atom from a haloalkyl group, a haloaryl group, and a haloheteroaryl group, respectively. The haloalkyl group, the haloaryl group, and the haloheteroaryl group are as described above.

[0033] Arylalkyl group The arylalkyl group is an alkyl group having one or more aryl groups, and the explanations regarding the alkyl group and aryl group are as above. The number of aryl groups in the arylalkyl group is, for example, 1 to 3, preferably 1 or 2, and more preferably 1.

[0034] arylalkenyl group The arylalkenyl group is an alkenyl group having one or more aryl groups, and the explanations regarding alkenyl groups and aryl groups are as described above. The number of aryl groups in the arylalkenyl group is, for example, 1 to 3, preferably 1 or 2, and more preferably 1.

[0035] Alkylcarbonyl and arylcarbonyl groups The alkylcarbonyl group and the arylcarbonyl group are groups represented by the formula: -CO-alkyl group and the formula: -CO-aryl group, respectively, and the alkyl group and the aryl group are as described above.

[0036] Alkyloxy groups, haloalkyloxy groups, heterocycloalkyloxy groups, and arylalkyloxy groups The alkyloxy group, haloalkyloxy group, heterocycloalkyloxy group, and arylalkyloxy group are groups represented by the formula: -O-alkyl group, the formula: -O-haloalkyl group, the formula: -O-heterocycloalkyl group, and the formula: -O-arylalkyl group, respectively, and the alkyl group, haloalkyl group, heterocycloalkyl group, and arylalkyl group are as described above.

[0037] Alkylthio groups, haloalkylthio groups, heterocycloalkylthio groups, and arylalkylthio groups The alkylthio group, haloalkylthio group, heterocycloalkylthio group, and arylalkylthio group are groups represented by the formula: -S-alkyl group, the formula: -S-haloalkyl group, the formula: -S-heterocycloalkyl group, and the formula: -S-arylalkyl group, respectively, and the alkyl group, haloalkyl group, heterocycloalkyl group, and arylalkyl group are as described above.

[0038] Alkyloxycarbonyl group The alkyloxycarbonyl group is a group represented by the formula: -CO-O-alkyl, and the explanation regarding the alkyl group is as above. The number of carbon atoms in the alkyloxycarbonyl group is preferably 1 to 10, more preferably 1 to 8, even more preferably 1 to 6, even more preferably 1 to 4, even more preferably 1 to 3, and even more preferably 1 or 2.

[0039] amino group The amino group is a group represented by the formula: -NH2 (primary amino group).

[0040] Monoalkylamino group A monoalkylamino group has the formula: -NH(-Q 1 )[where, Q 1 represents an alkyl group.], and the explanation regarding the alkyl group is as above. Q 1The alkyl group represented by the formula (I) preferably has 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms, even more preferably 1 to 6 carbon atoms, even more preferably 1 to 4 carbon atoms, even more preferably 1 to 3 carbon atoms, and even more preferably 1 or 2 carbon atoms.

[0041] Dialkylamino group Dialkylamino groups have the formula: -N(-Q 2 )(-Q 3 )[where, Q 2 and Q 3 Each of Q independently represents an alkyl group. ], and the alkyl group is as described above. 2 or Q 3 The alkyl group represented by the formula (I) preferably has 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms, even more preferably 1 to 6 carbon atoms, even more preferably 1 to 4 carbon atoms, even more preferably 1 to 3 carbon atoms, and even more preferably 1 or 2 carbon atoms.

[0042] Alicyclic amino group The alicyclic amino group is, for example, a 5- or 6-membered ring alicyclic amino group, and examples of the 5- or 6-membered ring alicyclic amino group include a morpholino group, a thiomorpholino group, a pyrrolidin-1-yl group, a pyrazolidin-1-yl group, an imidazolidin-1-yl group, a piperidin-1-yl group, etc. The alicyclic amino group may contain, in addition to the nitrogen atom having the bond of the alicyclic amino group, a heteroatom (for example, one heteroatom) independently selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom.

[0043] In one embodiment, the alicyclic amino group is a morpholino group.

[0044] Aminocarbonyl group, monoalkylaminocarbonyl group, dialkylaminocarbonyl group and alicyclic aminocarbonyl group The aminocarbonyl group, monoalkylaminocarbonyl group, dialkylaminocarbonyl group, and alicyclic aminocarbonyl group are groups represented by the formula: -CO-amino group, -CO-monoalkylamino group, -CO-dialkylamino group, and -CO-alicyclic amino group, respectively, and the explanations for the monoalkylamino group, dialkylamino group, and alicyclic amino group are as described above.

[0045] substituent The phrase "optionally having a substituent" means that the group may have one or more substituents. One or more substituents preferably means 1 to 3 substituents, more preferably 1 or 2 substituents.

[0046] Substituent group α Substituent group α is composed of the following substituents. (α-1) halogen atom (α-2) nitrile group (α-3) nitro group (α-4) amino group (α-5) alkyl group (α-6) haloalkyl group (α-7) monoalkylamino group (α-8) dialkylamino group (α-9) Alicyclic amino group (α-10) alkyloxycarbonyl group (α-11) aminocarbonyl group (α-12) monoalkylaminocarbonyl group (α-13) Dialkylaminocarbonyl group (α-14) Alicyclic aminocarbonyl group (α-15) A hydroxy group which may be protected by a protecting group (α-16) A thiol group which may be protected by a protecting group

[0047] Substituent group β The substituent group β is composed of the following substituents. (β-1) Substituent represented by formula (i) (β-2) Substituent represented by formula (ii)

[0048] The substituent groups α and β will be described below.

[0049] In (α-5), the alkyl group preferably has 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms, even more preferably 1 to 6 carbon atoms, even more preferably 1 to 4 carbon atoms, even more preferably 1 to 3 carbon atoms, and even more preferably 1 or 2 carbon atoms.

[0050] In (α-6), the number of carbon atoms in the haloalkyl group is preferably 1 to 10, more preferably 1 to 8, even more preferably 1 to 6, even more preferably 1 to 4, even more preferably 1 to 3, and even more preferably 1 or 2. The number of halogen atoms in the haloalkyl group is preferably 1 to 3, more preferably 1 or 2, and even more preferably 1.

[0051] (α-15) A hydroxy group which may be protected by a protecting group The hydroxy-protecting group is preferably one that can protect the hydroxy group during the target reaction and can be cleaved from the hydroxy group after the target reaction is completed. Examples of the hydroxy-protecting group include alkylcarbonyl-type protecting groups, arylcarbonyl-type protecting groups, arylalkyl-type protecting groups, alkyl-type protecting groups, arylalkyloxyalkyl-type protecting groups, alkyloxyalkyl-type protecting groups, silyl-type protecting groups, oxycarbonyl-type protecting groups, acetal-type protecting groups, and aryl-type protecting groups. These protecting groups may have one or more halogen atoms.

[0052] Examples of alkylcarbonyl-type protecting groups include alkylcarbonyl groups having 2 to 10 carbon atoms, which may have one or more substituents. The substituents may be selected from, for example, a halogen atom, a nitro group, a cyano group, a phenyl group, an alkyl group having 1 to 10 carbon atoms (preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms), an alkyloxy group having 1 to 10 carbon atoms (preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms), and an alkyloxycarbonyl group having 2 to 11 carbon atoms (preferably 2 to 9 carbon atoms, more preferably 2 to 7 carbon atoms, and even more preferably 2 to 5 carbon atoms). Examples of alkylcarbonyl groups having 2 to 10 carbon atoms, which may have one or more substituents, include an acetyl group, a propanoyl group, a butanoyl group, an isopropanoyl group, and a pivaloyl group. The alkylcarbonyl-type protecting group is preferably an alkylcarbonyl group having 2 to 5 carbon atoms, more preferably an acetyl group or a pivaloyl group, and even more preferably an acetyl group.

[0053] Examples of arylcarbonyl-type protecting groups include arylcarbonyl groups having 7 to 11 carbon atoms which may have one or more substituents. Specific examples of the substituents are the same as those of the alkylcarbonyl-type protecting groups. Examples of arylcarbonyl groups having 7 to 11 carbon atoms which may have one or more substituents include benzoyl, 4-nitrobenzoyl, 4-methyloxybenzoyl, 4-methylbenzoyl, 4-tert-butylbenzoyl, 4-fluorobenzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-phenylbenzoyl, and 4-methyloxycarbonylbenzoyl groups.

[0054] Examples of arylalkyl-type protecting groups include arylalkyl groups having 7 to 11 carbon atoms which may have one or more substituents. Specific examples of the substituents are the same as those of the alkylcarbonyl-type protecting group. Examples of arylalkyl groups having 7 to 11 carbon atoms which may have one or more substituents include benzyl, 1-phenylethyl, diphenylmethyl, 1,1-diphenylethyl, naphthylmethyl, and trityl. The arylalkyl-type protecting group is preferably a benzyl group.

[0055] Examples of alkyl-type protecting groups include alkyl groups having 1 to 10 carbon atoms which may have one or more substituents. Specific examples of the substituents are the same as those of the alkylcarbonyl-type protecting group. The alkyl-type protecting group is preferably an alkyl group having 1 to 5 carbon atoms which may have one or more substituents, more preferably a methyl group, an ethyl group, or a tert-butyl group, and even more preferably a methyl group.

[0056] Examples of the arylalkyloxyalkyl protecting group include arylalkyloxyalkyl groups such as an arylalkyloxymethyl group having 8 to 12 carbon atoms which may have one or more substituents, an arylalkyloxyethyl group having 9 to 13 carbon atoms which may have one or more substituents, and an arylalkyloxypropyl group having 10 to 14 carbon atoms which may have one or more substituents. Specific examples of the substituent are the same as those of the alkylcarbonyl protecting group. Examples of the arylalkyloxyalkyl protecting group include a benzyloxymethyl group which may have one or more substituents, preferably a benzyloxymethyl group which may be substituted with a halogen atom, a nitro group, a cyano group, a methyl group, or a methyloxy group, and more preferably a benzyloxymethyl group.

[0057] Examples of the alkyloxyalkyl-type protecting group include alkyloxyalkyl groups such as an alkyloxymethyl group having 2 to 10 carbon atoms which may have one or more substituents, an alkyloxyethyl group having 3 to 10 carbon atoms which may have one or more substituents, and an alkyloxypropyl group having 4 to 10 carbon atoms which may have one or more substituents. Specific examples of the substituent are the same as those of the alkylcarbonyl-type protecting group. The alkyloxyalkyl-type protecting group is preferably an alkyloxymethyl group having 2 to 10 carbon atoms which may have one or more substituents, more preferably an alkyloxymethyl group having 2 to 6 carbon atoms which may have a halogen atom, a nitro group, a cyano group, a methyloxy group, or an ethyloxy group, and even more preferably a methyloxymethyl group.

[0058] Examples of silyl-type protecting groups include silyl groups having a functional group selected from an alkyl group having 1 to 10 carbon atoms, which may have one or more substituents, an arylalkyl group having 7 to 11 carbon atoms, which may have one or more substituents, and an aryl group having 6 to 10 carbon atoms, which may have one or more substituents. Specific examples of the substituent are the same as those of the alkylcarbonyl-type protecting group. The silyl-type protecting group is preferably a silyl group having a functional group selected from an alkyl group having 1 to 10 carbon atoms and an aryl group having 6 to 10 carbon atoms, more preferably a silyl group having a functional group selected from an alkyl group having 1 to 5 carbon atoms and a phenyl group, and even more preferably a trimethylsilyl group (TMS), a triethylsilyl group (TES), a tert-butyldimethylsilyl group (TBS), or a tert-butyldiphenylsilyl group (TBDPS).

[0059] In one embodiment, the silyl-type protecting group is an alkylsilyl group which may have one or more substituents. The alkylsilyl group which may have one or more substituents is represented by the formula: -Si-R c (-R d )(-R e ) is a group represented by R c , R d and R eeach independently represents an alkyl group which may have one or more substituents or an aryl group which may have one or more substituents, and R c , R d and R e One or more (1, 2 or 3) of these groups represent an alkyl group which may have one or more substituents. The alkyl group and aryl group have the same meaning as above. The alkyl group preferably has 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. The alkyl group and aryl group may each have one or more substituents. The number of substituents which the alkyl group and aryl group may each have is preferably 1 to 3, more preferably 1 or 2. Specific examples of substituents which the alkyl group and aryl group may each have are the same as those for the alkylcarbonyl-type protecting group.

[0060] Examples of the alkylsilyl group include monoalkylsilyl groups such as t-butyldiphenylsilyl group (TBDPS) and methyldiphenylsilyl group (MDPS); dialkylsilyl groups such as dimethylphenylsilyl group; and trialkylsilyl groups such as trimethylsilyl group (TMS), triethylsilyl group (TES), dimethylisopropylsilyl group (IPDMS), diethylisopropylsilyl group (DEIPS), dimethylthexylsilyl group (TDS), t-butyldimethylsilyl group (TBS), triisopropylsilyl group (TIPS), and di-t-butylmethylsilyl group (DTBMS).

[0061] In one embodiment, the silyl-type protecting group is a trialkylsilyl group.

[0062] In one embodiment, the silyl-type protecting group is TMS or TBS.

[0063] Examples of oxycarbonyl-type protecting groups include alkyloxycarbonyl groups having 2 to 10 carbon atoms, which may have one or more substituents, alkenyloxycarbonyl groups having 3 to 10 carbon atoms, which may have one or more substituents, and arylalkyloxycarbonyl groups having 8 to 12 carbon atoms, which may have one or more substituents. Specific examples of the substituent are the same as those of the alkylcarbonyl-type protecting group. The oxycarbonyl-type protecting group is preferably an alkyloxycarbonyl group having 2 to 6 carbon atoms, an alkenyloxycarbonyl group having 3 to 6 carbon atoms, or a benzyloxycarbonyl group, more preferably a methyloxymethyl group, an allyloxycarbonyl group, or a benzyloxycarbonyl group.

[0064] Examples of the acetal-type protecting group include a tetrahydrofuranyl group and a tetrahydropyranyl group.

[0065] The aryl-type protecting group includes, for example, an aryl group such as a phenyl group.

[0066] The hydroxy group protected with a protecting group is preferably a group represented by the formula: -OQ. Q represents an alkyl group, a haloalkyl group, an aryl group, a haloaryl group, a heterocycloalkyl group, an alkylcarbonyl group, an arylcarbonyl group, an arylalkyl group, or an alkylsilyl group. The group represented by the formula: -OQ preferably has 1 to 10 carbon atoms, more preferably 1 to 8. Q is preferably an alkyl group, a heterocycloalkyl group, an alkylcarbonyl group, an arylalkyl group, or an alkylsilyl group, and more preferably an ethyl group, a tetrahydrofuranyl group, an acetyl group, a benzyl group, or a trialkylsilyl group.

[0067] (α-16) A thiol group which may be protected by a protecting group The thiol group-protecting group is preferably one that can protect the thiol group during the target reaction and can be detached from the thiol group after the target reaction is completed. Examples of the thiol group-protecting group include alkylcarbonyl-type protecting groups, arylcarbonyl-type protecting groups, arylalkyl-type protecting groups, alkyl-type protecting groups, arylalkyloxyalkyl-type protecting groups, alkyloxyalkyl-type protecting groups, silyl-type protecting groups, oxycarbonyl-type protecting groups, acetal-type protecting groups, and aryl-type protecting groups. These protecting groups may have one or more halogen atoms. The explanation of these protecting groups is as above.

[0068] The thiol group protected with a protecting group is preferably a group represented by the formula: -SQ, where Q is as described above.

[0069] (β-1) Substituent represented by formula (i) [ka]

[0070] In formula (i), R 11 , R 12 and R 13 each independently represents an alkyl group, a haloalkyl group, an aryl group, a haloaryl group, or a hydroxy group which may be protected by a protecting group. The hydroxy group which may be protected by a protecting group is preferably a group represented by the above formula: -OQ. a is 0 or more and 3 or less.

[0071] (β-2) Substituent represented by formula (ii) [ka]

[0072] In formula (ii), V 10represents an alkylene group, a haloalkylene group, an arylene group, a haloarylene group, a heteroarylene group, a haloheteroarylene group, an ester bond, an ether bond, or a carbonyl group. The alkylene group and the haloalkylene group each preferably have 1 to 10 carbon atoms, and more preferably have 1 to 8 carbon atoms. The arylene group and the haloarylene group each preferably have 4 to 14 carbon atoms, and more preferably have 6 to 14 carbon atoms. The heteroarylene group and the haloheteroarylene group each preferably have 4 to 14 carbon atoms. V 10 is preferably an alkylene group, more preferably a methylene group or an ethylene group.

[0073] In formula (ii), b represents 0 or 1.

[0074] In one embodiment, b is 0.

[0075] In one embodiment, b is 1.

[0076] In formula (ii), W 10 represents an alkylene group, a haloalkylene group, an arylene group, a haloarylene group, a heteroarylene group, a haloheteroarylene group, an ester bond, an ether bond, or a carbonyl group.

[0077] In one embodiment, W 10 is a heteroarylene group.

[0078] In one embodiment, W 10 is a five-membered heteroarylene group containing a sulfur atom as the heteroatom.

[0079] In one embodiment, W 10 is thienylene.

[0080] In formula (ii), c represents 0 or 1.

[0081] In one embodiment, c is 0.

[0082] In one embodiment, c is 1.

[0083] In formula (ii), X 10 represents a hydrogen atom, an alkyl group which may have a substituent, an aryl group which may have a substituent, or a heteroaryl group which may have a substituent. The alkyl group, aryl group, and heteroaryl group may each be unsubstituted or may have one or more substituents. The number of substituents which the alkyl group, aryl group, and heteroaryl group may each have is preferably 1 to 3, and more preferably 1 or 2. The one or more substituents may each be independently selected from substituent group α.

[0084] In one embodiment, the one or more substituents are each independently selected from a halogen atom, an alkyl group, a haloalkyl group, an alkyloxy group, a haloalkyloxy group, an alkylthio group, a haloalkylthio group, a heterocycloalkyloxy group, and a heterocycloalkylthio group.

[0085] In one embodiment, the one or more substituents are selected from a halogen atom, an alkyl group having 1 to 3 carbon atoms, an alkyloxy group having 1 to 3 carbon atoms, and a heterocycloalkyloxy group.

[0086] In one embodiment, the one or more substituents are selected from fluorine atoms, ethyloxy groups, and tetrahydrofuranyloxy groups.

[0087] In one embodiment, X 10 is an aryl group which may have a substituent or a heteroaryl group which may have a substituent.

[0088] In one embodiment, X 10 is an aryl group having a halogen atom, an alkyl group having 1 to 3 carbon atoms, an alkyloxy group or heterocycloalkyloxy group having 1 to 3 carbon atoms, or an unsubstituted heteroaryl group.

[0089] In one embodiment, X10 is a phenyl group having a fluorine atom, an ethyl group, an ethyloxy group or a tetrahydrofuranyloxy group, or an unsubstituted benzothiophenyl group.

[0090] ≪Compound (I)≫ Compound (I) is represented by the following formula (I): Compound (I) is a ketone derivative.

[0091] [ka]

[0092] In formula (I), R 1 and R 2 are each independently (1) an alkyl group which may have a substituent; (2) an alkenyl group which may have a substituent, (3) an optionally substituted cycloalkyl group, (4) an optionally substituted heterocycloalkyl group, (5) an optionally substituted aryl group, (6) an optionally substituted heteroaryl group, (7) an arylalkyl group which may have a substituent, or (8) An arylalkenyl group which may have a substituent Represents.

[0093] The functional groups (1) to (8) will be explained below.

[0094] (1) an alkyl group which may have a substituent The alkyl group is as described above. The alkyl group may be unsubstituted or may have one or more substituents. The number of substituents is preferably 1 to 3, more preferably 1 or 2. The one or more substituents may be independently selected from substituent groups α and β. One or more substituents may be selected from substituent group α, and one or more substituents may be selected from substituent group β.

[0095] (2) an alkenyl group which may have a substituent The alkenyl group has been described above. The alkenyl group may be unsubstituted or may have one or more substituents. The number of substituents is preferably 1 to 3, more preferably 1 or 2. The one or more substituents may be independently selected from substituent groups α and β. One or more substituents may be selected from substituent group α, and one or more substituents may be selected from substituent group β.

[0096] (3) an optionally substituted cycloalkyl group The cycloalkyl group is as described above. The cycloalkyl group may be unsubstituted or may have one or more substituents. The number of substituents is preferably 1 to 3, more preferably 1 or 2. The one or more substituents may be independently selected from substituent groups α and β. One or more substituents may be selected from substituent group α, and one or more substituents may be selected from substituent group β.

[0097] (4) an optionally substituted heterocycloalkyl group The heterocycloalkyl group is as described above. The heterocycloalkyl group may be unsubstituted or may have one or more substituents. The number of substituents is preferably 1 to 3, more preferably 1 or 2. The one or more substituents may be independently selected from substituent groups α and β. One or more substituents may be selected from substituent group α, and one or more substituents may be selected from substituent group β.

[0098] (5) an optionally substituted aryl group The aryl group has been described above. The aryl group may be unsubstituted or may have one or more substituents. The number of substituents is preferably 1 to 3, more preferably 1 or 2. The one or more substituents may be independently selected from substituent groups α and β. One or more substituents may be selected from substituent group α, and one or more substituents may be selected from substituent group β.

[0099] (6) Optionally substituted heteroaryl group The heteroaryl group is as described above. The heteroaryl group may be unsubstituted or may have one or more substituents. The number of substituents is preferably 1 to 3, more preferably 1 or 2. The one or more substituents may be independently selected from substituent groups α and β. One or more substituents may be selected from substituent group α, and one or more substituents may be selected from substituent group β.

[0100] (7) An arylalkyl group which may have a substituent The arylalkyl group has been described above. The arylalkyl group may be unsubstituted or may have one or more substituents. The number of substituents is preferably 1 to 3, more preferably 1 or 2. The one or more substituents may be independently selected from substituent groups α and β. One or more substituents may be selected from substituent group α, and one or more substituents may be selected from substituent group β.

[0101] (8) An arylalkenyl group which may have a substituent The arylalkenyl group has been described above. The arylalkenyl group may be unsubstituted or may have one or more substituents. The number of substituents is preferably 1 to 3, more preferably 1 or 2. The one or more substituents may be independently selected from substituent groups α and β. One or more substituents may be selected from substituent group α, and one or more substituents may be selected from substituent group β.

[0102] In the functional group (5), the carbon atoms located on both sides of the carbon atom having the bond of the aryl group (i.e., the carbon atom bonded to -CO- in formula (I)) preferably have no substituents. The remaining carbon atoms may have substituents.

[0103] In the functional group (6), the carbon atoms or heteroatoms located on both sides of the carbon atom having a bond of the heteroaryl group (i.e., the carbon atom bonding to -CO- in formula (I)) preferably have no substituents. The remaining carbon atoms or heteroatoms may have substituents.

[0104] In one embodiment, R 1 is the functional group (1), and R 2 R is any one of the functional groups (1) to (8). 1 and R 2 When both are functional groups (1), R 1 and R 2 may be the same or different.

[0105] In one embodiment, R 1 is the functional group (2), and R 2 R is any one of the functional groups (1) to (8). 1 and R 2 When both are functional groups (2), R 1 and R 2 may be the same or different.

[0106] In one embodiment, R 1 is the functional group (3), and R 2 R is any one of the functional groups (1) to (8). 1 and R 2 When both are functional groups (3), R 1 and R 2 may be the same or different.

[0107] In one embodiment, R 1 is the functional group (4), and R 2 R is any one of the functional groups (1) to (8). 1 and R 2 When both are functional groups (4), R 1 and R 2 may be the same or different.

[0108] In one embodiment, R 1 is the functional group (5), and R 2 R is any one of the functional groups (1) to (8). 1 and R 2 When both are functional groups (5), R 1 and R2 may be the same or different.

[0109] In one embodiment, R 1 is the functional group (6), and R 2 is any one of the functional groups (1) to (8). 1 and R 2 When both are functional groups (6), R 1 and R 2 may be the same or different.

[0110] In one embodiment, R 1 is the functional group (7), and R 2 is any one of the functional groups (1) to (8). 1 and R 2 When both are functional groups (7), R 1 and R 2 may be the same or different.

[0111] In one embodiment, R 1 is the functional group (8), and R 2 is any one of the functional groups (1) to (8). 1 and R 2 When both are functional groups (8), R 1 and R 2 may be the same or different.

[0112] In one embodiment, R 1 is an alkyl group which may have a substituent, preferably an alkyl group having 1 to 20 carbon atoms which may have a substituent, more preferably an alkyl group having 1 to 16 carbon atoms which may have a substituent, and even more preferably an alkyl group having 1 to 12 carbon atoms which may have a substituent.

[0113] In one embodiment, R 2 is a functional group represented by the following formula (iv):

[0114] In one embodiment, R 1is an alkyl group which may have a substituent, preferably an alkyl group having 1 to 20 carbon atoms which may have a substituent, more preferably an alkyl group having 1 to 16 carbon atoms which may have a substituent, and even more preferably an alkyl group having 1 to 12 carbon atoms which may have a substituent, and R 2 is a functional group represented by the following formula (iv):

[0115] [ka]

[0116] In formula (iv), Y 10 represents an alkylene group which may have a substituent, an arylene group which may have a substituent, or a heteroarylene group which may have a substituent. The alkylene group preferably has 1 to 10 carbon atoms, and more preferably 1 to 8 carbon atoms. The arylene group preferably has 4 to 14 carbon atoms, and more preferably 6 to 14 carbon atoms. The heteroarylene group preferably has 4 to 14 carbon atoms. The alkylene group, arylene group, and heteroarylene group may each be unsubstituted or may have one or more substituents. The one or more substituents may each independently be selected from substituent group α. The one or more substituents are preferably each independently selected from a halogen atom, an alkyl group, a haloalkyl group, an alkyloxy group, a haloalkyloxy group, an alkylthio group, a haloalkylthio group, and a hydroxy group which may be protected by a protecting group, and more preferably selected from a halogen atom, an alkyl group having 1 to 3 carbon atoms, an alkyloxy group having 1 to 3 carbon atoms, and a hydroxy group which may be protected by an alkylcarbonyl group (particularly an acetyl group) or an alkylsilyl group (particularly a trialkylsilyl group). The number of substituents which each of the alkylene group, arylene group, and heteroarylene group may have is preferably 1 to 3, and more preferably 1 or 2.

[0117] Y 10is preferably an arylene group having a substituent, more preferably an arylene group having a hydroxy group which may be protected by a halogen atom, an alkyl group having 1 to 3 carbon atoms, or an alkylcarbonyl group or an alkylsilyl group, and even more preferably a phenylene group having a hydroxy group which may be protected by a fluorine atom, a chlorine atom, a methyl group, or an acetyl group or a trialkylsilyl group (for example, TMS or TBS).

[0118] Y 10 is preferably an arylene group in which the carbon atoms on both sides of the carbon atom bonded to -CO- in formula (I) have no substituents and the remaining carbon atoms may have a substituent, or a heteroarylene group in which the carbon atoms or hetero atoms on both sides of the carbon atom bonded to -CO- in formula (I) have no substituents and the remaining carbon atoms or hetero atoms may have a substituent. 10 is more preferably a phenylene group which does not have a substituent at the ortho position relative to the carbon atom bonded to —CO— in formula (I) and which may have a substituent at the meta and / or para position.

[0119] In formula (iv), V 10 , W 10 , X 10 , b and c have the same meanings as in formula (ii).

[0120] In one embodiment, R 2 is a functional group represented by the following formula (vi):

[0121] In one embodiment, R 1 is an alkyl group which may have a substituent, preferably an alkyl group having 1 to 20 carbon atoms which may have a substituent, more preferably an alkyl group having 1 to 16 carbon atoms which may have a substituent, and even more preferably an alkyl group having 1 to 12 carbon atoms which may have a substituent, and R 2 is a functional group represented by the following formula (vi):

[0122] [ka]

[0123] In formula (vi), R 41 and R 42 R each independently represent a hydrogen atom or an amino-protecting group. The amino-protecting group may be any of carbamate, acyl, amide, sulfonamide, phthaloyl, and other protecting groups. Examples of carbamate-based protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, and allyloxycarbonyl. Examples of acyl-based protecting groups include acetyl, pivaloyl, and benzoyl. Examples of amide-based protecting groups include trifluoroacetyl. Examples of sulfonamide-based protecting groups include p-toluenesulfonyl and 2-nitrobenzenesulfonyl. The amino-protecting group is preferably an acyl- or amide-based protecting group. More preferably, the amino-protecting group is a pivaloyl or trifluoroacetyl group. R 41 and R 42 may be bonded to each other to form a protecting group for an amino group such as a phthaloyl group. 2 When compound (I) has the structure of formula (vi), compound (I) can be suitably used as an intermediate for remdesivir.

[0124] In one embodiment, R 2 is the same as a functional group possessed by an SGLT-2 inhibitor or an intermediate thereof, or is a functional group obtained by derivatizing a functional group possessed by an SGLT-2 inhibitor or an intermediate thereof. This allows compound (I) to be used as a raw material for producing an SGLT-2 inhibitor or a derivative thereof.

[0125] SGLT-2 inhibitors are useful as antidiabetic drugs. "SGLT-2" means sodium-glucose cotransporter-2. Examples of SGLT-2 inhibitors include canagliflozin (1-(β-D-glycopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene), empagliflozin ((1S)-1,5-anhydro-1-C-{4-chloro-3-[(4-{[(3S)-oxolan-3-yl]oxy}phenyl)methyl]phenyl}-D-glucitol), ipragliflozin ((1S)-1,5 -anhydro-1-C-{3-[(1-benzothiophen-2-yl)methyl]-4-fluorophenyl}-D-glucitol-(2S)-pyrrolidine-2-carboxylic acid), dapagliflozin ((2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethyloxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol), tofogliflozin, etc. are known.

[0126] SGLT-2 inhibitors such as canagliflozin, empagliflozin, ipragliflozin, dapagliflozin, and tofogliflozin, or intermediates thereof, have a functional group represented by the following formula (A).

[0127] In one embodiment, R 2 is a functional group represented by the following formula (A).

[0128] In one embodiment, R 1 is an alkyl group which may have a substituent, preferably an alkyl group having 1 to 20 carbon atoms which may have a substituent, more preferably an alkyl group having 1 to 16 carbon atoms which may have a substituent, and even more preferably an alkyl group having 1 to 12 carbon atoms which may have a substituent, and R 2 is a functional group represented by the following formula (A).

[0129] [ka]

[0130] In formula (A), d represents an integer of 0 to 4. d is preferably 1 to 3, more preferably 1 or 2, and even more preferably 1. When d is 2 or more, d R a may be the same or different.

[0131] In formula (A), d R a may each independently be selected from the substituent group α. a are each independently preferably selected from a halogen atom, an alkyl group, a haloalkyl group, an alkyloxy group, a haloalkyloxy group, an alkylthio group, a haloalkylthio group, and a hydroxy group which may be protected with a protecting group, and more preferably selected from a halogen atom, an alkyl group having 1 to 3 carbon atoms, an alkyloxy group having 1 to 3 carbon atoms, and a hydroxy group which may be protected with an alkylcarbonyl group (particularly an acetyl group) or an alkylsilyl group (particularly a trialkylsilyl group (e.g., TMS or TBS)).

[0132] In formula (A), Ar′ is a functional group represented by the following formula (v).

[0133] [ka]

[0134] In formula (v), W 10 , X 10 and c have the same meanings as in formula (ii).

[0135] In formula (A), Ar' is preferably a functional group represented by the following formula (Ar'-1), (Ar'-2) or (Ar'-3).

[0136] [ka]

[0137] In formulae (Ar'-1), (Ar'-2) and (Ar'-3), p is an integer of 0 to 5. p is preferably an integer of 0 to 3, more preferably an integer of 0 to 2, and even more preferably 0 or 1.

[0138] In formulae (Ar'-1), (Ar'-2) and (Ar'-3), p R b are each independently selected from Substituent Group α, an aryl group optionally having one or more substituents selected from Substituent Group α, and a heteroaryl group optionally having one or more substituents selected from Substituent Group α. b are preferably each independently selected from Substituent Group α and an aryl group optionally having one or more substituents selected from Substituent Group α. The one or more substituents selected from Substituent Group α are each independently preferably selected from a halogen atom, an alkyl group, a haloalkyl group, an alkyloxy group, a haloalkyloxy group, an alkylthio group, a haloalkylthio group, a heterocycloalkyloxy group, and a heterocycloalkylthio group, more preferably selected from a halogen atom, an alkyl group having 1 to 3 carbon atoms, an alkyloxy group having 1 to 3 carbon atoms, and a heterocycloalkyloxy group, and even more preferably selected from a fluorine atom, an ethyl group, an ethyloxy group, and a tetrahydrofuranyloxy group. The number of substituents that each of the aryl group and the heteroaryl group may have is preferably 1 to 3, and more preferably 1 or 2.

[0139] If p is 2 or more, p R b may be the same or different.

[0140] In formula (Ar'-1), p is preferably 1, and R bis preferably a phenyl group which may have a substituent, more preferably a phenyl group having a halogen atom, and even more preferably a phenyl group having a fluorine atom. The position to which the unsubstituted or substituted phenyl group is bonded is preferably the 2-position of the thiophene ring. In the phenyl group having a halogen atom, the position to which the halogen atom is bonded is preferably the 4-position of the benzene ring.

[0141] In formula (Ar'-2), p is preferably 0.

[0142] In formula (Ar'-3), p is preferably 1, and R b is preferably an alkyl group which may have a substituent, an alkyloxy group which may have a substituent, or a heterocycloalkyloxy group which may have a substituent. The alkyl group which may have a substituent is preferably an alkyl group having 1 to 3 carbon atoms, and more preferably an ethyl group. The alkyloxy group which may have a substituent is preferably an alkyloxy group having 1 to 3 carbon atoms, and more preferably a methoxy group or an ethoxy group. The heterocycloalkyloxy group which may have a substituent is preferably a tetrahydrofuranyloxy group. The position to which the alkyl group which may have a substituent, the alkyloxy group which may have a substituent, or the heterocycloalkyloxy group which may have a substituent is bonded is preferably the 4-position of the benzene ring.

[0143] When d=1, the functional group represented by formula (A) is preferably a functional group represented by the following formula (B) or (C).

[0144] In one embodiment, R 2 is a functional group represented by the following formula (B) or (C).

[0145] In one embodiment, R 1is an alkyl group which may have a substituent, preferably an alkyl group having 1 to 20 carbon atoms which may have a substituent, more preferably an alkyl group having 1 to 16 carbon atoms which may have a substituent, and even more preferably an alkyl group having 1 to 12 carbon atoms which may have a substituent, and R 2 is a functional group represented by the following formula (B) or (C).

[0146] [ka]

[0147] [ka]

[0148] In formulas (B) and (C), R a and Ar' have the same meaning as in formula (A).

[0149] In formula (B), R a is preferably selected from a halogen atom, an alkyl group, a haloalkyl group, an alkyloxy group, a haloalkyloxy group, an alkylthio group, and a haloalkylthio group, and more preferably selected from a halogen atom, an alkyl group having 1 to 3 carbon atoms, and an alkyloxy group having 1 to 3 carbon atoms.

[0150] In formula (C), R a is preferably selected from hydroxy groups which may be protected with a protecting group, more preferably selected from hydroxy groups which may be protected with an alkylcarbonyl group or an alkylsilyl group, and even more preferably selected from hydroxy groups which may be protected with an acetyl group or a trialkylsilyl group (e.g., TMS or TBS).

[0151] The functional group represented by formula (B) is preferably a functional group represented by the following formula (Ar-1), (Ar-2), (Ar-3) or (Ar-4), and the functional group represented by formula (C) is preferably a functional group represented by the following formula (Ar-5), where "Et" represents an ethyl group.

[0152] In one embodiment, R 2 is a functional group represented by the following formula (Ar-1), (Ar-2), (Ar-3), (Ar-4) or (Ar-5).

[0153] In one embodiment, R 1 is an alkyl group which may have a substituent, preferably an alkyl group having 1 to 20 carbon atoms which may have a substituent, more preferably an alkyl group having 1 to 16 carbon atoms which may have a substituent, and even more preferably an alkyl group having 1 to 12 carbon atoms which may have a substituent, and R 2 is a functional group represented by the following formula (Ar-1), (Ar-2), (Ar-3), (Ar-4) or (Ar-5).

[0154] [ka]

[0155] [ka]

[0156] In formula (Ar-5), R f represents a hydroxy group which may be protected with a protecting group. f is preferably a hydroxy group which may be protected with an alkylcarbonyl group or an alkylsilyl group, and more preferably a hydroxy group which may be protected with an acetyl group or a trialkylsilyl group (for example, TMS or TBS).

[0157] In one embodiment, compound (I) is compound (I-1) represented by the following formula (I-1).

[0158] [ka]

[0159] In formula (I-1), n ​​represents 1 or 2.

[0160] In formula (I-1), R each independently represents an alkyl group which may have a substituent or an aryl group which may have a substituent. The alkyl group and the aryl group have been described above. The alkyl group may be linear or branched, but is preferably linear. The alkyl group preferably has 1 to 10 carbon atoms, more preferably 1 to 8, even more preferably 1 to 6, even more preferably 1 to 4, and even more preferably 1 to 3 carbon atoms. The aryl group is preferably a phenyl group. The alkyl group and the aryl group may each be unsubstituted or may have one or more substituents. The number of substituents that the alkyl group and the aryl group may each have is preferably 1 to 3, more preferably 1 or 2. The one or more substituents may each be independently selected from substituent group α and β. One or more substituents may be selected from substituent group α, and one or more substituents may be selected from substituent group β. The one or more substituents are each preferably independently selected from a halogen atom, an alkyl group, a haloalkyl group, an alkyloxy group, a haloalkyloxy group, an alkylthio group, a haloalkylthio group, and a phenyl group, more preferably selected from a halogen atom, an alkyl group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms, a haloalkyloxy group having 1 to 4 carbon atoms, and a phenyl group, and even more preferably selected from a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms, and a phenyl group.

[0161] In formula (I-1), when n=1, the four Rs may be different from each other, but are preferably the same from the viewpoint of efficient introduction and removal of a hydroxy-protecting group represented by the formula: -CO-R. In one embodiment, all of the four Rs are methyl groups or phenyl groups.

[0162] In formula (I-1), when n=2, the five Rs may be different from each other, but are preferably the same from the viewpoint of efficient introduction and removal of the hydroxy-protecting group represented by the formula: -CO-R. In one embodiment, all of the five Rs are methyl groups or phenyl groups.

[0163] In one embodiment, compound (I-1) is compound (I-2) represented by the following formula (I-2):

[0164] [ka]

[0165] In formula (I-2), R has the same meaning as in formula (I-1).

[0166] In formula (I-2), the five R's may be different from each other, but are preferably the same from the viewpoint of efficient introduction and removal of the hydroxy-protecting group represented by the formula: -CO-R. In one embodiment, all of the five R's are methyl groups or phenyl groups.

[0167] In one embodiment, R in formula (I-1) or (I-2) 2 is a functional group represented by the above formula (iv).

[0168] In one embodiment, R in formula (I-1) or (I-2) 2 is a functional group represented by the above formula (vi).

[0169] In one embodiment, R in formula (I-1) or (I-2) 2 is a functional group represented by the above formula (A).

[0170] In one embodiment, R in formula (I-1) or (I-2) 2 is a functional group represented by the above formula (B).

[0171] In one embodiment, R in formula (I-1) or (I-2) 2 is a functional group represented by the above formula (Ar-1), (Ar-2), (Ar-3) or (Ar-4).

[0172] Compound (II) Compound (II) is selected from compound (IIa) and compound (IIb), which will be described later.

[0173] Compound (II-1) Compound (II) is selected from compound (IIa-1) and compound (IIb-1), which will be described later.

[0174] ≪Compound (IIa)≫ Compound (IIa) is represented by the following formula (IIa).

[0175] [ka]

[0176] In formula (IIa), R 1 has the same meaning as formula (I).

[0177] In formula (IIa), Y 1 represents -O- or -S-. When Y is -O-, compound (IIa) is an ester derivative, and when Y is -S-, compound (IIa) is a thioester derivative.

[0178] In formula (IIa), Z 1 represents a monovalent nitrogen-containing heterocyclic group having a partial structure (P1) represented by the following formula (P1).

[0179] [ka]

[0180] In formula (P1), (*1) is Y1 represents the site that binds to

[0181] The monovalent nitrogen-containing heterocyclic group contains the carbon atom and nitrogen atom in formula (P1) as ring-constituting atoms.

[0182] The monovalent nitrogen-containing heterocyclic group may contain one or more nitrogen atoms as ring-constituting atoms in addition to the nitrogen atom in formula (P1).

[0183] In one embodiment, the monovalent nitrogen-containing heterocyclic group does not contain any nitrogen atoms other than the nitrogen atom in formula (P1) as ring-constituting atoms. In this case, the number of nitrogen atoms contained as ring-constituting atoms in the monovalent nitrogen-containing heterocyclic group is 1.

[0184] In one embodiment, the monovalent nitrogen-containing heterocyclic group contains one or more nitrogen atoms as ring-constituting atoms in addition to the nitrogen atom in formula (P1). In this case, the total number of nitrogen atoms contained as ring-constituting atoms in the monovalent nitrogen-containing heterocyclic group is 2 or more. The total number of nitrogen atoms contained as ring-constituting atoms in the monovalent nitrogen-containing heterocyclic group is preferably 10 or less, more preferably 8 or less, and even more preferably 4 or less. The total number of nitrogen atoms contained as ring-constituting atoms in the monovalent nitrogen-containing heterocyclic group is, for example, 2, 3, or 4.

[0185] The monovalent nitrogen-containing heterocyclic group may contain one or more heteroatoms other than nitrogen atoms as ring-constituting atoms, for example, one or more heteroatoms selected from the group consisting of oxygen atoms and sulfur atoms. The total number of heteroatoms other than nitrogen atoms contained as ring-constituting atoms in the monovalent nitrogen-containing heterocyclic group is preferably 10 or less, more preferably 8 or less, and even more preferably 4 or less. The total number of heteroatoms other than nitrogen atoms contained as ring-constituting atoms in the monovalent nitrogen-containing heterocyclic group is, for example, 1, 2, or 3.

[0186] In one embodiment, the monovalent nitrogen-containing heterocyclic group does not contain any heteroatoms other than the nitrogen atom as ring atoms.

[0187] In one embodiment, the monovalent nitrogen-containing heterocyclic group contains one or more heteroatoms other than nitrogen atoms, such as one or more oxygen atoms and / or one or more sulfur atoms, as ring-constituting atoms. The total number of oxygen atoms contained as ring-constituting atoms in the monovalent nitrogen-containing heterocyclic group is preferably 10 or less, more preferably 8 or less, and even more preferably 4 or less. The total number of oxygen atoms contained as ring-constituting atoms in the monovalent nitrogen-containing heterocyclic group is, for example, 1, 2, or 3. The total number of sulfur atoms contained as ring-constituting atoms in the monovalent nitrogen-containing heterocyclic group is preferably 10 or less, more preferably 8 or less, and even more preferably 4 or less. The total number of sulfur atoms contained as ring-constituting atoms in the monovalent nitrogen-containing heterocyclic group is, for example, 1, 2, or 3.

[0188] The monovalent nitrogen-containing heterocyclic group may be a monovalent monocyclic group or a monovalent polycyclic (e.g., bicyclic or tricyclic) group. The monovalent polycyclic group is, for example, a monovalent fused ring group. The monovalent monocyclic group has, for example, 3 to 8 ring members, preferably 5 or 6 ring members. The monovalent fused ring group has, for example, 9 to 14 ring members, preferably 9 or 10 ring members. The monovalent nitrogen-containing heterocyclic group may or may not have aromaticity. That is, the monovalent nitrogen-containing heterocyclic group may be a monovalent aromatic heterocyclic group or a monovalent aliphatic heterocyclic group.

[0189] In one embodiment, the monovalent nitrogen-containing heterocyclic group is a monovalent monocyclic (eg, 5- or 6-membered monocyclic) group having aromatic character.

[0190] In one embodiment, the monovalent nitrogen-containing heterocyclic group is a monovalent monocyclic (eg, 5- or 6-membered monocyclic) group that lacks aromatic character.

[0191] In one embodiment, the monovalent nitrogen-containing heterocyclic group is a monovalent fused ring (eg, 9- or 10-membered bicyclic) group having aromatic character.

[0192] In one embodiment, the monovalent nitrogen-containing heterocyclic group is a monovalent fused ring (eg, 9- or 10-membered bicyclic) group that lacks aromatic character.

[0193] When the monovalent nitrogen-containing heterocyclic group has one or more resonance structures, it is sufficient that one of the resonance structures has the partial structure (P1).

[0194] The monovalent nitrogen-containing heterocyclic group can be selected from the following monovalent monocyclic and fused ring groups:

[0195] The following group derived from 2H-pyrrole [ka]

[0196] The following group derived from 2-pyrazoline [ka]

[0197] The following group derived from 2-imidazoline [ka]

[0198] The following group derived from 2-oxazoline [ka]

[0199] The following group derived from 2-thiazoline [ka]

[0200] The following group derived from pyrazole: [ka]

[0201] The following group derived from imidazole [ka]

[0202] The following group derived from 1,2,4-triazole [ka]

[0203] The following group derived from tetrazole: [ka]

[0204] The following group derived from oxazole: [ka]

[0205] The following group derived from isoxazole: [ka]

[0206] The following group derived from isothiazole: [ka]

[0207] The following group derived from thiazole: [ka]

[0208] The following group derived from 1,2,5-oxadiazole [ka]

[0209] The following group derived from 1,3,4-thiadiazole [ka]

[0210] The following group derived from 1,2,5-thiadiazole [ka]

[0211] The following group derived from pyridine [ka]

[0212] The following group derived from pyridazine [ka]

[0213] The following group derived from pyrimidine [ka]

[0214] The following group derived from pyrazine [ka]

[0215] The following group derived from 1,2,4-triazine [ka]

[0216] The following group derived from 1,3,5-triazine [ka]

[0217] The following group derived from 1,2,4,5-tetrazine [ka]

[0218] The following group derived from 1,2,3,4-tetrazine [ka]

[0219] The following group derived from 1,2,3,5-tetrazine [ka]

[0220] The following group derived from 4H-1,2-oxazine [ka]

[0221] The following group derived from 6H-1,2-oxazine [ka]

[0222] The following group derived from 4H-1,3-oxazine [ka]

[0223] The following group derived from 2H-1,3-oxazine [ka]

[0224] The following group derived from 6H-1,3-oxazine [ka]

[0225] The following group derived from 2H-1,4-oxazine [ka]

[0226] The following group derived from 6H-1,2-thiazine [ka]

[0227] The following group derived from 2H-1,4-thiazine [ka]

[0228] The following group derived from 3H-indole [ka]

[0229] The following group derived from 1H-indazole [ka]

[0230] The following group derived from benzimidazole: [ka]

[0231] The following group derived from benzoxazole: [ka]

[0232] The following group derived from benzothiazole [ka]

[0233] The following group derived from 5-azaindole [ka]

[0234] The following group derived from 6-azaindole [ka]

[0235] The following group derived from 7-azaindazole [ka]

[0236] The following group derived from pyrazolo[1,5-a]pyrimidine [ka]

[0237] The following groups derived from purines [ka]

[0238] The following group derived from benzo[d]isoxazole: [ka]

[0239] The following group derived from benzo[d]isothiazole: [ka]

[0240] The following group derived from benzo[d]oxazole: [ka]

[0241] The following group derived from benzo[d]thiazole: [ka]

[0242] The following group derived from quinoline [ka]

[0243] The following group derived from isoquinoline [ka]

[0244] The following group derived from quinoxaline [ka]

[0245] The following group derived from phthalazine [ka]

[0246] The following group derived from quinazoline [ka]

[0247] The following group derived from cinnoline [ka]

[0248] The following group derived from 1,8-naphthyridine [ka]

[0249] The following group derived from pyrido[3,2-d]pyrimidine [ka]

[0250] The following group derived from pyrido[4,3-d]pyrimidine [ka]

[0251] The following group derived from pyrido[3,4-b]pyrazine [ka]

[0252] The following group derived from pyrido[2,3-b]pyrazine: [ka]

[0253] The following group derived from pteridine [ka]

[0254] The following group derived from 2H-benzo[e][1,3]oxazine [ka]

[0255] The following group derived from 2H-benzo[b][1,4]oxazine [ka]

[0256] The following group derived from 4,5-dihydroazepine [ka]

[0257] The following groups derived from 2H-azepine [ka]

[0258] The following groups derived from 3H-azepine [ka]

[0259] The following groups derived from 4H-azepine [ka]

[0260] The following groups derived from 1,2-diazepine [ka]

[0261] The following groups derived from 1,3-diazepine [ka]

[0262] The following groups derived from 1,4-diazepine [ka]

[0263] The following groups derived from 1,4-thiazepine: [ka]

[0264] The following group derived from azocine [ka]

[0265] The following group derived from azecine [ka]

[0266] The monovalent nitrogen-containing heterocyclic group may be unsubstituted or may have one or more substituents. Either one or both of the carbon atom and nitrogen atom contained as ring-constituting atoms in the monovalent nitrogen-containing heterocyclic group may have a substituent. The number of substituents is preferably 1 to 3, more preferably 1 or 2. The one or more substituents may each be independently selected from substituent groups α and β. One or more substituents may be selected from substituent group α, and one or more substituents may be selected from substituent group β. The one or more substituents are each preferably independently selected from a halogen atom, an alkyl group, a haloalkyl group, an alkyloxy group, a haloalkyloxy group, an alkylthio group, a haloalkylthio group, and a phenyl group, more preferably a halogen atom, an alkyl group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms, a haloalkyloxy group having 1 to 4 carbon atoms, and a phenyl group, and even more preferably an alkyl group having 1 to 4 carbon atoms and a phenyl group.

[0267] Z 1 is preferably selected from the following group:

[0268] [ka]

[0269] [ka]

[0270] [ka] [In the formula, X represents —O—, —S—, or —N(—CH)—.]

[0271] [ka] [In the formula, X has the same meaning as defined above.]

[0272] [ka] [In the formula, X has the same meaning as defined above.]

[0273] [ka] [In the formula, X has the same meaning as defined above.]

[0274] [ka] [In the formula, X has the same meaning as defined above.]

[0275] In one embodiment, compound (IIa) is compound (IIa-1) represented by the following formula (IIa-1):

[0276] [ka]

[0277] In formula (IIa-1), R and n have the same meanings as in formula (I-1).

[0278] In one embodiment, compound (IIa-1) is compound (IIa-2) represented by the following formula (IIa-2):

[0279] [ka]

[0280] In formula (IIa-2), R has the same meaning as in formula (I-1).

[0281] In one embodiment, compound (IIa-2) is compound (IIa-3) represented by the following formula (IIa-3):

[0282] [ka]

[0283] In formula (IIa-3), R has the same meaning as in formula (I-1).

[0284] Compound (IIb) Compound (IIb) is represented by the following formula (IIb).

[0285] [ka]

[0286] In formula (IIb), R 1 and each independently have the same meaning as in formula (I). In formula (IIb), two R 1 may be the same or different, but are usually the same.

[0287] In formula (IIb), Y 2 and Y 3 Each independently represents -O- or -S-. 2 and Y 3 may be the same or different, but are usually the same. 2 and Y 3 are both -O- or -S-.

[0288] In formula (IIb), Z 2 represents a divalent nitrogen-containing heterocyclic group having a partial structure (P2) represented by the following formula (P2) and a partial structure (P3) represented by the following formula (P3).

[0289] [ka]

[0290] [ka]

[0291] In formula (P2), (*2) is Y 2 represents the site that binds to

[0292] In formula (P3), (*3) is Y 3 represents the site that binds to

[0293] In one embodiment, the divalent nitrogen-containing heterocyclic group is a group in which a monovalent nitrogen-containing heterocyclic group having a partial structure (P2) and a monovalent nitrogen-containing heterocyclic group having a partial structure (P3) are covalently bonded by a single bond. The monovalent nitrogen-containing heterocyclic group having the partial structure (P2) and the monovalent nitrogen-containing heterocyclic group having the partial structure (P3) may be the same or different. The above description of the monovalent nitrogen-containing heterocyclic group having the partial structure (P1) also applies to the monovalent nitrogen-containing heterocyclic group having the partial structure (P2) and the monovalent nitrogen-containing heterocyclic group having the partial structure (P3). When applied to the former, the partial structure (P1) is replaced with the partial structure (P2), and (*1) is replaced with (*2). When applied to the latter, the partial structure (P1) is replaced with the partial structure (P3), and (*1) is replaced with (*3). A monovalent nitrogen-containing heterocyclic group having the partial structure (P2) and a monovalent nitrogen-containing heterocyclic group having the partial structure (P3) are covalently bonded by a single bond at a position other than (*2) and (*3). Taking a group in which two monovalent nitrogen-containing heterocyclic groups, each having the partial structure (P1), are covalently bonded by a single bond at a position other than (*1) as an example, one of the partial structures (P1) and (*1) corresponds to the partial structures (P2) and (*2), and the other partial structure (P1) and (*1) corresponds to the partial structures (P3) and (*3).

[0294] In one embodiment, the divalent nitrogen-containing heterocyclic group is a group in which two groups selected from the monovalent monocyclic and fused ring groups exemplified in compound (IIa) are covalently bonded via a single bond.

[0295] The divalent nitrogen-containing heterocyclic group may be unsubstituted or may have one or more substituents. Either one or both of the carbon atom and nitrogen atom contained as ring-constituting atoms in the divalent nitrogen-containing heterocyclic group may have a substituent. The number of substituents is preferably 1 to 3, more preferably 1 or 2. The one or more substituents may each be independently selected from substituent groups α and β. One or more substituents may be selected from substituent group α, and one or more substituents may be selected from substituent group β. The one or more substituents are each preferably independently selected from a halogen atom, an alkyl group, a haloalkyl group, an alkyloxy group, a haloalkyloxy group, an alkylthio group, a haloalkylthio group, and a phenyl group, more preferably a halogen atom, an alkyl group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms, a haloalkyloxy group having 1 to 4 carbon atoms, and a phenyl group, and even more preferably an alkyl group having 1 to 4 carbon atoms and a phenyl group.

[0296] Z 2 is preferably selected from the following group:

[0297] [ka]

[0298] [ka] [In the formula, X has the same meaning as defined above.]

[0299] [ka] [wherein X is as defined above, t Bu represents a tert-butyl group.

[0300] [ka] [In the formula, X is as defined above, and Ph represents a phenyl group.]

[0301] The two X's in one compound may be the same or different.

[0302] In one embodiment, compound (IIb) is compound (IIb-1) represented by the following formula (IIb-1):

[0303] [ka]

[0304] In formula (IIb-1), R and n have the same meanings as in formula (I-1).

[0305] In formula (IIb-1), the two n's may be the same or different, but are usually the same.

[0306] In formula (IIb-1), eight (when one n is 1 and the other n is 1), nine (when one n is 1 and the other n is 2), or ten (when one n is 2 and the other n is 2) Rs may be different from each other, but are preferably the same from the viewpoint of efficient introduction and removal of a hydroxy-protecting group represented by the formula: -CO-R. In one embodiment, all of the eight, nine, or ten Rs are methyl groups or phenyl groups.

[0307] In one embodiment, compound (IIb-1) is compound (IIb-2) represented by the following formula (IIb-2):

[0308] [ka]

[0309] In formula (IIb-2), R has the same meaning as in formula (I-1).

[0310] In formula (IIb-2), the ten Rs may be different from each other, but are preferably the same from the viewpoint of efficient introduction and removal of the hydroxy-protecting group represented by the formula: -CO-R. In one embodiment, all of the ten Rs are methyl groups or phenyl groups.

[0311] Grignard Reagent (III) The Grignard reagent (III) is selected from the Grignard reagent (IIIa) represented by the following formula (IIIa) and the Grignard reagent (IIIb) represented by the following formula (IIIb).

[0312] [ka]

[0313] [ka]

[0314] In formulas (IIIa) and (IIIb), R 2 has the same meaning as formula (I).

[0315] In formulas (IIIa) and (IIIb), X 1 represents a halogen atom, which is preferably selected from a chlorine atom, a bromine atom, and an iodine atom, more preferably a chlorine atom and a bromine atom, and even more preferably a bromine atom.

[0316] <<Method for producing compounds (IIa), (IIb), (IIa-1), and (IIb-1)>> Compound (IIa) can be produced by a method comprising the step of contacting compound (IV) represented by the following formula (IV) with compound (Va) represented by the following formula (Va) in the presence of a base:

[0317] Compound (IIb) can be produced by a method comprising the step of contacting compound (IV) represented by the following formula (IV) with compound (Vb) represented by the following formula (Vb) in the presence of a base.

[0318] Compound (IIa-1) can be produced by a method comprising the step of contacting compound (IV-1) represented by the following formula (IV-1) with compound (Va) represented by the following formula (Va) in the presence of a base:

[0319] Compound (IIb-1) can be produced by a method comprising the step of contacting compound (IV-1) represented by the following formula (IV-1) with compound (Vb) represented by the following formula (Vb) in the presence of a base:

[0320] [ka]

[0321] [ka]

[0322] [ka]

[0323] [ka]

[0324] In formula (IV), R 1 has the same meaning as formula (I).

[0325] In formula (IV-1), R and n have the same meanings as in formula (I-1).

[0326] In formulas (Va) and (Vb), R 3 and R 4each independently represents a hydrogen atom or an alkali metal. Examples of alkali metals include lithium, sodium, and potassium.

[0327] In formula (Va), Y 1 and Z 1 has the same meaning as formula (IIa).

[0328] In formula (Vb), Y 2 , Y 3 and Z 2 has the same meaning as formula (IIb).

[0329] Compound (IV), compound (V-1), compound (Va) and compound (Vb) may each be a commercially available product or may be produced according to a conventional method.

[0330] In formula (IIa), Y 1 is an oxygen atom, and Z 1 When Y is the above group derived from pyridine, compound (Va) is 2-hydroxypyridine. 1 is a sulfur atom, and Z 1 When is the above group derived from pyridine, compound (Va) is 2-mercaptopyridine.

[0331] When compound (IV) or (IV-1) is contacted with compound (Va) or (Vb) in the presence of a base, the amount of compound (IV) or compound (IV-1) used and the amount of compound (Va) or (Vb) used are not particularly limited. When compound (IV) or (IV-1) is contacted with compound (Va) in the presence of a base, the amount of compound (Va) used is preferably 1 to 3 moles, more preferably 1 to 1.5 moles, per mole of compound (IV) or (IV-1). When compound (IV) or (IV-1) is contacted with compound (Vb) in the presence of a base, the amount of compound (Vb) used is preferably 0.5 to 1.5 moles, more preferably 0.5 to 0.75 moles, per mole of compound (IV) or (IV-1).

[0332] Examples of the base include triethylamine, diisopropylethylamine, dimethylaniline, pyridine, etc. Among these, triethylamine and diisopropylethylamine are preferred, and triethylamine is more preferred.

[0333] The amount of the base used is preferably 1 to 3 moles, more preferably 1 to 2 moles, and even more preferably 1 to 1.5 moles, per mole of compound (IV) or (IV-1).

[0334] The temperature when compound (IV) or (IV-1) is contacted with compound (Va) or (Vb) in the presence of a base is preferably −10 to 50° C., more preferably −5 to 40° C., even more preferably 0 to 30° C., and most preferably 0 to 20° C. By keeping the temperature during contact at 0 to 20° C., the purity of the resulting compound (IIa), (IIb), (IIa-1) or (IIb-1) can be further increased.

[0335] The time for contacting compound (IV) or (IV-1) with compound (Va) or (Vb) in the presence of a base is preferably 0.5 to 24 hours, more preferably 1 to 8 hours, and even more preferably 2 to 4 hours.

[0336] The contact of compound (IV) or (IV-1) with compound (Va) or (Vb) in the presence of a base can be carried out under an inert atmosphere (for example, under an argon atmosphere or a nitrogen atmosphere).

[0337] The contact of compound (IV) or (IV-1) with compound (Va) or (Vb) in the presence of a base is preferably carried out in a solvent. By mixing a base, compound (IV) or (IV-1), and compound (Va) or (Vb) in a solvent, compound (IV) or (IV-1) can be contacted with compound (Va) or (Vb) in the presence of a base. An organic solvent is preferably used as the solvent. One organic solvent may be used alone, or a mixture of two or more organic solvents may be used. Specific examples of organic solvents are as described above. The organic solvent is preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, diglyme, dichloromethane, toluene, xylene, hexane, and heptane, and more preferably dichloromethane.

[0338] The amount of the solvent used is preferably 1 to 100 mL, more preferably 2 to 10 mL, and even more preferably 3 to 10 mL, per 1 g of compound (IV) or (IV-1).

[0339] The above conditions for contacting compound (IV) or (IV-1) with compound (Va) or (Vb) can be combined as appropriate.

[0340] The obtained compound (IIa), (IIb), (IIa-1), or (IIb-1) may be used in the next step after isolation by a conventional method such as silica gel column chromatography, or may be used in the next step without isolation. For example, the obtained compound (IIa), (IIb), (IIa-1), or (IIb-1) may be used in the next step as a concentrated residue without being purified.

[0341] The structure of compound (IIa), (IIb), (IIa-1) or (IIb-1) can be confirmed by, for example, nuclear magnetic resonance (NMR) spectroscopic analysis.

[0342] <Method for producing compounds (IV) and (IV-1)> Compound (IV) can be produced by a method including a step of contacting compound (VI) represented by the following formula (VI) with a chlorinating agent.

[0343] Compound (IV-1) can be produced by a method including a step of contacting compound (VI-1) represented by the following formula (VI-1) with a chlorinating agent.

[0344] [ka]

[0345] [ka]

[0346] In formula (VI), R 1 has the same meaning as formula (I).

[0347] In formula (VI-1), R and n have the same meanings as in formula (I-1).

[0348] The compound (VI), the compound (VI-1) and the chlorinating agent may each be a commercially available product or may be prepared according to a conventional method.

[0349] Examples of the chlorinating agent include thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, etc. Among these, thionyl chloride and oxalyl chloride are preferred, and oxalyl chloride is more preferred.

[0350] The amount of the chlorinating agent used is preferably 0.2 to 10 moles, more preferably 0.5 to 5 moles, even more preferably 1 to 3 moles, and most preferably 1 to 2 moles, per mole of compound (VI) or (VI-1). By using 1 to 2 moles of the chlorinating agent, the purity of the obtained compound (IV) or (IV-1) can be further increased.

[0351] The temperature at which compound (VI) or (VI-1) is contacted with the chlorinating agent is preferably from -10 to 50°C, more preferably from 0 to 40°C, and even more preferably from 0 to 35°C.

[0352] The time for contacting compound (VI) or (VI-1) with the chlorinating agent is preferably 0.5 to 48 hours, more preferably 1 to 24 hours, and even more preferably 1 to 8 hours.

[0353] The contact of compound (VI) or (VI-1) with the chlorinating agent can be carried out under an inert atmosphere (for example, under an argon atmosphere or a nitrogen atmosphere).

[0354] The contact of compound (VI) or (VI-1) with the chlorinating agent is preferably carried out in a solvent. Compound (VI) or (VI-1) can be contacted with the chlorinating agent by mixing them in a solvent. An organic solvent is preferably used as the solvent. One organic solvent may be used alone, or a mixed solvent of two or more organic solvents may be used. Specific examples of organic solvents are as described above. The organic solvent is preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, diglyme, dichloromethane, toluene, xylene, hexane, and heptane, and more preferably dichloromethane.

[0355] The amount of solvent used is preferably 1 to 100 mL, more preferably 3 to 20 mL, even more preferably 3 to 15 mL, and most preferably 3 to 10 mL per gram of compound (VI) or (VI-1). By using 3 to 10 mL of solvent, the purity of the obtained compound (IV) or (IV-1) can be further increased.

[0356] The contact of compound (VI) or (VI-1) with the chlorinating agent is preferably carried out in the presence of a catalytic amount of N,N-dimethylformamide (DMF). Compound (VI) or (VI-1) can be contacted with the chlorinating agent in the presence of DMF by mixing compound (VI) or (VI-1), the chlorinating agent, and DMF in a solvent. Compound (IV) or (IV-1) can be produced under milder conditions by contacting compound (VI) or (VI-1) with the chlorinating agent in the presence of a catalytic amount of DMF.

[0357] The amount of DMF used is preferably 0.005 to 0.1 mol, more preferably 0.0075 to 0.1 mol, and even more preferably 0.01 to 0.1 mol, per 1 mol of compound (VI) or (VI-1).

[0358] The above conditions for contacting compound (VI) or (VI-1) with a chlorinating agent can be suitably combined.

[0359] The obtained compound (IV) or (VI-1) may be used in the next step after isolation by a conventional method such as silica gel column chromatography, or may be used in the next step without isolation. For example, the obtained compound (IV) or (VI-1) may be used in the next step as a concentrated residue without being purified.

[0360] The structure of compound (IV) or (VI-1) can be confirmed by, for example, nuclear magnetic resonance (NMR) spectroscopic analysis.

[0361] <Method for producing Grignard reagent (IIIa) or (IIIb)> Grignard reagent (IIIa) or (IIIb) can be produced by a method including the step of contacting a halide (VII) represented by the following formula (VII) with magnesium or magnesium activated with a magnesium activator, and optionally with LiCl. 2 is an optionally substituted aryl group or an optionally substituted heteroaryl group (for example, R 2is a functional group represented by the above formula (iv), R 2 is a functional group represented by the above formula (vi), R 2 is a functional group represented by the above formula (A), R 2 is a functional group represented by the above formula (B), R 2 is a functional group represented by the above formula (Ar-1), (Ar-2), (Ar-3) or (Ar-4), it is preferable to produce the Grignard reagent (IIIa) or (IIIb) by this method.

[0362] [ka]

[0363] When preparing Grignard reagent (IIIa), R in formula (VII) 2 and X 1 has the same meaning as in formula (IIIa). When producing Grignard reagent (IIIb), R in formula (VII) 2 and X 1 has the same meaning as formula (IIIb).

[0364] When contacting halide (VII), magnesium or magnesium activated with a magnesium activator, and optionally LiCl, the order of addition of the components is not particularly limited. For example, after activating magnesium with a magnesium activator, halide (VII) and optionally LiCl can be added to the magnesium activated with the magnesium activator, thereby contacting halide (VII), magnesium or magnesium activated with a magnesium activator, and optionally LiCl. When adding halide (VII) and LiCl to magnesium activated with a magnesium activator, LiCl may be added after halide (VII), or LiCl may be added after halide (VII).

[0365] Grignard reagent (IIIa) is formed by contacting halide (VII) with magnesium or magnesium activated with a magnesium activator in the absence of LiCl. Grignard reagent (IIIb) is formed by contacting halide (VII) with magnesium or magnesium activated with a magnesium activator in the presence of LiCl.

[0366] The halide (VII) may be a commercially available product or may be prepared according to a conventional method.

[0367] As magnesium, simple magnesium can be used. The magnesium may be in the form of powder, strips, or cuttings. The amount of magnesium used is preferably 1 to 5 mol, more preferably 1 to 4 mol, and even more preferably 1 to 3 mol per mol of halide (VII).

[0368] Examples of magnesium activators include 1,2-dibromoethane, bromine, iodine, trimethylsilyl chloride, and diisobutylaluminum halide (DIBAL-H), among which 1,2-dibromoethane, bromine, and DIBAL-H are preferred. One type of magnesium activator may be used alone, or two types of magnesium activators may be used in combination.

[0369] The magnesium activated with a magnesium activator can be prepared by contacting magnesium with a magnesium activator. The magnesium activated with a magnesium activator is a mixture of magnesium and a magnesium activator.

[0370] The amount of magnesium activator used is preferably 0.001 to 1.5 mol, more preferably 0.05 to 1.2 mol, and even more preferably 0.05 to 1 mol, per mol of magnesium. The "amount of magnesium activator used" means the amount of one magnesium activator used when one type of magnesium activator is used, and means the total amount of two or more magnesium activators used when two or more types of magnesium activators are used.

[0371] The amount of LiCl used is preferably 0.5 to 6 mol, more preferably 0.7 to 5 mol, and even more preferably 0.8 to 4 mol, per mol of halide (VII).

[0372] The temperature when the halide (VII) is contacted with magnesium or magnesium activated with a magnesium activator in the absence or presence of LiCl is preferably 20 to 120°C, more preferably 30 to 100°C, and even more preferably 40 to 90°C.

[0373] The time for contacting halide (VII) with magnesium or magnesium activated with a magnesium activator in the absence or presence of LiCl is preferably 0.1 to 5 hours, more preferably 0.2 to 4 hours, and even more preferably 0.3 to 3 hours.

[0374] The contact of halide (VII) with magnesium or magnesium activated with a magnesium activator in the absence or presence of LiCl can be carried out under an inert atmosphere (e.g., under an argon or nitrogen atmosphere).

[0375] The contact of the halide (VII) with magnesium or magnesium activated with a magnesium activator in the absence or presence of LiCl is preferably carried out in a solvent. The halide (VII) can be contacted with magnesium or magnesium activated with a magnesium activator in the absence or presence of LiCl by mixing the halide (VII), magnesium or magnesium activated with a magnesium activator, and optionally LiCl in a solvent.

[0376] When the contact of the halide (VII) with magnesium or magnesium activated with a magnesium activator in the presence of LiCl is carried out in a solvent, it is preferable to dissolve LiCl in a solvent to prepare a LiCl solution, and then contact the halide (VII), magnesium or magnesium activated with a magnesium activator, and the LiCl solution. By using the Grignard reagent (IIIb) thus prepared, the yield of the target compound (I) or (I-1) can be further increased.

[0377] When contacting the halide (VII), magnesium or magnesium activated with a magnesium activator, and a LiCl solution, the halide (VII) may be added to the LiCl solution, and then magnesium and optionally a magnesium activator may be added, or the magnesium and optionally a magnesium activator may be added to the LiCl solution, and then the halide (VII) may be added.

[0378] An organic solvent is preferably used as the solvent for contacting halide (VII) with magnesium or magnesium activated with a magnesium activator in the absence or presence of LiCl, or for preparing a LiCl solution. One organic solvent may be used alone, or a mixture of two or more organic solvents may be used. Specific examples of organic solvents are as described above. The organic solvent is preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, diglyme, dichloromethane, toluene, xylene, hexane, and heptane, and more preferably dichloromethane.

[0379] The amount of solvent used in contacting halide (VII) with magnesium or magnesium activated with a magnesium activator in the absence or presence of LiCl, or in producing a LiCl solution, is preferably 1 to 200 mL, more preferably 2 to 100 mL, and even more preferably 3 to 50 mL per gram of halide (VII).

[0380] The above conditions for contacting halide (VII) with magnesium or magnesium activated with a magnesium activator in the absence or presence of LiCl can be combined as appropriate.

[0381] <Method for producing Grignard reagent (IIIb)> The Grignard reagent (IIIb) can be produced by a method including a step of contacting a halide (VII) represented by the following formula (VII) with a Grignard reagent (VIII) represented by the following formula (VIII): 2 is an optionally substituted aryl group or an optionally substituted heteroaryl group (for example, R 2 is a functional group represented by the above formula (iv), R 2 is a functional group represented by the above formula (vi), R 2 is a functional group represented by the above formula (A), R 2is a functional group represented by the above formula (B), R 2 is a functional group represented by the above formula (Ar-1), (Ar-2), (Ar-3) or (Ar-4), it is preferable to produce the Grignard reagent (IIIb) by this method.

[0382] [ka]

[0383] [ka]

[0384] In formula (VII), R 2 has the same meaning as in formula (IIIb). 2 may be an isopropyl group, or may be a group other than an isopropyl group, but is usually a group other than an isopropyl group.

[0385] In formula (VII), X 1 has the same meaning as in formula (IIIb). 1 may be a chlorine atom or a halogen atom other than a chlorine atom. 1 is a bromine atom or an iodine atom.

[0386] R 2 has a chlorine atom (e.g., a chlorine atom bonded to a benzene ring) (e.g., R 2 is a functional group represented by the above formula (Ar-3) or (Ar-4), X in formula (VII) 1 is preferably a halogen atom other than a chlorine atom. 1 is a bromine atom or an iodine atom.

[0387] In formula (VIII), i Pr represents an isopropyl group.

[0388] The halide (VII) and the Grignard reagent (VIII) may be commercially available products or may be produced according to a conventional method. The Grignard reagent (VIII) is also called a turbo Grignard reagent.

[0389] The amount of the Grignard reagent (VIII) used is preferably 0.9 to 2.5 mol, more preferably 1.0 to 2.0 mol, and even more preferably 1.0 to 1.5 mol, relative to 1 mol of the halide (VII).

[0390] The temperature when the halide (VII) is brought into contact with the Grignard reagent (VIII) is preferably from -50 to 20°C, more preferably from -40 to 10°C, and even more preferably from -30 to 5°C.

[0391] The time for contacting the halide (VII) with the Grignard reagent (VIII) is preferably 0.1 to 5 hours, more preferably 0.2 to 4 hours, and even more preferably 0.3 to 3 hours.

[0392] The contact of the halide (VII) with the Grignard reagent (VIII) can be carried out under an inert atmosphere (for example, under an argon atmosphere or a nitrogen atmosphere).

[0393] The contact between the halide (VII) and the Grignard reagent (VIII) is preferably carried out in a solvent. The halide (VII) and the Grignard reagent (VIII) can be brought into contact by mixing them in a solvent. An organic solvent is preferably used as the solvent. One organic solvent may be used alone, or a mixed solvent of two or more organic solvents may be used. Specific examples of the organic solvent are as described above. The organic solvent is preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, diglyme, dichloromethane, toluene, xylene, hexane, and heptane, and more preferably dichloromethane.

[0394] The amount of the solvent used is preferably 1 to 20 mL, more preferably 1.5 to 10 mL, and even more preferably 2 to 5 mL per 1 g of halide (VII).

[0395] The above conditions for contacting the halide (VII) with the Grignard reagent (VIII) can be combined as appropriate.

[0396] <First aspect> A first aspect of the present invention is a method for producing a pharmaceutical composition comprising the steps of: (S1) A step of producing compound (I) by contacting compound (II) with Grignard reagent (III) in the presence of a copper salt at a temperature of −10 to 50° C. The present invention relates to a method for producing compound (I), comprising:

[0397] The copper salt is selected from CuCN (copper(I) cyanide) and CuCl (copper(I) chloride). One type of copper salt may be used alone, or two types of copper salts may be used in combination.

[0398] The amount of copper salt used is 0.01 to 1 mole per mole of Compound (II). When one type of copper salt is used, the "amount of copper salt used" refers to the amount of the one type of copper salt used, and when two types of copper salts are used, it refers to the total amount of the two types of copper salts used.

[0399] As compound (II), either compound (IIa) or (IIb) may be used, or both compounds (IIa) and (IIb) may be used. The "amount of compound (II) used" means the amount of one compound used when one compound is used as compound (II), and means the total amount of two or more compounds used when two or more compounds are used as compound (II).

[0400] As the Grignard reagent (III), either the Grignard reagent (IIIa) or (IIIb) may be used, or both the Grignard reagents (IIIa) and (IIIb) may be used. When both the Grignard reagents (IIIa) and (IIIb) are used, the amount of the Grignard reagent (IIIb) used is, for example, 10% by mass or more and 90% by mass or less based on the total mass of the Grignard reagents (IIIa) and (IIIb). The "amount of the Grignard reagent (III) used" means the amount of the Grignard reagent used when one type of Grignard reagent is used as the Grignard reagent (III), and means the total amount of the two or more Grignard reagents used when two or more types of Grignard reagents are used as the Grignard reagent (III).

[0401] In the first aspect of the present invention, compound (II) is contacted with Grignard reagent (III) at a temperature of −10 to 50° C. in the presence of a catalytic amount of a copper salt selected from CuCN and CuCl, thereby increasing the regioselectivity and rate of the reaction and thereby improving the yield of compound (I) under mild reaction conditions that do not require low temperatures.

[0402] A copper salt reacts with a Grignard reagent (III) to form an organocopper reagent, which then reacts with compound (II) to form compound (I). The reaction between the organocopper reagent and compound (II) is thought to contribute to improving the yield of compound (I). The organocopper reagent is also called an organocuprate reagent.

[0403] In addition, the coordination of a copper salt to compound (II) (coordination of a copper salt to the partial structure (P1) of compound (IIa) or coordination of a copper salt to the partial structures (P2) and (P3) of compound (IIb)) forms a copper complex, which activates the carbonyl group (=O) of compound (II) and accelerates the reaction between compound (II) and an organocopper reagent, which is also thought to contribute to the improvement in the yield of compound (I).

[0404] When the copper salt is CuCN or CuCl and the compound (II) is the compound (IIa), it is believed that the copper complex represented by the following formula is formed by the coordination of CuCN or CuCl to the partial structure (P1) of the compound (IIa).

[0405] [ka]

[0406] When the copper salt is CuCN or CuCl and the compound (II) is the compound (IIa-3), it is believed that the coordination of CuCN or CuCl to the partial structure (P1) of the compound (IIa-3) forms a copper complex represented by the following formula:

[0407] [ka]

[0408] From the viewpoint of more effectively improving the yield of compound (I), the amount of Grignard reagent (III) used is preferably 0.5 to 3 mol, more preferably 0.7 to 2 mol, and even more preferably 0.8 to 1.5 mol, per 1 mol of compound (II).

[0409] When Grignard reagent (IIIb) is used, the amount of LiCl used is preferably 0.1 to 10 mol, more preferably 0.5 to 5 mol, and even more preferably 0.8 to 4 mol per mol of compound (II). When LiCl is used, as described above, it is preferable to dissolve LiCl in a solvent (preferably an organic solvent) to prepare a LiCl solution, and then contact halide (VII), magnesium or magnesium activated with a magnesium activator, and the LiCl solution to prepare Grignard reagent (IIIb). This can further increase the yield of the target compound (I).

[0410] From the viewpoint of more effectively improving the yield of compound (I), the amount of copper salt used is preferably 0.03 to 1 mol, more preferably 0.05 to 0.5 mol, even more preferably 0.07 to 0.4 mol, and even more preferably 0.1 to 0.3 mol, per 1 mol of compound (II).

[0411] From the viewpoint of more effectively improving the yield of compound (I), the temperature when compound (II) is contacted with Grignard reagent (III) in the presence of a copper salt is preferably −5 to 40° C., more preferably −2 to 30° C., and even more preferably 0 to 30° C.

[0412] In one embodiment, the reaction mixture containing the copper salt, compound (II) and Grignard reagent (III) is prepared at a temperature of 0°C ± 10°C, preferably 0°C ± 5°C, and then the temperature of the reaction mixture is maintained at room temperature, where room temperature means 20°C ± 10°C, preferably 20°C ± 5°C.

[0413] From the viewpoint of more effectively improving the yield of compound (I), the time for which compound (II) is contacted with Grignard reagent (III) in the presence of a copper salt is preferably 0.5 to 48 hours, more preferably 1 to 36 hours, and even more preferably 1 to 24 hours.

[0414] The contact of compound (II) with Grignard reagent (III) in the presence of a copper salt can be carried out, for example, under an inert atmosphere (for example, under an argon atmosphere or a nitrogen atmosphere).

[0415] The contact of compound (II) with Grignard reagent (III) in the presence of a copper salt is preferably carried out in a solvent. By mixing the copper salt, compound (II), and Grignard reagent (III) in a solvent, compound (II) can be contacted with Grignard reagent (III) in the presence of the copper salt. An organic solvent is preferably used as the solvent. One organic solvent may be used alone, or a mixture of two or more organic solvents may be used. Specific examples of organic solvents are as described above. The organic solvent is preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, diglyme, dichloromethane, toluene, xylene, hexane, and heptane, and more preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, dichloromethane, and toluene.

[0416] The amount of the solvent used is preferably 1 to 100 mL, more preferably 3 to 20 mL, and even more preferably 5 to 10 mL per 1 g of compound (II).

[0417] The copper salt, compound (II) and Grignard reagent (III) may each be a commercially available product or may be prepared according to a conventional method.

[0418] Compound (IIa) can be produced by a method comprising contacting compound (IV) with compound (Va) in the presence of a base. Compound (IIb) can be produced by a method comprising contacting compound (IV) with compound (Vb) in the presence of a base. The details of these methods are as described above.

[0419] The method for producing compound (I) comprises the following steps: (T1a) a step of contacting compound (IV) with compound (Va) in the presence of a base to produce compound (IIa); or (T1b) A step of producing compound (IIb) by contacting compound (IV) with compound (Vb) in the presence of a base. The process may further comprise the steps of: Step (T1a) is carried out before step (S1), and compound (IIa) produced in step (T1a) is used in step (S1); Step (T1b) is carried out before step (S1), and compound (IIb) produced in step (T1b) is used in step (S1).

[0420] Compound (IV) can be prepared by a process comprising contacting compound (VI) with a chlorinating agent, as described above.

[0421] The method for producing compound (I) comprises the following steps: (U1) A step of producing compound (IV) by contacting compound (VI) with a chlorinating agent Step (U1) may be carried out before step (T1a) or (T1b), and compound (IV) produced in step (U1) is used in step (T1a) or (T1b).

[0422] Grignard reagent (IIIa) or (IIIb) can be produced by a method including a step of contacting halide (VII), magnesium or magnesium activated with a magnesium activator, and optionally LiCl. The method is described above. When LiCl is used, it is preferable to first dissolve LiCl in a solvent (preferably an organic solvent) to produce a LiCl solution, as described above, and then contact halide (VII), magnesium or magnesium activated with a magnesium activator, and the LiCl solution to produce Grignard reagent (IIIb). This can further increase the yield of the target compound (I).

[0423] Grignard reagent (IIIb) can be prepared by a method comprising contacting halide (VII) with Grignard reagent (VIII), as described above.

[0424] The method for producing compound (I) comprises the following steps: (W1a) contacting halide (VII) with magnesium or magnesium activated with a magnesium activator, and optionally LiCl to produce Grignard reagent (IIIa) or (IIIb); or (W1b) A step of contacting a halide (VII) with a Grignard reagent (VIII) to produce a Grignard reagent (IIIb). The step (W1a) is carried out before the step (S1), and the Grignard reagent (IIIa) or (IIIb) produced in the step (W1a) is used in the step (S1). The step (W1b) is carried out before the step (S1), and the Grignard reagent (IIIb) produced in the step (W1b) is used in the step (S1).

[0425] When the method for producing compound (I) includes step (W1a) and LiCl is used in step (W1a), it is preferable to first dissolve LiCl in a solvent (preferably an organic solvent) to produce a LiCl solution, and then contact halide (VII), magnesium or magnesium activated with a magnesium activator, and the LiCl solution to produce Grignard reagent (IIIb). This can further increase the yield of the target compound (I).

[0426] Compound (I) can be isolated from the reaction mixture by a conventional method. For example, a quenching liquid such as water is added to the reaction mixture to quench the reaction, the reaction mixture is filtered, the filtrate is washed with an organic solvent such as ethyl acetate, the organic layer is separated, the organic layer is washed with a brine solution or the like, dried over anhydrous sodium sulfate or the like, filtered, and the filtrate is concentrated to obtain a crude product. Compound (I) can be isolated by purifying the crude product by silica gel column chromatography or the like.

[0427] The structure of Compound (I) can be confirmed, for example, by nuclear magnetic resonance (NMR) spectroscopy.

[0428] Hereinafter, an embodiment of step (S1) will be described.

[0429] First Embodiment In the first embodiment, the step (S1) comprises the following steps: (S1a) preparing a first mixture containing compound (II) and a copper salt; and (S1b) contacting the first mixture with a Grignard reagent (III) to produce compound (I); Includes.

[0430] In step (S1b), a copper salt reacts with Grignard reagent (III) to form an organocopper reagent, and the formed organocopper reagent reacts with compound (II) to form compound (I). The reaction between the organocopper reagent and compound (II) is thought to contribute to an improvement in the yield of compound (I). In addition, coordination of the copper salt to compound (II) forms a copper complex, which activates the carbonyl group (=O) of compound (II) and accelerates the reaction between compound (II) and the organocopper reagent. This is also thought to contribute to an improvement in the yield of compound (I).

[0431] According to the first embodiment, compound (I) can be produced using smaller amounts of copper salt and Grignard reagent (III) than in the second embodiment.

[0432] <Process (S1a)> The first mixture can be prepared by mixing Compound (II) and a copper salt. When mixing Compound (II) and a copper salt, the copper salt may be added to Compound (II) and then mixed, or Compound (II) may be added to the copper salt and then mixed.

[0433] The temperature at which compound (II) and the copper salt are mixed is preferably -10 to 50°C, more preferably -5 to 40°C, even more preferably -2 to 30°C, and even more preferably 0 to 30°C.

[0434] The time for mixing compound (II) and the copper salt is preferably 0.2 to 1 hour, more preferably 0.3 to 1 hour, and even more preferably 0.5 to 1 hour.

[0435] The compound (II) and the copper salt can be mixed, for example, under an inert atmosphere (for example, under an argon atmosphere or a nitrogen atmosphere).

[0436] The compound (II) and the copper salt are preferably mixed in a solvent. An organic solvent is preferably used as the solvent. One organic solvent may be used alone, or a mixed solvent of two or more organic solvents may be used. Specific examples of the organic solvent are as described above. The organic solvent is preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, diglyme, dichloromethane, toluene, xylene, hexane, and heptane, and more preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, dichloromethane, and toluene.

[0437] The amount of the solvent used is preferably 1 to 100 mL, more preferably 3 to 20 mL, and even more preferably 5 to 10 mL per 1 g of compound (II).

[0438] The above conditions for mixing Compound (II) with the copper salt can be combined as appropriate.

[0439] <Process (S1b)> When the first mixture is brought into contact with the Grignard reagent (III), the Grignard reagent (III) may be added to the first mixture and mixed, or the first mixture may be added to the Grignard reagent (III) and mixed.

[0440] When the first mixture is contacted with the Grignard reagent (III), it is preferable to add the Grignard reagent (III) dropwise to the first mixture. This allows the Grignard reagent (III) to be converted to the organocopper reagent effectively (preferably completely). Furthermore, as will be described later, this also prevents overreaction.

[0441] When the first mixture is contacted with Grignard reagent (III), the copper salt reacts with Grignard reagent (III) to form an organocopper reagent, and the formed organocopper reagent reacts with compound (II) to form compound (I). If additional Grignard reagent (III) is added before the reaction between the formed organocopper reagent and compound (II) is complete, an over-reaction between the additional Grignard reagent (III) and the formed compound (I) (a reaction in which the formed compound (I) reacts with the additional Grignard reagent (III) to form an alcohol) may occur. Such an over-reaction can be prevented by adding Grignard reagent (III) dropwise to the first mixture.

[0442] The temperature at which the first mixture is brought into contact with the Grignard reagent (III) is preferably -10 to 50°C, more preferably -5 to 40°C, even more preferably -2 to 30°C, and even more preferably 0 to 30°C.

[0443] The time for which the first mixture is contacted with the Grignard reagent (III) is preferably 1 to 48 hours, more preferably 1 to 36 hours, and even more preferably 1 to 24 hours.

[0444] The contact of the first mixture with the Grignard reagent (III) can be carried out, for example, under an inert atmosphere (for example, under an argon atmosphere or a nitrogen atmosphere).

[0445] An additional solvent may be added when the first mixture is contacted with the Grignard reagent (III). An organic solvent is preferably used as the additional solvent. One organic solvent may be used alone, or a mixture of two or more organic solvents may be used. Specific examples of the organic solvent are the same as those described above. The organic solvent is preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, diglyme, dichloromethane, toluene, xylene, hexane, and heptane, and more preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, dichloromethane, and toluene.

[0446] The above conditions for contacting the first mixture with the Grignard reagent (III) can be combined as appropriate.

[0447] Second Embodiment In the second embodiment, the step (S1) comprises the following steps: (S1c) preparing a second mixture containing a copper salt and a Grignard reagent (III); and (S1d) A step of contacting the second mixture with compound (II) to produce compound (I). Includes.

[0448] In step (S1c), a copper salt reacts with Grignard reagent (III) to form an organocopper reagent, and in step (S1d), the organocopper reagent formed in step (S1c) reacts with compound (II) to form compound (I). The reaction between the organocopper reagent and compound (II) is thought to contribute to an improvement in the yield of compound (I). In addition, the coordination of the copper salt to compound (II) forms a copper complex, which activates the carbonyl group (=O) of compound (II) and accelerates the reaction between compound (II) and the organocopper reagent, which is also thought to contribute to an improvement in the yield of compound (I).

[0449] <Process (S1c)> The second mixture can be prepared by mixing a copper salt and a Grignard reagent (III). When mixing the copper salt and the Grignard reagent (III), the Grignard reagent (III) may be added to the copper salt, or the copper salt may be added to the Grignard reagent (III) and then mixed.

[0450] When the copper salt and the Grignard reagent (III) are mixed, it is preferable to add the Grignard reagent (III) dropwise to the copper salt, which allows the Grignard reagent (III) to be converted into the organocopper reagent effectively (preferably completely).

[0451] The temperature at which the copper salt and the Grignard reagent (III) are mixed is preferably -10 to 50°C, more preferably -5 to 40°C, even more preferably -2 to 30°C, and even more preferably 0 to 30°C.

[0452] The time for mixing the copper salt and the Grignard reagent (III) is preferably 0.2 to 1 hour, more preferably 0.3 to 1 hour, and even more preferably 0.5 to 1 hour.

[0453] The copper salt and the Grignard reagent (III) can be mixed, for example, under an inert atmosphere (for example, under an argon atmosphere or a nitrogen atmosphere).

[0454] The copper salt and Grignard reagent (III) are preferably mixed in a solvent. An organic solvent is preferably used as the solvent. One organic solvent may be used alone, or a mixture of two or more organic solvents may be used. Specific examples of the organic solvent are as described above. The organic solvent is preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, diglyme, dichloromethane, toluene, xylene, hexane, and heptane, and more preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, dichloromethane, and toluene.

[0455] The amount of the solvent used is preferably 1 to 100 mL, more preferably 3 to 50 mL, and even more preferably 5 to 30 mL, per 1 g of Grignard reagent (III).

[0456] The above conditions for mixing the copper salt and the Grignard reagent (III) can be combined as appropriate.

[0457] <Process (S1d)> When the second mixture is contacted with compound (II), compound (II) may be added to the second mixture and mixed, or the second mixture may be added to compound (II) and mixed.

[0458] The temperature at which the second mixture is brought into contact with compound (II) is preferably -10 to 50°C, more preferably -5 to 40°C, even more preferably -2 to 30°C, and even more preferably 0 to 30°C.

[0459] The time for contacting the second mixture with compound (II) is preferably 1 to 48 hours, more preferably 1 to 36 hours, and even more preferably 1 to 24 hours.

[0460] The contact of the second mixture with compound (II) can be carried out, for example, under an inert atmosphere (for example, under an argon atmosphere or a nitrogen atmosphere).

[0461] An additional solvent may be added when the second mixture is brought into contact with compound (II). An organic solvent is preferably used as the additional solvent. One organic solvent may be used alone, or a mixture of two or more organic solvents may be used. Specific examples of the organic solvent are the same as those described above. The organic solvent is preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, diglyme, dichloromethane, toluene, xylene, hexane, and heptane, and more preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, dichloromethane, and toluene.

[0462] The above conditions for contacting the second mixture with compound (II) can be combined as appropriate.

[0463] Third Embodiment In the third embodiment, the step (S1) comprises the following steps: (S1e) preparing a third mixture containing compound (II), magnesium or magnesium activated with a magnesium activator, and optionally LiCl; and (S1f) contacting the third mixture with a copper salt and a halide (VII) to produce compound (I). Includes.

[0464] In step (S1f), a Grignard reagent (III) is formed, the Grignard reagent (III) reacts with a copper salt to form an organocopper reagent, and the organocopper reagent reacts with compound (II) to form compound (I). The reaction between the organocopper reagent and compound (II) is thought to contribute to an improvement in the yield of compound (I). In addition, the coordination of the copper salt to compound (II) forms a copper complex, which activates the carbonyl group (=O) of compound (II) and accelerates the reaction between compound (II) and the organocopper reagent. This is also thought to contribute to an improvement in the yield of compound (I).

[0465] <Process (S1e)> The third mixture can be prepared by mixing compound (II), magnesium or magnesium activated with a magnesium activator, and optionally LiCl. The order of adding the components is not particularly limited. For example, the third mixture can be prepared by activating magnesium with a magnesium activator, and then adding compound (II) and optionally LiCl to the magnesium activated with the magnesium activator and mixing them. When compound (II) and LiCl are added to magnesium activated with a magnesium activator, compound (II) may be added first and then LiCl may be added, or LiCl may be added first and then compound (II).

[0466] As magnesium, simple magnesium can be used. The magnesium may be in the form of powder, strips, or cuttings. The amount of magnesium used is preferably 1 to 4 mol, more preferably 1 to 3 mol, and even more preferably 1 to 2.5 mol, per mol of Compound (II).

[0467] Examples of magnesium activators include 1,2-dibromoethane, bromine, iodine, trimethylsilyl chloride, and diisobutylaluminum halide (DIBAL-H), among which 1,2-dibromoethane, bromine, and DIBAL-H are preferred. One type of magnesium activator may be used alone, or two types of magnesium activators may be used in combination.

[0468] The magnesium activated with a magnesium activator can be prepared by contacting magnesium with a magnesium activator. The magnesium activated with a magnesium activator is a mixture of magnesium and a magnesium activator.

[0469] The amount of magnesium activator used is preferably 0.001 to 1.5 mol, more preferably 0.05 to 1.2 mol, and even more preferably 0.05 to 1 mol, per mol of magnesium. The "amount of magnesium activator used" means the amount of one magnesium activator used when one type of magnesium activator is used, and means the total amount of two or more magnesium activators used when two or more types of magnesium activators are used.

[0470] The third mixture may contain LiCl. When the third mixture does not contain LiCl, Grignard reagent (IIIa) is formed in step (S1f). When the third mixture contains LiCl, Grignard reagent (IIIb) is formed in step (S1f).

[0471] The amount of LiCl used is preferably 0.1 to 10 mol, more preferably 0.5 to 5 mol, and even more preferably 0.8 to 4 mol, per mol of Compound (II).

[0472] The mixing temperature when preparing the third mixture is preferably from -10 to 120°C, more preferably from -5 to 100°C, and even more preferably from -5 to 90°C.

[0473] The mixing time when preparing the third mixture is preferably 0.1 to 10 hours, more preferably 0.2 to 5 hours, and even more preferably 0.4 to 4 hours.

[0474] The mixing when preparing the third mixture can be carried out, for example, under an inert atmosphere (for example, under an argon atmosphere or a nitrogen atmosphere).

[0475] The mixing for preparing the third mixture is preferably carried out in a solvent.

[0476] When the mixing for preparing the third mixture is carried out in a solvent, it is preferable to dissolve LiCl in a solvent to prepare a LiCl solution, and then contact Compound (II), magnesium or magnesium activated with a magnesium activator, and the LiCl solution, thereby further increasing the yield of the target compound (I).

[0477] When compound (II), magnesium or magnesium activated with a magnesium activator, and a LiCl solution are brought into contact with each other, compound (II) may be added to the LiCl solution, followed by the addition of magnesium and, optionally, the addition of a magnesium activator, or magnesium and, optionally, the addition of a magnesium activator to the LiCl solution, followed by the addition of compound (II).

[0478] An organic solvent is preferably used as the solvent used in the mixing step for preparing the third mixture or in the production of the LiCl solution. One organic solvent may be used alone, or a mixture of two or more organic solvents may be used. Specific examples of the organic solvent are as described above. The organic solvent is preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, diglyme, dichloromethane, toluene, xylene, hexane, and heptane, and more preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, dichloromethane, and toluene.

[0479] The amount of the solvent used in mixing to prepare the third mixture or in producing the LiCl solution is preferably 3 to 100 mL, more preferably 4 to 50 mL, and even more preferably 5 to 30 mL, per 1 g of compound (II).

[0480] The above-mentioned conditions for mixing when preparing the third mixture can be combined as appropriate.

[0481] <Process (S1f)> The third mixture can be contacted with the copper salt and the halide (VII) by mixing them with the copper salt and the halide (VII). The order of addition of the components is not particularly limited. For example, the third mixture and the copper salt may be mixed, and then the halide (VII) may be added to the resulting mixture, or the third mixture and the halide (VII) may be mixed, and then the copper salt may be added to the resulting mixture, and then mixed. When mixing the third mixture and the copper salt, the copper salt may be added to the third mixture and then mixed, or the third mixture may be added to the copper salt and then mixed. When mixing the third mixture and the halide (VII), the halide (VII) may be added to the third mixture and then mixed, or the third mixture may be added to the halide (VII) and then mixed.

[0482] When the third mixture is contacted with the copper salt and the halide (VII), the halide (VII) is preferably added dropwise. This allows for efficient (preferably complete) conversion of the Grignard reagent (III) to the organocopper reagent. Furthermore, as described below, this also prevents overreaction.

[0483] When the third mixture is contacted with the copper salt and the halide (VII), a Grignard reagent (III) is formed, the Grignard reagent (III) reacts with the copper salt to form an organocopper reagent, and the organocopper reagent reacts with compound (II) to form compound (I). If additional halide (VII) is added before the reaction between the organocopper reagent and compound (II) is complete, an over-reaction between the Grignard reagent (III) formed from the additional halide (VII) and the formed compound (I) (a reaction in which the formed compound (I) reacts with the Grignard reagent (III) formed from the additional halide (VII) to form an alcohol) may occur. When the third mixture is contacted with the copper salt and the halide (VII), adding the halide (VII) dropwise can prevent such an over-reaction.

[0484] The amount of halide (VII) used is preferably 3 to 5 moles, more preferably 2 to 3 moles, and even more preferably 1 to 2 moles, per mole of compound (II).

[0485] The temperature when the third mixture, the copper salt, and the halide (VII) are brought into contact with each other is preferably -10 to 50°C, more preferably -5 to 40°C, even more preferably -2 to 30°C, and even more preferably 0 to 30°C.

[0486] The time for which the third mixture, the copper salt, and the halide (VII) are contacted is preferably 0.5 to 10 hours, more preferably 1 to 5 hours, and even more preferably 2 to 4 hours.

[0487] The contact of the third mixture with the copper salt and the halide (VII) can be carried out, for example, under an inert atmosphere (for example, under an argon atmosphere or a nitrogen atmosphere).

[0488] An additional solvent may be added when the third mixture, the copper salt, and the halide (VII) are brought into contact with each other. An organic solvent is preferably used as the additional solvent. One organic solvent may be used alone, or a mixture of two or more organic solvents may be used. Specific examples of the organic solvent are the same as those described above. The organic solvent is preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, diglyme, dichloromethane, toluene, xylene, hexane, and heptane, and more preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, dichloromethane, and toluene.

[0489] The above conditions for contacting the third mixture with the copper salt and the halide (VII) can be combined as appropriate.

[0490] <Fourth embodiment> In the fourth embodiment, the step (S1) comprises the following steps: (S1g) preparing a fourth mixture containing compound (II) and halide (VII); and (S1h) contacting the fourth mixture with a copper salt and a Grignard reagent (VIII) to produce compound (I). Includes.

[0491] In step (S1h), a Grignard reagent (IIIb) is formed, the Grignard reagent (IIIb) reacts with a copper salt to form an organocopper reagent, and the organocopper reagent reacts with compound (II) to form compound (I). The reaction between the organocopper reagent and compound (II) is thought to contribute to an improvement in the yield of compound (I). In addition, the coordination of the copper salt to compound (II) forms a copper complex, which activates the carbonyl group (=O) of compound (II) and accelerates the reaction between compound (II) and the organocopper reagent. This is also thought to contribute to an improvement in the yield of compound (I).

[0492] <Process (S1g)> The fourth mixture can be prepared by mixing the compound (II) and the halide (VII). The order of adding the components is not particularly limited.

[0493] The amount of halide (VII) used is preferably 3 to 5 moles, more preferably 2 to 3 moles, and even more preferably 1 to 2 moles, per mole of compound (II).

[0494] The temperature at which compound (II) and halide (VII) are mixed is preferably -10 to 50°C, more preferably -5 to 40°C, even more preferably -2 to 30°C, and even more preferably 0 to 30°C.

[0495] The time for mixing compound (II) and halide (VII) is preferably 0.5 to 10 hours, more preferably 1 to 5 hours, and even more preferably 2 to 4 hours.

[0496] The compound (II) and the halide (VII) can be mixed, for example, under an inert atmosphere (for example, under an argon atmosphere or a nitrogen atmosphere).

[0497] The compound (II) and the halide (VII) are preferably mixed in a solvent. An organic solvent is preferably used as the solvent. One organic solvent may be used alone, or a mixed solvent of two or more organic solvents may be used. Specific examples of the organic solvent are as described above. The organic solvent is preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, diglyme, dichloromethane, toluene, xylene, hexane, and heptane, and more preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, dichloromethane, and toluene.

[0498] The amount of the solvent used is preferably 3 to 100 mL, more preferably 4 to 50 mL, and even more preferably 5 to 30 mL, per 1 g of Compound (II).

[0499] The above conditions for mixing the compound (II) and the halide (VII) can be combined as appropriate.

[0500] <Process (S1h)> The fourth mixture, the copper salt, and the Grignard reagent (VIII) can be brought into contact with each other by mixing them. The order of addition of the components is not particularly limited. For example, the fourth mixture and the copper salt may be mixed, and then the Grignard reagent (VIII) may be added to the resulting mixture and mixed therewith, or the fourth mixture and the Grignard reagent (VIII) may be mixed, and then the copper salt may be added and mixed therewith. When mixing the fourth mixture and the copper salt, the copper salt may be added to the fourth mixture and mixed therewith, or the fourth mixture may be added to the copper salt and mixed therewith. When mixing the fourth mixture and the Grignard reagent (VIII), the Grignard reagent (VIII) may be added to the fourth mixture and mixed therewith, or the fourth mixture may be added to the Grignard reagent (VIII) and mixed therewith.

[0501] When the fourth mixture, the copper salt, and the Grignard reagent (VIII) are brought into contact with each other, the Grignard reagent (VIII) is preferably added dropwise. This allows for efficient (preferably complete) conversion of the Grignard reagent (IIIb) to the organocopper reagent. Furthermore, as described below, this also prevents overreaction.

[0502] When the fourth mixture is contacted with the copper salt and the Grignard reagent (VIII), a Grignard reagent (IIIb) is formed, the Grignard reagent (IIIb) reacts with the copper salt to form an organocopper reagent, and the organocopper reagent reacts with compound (II) to form compound (I). If additional Grignard reagent (VIII) is added before the reaction between the organocopper reagent and compound (II) is complete, an over-reaction between the Grignard reagent (IIIb) formed from the additional Grignard reagent (VIII) and the formed compound (I) (a reaction in which the formed compound (I) reacts with the Grignard reagent (IIIb) formed from the additional Grignard reagent (VIII) to form an alcohol) may occur. When the fourth mixture is contacted with the copper salt and the Grignard reagent (VIII), adding the Grignard reagent (VIII) dropwise can effectively prevent such an over-reaction.

[0503] The amount of Grignard reagent (VIII) used is preferably 3 to 5 moles, more preferably 2 to 3 moles, and even more preferably 1 to 2 moles, per mole of compound (II).

[0504] The temperature when the fourth mixture, the copper salt, and the Grignard reagent (VIII) are brought into contact with each other is preferably -10 to 50°C, more preferably -5 to 40°C, even more preferably -2 to 30°C, and even more preferably 0 to 30°C.

[0505] The time for which the fourth mixture, the copper salt, and the Grignard reagent (VIII) are contacted is preferably 3 to 5 hours, more preferably 2 to 3 hours, and even more preferably 1 to 2 hours.

[0506] The contact of the fourth mixture with the copper salt and the Grignard reagent (VIII) can be carried out, for example, under an inert atmosphere (for example, under an argon atmosphere or a nitrogen atmosphere).

[0507] An additional solvent may be added when the fourth mixture, the copper salt, and the Grignard reagent (VIII) are brought into contact with each other. An organic solvent is preferably used as the additional solvent. One organic solvent may be used alone, or a mixture of two or more organic solvents may be used. Specific examples of the organic solvent are the same as those described above. The organic solvent is preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, diglyme, dichloromethane, toluene, xylene, hexane, and heptane, and more preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, dichloromethane, and toluene.

[0508] The above conditions for contacting the fourth mixture, the copper salt, and the Grignard reagent (VIII) can be combined as appropriate.

[0509] <Second mode> A second aspect of the present invention is a method for producing a pharmaceutical composition comprising the steps of: (S2) A step of producing compound (I-1) by contacting compound (II-1) with Grignard reagent (III) in the absence of a copper salt. The second aspect of the present invention differs from the first aspect of the present invention in that no copper salt is used.

[0510] As compound (II-1), either compound (IIa-1) or (IIb-1) may be used, or both compounds (IIa-1) and (IIb-1) may be used. The "amount of compound (II-1) used" means the amount of one compound used when one compound is used as compound (II-1), and means the total amount of two or more compounds used when two or more compounds are used as compound (II-1).

[0511] As the Grignard reagent (III), either the Grignard reagent (IIIa) or (IIIb) may be used, or both the Grignard reagents (IIIa) and (IIIb) may be used. When both the Grignard reagents (IIIa) and (IIIb) are used, the amount of the Grignard reagent (IIIb) used is, for example, 10% by mass or more and 90% by mass or less based on the total mass of the Grignard reagents (IIIa) and (IIIb). The "amount of the Grignard reagent (III) used" means the amount of the Grignard reagent used when one type of Grignard reagent is used as the Grignard reagent (III), and means the total amount of the two or more Grignard reagents used when two or more types of Grignard reagents are used as the Grignard reagent (III).

[0512] In the second aspect of the present invention, the yield of compound (I-1) can be improved under mild reaction conditions that do not require low temperatures by contacting compound (II-1) with Grignard reagent (III) in the absence of a copper salt.

[0513] From the viewpoint of more effectively improving the yield of compound (I-1), the amount of Grignard reagent (III) used is preferably 0.5 to 3 mol, more preferably 0.7 to 2 mol, and even more preferably 0.8 to 1.5 mol, per 1 mol of compound (II-1).

[0514] When using Grignard reagent (IIIb), the amount of LiCl used is preferably 0.1 to 10 mol, more preferably 0.5 to 5 mol, and even more preferably 0.8 to 4 mol per mol of compound (II-1). When LiCl is used, as described above, it is preferable to dissolve LiCl in a solvent (preferably an organic solvent) to prepare a LiCl solution, and then contact halide (VII), magnesium or magnesium activated with a magnesium activator, and the LiCl solution to prepare Grignard reagent (IIIb). This can further increase the yield of the target compound (I-1).

[0515] From the viewpoint of more effectively improving the yield of compound (I-1), the temperature at which compound (II-1) is contacted with Grignard reagent (III) to produce compound (I-1) is preferably −10 to 50° C., more preferably −5 to 40° C., even more preferably −2 to 30° C., and even more preferably 0 to 30° C.

[0516] The time for contacting compound (II-1) with Grignard reagent (III) is preferably 0.5 to 48 hours, more preferably 1 to 36 hours, and even more preferably 1 to 24 hours.

[0517] The contact of compound (II-1) with Grignard reagent (III) can be carried out, for example, under an inert atmosphere (for example, under an argon atmosphere or a nitrogen atmosphere).

[0518] The contact between compound (II-1) and Grignard reagent (III) is preferably carried out in a solvent. Compound (II-1) and Grignard reagent (III) can be contacted by mixing them in a solvent. An organic solvent is preferably used as the solvent. One organic solvent may be used alone, or a mixed solvent of two or more organic solvents may be used. Specific examples of organic solvents are as described above. The organic solvent is preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, diglyme, dichloromethane, toluene, xylene, hexane, and heptane, and more preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, dichloromethane, and toluene.

[0519] The amount of the solvent used is preferably 1 to 100 mL, more preferably 3 to 20 mL, and even more preferably 5 to 10 mL per 1 g of compound (II-1).

[0520] The compound (II-1) and the Grignard reagent (III) may each be a commercially available product or may be prepared according to a conventional method.

[0521] Compound (IIa-1) can be produced by a method comprising contacting compound (IV-1) with compound (Va) in the presence of a base. Compound (IIb-1) can be produced by a method comprising contacting compound (IV-1) with compound (Vb) in the presence of a base. The details of these methods are as described above.

[0522] The method for producing compound (I-1) comprises the following steps: (T2a) a step of contacting compound (IV-1) with compound (Va) in the presence of a base to produce compound (IIa-1); or (T2b) A step of producing compound (IIb-1) by contacting compound (IV-1) with compound (Vb) in the presence of a base. The process may further comprise the steps of: Step (T2a) is carried out before step (S2), and compound (IIa-1) produced in step (T2a) is used in step (S2); Step (T2b) is carried out before step (S2), and compound (IIb-1) produced in step (T2b) is used in step (S2).

[0523] Compound (IV-1) can be produced by a method comprising the step of contacting compound (VI-1) with a chlorinating agent, as described above.

[0524] The method for producing compound (I-1) comprises the following steps: (U2) A step of producing compound (IV-1) by contacting compound (VI-1) with a chlorinating agent Step (U2) may be carried out before step (T2a) or (T2b), and compound (IV-1) produced in step (U2) is used in step (T2a) or (T2b).

[0525] Grignard reagent (IIIa) or (IIIb) can be produced by a method including a step of contacting halide (VII), magnesium or magnesium activated with a magnesium activator, and optionally LiCl. The method is described above. When LiCl is used, it is preferable to first dissolve LiCl in a solvent (preferably an organic solvent) to produce a LiCl solution, as described above, and then contact halide (VII), magnesium or magnesium activated with a magnesium activator, and the LiCl solution to produce Grignard reagent (IIIb). This can further increase the yield of the target compound (I-1).

[0526] Grignard reagent (IIIb) can be prepared by a method comprising contacting halide (VII) with Grignard reagent (VIII), as described above.

[0527] The method for producing compound (I-1) comprises the following steps: (W2a) contacting halide (VII) with magnesium or magnesium activated with a magnesium activator, and optionally with LiCl to produce Grignard reagent (IIIa) or (IIIb); or (W2b) A step of contacting a halide (VII) with a Grignard reagent (VIII) to produce a Grignard reagent (IIIb). The process may further comprise the steps of: Step (W2a) is carried out before step (S2), and the Grignard reagent (IIIa) or (IIIb) produced in step (W2a) is used in step (S2); Step (W2b) is carried out before step (S2), and the Grignard reagent (IIIb) produced in step (W2b) is used in step (S2).

[0528] When the method for producing compound (I-1) includes step (W2a) and LiCl is used in step (W2a), it is preferable to dissolve LiCl in a solvent (preferably an organic solvent) to produce a LiCl solution, and then contact halide (VII), magnesium or magnesium activated with a magnesium activator, and the LiCl solution to produce Grignard reagent (IIIb). This can further increase the yield of the target compound (I-1).

[0529] Compound (I-1) can be isolated from the reaction mixture by a conventional method. For example, a quenching liquid such as water is added to the reaction mixture to quench the reaction, the reaction mixture is filtered, the filtrate is washed with an organic solvent such as ethyl acetate, the organic layer is separated, the organic layer is washed with a brine solution or the like, dried over anhydrous sodium sulfate or the like, filtered, and the filtrate is concentrated to obtain a crude product. Compound (I-1) can be isolated by purifying the crude product by silica gel column chromatography or the like.

[0530] The structure of compound (I-1) can be confirmed, for example, by nuclear magnetic resonance (NMR) spectroscopic analysis.

[0531] Hereinafter, an embodiment of step (S2) will be described.

[0532] First Embodiment In the first embodiment, the step (S2) comprises the following steps: (S2a) preparing a fifth mixture containing compound (II-1), magnesium or magnesium activated with a magnesium activator, and optionally LiCl; and (S2b) a step of contacting the fifth mixture with halide (VII) to produce compound (I-1) Includes:

[0533] In step (S2b), a Grignard reagent (IIIb) is formed, and the formed Grignard reagent (IIIb) reacts with compound (II-1) to form compound (I-1).

[0534] <Process (S2a)> Step (2a) can be carried out in the same manner as step (S1e), except that no copper salt is used and compound (II-1) is used instead of compound (II). The above explanation for step (S1e) also applies to step (S2a). In this explanation, "compound (II)" is replaced with "compound (II-1)" and "third mixture" is replaced with "fifth mixture."

[0535] When LiCl is used in step (S2a), it is preferable to prepare a LiCl solution by dissolving LiCl in a solvent (preferably an organic solvent) as described above, and then contact compound (II-1), magnesium or magnesium activated with a magnesium activator, and the LiCl solution to prepare a fifth mixture, which can further increase the yield of the target compound (I-1).

[0536] When compound (II-1), magnesium or magnesium activated with a magnesium activator, and a LiCl solution are brought into contact with each other, compound (II-1) may be added to the LiCl solution, followed by the addition of magnesium and, optionally, the addition of a magnesium activator; alternatively, magnesium and, optionally, the addition of a magnesium activator to the LiCl solution, followed by the addition of compound (II-1).

[0537] <Process (S2b)> Step (2b) can be carried out in the same manner as step (S1f), except that the fifth mixture is used instead of the third mixture. The above explanation for step (S1f) also applies to step (S2b). When applied, "compound (II)" should be read as "compound (II-1)", "third mixture" as "fifth mixture", and "compound (I)" as "compound (I-1)".

[0538] Second Embodiment In the second embodiment, the step (S2) comprises the following steps: (S2c) preparing a sixth mixture containing compound (II-1) and halide (VII); and (S2d) contacting the sixth mixture with Grignard reagent (VIII) to produce compound (I-1) Includes.

[0539] In step (S2d), a Grignard reagent (IIIb) is formed, and the formed Grignard reagent (IIIb) reacts with compound (II-1) to form compound (I-1).

[0540] <Process (S2c)> Step (2c) can be carried out in the same manner as step (S1g), except that no copper salt is used and compound (II-1) is used instead of compound (II). The above explanation for step (S1g) also applies to step (S2c). In this explanation, "compound (II)" is replaced with "compound (II-1)" and "fourth mixture" is replaced with "sixth mixture."

[0541] <Process (S2d)> Step (2d) can be carried out in the same manner as step (S1h), except that the sixth mixture is used instead of the fourth mixture. The above explanation for step (S1h) also applies to step (S2d). When applied, "compound (II)" should be read as "compound (II-1)", "fourth mixture" as "sixth mixture", and "compound (I)" as "compound (I-1)". [Example]

[0542] Examples of the present invention will be described below. Hereinafter, "THF" represents tetrahydrofuran, "Ac" represents an acetyl group, and "Et" represents an ethyl group.

[0543] <Production Example 1> Compound 2a ((2R,3R,4S,5R)-6-oxo-6-(pyridin-2-ylthio)hexane-1,2,3,4,5-pentyl pentaacetate) was produced from compound 1 ((2R,3S,4R,5R)-2,3,4,5,6-pentaacetoxyhexanoic acid) according to the following reaction scheme.

[0544] [ka]

[0545] To a solution of compound 1 (700 mg, 1.722 mmol, 1.0 equiv.) in dichloromethane (7 mL), N,N-dimethylformamide (DMF) (just 2-3 drops, approximately 0.05 equiv.) was added at 0 °C, followed by the addition of oxalyl chloride (437 mg, 3.448 mmol, 2.0 equiv.) at 0 °C. The reaction mixture was stirred at room temperature under an argon atmosphere for 2 h. The progress of the reaction was monitored by TLC. The reaction mixture was evaporated and co-distilled with toluene (3.0 mL). The residue was then dried under vacuum for 2 h to give (2R,3R,4S,5R)-6-chloro-6-oxohexane-1,2,3,4,5-pentyl pentaacetate.

[0546] Under an argon atmosphere, 2-mercaptopyridine (383 mg, 3.448 mmol, 2.0 equiv.) and dichloromethane (6 mL) were added to an oven-dried Schlenk tube. Then, under an argon atmosphere, triethylamine (EtN) (264 mL, 1.896 mmol, 1.1 equiv.) was added dropwise to the reaction mixture at 0 °C. Then, under an argon atmosphere, (2R,3R,4S,5R)-6-chloro-6-oxohexane-1,2,3,4,5-pentyl pentaacetate was added dropwise to the reaction mixture using THF (2 mL × 1) at 0 °C. The reaction temperature was gradually raised to room temperature and stirred at room temperature for 4 hours. The progress of the reaction was monitored by TLC. Water (5 mL) was added to the reaction mixture to quench the reaction, followed by the addition of ethyl acetate (25 mL), and the organic layer was separated. The organic layer was washed with brine solution (15 mL×5), dried over anhydrous sodium sulfate, and filtered. The solvent was removed by vacuum to give 820 mg (quantitative yield) of compound 2a as a brown sticky solid.

[0547] The analytical results of the obtained compound 2a are shown below. 1H NMR(500MHz, CDCl3, 25℃):δ 8.62(ddd,J=4.8,1.9,0.8Hz,1H),7.76(td,J=7.7,1.9Hz,1H),7.57-7.55(m,1H),7. 32(ddd,J=7.7,4.8,1.1Hz,1H),5.70(dd,J=5.1,3.7Hz,1H),5.63(d,J=3.7Hz,1H),5. 52(dd,J=6.3,5.2Hz,1H),5.12-5.03(m,1H),4.31(dd,J=12.2,4.5Hz,1H),4.14(dd, J=12.2,5.3Hz,1H),2.31(s,3H),2.13(s,3H),2.11(s,3H),2.09(s,3H),2.06(s,3H). 13 C NMR(125MHz, CDCl3, 25℃):δ 194.02,170.54,169.85,169.74,169.60,150.67,137.48,130.43,124.0 6,76.00,69.43,68.90,68.56,61.39,20.82,20.79,20.74,20.67,20.52. HRMS: [M+H] + C 21 H 26 NO 11 S Calculated value: 500.1221, Measured value: 500.1221.

[0548] Example 1A Compound 3 ((2R,3R,4S,5R)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-oxohexane-1,2,3,4,5-pentyl pentaacetate) was produced from compound 2a ((2R,3R,4S,5R)-6-oxo-6-(pyridin-2-ylthio)hexane-1,2,3,4,5-pentyl pentaacetate) according to the following reaction scheme.

[0549] [ka]

[0550] In an oven-dried Schlenk tube, under an argon atmosphere, 1,2-dibromoethane (0.050 mL, exactly 1-2 drops) was added to a mixture containing magnesium turnings (19 mg, 0.801 mmol, 2.0 equiv.) and THF (3 mL). Then, under an argon atmosphere, 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (156 mg, 0.480 mmol, 1.2 equiv.) was added. The reaction mixture was then refluxed at 75-80 °C for 3 h. After cooling to room temperature, the reaction mixture was transferred to another Schlenk tube using THF (2 mL). Thus, the Grignard reagent (ArMgBr) was prepared.

[0551] In another oven-dried Schlenk tube, under an argon atmosphere, a solution of compound 2a (200 mg, 0.400 mmol, 1.0 equiv.) in THF (2 mL) was added to a solution of CuCl (copper(I) chloride) (12 mg, 0.120 mmol, 0.3 equiv.) in THF (1 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. The Grignard reagent prepared above was added dropwise to the reaction mixture at 0 °C. The total amount of THF in the reaction mixture after the addition of the Grignard reagent was 5 mL. The reaction temperature was gradually raised to room temperature and stirred at room temperature for 24 h. The progress of the reaction was monitored by TLC. Water (2 mL) was added to the reaction mixture to quench the reaction. The reaction mixture was filtered through a Celite pad, the bed was washed with ethyl acetate (10 mL × 2), and the organic layer was separated. The organic layer was washed with brine solution (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The solvent was removed under vacuum to give the crude compound, which was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 9 to 4 / 6) to give 166 mg (71% yield) of compound 3 as an off-white fluffy solid.

[0552] The analytical results of the obtained compound 3 are shown below. 1H NMR(500MHz, CDCl3, 25℃):δ 7.74(d,J=2.1Hz,1H),7.71(dd,J=8.3,2.2Hz,1H),7.47(d,J=8.3Hz,1H),7.12-7.08(m,2H),6.8 4-6.79(m,2H),6.01(d,J=5.1Hz,1H),5.67(dd,J=5.0,4.4Hz,1H),5.46(dd,J=7.0,4.3Hz,1H),5 .10(ddd,J=6.9,5.9,2.9Hz,1H),4.29(dd,J=12.5,2.9Hz,1H),4.11-4.06(m,3H),3.99(q,J=7.0 Hz,2H),2.10(s,3H),2.05(s,3H),2.04(s,3H),2.039(s,3H),1.93(s,3H),1.39(t,J=7.0Hz,3H).

[0553] Example 2A Compound 3 was prepared from compound 2a according to the following reaction scheme.

[0554] [ka]

[0555] In an oven-dried Schlenk tube, under an argon atmosphere, 1,2-dibromoethane (0.050 mL, exactly 1-2 drops) was added to a mixture containing magnesium turnings (19 mg, 0.801 mmol, 2.0 equiv.) and THF (3 mL). Then, under an argon atmosphere, 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (156 mg, 0.480 mmol, 1.2 equiv.) was added. The reaction mixture was then refluxed at 75-80 °C for 3 h. After cooling to room temperature, the reaction mixture was transferred to another Schlenk tube using THF (2 mL). Thus, the Grignard reagent (ArMgBr) was prepared.

[0556] In another oven-dried Schlenk tube, under an argon atmosphere, a solution of compound 2a (200 mg, 0.400 mmol, 1.0 equiv.) in THF (2 mL) was added to a solution of CuCl (4 mg, 0.040 mmol, 0.1 equiv.) in THF (1 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 minutes. The Grignard reagent prepared above was added dropwise to the reaction mixture at 0 °C. The total amount of THF in the reaction mixture after the addition of the Grignard reagent was 5 mL. The reaction temperature was gradually raised to room temperature and stirred at room temperature for 24 hours. The progress of the reaction was monitored by TLC. Water (2 mL) was added to the reaction mixture to quench the reaction. The reaction mixture was filtered through a Celite pad, the bed was washed with ethyl acetate (10 mL × 2), and the organic layer was separated. The organic layer was washed with brine solution (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The solvent was removed under vacuum to give the crude compound. The crude compound was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 9 to 4 / 6) to obtain 167 mg (72% yield) of compound 3 as an off-white fluffy solid. The analytical results of the obtained compound 3 were the same as those in Example 1A.

[0557] Example 3A Compound 3 was prepared from compound 2a according to the following reaction scheme.

[0558] [ka]

[0559] In an oven-dried Schlenk tube, under an argon atmosphere, 1,2-dibromoethane (0.050 mL, exactly 1-2 drops) was added to a mixture containing magnesium turnings (22.4 mg, 0.921 mmol, 2.0 equiv.) and THF (3 mL). Then, under an argon atmosphere, 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (150 mg, 0.460 mmol, 1.0 equiv.) was added. The reaction mixture was then refluxed at 75-80 °C for 3 h. After cooling to room temperature, the reaction mixture was transferred to another Schlenk tube using THF (3.9 mL). Thus, the Grignard reagent (ArMgBr) was prepared.

[0560] In another oven-dried Schlenk tube, under an argon atmosphere, a solution of compound 2a (276 mg, 0.553 mmol, 1.2 equiv.) in THF (2 mL) was added to a solution of CuCl (4.6 mg, 0.046 mmol, 0.1 equiv.) in THF (1 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 minutes. The Grignard reagent prepared above was added dropwise to the reaction mixture at 0 °C. The total amount of THF in the reaction mixture after the addition of the Grignard reagent was 6.9 mL. The reaction temperature was gradually raised to room temperature and stirred at room temperature for 24 hours. The progress of the reaction was monitored by TLC. Water (2 mL) was added to the reaction mixture to quench the reaction. The reaction mixture was filtered through a Celite pad, the bed was washed with ethyl acetate (10 mL × 2), and the organic layer was separated. The organic layer was washed with brine solution (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The solvent was removed under vacuum to give the crude compound. The crude compound was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 9 to 4 / 6) to obtain 201 mg (yield 69%) of compound 3 as an off-white fluffy solid. The analytical results of the obtained compound 3 were the same as those in Example 1A.

[0561] Example 4A Compound 3 was prepared from compound 2a according to the following reaction scheme.

[0562] [ka]

[0563] In an oven-dried Schlenk tube, under an argon atmosphere, 1,2-dibromoethane (0.050 mL, exactly 1-2 drops) was added to a mixture containing magnesium turnings (19 mg, 0.801 mmol, 2.0 equiv.) and THF (3 mL). Then, under an argon atmosphere, 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (156 mg, 0.480 mmol, 1.2 equiv.) was added. The reaction mixture was then refluxed at 75-80 °C for 3 h. After cooling to room temperature, the reaction mixture was transferred to another Schlenk tube using THF (2 mL). Thus, the Grignard reagent (ArMgBr) was prepared.

[0564] In another oven-dried Schlenk tube, under an argon atmosphere, a solution of compound 2a (200 mg, 0.400 mmol, 1.0 equiv.) in THF (2 mL) was added to a solution of CuCl (1.2 mg, 0.012 mmol, 0.03 equiv.) in THF (1 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. The Grignard reagent prepared above was added dropwise to the reaction mixture at 0 °C. The total amount of THF in the reaction mixture after the addition of the Grignard reagent was 5 mL. The reaction temperature was gradually raised to room temperature and stirred at room temperature for 24 h. The progress of the reaction was monitored by TLC. Water (2 mL) was added to the reaction mixture to quench the reaction. The reaction mixture was filtered through a Celite pad, the bed was washed with ethyl acetate (10 mL × 2), and the organic layer was separated. The organic layer was washed with brine solution (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The solvent was removed under vacuum to give the crude compound. The crude compound was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 9 to 4 / 6) to obtain 149 mg (yield 64%) of compound 3 as an off-white fluffy solid. The analytical results of the obtained compound 3 were the same as those in Example 1A.

[0565] Example 5A Compound 3 was produced from compound 2b ((2R,3R,4S,5R)-6-oxo-6-(pyridin-2-yloxy)hexane-1,2,3,4,5-pentyl pentaacetate) according to the following reaction scheme.

[0566] [ka]

[0567] In an oven-dried Schlenk tube, under an argon atmosphere, 1,2-dibromoethane (0.050 mL, exactly 1-2 drops) was added to a mixture containing magnesium turnings (19 mg, 0.827 mmol, 2.0 equiv.) and THF (3 mL). Then, under an argon atmosphere, 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (161 mg, 0.496 mmol, 1.2 equiv.) was added. The reaction mixture was then refluxed at 75-80 °C for 3 h. After cooling to room temperature, the reaction mixture was transferred to another Schlenk tube using THF (2 mL). Thus, the Grignard reagent (ArMgBr) was prepared.

[0568] In another oven-dried Schlenk tube, under an argon atmosphere, a solution of compound 2b (200 mg, 0.413 mmol, 1.0 equiv.) in THF (2 mL) was added to a solution of CuCl (5.5 mg, 0.041 mmol, 0.1 equiv.) in THF (1 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 minutes. The Grignard reagent prepared above was added dropwise to the reaction mixture at 0 °C. The total amount of THF in the reaction mixture after the addition of the Grignard reagent was 5 mL. The reaction temperature was gradually raised to room temperature and stirred at room temperature for 24 hours. The progress of the reaction was monitored by TLC. Water (2 mL) was added to the reaction mixture to quench the reaction. The reaction mixture was filtered through a Celite pad, the bed was washed with ethyl acetate (10 mL × 2), and the organic layer was separated. The organic layer was washed with brine solution (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The solvent was removed under vacuum to give the crude compound. The crude compound was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 9 to 4 / 6) to obtain 155 mg (yield 59%) of compound 3 as an off-white fluffy solid. The analytical results of the obtained compound 3 were the same as those in Example 1A.

[0569] Example 6A Compound 3 was prepared from compound 2a according to the following reaction scheme.

[0570] [ka]

[0571] In an oven-dried Schlenk tube, under an argon atmosphere, 1,2-dibromoethane (0.050 mL, exactly 1-2 drops) was added to a mixture containing magnesium turnings (19 mg, 0.801 mmol, 2.0 equiv.) and THF (3 mL). Then, under an argon atmosphere, 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (156 mg, 0.480 mmol, 1.2 equiv.) was added. The reaction mixture was then refluxed at 75-80 °C for 3 h. After cooling to room temperature, the reaction mixture was transferred to another Schlenk tube using THF (2 mL) and cooled to 0 °C. LiCl (17 mg, 0.400 mmol, 1.0 equiv.) was then added and stirred at room temperature for 1 h. Thus, the Grignard reagent (ArMgBr·LiCl) was prepared.

[0572] In a separate oven-dried Schlenk tube, under an argon atmosphere, a solution of compound 2a (200 mg, 0.400 mmol, 1.0 equiv.) in THF (2 mL) was added to a solution of CuCl (4 mg, 0.040 mmol, 0.1 equiv.) in THF (1 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. The Grignard reagent (ArMgBr·LiCl) prepared above was added dropwise to the reaction mixture at 0 °C. The total amount of THF in the reaction mixture after the addition of the Grignard reagent was 5 mL. The reaction temperature was gradually raised to room temperature and stirred at room temperature for 24 h. The progress of the reaction was monitored by TLC. The reaction mixture was quenched by adding water (2 mL). The reaction mixture was filtered through a Celite pad, the bed was washed with ethyl acetate (10 mL × 2), and the organic layer was separated. The organic layer was washed with brine solution (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The solvent was removed by vacuum pumping to obtain a crude compound. The crude compound was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 9 to 4 / 6) to obtain 172 mg (73% yield) of compound 3 as an off-white fluffy solid. The analytical results of the obtained compound 3 were the same as those in Example 1A.

[0573] Example 7A Compound 3 was prepared from compound 2a according to the following reaction scheme.

[0574] [ka]

[0575] In an oven-dried Schlenk tube, under an argon atmosphere, 1,2-dibromoethane (0.050 mL, exactly 1-2 drops) was added to a mixture containing magnesium turnings (24 mg, 1.001 mmol, 2.0 equiv.) and THF (3 mL). Then, under an argon atmosphere, 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (195 mg, 0.600 mmol, 1.2 equiv.) was added. The reaction mixture was refluxed at 75-80 °C for 3 h. After cooling to room temperature, the reaction mixture was transferred to another Schlenk tube using THF (3.3 mL) and cooled to 0 °C. LiCl (64 mg, 1.501 mmol, 3.0 equiv.) was added and stirred at room temperature for 1 h. Thus, the Grignard reagent (ArMgBr·LiCl) was prepared.

[0576] In a separate oven-dried Schlenk tube, under an argon atmosphere, a solution of compound 2a (250 mg, 0.500 mmol, 1.0 equiv.) in THF (2 mL) was added to a solution of CuCl (49 mg, 0.500 mmol, 1.0 equiv.) in THF (1 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. The Grignard reagent (ArMgBr·LiCl) prepared above was added dropwise to the reaction mixture at 0 °C. The total amount of THF in the reaction mixture after the addition of the Grignard reagent was 6.3 mL. The reaction temperature was gradually raised to room temperature and stirred at room temperature for 20 h. The progress of the reaction was monitored by TLC. The reaction mixture was quenched by adding water (2 mL). The reaction mixture was filtered through a Celite pad, the bed was washed with ethyl acetate (10 mL × 2), and the organic layer was separated. The organic layer was washed with brine solution (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The solvent was removed by vacuum pumping to obtain a crude compound. The crude compound was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 9 to 4 / 6) to obtain 206 mg (yield 64%) of compound 3 as an off-white fluffy solid. The analytical results of the obtained compound 3 were the same as those in Example 1A.

[0577] Example 8A Compound 3 was prepared from compound 2a according to the following reaction scheme.

[0578] [ka]

[0579] In an oven-dried Schlenk tube, under an argon atmosphere, 1,2-dibromoethane (0.050 mL, exactly 1-2 drops) was added to a mixture containing magnesium turnings (19 mg, 0.801 mmol, 2.0 equiv.) and THF (3 mL). Then, under an argon atmosphere, 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (156 mg, 0.480 mmol, 1.2 equiv.) was added. The reaction mixture was then refluxed at 75-80 °C for 3 h. After cooling to room temperature, the reaction mixture was transferred to another Schlenk tube using THF (2 mL). Thus, the Grignard reagent (ArMgBr) was prepared.

[0580] In another oven-dried Schlenk tube, under an argon atmosphere, a solution of compound 2a (200 mg, 0.400 mmol, 1.0 equiv.) in THF (2 mL) was added to a solution of CuCN (copper(I) cyanide) (3.5 mg, 0.040 mmol, 0.1 equiv.) in THF (1 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. The Grignard reagent prepared above was added dropwise to the reaction mixture at 0 °C. The total amount of THF in the reaction mixture after the addition of the Grignard reagent was 5 mL. The reaction temperature was gradually raised to room temperature and stirred at room temperature for 24 h. The progress of the reaction was monitored by TLC. Water (2 mL) was added to the reaction mixture to quench the reaction. The reaction mixture was filtered through a Celite pad, the bed was washed with ethyl acetate (10 mL × 2), and the organic layer was separated. The organic layer was washed with brine solution (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The solvent was removed by vacuum pumping to obtain a crude compound. The crude compound was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 9 to 4 / 6) to obtain 179 mg (76% yield) of compound 3 as an off-white fluffy solid. The analytical results of the obtained compound 3 were the same as those in Example 1A.

[0581] Example 9A Compound 3 was prepared from compound 2a according to the following reaction scheme.

[0582] [ka]

[0583] In an oven-dried Schlenk tube, under an argon atmosphere, 1,2-dibromoethane (0.050 mL, exactly 1-2 drops) was added to a mixture containing magnesium turnings (19 mg, 0.801 mmol, 2.0 equiv.) and THF (3 mL). Then, under an argon atmosphere, 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (195 mg, 0.600 mmol, 1.5 equiv.) was added. The reaction mixture was then refluxed at 75-80 °C for 3 h. After cooling to room temperature, the reaction mixture was transferred to another Schlenk tube using THF (2 mL). Thus, the Grignard reagent (ArMgBr) was prepared.

[0584] In another oven-dried Schlenk tube, under an argon atmosphere, a solution of compound 2a (200 mg, 0.400 mmol, 1.0 equiv.) in THF (2 mL) was added to a solution of CuCN (3.5 mg, 0.040 mmol, 0.1 equiv.) in THF (1 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 minutes. The Grignard reagent prepared above was added dropwise to the reaction mixture at 0 °C. The total amount of THF in the reaction mixture after the addition of the Grignard reagent was 5 mL. The reaction temperature was gradually raised to room temperature and stirred at room temperature for 24 hours. The progress of the reaction was monitored by TLC. Water (2 mL) was added to the reaction mixture to quench the reaction. The reaction mixture was filtered through a Celite pad, the bed was washed with ethyl acetate (10 mL × 2), and the organic layer was separated. The organic layer was washed with brine solution (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The solvent was removed under vacuum to give the crude compound. The crude compound was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 9 to 4 / 6) to obtain 200 mg (79% yield) of compound 3 as an off-white fluffy solid. The analytical results of the obtained compound 3 were the same as those in Example 1A.

[0585] <Comparative Example 1A> An attempt was made to produce compound 3 from compound 2a according to the following reaction scheme.

[0586] [ka]

[0587] In an oven-dried Schlenk tube, under an argon atmosphere, 1,2-dibromoethane (0.050 mL, exactly 1-2 drops) was added to a mixture containing magnesium turnings (48 mg, 2.004 mmol, 4.0 equiv.) and THF (3 mL). Then, under an argon atmosphere, 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (374 mg, 1.151 mmol, 2.3 equiv.) was added. The reaction mixture was then refluxed at 75-80 °C for 3 h. After cooling to room temperature, the reaction mixture was transferred to another Schlenk tube using THF (3.3 mL) and cooled to 0 °C. LiCl (23 mg, 0.551 mmol, 1.1 equiv.) was then added and stirred at room temperature for 1 h. Thus, the Grignard reagent (ArMgBr·LiCl) was prepared.

[0588] In a separate oven-dried Schlenk tube, under an argon atmosphere, a solution of compound 2a (250 mg, 0.500 mmol, 1.0 equiv.) in THF (2 mL) was added to a solution of CuCl (74 mg, 0.750 mmol, 1.5 equiv.) in THF (1 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. The Grignard reagent (ArMgBr·LiCl) prepared above was added dropwise to the reaction mixture at room temperature and stirred for 10 min. The total amount of THF in the reaction mixture after the addition of the Grignard reagent was 6.3 mL. The reaction mixture was then stirred at 60 °C for 18 h. The progress of the reaction was monitored by TLC. The reaction was stopped because no formation of compound 3 was observed.

[0589] <Comparative example 2A> An attempt was made to produce compound 3 from compound 2a according to the following reaction scheme.

[0590] [ka]

[0591] In an oven-dried Schlenk tube, under an argon atmosphere, 1,2-dibromoethane (0.050 mL, exactly 1-2 drops) was added to a mixture containing magnesium turnings (48 mg, 2.004 mmol, 4.0 equiv.) and THF (3 mL). Then, under an argon atmosphere, 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (374 mg, 1.151 mmol, 2.3 equiv.) was added. The reaction mixture was then refluxed at 75-80 °C for 3 h. After cooling to room temperature, the reaction mixture was transferred to another Schlenk tube using THF (3.3 mL) and cooled to 0 °C. LiCl (23 mg, 0.551 mmol, 1.1 equiv.) was then added and stirred at room temperature for 1 h. Thus, the Grignard reagent (ArMgBr·LiCl) was prepared.

[0592] In a separate oven-dried Schlenk tube, under an argon atmosphere, a solution of compound 2a (250 mg, 0.500 mmol, 1.0 equiv.) in THF (2 mL) was added to a solution of CuCl (74 mg, 0.750 mmol, 1.5 equiv.) in THF (1 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. The Grignard reagent (ArMgBr·LiCl) prepared above was added dropwise to the reaction mixture at room temperature. The total amount of THF in the reaction mixture after the addition of the Grignard reagent was 6.3 mL. The reaction mixture was stirred at room temperature for 18 h. The progress of the reaction was monitored by TLC. The reaction mixture was quenched by adding water (2 mL). The reaction mixture was filtered through a Celite pad, the bed was washed with ethyl acetate (10 mL × 2), and the organic layer was separated. The organic layer was washed with brine solution (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The solvent was removed in vacuo to give the crude compound. The crude compound was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 9 to 4 / 6) to obtain 101 mg (32% yield) of compound 3 as an off-white fluffy solid. The analytical results of the obtained compound 3 were the same as those in Example 1A.

[0593] <Comparative example 3A> An attempt was made to produce compound 3 from compound 2a according to the following reaction scheme.

[0594] [ka]

[0595] In an oven-dried Schlenk tube, under an argon atmosphere, 1,2-dibromoethane (0.050 mL, exactly 1-2 drops) was added to a mixture containing magnesium turnings (4.8 mg, 0.200 mmol, 2.0 equiv.) and THF (1 mL). Then, under an argon atmosphere, 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (32 mg, 0.100 mmol, 1.0 equiv.) was added. The reaction mixture was then refluxed at 75-80 °C for 3 h. After cooling to room temperature, the reaction mixture was transferred to another Schlenk tube using THF (0.2 mL). Thus, the Grignard reagent (ArMgBr) was prepared.

[0596] In another oven-dried Schlenk tube, under an argon atmosphere, a solution of compound 2a (50 mg, 0.100 mmol, 1.0 equiv.) in THF (0.8 mL) was added to a solution of CuCN (9 mg, 0.100 mmol, 1.0 equiv.) in THF (0.3 mL) at 0°C. The reaction mixture was stirred at 0°C for 10 minutes. The Grignard reagent prepared above was added dropwise to the reaction mixture at -15°C. The total amount of THF in the reaction mixture after the addition of the Grignard reagent was 1.3 mL. The reaction mixture was stirred at -15°C for 2 hours. The progress of the reaction was monitored by TLC. The formation of compound 3 was not observed, so the reaction was stopped.

[0597] <Comparative example 4A> An attempt was made to produce compound 3 from compound 2a according to the following reaction scheme.

[0598] [ka]

[0599] In an oven-dried Schlenk tube, under an argon atmosphere, 1,2-dibromoethane (0.050 mL, exactly 1-2 drops) was added to a mixture containing magnesium turnings (4.8 mg, 0.200 mmol, 2.0 equiv.) and THF (1 mL). Then, under an argon atmosphere, 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (32 mg, 0.100 mmol, 1.0 equiv.) was added. The reaction mixture was then refluxed at 75-80 °C for 3 h. After cooling to room temperature, the reaction mixture was transferred to another Schlenk tube using THF (0.2 mL). Thus, the Grignard reagent (ArMgBr) was prepared.

[0600] In another oven-dried Schlenk tube, under an argon atmosphere, a solution of compound 2a (50 mg, 0.100 mmol, 1.0 equiv.) in THF (0.8 mL) was added to a solution of CuCN (13.4 mg, 0.150 mmol, 1.5 equiv.) in THF (0.3 mL) at 0°C. The reaction mixture was stirred at 0°C for 10 minutes. The Grignard reagent prepared above was added dropwise to the reaction mixture at -15°C. The total amount of THF in the reaction mixture after the addition of the Grignard reagent was 1.3 mL. The reaction mixture was stirred at -15°C for 2 hours. The progress of the reaction was monitored by TLC. Since no product formation was observed, the reaction was stopped.

[0601] <Comparative example 5A> An attempt was made to produce compound 3 from compound 2a according to the following reaction scheme.

[0602] [ka]

[0603] In an oven-dried Schlenk tube, under an argon atmosphere, 1,2-dibromoethane (0.050 mL, exactly 1-2 drops) was added to a mixture containing magnesium turnings (19 mg, 0.801 mmol, 2.0 equiv.) and THF (3 mL). Then, under an argon atmosphere, 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (156 mg, 0.480 mmol, 1.2 equiv.) was added. The reaction mixture was then refluxed at 75-80 °C for 3 h. After cooling to room temperature, the reaction mixture was transferred to another Schlenk tube using THF (2 mL). Thus, the Grignard reagent (ArMgBr) was prepared.

[0604] In another oven-dried Schlenk tube, under an argon atmosphere, a solution of compound 2a (200 mg, 0.400 mmol, 1.0 equiv.) in THF (2 mL) was added to a solution of CuCl (copper(II) chloride) (5.3 mg, 0.040 mmol, 0.1 equiv.) in THF (1 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. The Grignard reagent prepared above was added dropwise to the reaction mixture at 0 °C. The total amount of THF in the reaction mixture after the addition of the Grignard reagent was 5 mL. The reaction temperature was gradually raised to room temperature and stirred at room temperature for 24 h. The progress of the reaction was monitored by TLC. Water (2 mL) was added to the reaction mixture to quench the reaction. The reaction mixture was filtered through a Celite pad, the bed was washed with ethyl acetate (10 mL × 2), and the organic layer was separated. The organic layer was washed with brine solution (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The solvent was removed by vacuum pumping to obtain a crude compound. The crude compound was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 9 to 4 / 6) to obtain 124 mg (49% yield) of compound 3 as an off-white fluffy solid. The analytical results of the obtained compound 3 were the same as those in Example 1A.

[0605] <Comparative Example 6A> An attempt was made to produce compound 3 from compound 2a according to the following reaction scheme.

[0606] [ka]

[0607] In an oven-dried Schlenk tube, under an argon atmosphere, 1,2-dibromoethane (0.050 mL, exactly 1-2 drops) was added to a mixture containing magnesium turnings (19 mg, 0.801 mmol, 2.0 equiv.) and THF (3 mL). Then, under an argon atmosphere, 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (156 mg, 0.480 mmol, 1.2 equiv.) was added. The reaction mixture was then refluxed at 75-80 °C for 3 h. After cooling to room temperature, the reaction mixture was transferred to another Schlenk tube using THF (2 mL). Thus, the Grignard reagent (ArMgBr) was prepared.

[0608] In another oven-dried Schlenk tube, under an argon atmosphere, a solution of compound 2a (200 mg, 0.400 mmol, 1.0 equiv.) in THF (2 mL) was added to a solution of CuTC (copper(I) thiophene-2-carboxylate) (7.6 mg, 0.040 mmol, 0.1 equiv.) in THF (1 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. The Grignard reagent prepared above was added dropwise to the reaction mixture at 0 °C. The total amount of THF in the reaction mixture after the addition of the Grignard reagent was 5 mL. The reaction temperature was gradually raised to room temperature and stirred at room temperature for 24 h. The progress of the reaction was monitored by TLC. Water (2 mL) was added to the reaction mixture to quench the reaction. The reaction mixture was filtered through a Celite pad, the bed was washed with ethyl acetate (10 mL × 2), and the organic layer was separated. The organic layer was washed with brine solution (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The solvent was removed by vacuum pumping to obtain a crude compound. The crude compound was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 9 to 4 / 6) to obtain 142 mg (56% yield) of compound 3 as an off-white fluffy solid. The analytical results of the obtained compound 3 were the same as those in Example 1A.

[0609] <Comparative example 7A> An attempt was made to produce compound 3 from compound 2a according to the following reaction scheme.

[0610] [ka]

[0611] In an oven-dried Schlenk tube, under an argon atmosphere, 1,2-dibromoethane (0.050 mL, exactly 1-2 drops) was added to a mixture containing magnesium turnings (19 mg, 0.801 mmol, 2.0 equiv.) and THF (3 mL). Then, under an argon atmosphere, 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (156 mg, 0.480 mmol, 1.2 equiv.) was added. The reaction mixture was then refluxed at 75-80 °C for 3 h. After cooling to room temperature, the reaction mixture was transferred to another Schlenk tube using THF (2 mL). Thus, the Grignard reagent (ArMgBr) was prepared.

[0612] In another oven-dried Schlenk tube, under an argon atmosphere, a solution of compound 2a (200 mg, 0.400 mmol, 1.0 equiv.) in THF (2 mL) was added to a solution of CuBr (copper(I) bromide) (5.7 mg, 0.040 mmol, 0.1 equiv.) in THF (1 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. The Grignard reagent prepared above was added dropwise to the reaction mixture at 0 °C. The total amount of THF in the reaction mixture after the addition of the Grignard reagent was 5 mL. The reaction temperature was gradually raised to room temperature and stirred at room temperature for 24 h. The progress of the reaction was monitored by TLC. Water (2 mL) was added to the reaction mixture to quench the reaction. The reaction mixture was filtered through a Celite pad, the bed was washed with ethyl acetate (10 mL × 2), and the organic layer was separated. The organic layer was washed with brine solution (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The solvent was removed by vacuum pumping to obtain a crude compound. The crude compound was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 9 to 4 / 6) to obtain 129 mg (51% yield) of compound 3 as an off-white fluffy solid. The analytical results of the obtained compound 3 were the same as those in Example 1A.

[0613] <Comparative Example 8A> An attempt was made to produce compound 3 from compound 2a according to the following reaction scheme.

[0614] [ka]

[0615] In an oven-dried Schlenk tube, under an argon atmosphere, 1,2-dibromoethane (0.050 mL, exactly 1-2 drops) was added to a mixture containing magnesium turnings (19 mg, 0.801 mmol, 2.0 equiv.) and THF (3 mL). Then, under an argon atmosphere, 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (156 mg, 0.480 mmol, 1.2 equiv.) was added. The reaction mixture was then refluxed at 75-80 °C for 3 h. After cooling to room temperature, the reaction mixture was transferred to another Schlenk tube using THF (2 mL). Thus, the Grignard reagent (ArMgBr) was prepared.

[0616] In another oven-dried Schlenk tube, under an argon atmosphere, a solution of compound 2a (200 mg, 0.400 mmol, 1.0 equiv.) in THF (2 mL) was added to a solution of CuI (copper(I) iodide) (7.6 mg, 0.040 mmol, 0.1 equiv.) in THF (1 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 minutes. The Grignard reagent prepared above was added dropwise to the reaction mixture at 0 °C. The total amount of THF in the reaction mixture after the addition of the Grignard reagent was 5 mL. The reaction temperature was gradually raised to room temperature and stirred at room temperature for 24 hours. The progress of the reaction was monitored by TLC. Water (2 mL) was added to the reaction mixture to quench the reaction. The reaction mixture was filtered through a Celite pad, the bed was washed with ethyl acetate (10 mL × 2), and the organic layer was separated. The organic layer was washed with brine solution (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The solvent was removed by vacuum pumping to obtain a crude compound. The crude compound was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 9 to 4 / 6) to obtain 117 mg (46% yield) of compound 3 as an off-white fluffy solid. The analytical results of the obtained compound 3 were the same as those in Example 1A.

[0617] <Comparative example 9A> An attempt was made to produce compound 3 from compound 2a according to the following reaction scheme.

[0618] [ka]

[0619] In an oven-dried Schlenk tube, under an argon atmosphere, 1,2-dibromoethane (0.050 mL, exactly 1-2 drops) was added to a mixture containing magnesium turnings (19 mg, 0.801 mmol, 2.0 equiv.) and THF (3 mL). Then, under an argon atmosphere, 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (156 mg, 0.480 mmol, 1.2 equiv.) was added. The reaction mixture was then refluxed at 75-80 °C for 3 h. After cooling to room temperature, the reaction mixture was transferred to another Schlenk tube using THF (2 mL). Thus, the Grignard reagent (ArMgBr) was prepared.

[0620] In another oven-dried Schlenk tube, under an argon atmosphere, a solution of compound 2a (200 mg, 0.400 mmol, 1.0 equiv.) in THF (2 mL) was added to a solution of FeCl3 (iron(III) chloride) (6.5 mg, 0.040 mmol, 0.1 equiv.) in THF (1 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. The Grignard reagent prepared above was added dropwise to the reaction mixture at 0 °C. The total amount of THF in the reaction mixture after the addition of the Grignard reagent was 5 mL. The reaction temperature was gradually raised to room temperature and stirred at room temperature for 24 h. The progress of the reaction was monitored by TLC. Water (2 mL) was added to the reaction mixture to quench the reaction. The reaction mixture was filtered through a Celite pad, the bed was washed with ethyl acetate (10 mL × 2), and the organic layer was separated. The organic layer was washed with brine solution (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The solvent was removed by vacuum pumping to obtain a crude compound. The crude compound was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 9 to 4 / 6) to obtain 48 mg (yield 19%) of compound 3 as an off-white fluffy solid. The analytical results of the obtained compound 3 were the same as those in Example 1A.

[0621] <Comparative Example 10A> An attempt was made to produce compound 3 from compound 2a according to the following reaction scheme.

[0622] [ka]

[0623] In an oven-dried Schlenk tube, under an argon atmosphere, 1,2-dibromoethane (0.050 mL, exactly 1-2 drops) was added to a mixture containing magnesium turnings (19 mg, 0.801 mmol, 2.0 equiv.) and THF (3 mL). Then, under an argon atmosphere, 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (156 mg, 0.480 mmol, 1.2 equiv.) was added. The reaction mixture was then refluxed at 75-80 °C for 3 h. After cooling to room temperature, the reaction mixture was transferred to another Schlenk tube using THF (2 mL). Thus, the Grignard reagent (ArMgBr) was prepared.

[0624] In another oven-dried Schlenk tube, under an argon atmosphere, a solution of compound 2a (200 mg, 0.400 mmol, 1.0 equiv.) in THF (2 mL) was added to a solution of Fe(acac)3 (iron(III) acetylacetonate) (14 mg, 0.040 mmol, 0.1 equiv.) in THF (1 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. The Grignard reagent prepared above was added dropwise to the reaction mixture at 0 °C. The total amount of THF in the reaction mixture after the addition of the Grignard reagent was 5 mL. The reaction temperature was gradually raised to room temperature and stirred at room temperature for 24 h. The progress of the reaction was monitored by TLC. Water (2 mL) was added to the reaction mixture to quench the reaction. The reaction mixture was filtered through a Celite pad, the bed was washed with ethyl acetate (10 mL × 2), and the organic layer was separated. The organic layer was washed with brine solution (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The solvent was removed by vacuum pumping to obtain a crude compound. The crude compound was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 9 to 4 / 6) to obtain 73 mg (29% yield) of compound 3 as an off-white fluffy solid. The analytical results of the obtained compound 3 were the same as those in Example 1A.

[0625] Example 1B Compound 3 was prepared from compound 2a according to the following reaction scheme.

[0626] [ka]

[0627] In an oven-dried Schlenk tube, under an argon atmosphere, 1,2-dibromoethane (0.050 mL, exactly 1-2 drops) was added to a mixture containing magnesium turnings (19 mg, 0.801 mmol, 2.0 equiv.) and THF (3 mL). Then, under an argon atmosphere, 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (156 mg, 0.480 mmol, 1.2 equiv.) was added. The reaction mixture was then refluxed at 75-80 °C for 3 h. After cooling to room temperature, the reaction mixture was transferred to another Schlenk tube using THF (3 mL). Thus, the Grignard reagent (ArMgBr) was prepared.

[0628] Compound 2a (200 mg, 0.400 mmol, 1.0 equiv.) in THF (2 mL) was added to another oven-dried Schlenk tube under an argon atmosphere at 0°C. The reaction mixture was stirred at 0°C for 10 minutes. The Grignard reagent prepared above was added dropwise to the reaction mixture at 0°C. The total amount of THF in the reaction mixture after the addition of the Grignard reagent was 5 mL. The reaction temperature was gradually raised to room temperature. The reaction mixture was stirred at room temperature for 24 hours. The progress of the reaction was monitored by TLC. Water (2 mL) was added to the reaction mixture to quench the reaction. The reaction mixture was filtered through a Celite pad, the bed was washed with ethyl acetate (10 mL × 2), and the organic layer was separated. The organic layer was washed with brine solution (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The solvent was removed under vacuum to give the crude compound. The crude compound was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 9 to 4 / 6) to obtain 148 mg (yield 63%) of compound 3 as an off-white fluffy solid. The analytical results of the obtained compound 3 were the same as those in Example 1A.

[0629] Example 2B Compound 3 was prepared from compound 2a according to the following reaction scheme.

[0630] [ka]

[0631] In an oven-dried Schlenk tube, under an argon atmosphere, 1,2-dibromoethane (0.050 mL, exactly 1-2 drops) was added to a mixture containing magnesium turnings (24 mg, 1.001 mmol, 2.0 equiv.) and THF (3 mL). Then, under an argon atmosphere, 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (195 mg, 0.600 mmol, 1.2 equiv.) was added. The reaction mixture was then refluxed at 75-80 °C for 3 h. After cooling to room temperature, the reaction mixture was transferred to another Schlenk tube using THF (4.3 mL) and cooled to 0 °C. LiCl (64 mg, 1.501 mmol, 3.0 equiv.) was added and stirred at room temperature for 1 h. Thus, the Grignard reagent (ArMgBr·LiCl) was prepared.

[0632] In a separate oven-dried Schlenk tube, a solution of compound 2a (250 mg, 0.500 mmol, 1.0 equiv.) in THF (2 mL) was added at 0 °C under an argon atmosphere. The reaction mixture was stirred at 0 °C for 10 min. The Grignard reagent (ArMgBr·LiCl) prepared above was added dropwise to the reaction mixture at 0 °C. The total amount of THF in the reaction mixture after the addition of the Grignard reagent was 6.3 mL. The reaction temperature was gradually raised to room temperature and stirred at room temperature for 20 h. The progress of the reaction was monitored by TLC. Water (2 mL) was added to the reaction mixture to quench the reaction. The reaction mixture was filtered through a Celite pad, the bed was washed with ethyl acetate (10 mL × 2), and the organic layer was separated. The organic layer was washed with brine solution (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The solvent was removed under vacuum to obtain the crude compound. The crude compound was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 9 to 4 / 6) to obtain 193 mg (yield 60%) of compound 3 as an off-white fluffy solid. The analytical results of the obtained compound 3 were the same as those in Example 1A.

[0633] Example 3B Compound 3 was prepared from compound 2b according to the following reaction scheme.

[0634] [ka]

[0635] In an oven-dried Schlenk tube, under an argon atmosphere, 1,2-dibromoethane (0.050 mL, exactly 1-2 drops) was added to a mixture containing magnesium turnings (19 mg, 0.827 mmol, 2.0 equiv.) and THF (3 mL). Then, under an argon atmosphere, 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (161 mg, 0.496 mmol, 1.2 equiv.) was added. The reaction mixture was then refluxed at 75-80 °C for 3 h. After cooling to room temperature, the reaction mixture was transferred to another Schlenk tube using THF (3 mL). Thus, the Grignard reagent (ArMgBr) was prepared.

[0636] A solution of compound 2b (200 mg, 0.413 mmol, 1.0 equiv.) in THF (2 mL) was added to another oven-dried Schlenk tube under an argon atmosphere at 0 °C. The reaction mixture was stirred at 0 °C for 10 minutes. The Grignard reagent prepared above was added dropwise to the reaction mixture at 0 °C. The total amount of THF in the reaction mixture after the addition of the Grignard reagent was 5 mL. The reaction temperature was gradually raised to room temperature and stirred at room temperature for 24 hours. The progress of the reaction was monitored by TLC. Water (2 mL) was added to the reaction mixture to quench the reaction. The reaction mixture was filtered through a Celite pad, the bed was washed with ethyl acetate (10 mL × 2), and the organic layer was separated. The organic layer was washed with brine solution (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The solvent was removed under vacuum to give the crude compound. The crude compound was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 9 to 4 / 6) to obtain 147 mg (56% yield) of compound 3 as an off-white fluffy solid. The analytical results of the obtained compound 3 were the same as those in Example 1A.

[0637] Example 1C Compound 2a was prepared from compound 1 according to the following reaction scheme.

[0638] [ka]

[0639] Under an argon atmosphere, compound 1 (500 mg, 1.23 mmol, 1.0 equiv.) was dissolved in dichloromethane (DCM) (5 mL) and cooled to 0 °C. To the resulting solution, N,N-dimethylformamide (DMF) (0.005 mL, 0.062 mmol, 0.05 equiv.) was added dropwise, followed by oxalyl chloride (0.211 mL, 2.46 mmol, 2.0 equiv.). The reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was evaporated and then co-evaporated with toluene (2.0 mL). The residue was dried under vacuum for 2 hours to give (2R,3R,4S,5R)-6-chloro-6-oxohexane-1,2,3,4,5-pentyl pentaacetate as an oil.

[0640] Under an argon atmosphere, a solution of 2-mercaptopyridine (2-PySH) (274 mg, 2.46 mmol, 2.0 equiv.) in dichloromethane (DCM) (2 mL) was cooled to 0 °C, and then triethylamine (EtN) (0.189 mL, 1.35 mmol, 1.1 equiv.) was added dropwise, followed by a solution of (2R,3R,4S,5R)-6-chloro-6-oxohexane-1,2,3,4,5-pentyl pentaacetate in dichloromethane (2 mL). The reaction mixture was stirred at room temperature for 4 hours. Ethyl acetate was added to the reaction mixture, and the reaction was quenched by adding water. The organic layer was separated. The organic layer was washed with water to remove 2-mercaptopyridine, washed with brine, dried over anhydrous sodium sulfate, and evaporated. The residue was dried under vacuum for 4 hours to give 722 mg (118% yield) of compound 2a as an oil. The crude compound obtained was used in the next step without further purification.

[0641] Compound 4 ((2R,3R,4S,5R)-6-(4-chloro-3-(4-(((R)-tetrahydrofuran-3-yl)oxo)benzyl)phenyl)-6-oxohexane-1,2,3,4,5-pentylpentaacetate) was produced from compound 2a according to the following reaction scheme.

[0642] [ka]

[0643] In an oven-dried Schlenk tube, (R)-3-(4-(2-chloro-5-iodobenzyl)phenoxy)tetrahydrofuran (ArI) (719 mg, 1.74 mmol, 1.2 equiv.) was dissolved in THF (2 mL) and cooled to −15° C. The resulting solution was added with 1.3 M i PrMgCl LiCl (Aldrich, 1.33 mL, 1.74 mmol, 1.2 equivalents) was added dropwise and stirred for 1 hour to prepare the Grignard reagent (ArMgI LiCl).

[0644] To another oven-dried Schlenk tube, under an argon atmosphere, CuCN (12.9 mg, 0.145 mmol, 0.1 equiv) was added followed by THF (3.5 mL). After cooling the mixture to -15 °C, a solution of compound 2a (722 mg, 1.45 mmol, 1.0 equiv) in THF (7 mL) was added dropwise, and the reaction mixture was maintained for 10 min. The Grignard reagent (ArMgI·LiCl) prepared above was added dropwise to the reaction mixture over 10 min. The reaction temperature was gradually raised to room temperature and stirred at room temperature for 23 h. Ethyl acetate was added to the reaction mixture, followed by the addition of water to quench the reaction. The reaction mixture was filtered through a Celite pad, the bed was washed with ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated NaHCO3 solution, water, and brine solution, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under vacuum to give the crude compound. The crude compound was purified by silica gel column chromatography to obtain 663 mg (yield: 68%, yield from compound 1: 80%) of compound 4 as a pale yellow solid.

[0645] The analytical results of the obtained compound 4 are shown below. 1 H-NMR(500MHz, CDCl3):δ 7.74(d,J=2.0Hz,1H),7.71(dd,J=8.5,2.5Hz,1H),7.47(d,J=8.5Hz,1H),7.10(d,J=9Hz,2H),6.79(d,J =8.7Hz,2H),6.00(d,J=5.0Hz,1H),5.67(dd,J=5.0,4.5Hz,1H),5.45(dd,J=7.0,4.5Hz,1H),5.10(ddd,J =7.0,6.0,3.0Hz,1H),4.91-4.86(m,1H),4.30(dd,J=12.5,3.0Hz,1H),4.12-4.06(m,3H),4.00-3.94(m, 3H), 3.89(td,J=8.0,4.5Hz,1H),2.24-2.13(m,2H),2.10(s,3H),2.05(s,3H),2.05(s,6H),1.94(s,3H). 13 C{ 1 H}-NMR(125MHz, CDCl3):δ 192.4,170.7,169.9,169.7,169.5,156.2,140.4,140.1,133.6,131.0,131.0,130.2,130.1,12 7.6,115.6,73.2,72.4,69.4,68.7,68.6,67.3,61.8,38.4,33.1,20.8,20.8,20.6,20.4,20.4.

[0646] Example 1D (Preparation of Grignard reagent EG-B03MgBr·LiCl) The Grignard reagent EG-B03MgBr·LiCl (4-chloro[4-[(3S)-tetrahydro-3-furyloxy]benzyl]phenylmagnesium bromide·lithium chloride complex) was prepared according to the following reaction scheme.

[0647] [ka]

[0648] Lithium chloride (0.634 g, 14.96 mmol, 1.1 equiv.) was suspended in THF (30 mL, 6 v / w) in an oven-dried flask under a nitrogen atmosphere and stirred at 20–25°C for 30 min. Note that "v / w" refers to the amount (mL) of the liquid used per 1 g of compound EG-B03 (hereinafter the same). After stirring, it was confirmed that the lithium chloride had dissolved. Compound EG-B03 (5.0 g, 13.60 mmol, 1 equiv.), magnesium (0.463 g, 19.04 mmol, 1.4 equiv.), and 1,2-dibromoethane (58.60 μL, 0.68 mmol, 0.05 equiv.) were added sequentially to the resulting lithium chloride solution. The reaction mixture was heated to 60–65°C and stirred for 1.5 h. Completion of the reaction was confirmed by high-performance liquid chromatography (HPLC). In this way, the Grignard reagent EG-B03MgBr·LiCl was produced.

[0649] (Production of Compound EG-A04) Compound EG-A04 ((2R,3R,4S,5R)-6-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-oxohexane-1,2,3,4,5-pentanylpentaethanolate) was prepared according to the following reaction scheme.

[0650] [ka]

[0651] In an oven-dried flask, copper(I) chloride (1.35 g, 13.60 mmol, 1.0 equiv.) and compound 2a (7.81 g, 15.64 mmol, 1.15 equiv.) were dissolved in THF (5 mL, 1 v / w) and toluene (15 mL, 3 v / w). The resulting solution was cooled to 0–10 °C under a nitrogen atmosphere, and the Grignard reagent EG-B03MgBr·LiCl prepared above was added dropwise over 30 min at 0–10 °C. After the dropwise addition, the mixture was stirred at 0–10 °C for 30 min. After stirring, the reaction was quenched with water and filtered through Celite. After washing with ethyl acetate (25 mL, 5 v / w), 10% hydrochloric acid (10 mL, 2 v / w) was added and the mixture was stirred for 3 h. The organic layer was separated from the aqueous layer, washed with saturated aqueous sodium bicarbonate (20 mL, 4 v / w) and saturated brine (20 mL, 4 v / w), and dried over anhydrous sodium sulfate. After drying, the mixture was gravity filtered and the solvent was evaporated to obtain 9.20 g (83.3% yield calculated from the purity) of EG-A04 as a yellow oil.

[0652] The analytical results of the obtained compound EG-A04 ((2R,3R,4S,5R)-6-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-oxohexane-1,2,3,4,5-pentanylpentaethanolate) are shown below. 1 H-NMR(400MHz,CDCl3) δ(ppm):7.79-7.66(m,2H),7.46(d,J=8.3Hz,1H),7.15-7.04(m,2H),6.81-6.70(m 2H),5.99(d,J=5.2Hz,1H),5.66(dd,J=5.1,4.4Hz,1H),5.43(dd,J=7.0,4.3 Hz,1H),5.08(ddd,J=6.9,5.9,2.9Hz,1H),4.87(ddd,J=8.1,4.5,2.3Hz,1H), 4.33-4.23(m,1H),4.10-4.04(m,3H),3.99-3.92(m,3H),3.86(dt,J=11.1,5. 0Hz,1H),2.22-2.10(m,2H),2.09(s,3H),2.03(s,J=1.6Hz,9H),1.92(s,3H). 13 C-NMR (100MHz, CDCl3) δ(ppm):192.35,170.67,169.82,169.65,169.45,156.07,140.28,140.00,133.50,130.95,130.90,130.08,129.98, 127.48,115.48,73.09,72.30,69.28,68.62,68.46,67.17,61.71,38.29,32.98,20.74,20.67,20.51,20.36,20.29. LCMS: [M+Na]+calc. for C 33 H 37 ClNaO 13 =699.1820;found,699.14.

[0653] Example 1E (Preparation of Grignard Reagent EG-B03MgBr·LiCl) The Grignard reagent EG-B03MgBr·LiCl was prepared using compound EG-B03 (25.0 g, 68.0 mmol, 1.0 equivalents) in the same manner as in Example 1D.

[0654] (Production of Compound EG-A04) Compound EG-A04 was prepared according to the following reaction scheme.

[0655] [ka]

[0656] In an oven-dried flask, compound 2a (39.10 g, 78.2 mmol, 1.15 equiv.) was dissolved in THF (25 mL, 1 v / w) and toluene (75 mL, 3 v / w) and cooled to 0–10 °C. Note that "v / w" refers to the amount (mL) of the corresponding liquid used per 1 g of EG-B03 (hereinafter the same). The Grignard reagent EG-B03MgBr·LiCl prepared above was added dropwise over 30 min at 0–10 °C. After the dropwise addition, the mixture was stirred at the same temperature for 30 min. After stirring, 10% hydrochloric acid (75 mL, 3 v / w) was added and the mixture was stirred at room temperature for an additional 2 h. After stirring, ethyl acetate (250 mL, 10 v / w) was added and the mixture was separated. The organic layer was washed with saturated aqueous sodium bicarbonate (100 mL, 4 v / w) and saturated brine (100 mL, 4 v / w) and dried over anhydrous sodium sulfate. After drying, the mixture was filtered and the solvent was distilled off to obtain 45.95 g (yield calculated from purity: 88.10%) of compound EG-A04 as a yellow oily substance. The analytical results of the obtained compound EG-A04 were the same as those of Example 1D.

[0657] <Reference example 1> (Production of Compound EG-A05) Compound EG-A05 ((2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol) was produced according to the following reaction scheme.

[0658] [ka]

[0659] In an oven-dried flask, compound EG-A04 (2.0 g, 2.59 mmol, 1.0 equivalent) was dissolved in THF (20 mL, 10 v / w), and methanesulfonic acid (1.42 g, 12.95 mmol, 5.0 equivalent) dissolved in methanol (20 mL, 10 v / w) was slowly added dropwise at a temperature of -10 to -15°C. Note that "v / w" refers to the amount (mL) of the liquid used per 1 g of compound EG-A04 (the same applies hereinafter). After the dropwise addition, the mixture was stirred at a temperature of -10 to -15°C for 30 minutes, and then at room temperature for 36 hours. The reaction was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate. After drying, the mixture was filtered, and the solvent was evaporated to obtain a crude product. This crude product was purified by silica gel column chromatography to obtain 0.98 g (yield 69%) of compound EG-A05 as a white solid.

[0660] The analytical results of the obtained compound EG-A05 ((2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol) are shown below. 1 H-NMR(500MHz,DMSO-d6) δ(ppm):7.37-7.27(m,2H),7.22(dd,J=8.1,2.0Hz,1H),7.04(d,J=8.5Hz,2H),6.70(d,J=8.7Hz,2H),4.99-4.51 (m,3H),4.19-3.70(m,10H),3.67-3.46(m,2H),3.23-3.10(m,1H),3.06(s,1H),2.89(s,3H),2.21-1.95(m,4H). 13 C-NMR (100MHz, CDCl3) δ(ppm):155.84,138.62,136.73,134.39,131.95,130.01,129.90,129.33,126.80,115.3 8,101.02,77.30,77.27,74.76,73.05,72.60,70.22,67.24,62.07,49.26,38.49,33.00. LCMS: [M+Na]+calc. for C 24 H 29 ClNaO8=503.144;found,503.10.

[0661] <Reference example 2> (Manufacturing of Empagliflozin) Empagliflozin was produced according to the following reaction scheme:

[0662] [ka]

[0663] In an oven-dried flask, compound EG-A05 (0.46 g, 0.956 mmol, 1.0 equivalent) was dissolved in dichloromethane (4.6 mL, 10 v / w) and cooled to -35 to -45°C. Note that "v / w" refers to the amount (mL) of the target liquid used per 1 g of compound EG-A05 (hereinafter the same). Subsequently, triethylsilane (0.250 g, 2.15 mmol, 2.25 equivalents) was added dropwise over 30 minutes. The mixture was then stirred at -35 to -45°C for 2 hours and then at 0 to 5°C for another 2 hours. After the reaction, the reaction was quenched with saturated aqueous sodium bicarbonate solution, and the pH was adjusted to 7 to 8. The organic and aqueous layers were separated, washed with water, and dried over anhydrous sodium sulfate. After drying, the mixture was filtered, and the solvent was removed by distillation to obtain a crude product. This crude product was triturated with methyl t-butyl ether and 2-propanol to obtain 0.320 g (yield 74.2%) of empagliflozin as a white solid.

[0664] The analytical results of the obtained empagliflozin are shown below. 1H-NMR (400 MHz, DMSO-d6) δ(ppm):7.39-7.28(m,2H),7.20(d,J=8.3Hz,1H),7.07(d,J=8.4Hz,2H),6.7 9(d,J=8.6Hz,2H),4.99-4.89(m,3H),4.78(ddd,J=15.0,5.8,1.1Hz,1H),4. 50-4.34(m,1H),4.03-3.89(m,3H),3.73(m,5H),3.41(dt,J=10.5,5.5Hz,1H ),3.30-2.93(m,3H),2.14(dtd,J=14.4,8.2,6.3Hz,1H),1.98-1.77(m,1H). 13 C-NMR(100MHz,DMSO-d6) δ(ppm):155.47,139.69,137.71,131.90,131.55,130.81,129.65,128.65,127.38,115.15,81.20,80.67,78. 28,76.92,74.69,72.27,70.27,66.38,61.33,40.11,39.91,39.70,39.49,39.28,39.07,38.86,37.60,32.43. LCMS: [M+Na]+calc. for C 23 H 27 ClNaO7=473.1343;found,473.09.

[0665] Example 1F (Production of TBS protected compound 1) According to the following reaction scheme, a TBS-protected compound of (4-(4-ethylbenzyl)-2-iodophenyl)methanol (EBIPM), i.e., tert-butyl((4-(4-ethylbenzyl)-2-iodobenzyl)oxy)dimethylsilane (hereinafter referred to as "TBS-protected compound 1"), was produced.

[0666] [ka]

[0667] In an oven-dried flask under argon, (4-(4-ethylbenzyl)-2-iodophenyl)methanol (EBIPM) (352 mg, 0.999 mmol, 1.0 equiv.) was dissolved in 5 mL of dimethylformamide (DMF) and cooled to 0 °C. To the resulting solution, imidazole (ImH) (102 mg, 1.50 mmol, 1.5 equiv.) was added, followed by tert-butyldimethylchlorosilane (TBSCl) (181 mg, 1.20 mmol, 1.2 equiv.). The resulting reaction mixture was warmed to room temperature and stirred overnight. Water was added to the reaction mixture to quench the reaction, followed by dilution with ethyl acetate. The aqueous layer was extracted three times with ethyl acetate. The ethyl acetate used for extraction was collected, washed with brine, dried over anhydrous sodium sulfate (NaSO), and filtered. The ethyl acetate was removed by vacuum pumping. The crude mixture was purified by silica gel column chromatography to give colorless TBS-protected product 1 (422 mg, 91% yield).

[0668] The analytical results of the obtained TBS protected product 1 (tert-butyl((4-(4-ethylbenzyl)-2-iodobenzyl)oxy)dimethylsilane) are shown below. 1 H-NMR(500MHz,CDCl3) δ 7.62(d,J=1.5Hz,1H),7.40(d,J=8.0Hz,1H),7.17(dd,J=8.0,1.5Hz,1H),7.12(d,J=8.5Hz,2H),7.08(d,J=8 .5Hz,2H),4.59(s,2H),3.87(s,2H),2.61(q,J=7.5Hz,2H),1.22(t,J=7.5Hz,3H),0.95(s,9H),0.12(s,6H). 13 C{ 1 H}-NMR(125MHz, CDCl3) δ 142.3,142.0,140.6,138.9,137.7,128.9,128.1,127.4,96.0,69.2,40.6,28.5,26.0,18.5,15.7,-5.2.

[0669] (Production of TBS protected compound 2) According to the following reaction scheme, (2R,3R,4S,5R)-6-(2-(((tert-butyldimethylsilyl)oxy)methyl)-5-(4-ethylbenzyl)phenyl)-6-oxohexane-1,2,3,4,5-pentyl pentaacetate (hereinafter referred to as "TBS protected compound 2") was produced.

[0670] [ka]

[0671] In an oven-dried Schlenk tube, under an argon atmosphere, the TBS-protected compound 1 (ArI) (413 mg, 0.886 mmol, 1.1 equivalents) prepared above was dissolved in THF (0.8 mL) and cooled to -25°C. i PrMgCl LiCl (Aldrich, 0.682 mL, 0.886 mmol, 1.1 equivalents) was added dropwise and stirred for 1 hour to prepare the Grignard reagent (ArMgI LiCl).

[0672] In another oven-dried Schlenk tube, under an argon atmosphere, CuCN (6.6 mg, 0.0738 mmol, 0.09 equiv.) and THF (0.2 mL) were added. CuCN was suspended in THF and cooled to -25 °C. A solution of compound 2a (401 mg, 0.803 mmol, 1.0 equiv.) in THF (1 mL) was added to the suspension, followed by washing twice with THF (0.25 mL). The Grignard reagent prepared above was added dropwise to the washed suspension, and the Schlenk tube containing the Grignard reagent was washed twice with THF (0.25 mL). The resulting reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was quenched with water and diluted with ethyl acetate. The mixture was passed through Celite and washed with ethyl acetate. The organic layer was washed with saturated aqueous NH4Cl (2 mL), water, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated. The resulting crude mixture was purified by silica gel column chromatography to give TBS-protected derivative 2 (306 mg, yield 52%) as a colorless oil.

[0673] The analytical results of the TBS protected product 2 ((2R,3R,4S,5R)-6-(2-(((tert-butyldimethylsilyl)oxy)methyl)-5-(4-ethylbenzyl)phenyl)-6-oxohexane-1,2,3,4,5-pentyl pentaacetate) are shown below. 1 H-NMR(500MHz,CDCl3) δ 7.77(d,J=8.0Hz,0.8H),7.69(d,J=2.0Hz,0.8H),7.49(d,J=8.0Hz,0.2H),7.40(dd,J=8.0,1 .5Hz,0.8H),7.15-7.07(m,4.2H),6.85(d,J=2.0Hz,0.2H),6.10(d,J=5.0Hz,0.8H),5.70(t,J =4.0Hz,0.2H),5.63(t,J=5.0Hz,0.8H),5.61-5.59(m,0.2H),5.52(dd,J=6.5,5.0Hz,0.8H), 5.43(d,J=4.0Hz,0.2H),5.17-5.13(m,0.2H),5.09-5.03(m,1.6H),4.75(d,J=16Hz,0.8H),4. 68(d,J=14.5Hz,0.2H),4.59(d,J=14.5Hz,0.2H),4.31(dd,J=12,3.5Hz,0.2H),4.22(dd,J=1 2,3.5Hz,0.8H),4.16(dd,J=12.5,5.5Hz,0.2H),4.04(dd,J=12.5,5.5Hz,0.8H),3.99(s,1.6H) ),3.93(s,0.4H),2.64-2.57(m,2H),2.20(s,0.6H),2.09-2.02(m,11.4H),2.00(s,0.6H),1.8 2(s,2.4H),1.23-1.19(m,3H),0.95(s,7.2H),0.93(s,1.8H),0.11(s,2H),0.11-0.09(m,6H). 13 C{ 1H}-NMR(125MHz,CDCl3) δ 195.3,170.7,170.5,169.8,169.7,169.6,169.6,169.6,169.5,169.3,165.4,146.5,142.2,142.1,14 1.7,141.4,139.6,137.9,137.7,133.5,132.0,131.3,129.0,128.9,128.8,128.1,128.0,127.5,127.2 ,127.1,121.4,73.2,70.2,69.5,68.9,68.8,68.6,68.4,68.1,62.6,61.7,61.5,59.4,41.0,31.6,28.4,26.0,25.93,22.7,20.8,20.7,20.6,20.6,20.4,20.4,20.1,18.4,18.3,15.7,14.1,-5.4,-5.4,-5.4. HRMS: [M+Na]+calculated for C 38 H 52 O 12 NaSi,751.3120;found,751.3150.

[0674] <Reference example 3> (Manufacturing of Tofogliflozin) Tofogliflozin was produced according to the following reaction scheme.

[0675] [ka]

[0676] In an oven-dried flask under an argon atmosphere, the TBS-protected derivative 2 (208 mg, 0.285 mmol, 1.0 equiv.) prepared in Example 1F was dissolved in THF (0.6 mL) and cooled to -15°C. To the resulting solution, methanesulfonic acid (MsOH) (0.185 mL, 2.85 mmol, 10.0 equiv.) dissolved in methanol (MeOH) (2.9 mL) was added dropwise. After maintaining at -15°C for 15 minutes, the reaction mixture was warmed to room temperature and stirred for 24 hours. The reaction mixture was diluted with ethyl acetate and quenched with saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted three times with ethyl acetate. The ethyl acetate used for extraction was collected, washed with brine, dried over anhydrous sodium sulfate, and then concentrated. The resulting crude mixture was purified by silica gel column chromatography to give tofogliflozin (63 mg, 57% yield) as an off-white solid.

[0677] The analytical results of the obtained tofogliflozin are shown below. 1 H-NMR(500MHz,CD3OD) δ 7.23-7.18(m,3H),7.13-7.08(m,4H),5.14(d,J=12.5Hz,1H),5.08(d,J=12.5Hz,1H),3.96(s,2H),3.85 -3.75(m,4H),3.66(dd,J=12.0,5.5Hz),3.49-3.43(m,1H),2.59(q,J=7.5Hz,2H),1.20(t,J=7.5Hz,3H). 13 C{ 1 H}-NMR(125MHz,CD3OD)δ143.2,42.6,140.2,139.9,139.7,131.1,129.9,128 .9,123.6,121.8,111.6,76.4,76.2,74.9,73.4,71.9,62.8,42.3,29.4,16.2.

[0678] Example 1G (Production of TMS protected compound 1) According to the following reaction scheme, a TMS-protected product of (4-(4-ethylbenzyl)-2-iodophenyl)methanol (EBIPM), i.e., ((4-(4-ethylbenzyl)-2-iodobenzyl)oxy)trimethylsilane (hereinafter referred to as "TMS-protected product 1"), was produced.

[0679] [ka]

[0680] In an oven-dried flask under an argon atmosphere, (4-(4-ethylbenzyl)-2-iodophenyl)methanol (EBIPM) (1.82 g, 5.17 mmol, 1.0 equiv.) was dissolved in THF (17.5 mL). Triethylamine (EtN) (1.44 mL, 10.3 mmol, 2.0 equiv.) was added to the resulting solution, followed by the addition of chlorotrimethylsilane (0.984 mL, 7.75 mmol, 1.5 equiv.) at 0 °C. The resulting reaction mixture was warmed to room temperature and stirred for 1 h. The reaction was quenched with ice water and diluted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and evaporated. The resulting crude product was dried in vacuo to give TMS-protected derivative 1 (1.96 g, 90% yield) as a colorless oil. The resulting TMS-protected derivative 1 was used in the next step without further purification.

[0681] The analytical results of the obtained TMS protected product 1 (((4-(4-ethylbenzyl)-2-iodobenzyl)oxy)trimethylsilane) are shown below. 1 H-NMR(500MHz,CDCl3) δ 7.63(s,1H),7.37(d,J=8.0Hz,1H),7.17(d,J=8.0Hz,1H),7.11(d,J=7.5Hz,2H),7.07(d,J=7. 5Hz, 2H), 4.58 (s, 2H), 3.86 (s, 2H), 2.61 (q, J = 7.5Hz, 2H), 1.21 (t, J = 7.5Hz, 3H), 0.18 (s, 9H). 13 C{ 1H}-NMR(125MHz, CDCl3) δ 142.2,142.2,140.3,139.1,137.7,128.9,128.8,128.1,127.7,96.5,68.7,40.6,28.5,15.7,-0.3.

[0682] (Production of TMS protected compound 2) According to the following reaction scheme, (2R,3R,4S,5R)-6-(5-(4-ethylbenzyl)-2-(((tert-trimethylsilyl)oxy)methyl)phenyl)-6-oxohexanebenzyl)phenyl)-6-oxohexane-1,2,3,4,5-pentyl pentaacetate (referred to as "TMS protected product 2") was produced.

[0683] [ka]

[0684] In an oven-dried Schlenk tube, the TMS-protected compound 1 (ArI) (534 mg, 1.26 mmol, 1.2 equivalents) prepared above was dissolved in THF (1.2 mL) under an argon atmosphere and cooled to -25°C. i PrMgCl LiCl (Aldrich, 0.968 mL, 1.26 mmol, 1.2 equivalents) was added dropwise and stirred for 1 hour to prepare the Grignard reagent (ArMgI LiCl).

[0685] CuCN (9.4 mg, 0.105 mmol, 0.1 equiv.) and THF (0.4 mL) were added to another oven-dried Schlenk tube under an argon atmosphere. CuCN was suspended in THF, and the resulting suspension was cooled to -25 °C. A solution of compound 2a (524 mg, 1.049 mmol, 1.0 equiv.) in THF (3 mL) was added to the above suspension, followed by washing twice with THF (0.5 mL). The Grignard reagent prepared above was added dropwise to the washed suspension, and the Schlenk tube containing the Grignard reagent was washed twice with THF (0.5 mL). The resulting reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was quenched with water and diluted with ethyl acetate. The mixture was passed through Celite and washed with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and evaporated. The resulting crude mixture was purified by silica gel column chromatography to give TMS-protected derivative 2 (134 mg, yield 19%) as a colorless oil.

[0686] The analytical results of the obtained TMS protected product 2 ((2R,3R,4S,5R)-6-(5-(4-ethylbenzyl)-2-(((tert-trimethylsilyl)oxy)methyl)phenyl)-6-oxohexanebenzyl)phenyl)-6-oxohexane-1,2,3,4,5-pentyl pentaacetate) are shown below. 1H-NMR(500MHz,CDCl3) δ 7.71(d,J=8.0Hz,1H),7.65(d,J=1.5Hz,1H),7.39(dd,J=8.0,1.5Hz,1H),7.12(d,J=8.0Hz,2H),7.09(d,J=8.0Hz,2 H),6.07(d,J=5.0Hz,1H),5.63(t,J=5.0Hz,1H),5.52(dd,J=6.5,5.0Hz,1H),5.07(td,J=6.5,3.0Hz,1H),4.99(d,J= 15.5Hz,1H),4.73(d,J=15.5Hz,1H),4.23(dd,J=12.5,3.0Hz,1H),4.05(dd,J=12.5,6.0Hz,1H),3.98(s,2H),2.61(q ,J=7.6Hz,2H),2.06(s,3H),2.05(s,3H),2.04(s,3H),2.02(s,3H),1.82(s,3H),1.21(t,J=7.6Hz,3H),0.16(s,9H). 13 C{ 1 H}-NMR(125MHz,CDCl3) δ 195.6,170.7,169.9,169.7,169.6,169.3,142.2,141.2,139.7,137.8,133.4,132.4,129.0,128.8,1 28.1,127.4,73.4,69.5,68.8,68.6,62.1,61.7,41.0,28.5,20.8,20.7,20.6,20.4,20.1,15.7,-0.5.

[0687] Example 1H According to the following reaction scheme, (2R,3R,4S,5R)-6-(2-(acetoxymethyl)-5-(4-ethylbenzyl)phenyl)-6-oxohexane-1,2,3,4,5-pentyl pentaacetate (hereinafter referred to as "Ac protected form") was produced.

[0688] [ka]

[0689] In an oven-dried Schlenk tube, under an argon atmosphere, ((4-(4-ethylbenzyl)-2-iodobenzyl)acetate (ArI) (214 mg, 0.543 mmol, 1.2 equiv.) was dissolved in THF (1.5 mL) and cooled to -40°C. The resulting solution was added with 1.3 M i PrMgCl LiCl (Aldrich, 0.418 mL, 543 mmol, 1.2 equivalents) was added dropwise and stirred for 40 minutes. The resulting solution was gradually warmed to -30 °C and stirred for 1 hour. Thus, the Grignard reagent (ArMgI LiCl) was prepared.

[0690] CuCN (4.1 mg, 0.0452 mmol, 0.1 equiv.) and THF (0.5 mL) were added to another oven-dried Schlenk tube under an argon atmosphere. CuCN was suspended in THF, and the resulting suspension was cooled to -40 °C. A solution of compound 2a (226 mg, 0.452 mmol, 1.0 equiv.) in THF (2 mL) was added to the above suspension, followed by washing twice with THF (0.5 mL). The Grignard reagent prepared above was added dropwise to the washed suspension, and the Schlenk tube containing the Grignard reagent was washed twice with THF (0.5 mL). The resulting reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was quenched with water and diluted with ethyl acetate. The mixture was passed through Celite and washed with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and evaporated. The resulting crude mixture was purified by silica gel column chromatography to give the Ac-protected product (15 mg, yield 5%) as a colorless oil.

[0691] The analytical results of the obtained Ac-protected product ((2R,3R,4S,5R)-6-(2-(acetoxymethyl)-5-(4-ethylbenzyl)phenyl)-6-oxohexane-1,2,3,4,5-pentyl pentaacetate) are shown below. 1H-NMR(500MHz,CDCl3) δ 7.61(d,J=1.5Hz,1H),7.44(d,J=8.0Hz,1H),7.34(dd,J=8.0,1.5Hz,1H),7.14(d,J=8.0Hz,2H),7.08(d,J=8 .0Hz,2H),5.62(dd,J=5.0,4.0Hz,1H),5.55(d,J=14.0Hz,1H),5.50(dd,J=6.5,5.0Hz,1H),5.40(d,J=14.0Hz ,1H),5.36(d,J=4.0Hz,1H),5.09-5.05(m,1H),4.29(dd,J=12.0,4.0Hz,1H),4.12(dd,J=12.0,5.5Hz,1H),3 .99(s,2H),2.62(q,J=7.6Hz,2H),2.56(s,3H),2.19(s,3H),2.04(s,9H),1.96(s,3H),1.22(t,J=7.5Hz,3H). HRMS: [M+Na]+calculated for C 34 H 40 O 13 Na,679.2361;found,679.2361.

[0692] <Production Example 2> Compound 2a ((2R,3R,4S,5R)-6-oxo-6-(pyridin-2-ylthio)hexane-1,2,3,4,5-pentyl pentaacetate) was prepared according to the following reaction scheme.

[0693] [ka]

[0694] Under a nitrogen atmosphere, compound 50 (5 g, 0.0123 mol, 1.0 equiv.) was dissolved in dichloromethane (DCM) (25 mL) and cooled to 0–10 °C. Dimethylformamide (DMF) (0.045 g, 0.615 mmol, 0.05 equiv.) was added dropwise to the resulting solution, followed by the slow addition of oxalyl chloride ((COCl)2) (1.37 mL, 0.016 mol, 1.3 equiv.). The resulting mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by high-performance liquid chromatography (HPLC). After evaporation of all volatiles and azeotroping with toluene (15 mL), the crude product was dried under vacuum for 1 h to give compound 60 as an oil.

[0695] Under a nitrogen atmosphere, 2-pyridinethiol (2-PySH) (1.64 g, 0.0135 mol, 1.2 equiv.) in DCM (20 mL) was cooled to 0-10 °C. Triethylamine (TEA) (1.90 mL, 0.0135 mmol, 1.1 equiv.) was added dropwise to the resulting solution. Compound 60 dissolved in DCM (20 mL) was then added dropwise, washing twice with DCM (5 mL). The resulting reaction mixture was stirred at 0-10 °C for 3 h. The reaction progress was monitored by HPLC. The reaction was then quenched by the addition of water. The organic layer was washed with water. The organic layer was dried over anhydrous sodium sulfate and filtered. The resulting solvent was removed under vacuum, and the crude residue was further dried under vacuum for 1 h to give crude compound 2a (6.4 g, 104% yield) as a yellow oil. The crude product was further purified by trituration with methyl tert-butyl ether (MTBE) and hexanes and dried to give purified compound 2a (5.62 g, 91.40% yield) as an off-white solid.

[0696] The analytical results of the obtained compound 2a are shown below. Melting point: 79-83℃ FTIR(NaCl):2959,1754,1450,1423,1378,1222,1047,955cm -1 1H-NMR(600MHz,CDCl3-d6) δ (ppm):8.61-8.52(m,1H),7.76-7.70(m,1H),7.54(ddd,J=7.9,1.7,1.0Hz,1H),7.32-7.25(m,1H),5.67(ddd,J=5.1,3.7,0.5Hz,1H),5.60(dd,J=3.7,0.6Hz,1H),5.49(dd,J=6.0,5.5Hz,1H),5.05(dt,J=5.9,4.9Hz,1H),4.28(dd,J=12.2,4.5Hz,1H),4.11(dd,J=12.2,5.3Hz,1H),2.28(s,3H),2.11(s,3H),2.07(s,6H),2.03(s,3H) 13 C-NMR (151MHz,CDCl3-d6,30℃) δ(ppm):193.85,170.42,169.73,169.61,169.48,150.52,149.89,137.34,130.30,123.92,75.89,69.36,68.85,68.52,61.32,20.70,20.67,20.62,20.55,20.40 LCMS:[M]+calcd.for C 21 H 25 NO 11 S=500.1148;found 500.2;HPLC Purity=97.72%

Claims

1. The following formula (I): 【Chemical 1】 [In the formula, R １ and R ２ each independently represents an alkyl group which may have a substituent, an alkenyl group which may have a substituent, a cycloalkyl group which may have a substituent, a heterocycloalkyl group which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an arylalkyl group which may have a substituent, or an arylalkenyl group which may have a substituent.] A method for producing compound (I) represented by the following formula: The method comprises the steps of: (S1) in the presence of a copper salt, The following formula (IIa): 【Chemistry 2】 [In the formula, R １ is as defined above, Y １ represents —O— or —S—; Z １ teeth, The following formula (P1): 【Chemistry 3】 (Wherein, (*1) represents Y １ represents the site that binds to wherein the monovalent nitrogen-containing heterocyclic group has a partial structure (P1) represented by the following formula: Compound (IIa) represented by the formula: The following formula (IIb): 【Chemistry 4】 [In the formula, R １ is as defined above, Y ２ and Y ３ each independently represents —O— or —S—, Z ２ is expressed by the following formula (P2): 【Chemistry 5】 (Wherein, (*2) represents Y ２ represents the site that binds to and a partial structure (P2) represented by the following formula (P3): 【Chemistry 6】 (Wherein, (*3) represents Y ３ represents the site that binds to and a partial structure (P3) represented by the following formula (I): wherein the divalent nitrogen-containing heterocyclic group may have a substituent.] Compound (IIb) represented by Compound (II) selected from The following formula (IIIa): 【Chemistry 7】 [In the formula, R ２ has the same meaning as above, and X １ represents a halogen atom. a Grignard reagent (IIIa) represented by The following formula (IIIb): 【Chemistry 8】 [In the formula, R ２ and X １ has the same meaning as above.] Grignard reagent (IIIb) represented by a Grignard reagent (III) selected from at a temperature of −10 to 50° C. to produce compound (I), the copper salt is selected from CuCN and CuCl; The method described above, wherein the amount of the copper salt used is 0.01 to 1 mole per mole of the compound (II).

2. Said Z １ However, the following group: 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 [Wherein, X is —O—, —S— or —N(—CH ３ ) represents -. 【Chemistry 12】 [In the formula, X has the same meaning as defined above.] 【Chemistry 13】 [In the formula, X has the same meaning as defined above.] 【Chemistry 14】 [In the formula, X has the same meaning as defined above.] 【Chemistry 15】 [In the formula, X has the same meaning as defined above.] is selected from Said Z ２ However, the following group: 【Chemistry 16】 【Chemistry 17】 [In the formula, X has the same meaning as defined above.] 【Chemistry 18】 wherein X is as defined above, ｔ Bu represents a tert-butyl group. 【Chemistry 19】 [In the formula, X is as defined above, and Ph represents a phenyl group.] The method of claim 1 , wherein the compound is selected from the group consisting of:

3. 3. The method according to claim 1, wherein the amount of the Grignard reagent (III) used is 0.5 to 3 moles per mole of the compound (II).

4. The step (S1) includes the following steps: (S1a) preparing a first mixture containing the compound (II) and the copper salt; and (S1b) a step of contacting the first mixture with the Grignard reagent (III) to produce the compound (I).

3. The method of claim 1 or 2, comprising:

5. The step (S1) includes the following steps: (S1c) preparing a second mixture containing the copper salt and the Grignard reagent (III); and (S1d) A step of contacting the second mixture with the compound (II) to produce the compound (I).

3. The method of claim 1 or 2, comprising:

6. The method comprises the steps of: (T1a) in the presence of a base, The following formula (IV): 【Chemistry 20】 [In the formula, R １ has the same meaning as above.] Compound (IV) represented by The following (Va): 【Chemical 21】 [In the formula, R ３ represents a hydrogen atom or an alkali metal; Y １ and Z １ has the same meaning as above.] A compound (Va) represented by the formula: to produce compound (IIa); or (T1b) in the presence of a base, The compound (IV), The following (Vb): ​ [In the formula, R ３ and R ４ each independently represents a hydrogen atom or an alkali metal; Y ２ , Y ３ and Z ２ has the same meaning as above.] and a compound (Vb) represented by the formula: to produce compound (IIb). The method of claim 1 or 2, further comprising:

7. 7. The method according to claim 6, wherein the base used in step (T1a) and the base used in step (T1b) are each independently selected from triethylamine, diisopropylethylamine, dimethylaniline, and pyridine.

8. The method comprises the steps of: (U1) Formula (VI): 【Chemical 23】 Compound (VI) represented by the formula: a chlorinating agent; The method of claim 6, further comprising contacting the compound (IV) with

9. The method according to claim 8, wherein in the step (U1), the compound (VI) is contacted with the chlorinating agent in the presence of a catalytic amount of N,N-dimethylformamide.

10. 9. The process according to claim 8, wherein the chlorinating agent used in step (U1) is selected from thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus oxychloride and phosphorus pentachloride.

11. The method comprises the steps of: (W1a) Formula (VII): 【Chemistry 24】 [In the formula, R ２ and X １ has the same meaning as above.] and a halide (VII) represented by magnesium or magnesium activated with a magnesium activator; optionally LiCl, to produce the Grignard reagent (IIIa) or (IIIb); or (W1b) the halide (VII), The following formula (VIII): 【Chemistry 25】 [In the formula, ｉ Pr represents an isopropyl group. a Grignard reagent (VIII) represented by The method according to claim 1 or 2, further comprising the step of contacting the Grignard reagent (IIIb) with

12. The method includes the step (W1a), 12. The method according to claim 11, wherein in the step (W1a), LiCl is dissolved in an organic solvent to prepare a LiCl solution, and then the halide (VII), the magnesium or magnesium activated with a magnesium activator, and the LiCl solution are contacted to prepare the Grignard reagent (IIIb).

13. The step (S1) includes the following steps: (S1e) preparing a third mixture containing the compound (II), magnesium or magnesium activated with a magnesium activator, and optionally LiCl; and (S1f) Reacting the third mixture, the copper salt, and a compound represented by the following formula (VII): 【Chemical 26】 [In the formula, R ２ and X １ has the same meaning as above.] a step of producing the compound (I) by contacting the compound (I) with a halide (VII) represented by the following formula:

3. The method of claim 1 or 2, comprising:

14. The step (S1) includes the following steps: (S1g) Reacting the compound (II) with a compound of the following formula (VII): 【Chemical 27】 [In the formula, R ２ and X １ has the same meaning as above.] and preparing a fourth mixture comprising a halide (VII) represented by the formula: (S1h) Reacting the fourth mixture, the copper salt, and a compound represented by the following formula (VIII): ​ [In the formula, ｉ Pr represents an isopropyl group. to produce the compound (I) by contacting the compound (I) with a Grignard reagent (VIII) represented by the following formula:

3. The method of claim 1 or 2, comprising:

15. The following formula (I-1): 【Chemical Formula 29】 [In the formula, n represents 1 or 2; R each independently represents an alkyl group which may have a substituent or an aryl group which may have a substituent; R ２ represents an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted arylalkyl group, or an optionally substituted arylalkenyl group.] A method for producing a compound (I-1) represented by the following formula: The method comprises the steps of: (S2) the absence of copper salts; The following formula (IIa-1): 【Chemistry 30】 [In the formula, n and R are as defined above, Y １ represents —O— or —S—; Z １ is expressed by the following formula (P1): 【Chemical 31】 (Wherein, (*1) represents Y １ represents the site that binds to wherein the monovalent nitrogen-containing heterocyclic group has a partial structure (P1) represented by the following formula: Compound (IIa-1) represented by the formula: The following formula (IIb-1): 【Chemical 32】 [In the formula, n and R are as defined above, Y ２ and Y ３ each independently represents —O— or —S—, Z ２ is expressed by the following formula (P2): 【Chemical 33】 (Wherein, (*2) represents Y ２ represents the site that binds to and a partial structure (P2) represented by the following formula (P3): 【Chemical 34】 (Wherein, (*3) represents Y ３ represents the site that binds to and a partial structure (P3) represented by the following formula (I): wherein the divalent nitrogen-containing heterocyclic group may have a substituent.] Compound (IIb-1) represented by Compound (II-1) selected from The following formula (IIIa): 【Chemical 35】 [In the formula, R ２ has the same meaning as above, and X １ represents a halogen atom. a Grignard reagent (IIIa) represented by The following formula (IIIb): 【Chemical 36】 [In the formula, R ２ and X １ has the same meaning as above.] Grignard reagent (IIIb) represented by a Grignard reagent (III) selected from to produce compound (I-1).

16. The method according to claim 15, wherein the amount of the Grignard reagent (III) used is 0.5 to 3 moles per mole of the compound (II-1).

17. The method comprises the steps of: (T2a) in the presence of a base, The following formula (IV-1): 【Chemical 37】 [In the formula, n and R are as defined above.] Compound (IV-1) represented by the formula: The following (Va): 【Chemical 38】 [In the formula, R ３ represents a hydrogen atom or an alkali metal; Y １ and Z １ has the same meaning as above.] A compound (Va) represented by the formula: to produce compound (IIa-1); or (T2b) in the presence of a base, The compound (IV-1), The following (Vb): 【Chemical 39】 [In the formula, R ３ and R ４ each independently represents a hydrogen atom or an alkali metal; Y ２ , Y ３ and Z ２ has the same meaning as above.] and a compound (Vb) represented by the formula: to produce compound (IIb-1).

17. The method of claim 15 or 16, further comprising:

18. 18. The method of claim 17, wherein the base is selected from triethylamine, diisopropylethylamine, dimethylaniline, and pyridine.

19. The method comprises the steps of: (U2) The following formula (VI-1): 【Chemistry 40】 Compound (VI-1) represented by the formula: a chlorinating agent; The method according to claim 17, further comprising the step of producing compound (IV-1) by contacting

20. The method according to claim 19, wherein in the step (U2), the compound (VI-1) is contacted with the chlorinating agent in the presence of a catalytic amount of N,N-dimethylformamide.

21. 20. The method of claim 19, wherein the chlorinating agent is selected from thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus oxychloride and phosphorus pentachloride.

22. The method comprises the steps of: (W2a) Formula (VII): 【Chemistry 41】 [In the formula, R ２ and X １ has the same meaning as above.] and a halide (VII) represented by magnesium or magnesium activated with a magnesium activator; optionally LiCl, to produce the Grignard reagent (IIIa) or (IIIb); or (W2b) the halide (VII), The following formula (VIII): 【Chemistry 42】 [In the formula, ｉ Pr represents an isopropyl group. a Grignard reagent (VIII) represented by The method of claim 15 or 16, further comprising contacting the Grignard reagent (IIIb) with

23. The method includes the step (W2a), 23. The method according to claim 22, wherein in the step (W2a), LiCl is dissolved in an organic solvent to prepare a LiCl solution, and then the halide (VII), the magnesium or magnesium activated with a magnesium activator, and the LiCl solution are contacted to prepare the Grignard reagent (IIIb).

24. The step (S2) comprises the following steps: (S2a) preparing a fifth mixture containing the compound (II-1), magnesium or magnesium activated with a magnesium activator, and optionally LiCl; and (S2b) The fifth mixture and a compound represented by the following formula (VII): 【Chemistry 43】 [In the formula, R ２ and X １ has the same meaning as above.] a step of producing the compound (I-1) by contacting the compound (I-1) with a halide (VII) represented by the following formula:

17. The method of claim 15 or 16, comprising:

25. The step (S2) comprises the following steps: (S2c) Reacting the compound (II-1) with a compound of the following formula (VII): 【Chemical 44】 [In the formula, R ２ and X １ has the same meaning as above.] and preparing a sixth mixture comprising a halide (VII) represented by the formula: (S2d) The sixth mixture and a compound represented by the following formula (VIII): 【Chemistry 45】 [In the formula, ｉ Pr represents an isopropyl group. a step of producing the compound (I-1) by contacting the compound (I-2) with a Grignard reagent (VIII) represented by the following formula:

17. The method of claim 15 or 16, comprising:

26. The following formula (IIIb): 【Chemistry 46】 [In the formula, R ２ represents an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted arylalkyl group, or an optionally substituted arylalkenyl group, X １ represents a halogen atom. A method for producing a Grignard reagent (IIIb) represented by the following formula: The following formula (VII): 【Chemistry 47】 [In the formula, R ２ and X １ has the same meaning as above.] and a halide (VII) represented by The following formula (VIII): 【Chemistry 48】 [In the formula, ｉ Pr represents an isopropyl group. a Grignard reagent (VIII) represented by to produce the Grignard reagent (IIIb).

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