Acetylthiocarboxylic acid derivative and production method thereof, acetylthioacid chloride derivative and production method thereof, acetylthioketone derivative and production method thereof, as well as production method of thioglycoside derivative

Abstract

To provide: a novel acetylthiocarboxylic acid derivative; an acetylthioacid chloride derivative; an acetylthioketone derivative; production methods thereof; and a production method of a thioglycoside derivative.SOLUTION: Provided is an acetylthiocarboxylic acid derivative represented by formula (2). Each of R1-R4 is independently a protective group. A production method of the compound represented by formula (2) includes bringing a halocarboxylic acid derivative represented by formula (1) into contact with thioacetic acid or a salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to acetylthiocarboxylic acid derivatives and methods for producing them, acetylthioacid chloride derivatives and methods for producing them, acetylthioketone derivatives and methods for producing them, and methods for producing thioglycoside derivatives. [Background technology]

[0002] Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are useful as antidiabetic drugs. SGLT-2 inhibitors have a structure in which an aglycone moiety is directly linked to a gluconolactone ring or a thiogluconolactone ring. Known SGLT-2 inhibitors include canagliflozin, dapagliflozin, ipragliflozin, empagliflozin, luseogliflozin, and tofogliflozin, as shown in the following formulas.

[0003] [ka] [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Japanese Patent Application Publication No. 2022-159769 [Patent Document 2] International Publication No. 2016 / 098016 [Patent Document 3] Patent Publication No. 2021-161106 [Patent Document 4] Japanese Patent Application Publication No. 2019-210283 Summary of the Invention [Problem to be solved by the invention]

[0005] An object of the present invention is to provide novel compounds, namely, acetylthiocarboxylic acid derivatives, acetylthioacid chloride derivatives, and acetylthioketone derivatives, as well as methods for producing these compounds and thioglycoside derivatives. [Means for solving the problem]

[0006] According to one aspect, there is provided an acetylthiocarboxylic acid derivative represented by the following formula (2):

[0007] [ka]

[0008] In equation (2), R 1 , R 2 , R 3 , and R 4 are each independently a protecting group.

[0009] According to another aspect, there is provided an acetylthioacid chloride derivative represented by the following formula (3):

[0010] [ka]

[0011] In equation (3), R 1 , R 2 , R 3 , and R 4 are each independently a protecting group.

[0012] According to another aspect, there is provided an acetylthioketone derivative represented by the following formula (4A):

[0013] [ka]

[0014] In formula (4A), R 1 , R 2 , R3 , and R 4 are each independently a protecting group.

[0015] According to another aspect, there is provided a method for producing an acetylthiocarboxylic acid derivative according to the above aspect, which comprises contacting a halocarboxylic acid derivative represented by the following formula (1) with thioacetic acid or a salt thereof:

[0016] [ka]

[0017] In formula (1), R 1 , R 2 , R 3 , and R 4 are each independently a protecting group. 1 is a halogen atom.

[0018] According to another aspect, there is provided a method for producing an acetylthioacid chloride derivative represented by formula (3), which comprises contacting an acetylthiocarboxylic acid derivative represented by formula (2) according to the other aspect with a chlorinating agent.

[0019] [ka]

[0020] In equation (3), R 1 , R 2 , R 3 , and R 4 has the same meaning as in the above formula (2).

[0021] According to another aspect, there is provided a method for producing an acetylthioketone derivative represented by formula (4A), which comprises contacting a copper complex obtained by contacting a Grignard reagent represented by the following formula (IVA) with a monovalent copper ion reagent, with the acetylthioacid chloride derivative represented by formula (3) according to another aspect.

[0022] [ka]

[0023] In formula (IVa), X 10 is a chlorine atom or a bromine atom.

[0024] [ka]

[0025] In formula (4A), R 1 , R 2 , R 3 , and R 4 has the same meaning as in formula (3).

[0026] According to another aspect, there is provided a method for producing a thioglycoside derivative represented by the following formula (5A): The method comprises contacting an acetylthioketone derivative represented by formula (4A) according to another aspect with a base.

[0027] [ka] [Effects of the Invention]

[0028] According to the present invention, there are provided novel compounds, namely, acetylthiocarboxylic acid derivatives, acetylthioacid chloride derivatives, acetylthioketone derivatives, methods for producing these compounds, and methods for producing thioglycoside derivatives. DETAILED DESCRIPTION OF THE INVENTION

[0029] According to an embodiment, novel compounds, namely, acetylthiocarboxylic acid derivatives, acetylthioacid chloride derivatives, acetylthioketone derivatives, methods for producing these compounds, and methods for producing thioglycoside derivatives, are provided. These compounds can be used to efficiently produce SGLT-2 inhibitors, particularly luseogliflozin.

[0030] The structure of SGLT-2 inhibitors is roughly divided into a sugar moiety consisting of gluconolactone or thiogluconolactone and various aglycone moieties bound to this sugar moiety. Luseogliflozin is a compound represented by the following formula (II) that has a sugar moiety consisting of thiogluconolactone.

[0031] [ka]

[0032] As a method for producing an SGLT-2 inhibitor, a method using a protected gluconolactone represented by the following formula (Ia) has been studied.

[0033] [ka]

[0034] In formula (Ia), R 3 , R 4 , R 5 , and R 6 and each independently represent a protecting group. In the process of producing luseogliflozin using this protected gluconolactone, a step of introducing a sulfur atom is required.

[0035] The present inventors attempted to introduce a thiol group into the deoxyhalogenogluconic acid derivative represented by the following formula (III) obtained from the protected gluconolactone, but were unable to obtain the desired compound. 3 , R 4 , R 5 , and R 6 is a protecting group and X is a halogen atom.

[0036] [ka]

[0037] This is thought to be because the reagent used to introduce the thiol group, such as potassium thioacetate, is strongly basic, and therefore the ester bond of the deoxyhalogenogluconic acid derivative is hydrolyzed.

[0038] In response to these problems, the present inventors have discovered a method for obtaining an acetylthiocarboxylic acid derivative represented by the above formula (2) using a halocarboxylic acid derivative represented by the above formula (1). This halocarboxylic acid derivative represented by the formula (1) has a carboxyl group instead of the methyl ester group in formula (III). Even when this halocarboxylic acid derivative represented by the formula (1) is reacted with a strongly basic reagent such as potassium thioacetate, the acetylthiocarboxylic acid derivative represented by the above formula (2) can be obtained without hydrolysis. According to the method using such an acetylthiocarboxylic acid derivative represented by the formula (2) as an intermediate, luseogliflozin can be produced by omitting several steps compared to conventional methods. Therefore, the method according to the embodiment allows luseogliflozin to be produced efficiently and at low cost.

[0039] Hereinafter, the invention according to the embodiment will be described in detail.

[0040] <1. Method for producing the aglycone part> The method for producing the aglycone portion includes, for example, obtaining a halogeno-2,4-substituted benzoic acid derivative represented by formula (VI) from a 2,4-substituted benzoic acid derivative represented by formula (V), obtaining a benzophenone derivative represented by formula (VIII) from a halogeno-2,4-substituted benzoic acid derivative represented by formula (VI), and obtaining a halogenobenzene derivative represented by formula (IX) from a benzophenone derivative represented by formula (VIII).

[0041] (1-1. Method for producing halogeno-2,4-substituted benzoic acid derivatives) The halogeno-2,4-substituted benzoic acid derivative is represented by the following formula (VI).

[0042] [ka]

[0043] In formula (VI), R 10 and R 11 are each independently, for example, a hydrogen atom, a halogen atom, an alkyl group having 1 to 5 carbon atoms, or an alkoxy group having 1 to 5 carbon atoms. 10 and R 11 are preferably each independently a hydrogen atom, a chlorine atom, a fluorine atom, a methyl group, or a methoxy group. 10 is a hydrogen atom, R 11 is preferably a chlorine atom, a fluorine atom, or a methyl group. 10 is a methoxy group, R 11 is preferably a methyl group.

[0044] X 10 is a chlorine atom or a bromine atom. 10 is preferably a bromine atom.

[0045] A method for producing a halogeno-2,4-substituted benzoic acid derivative represented by formula (VI) comprises, for example, contacting a 2,4-substituted benzoic acid derivative represented by the following formula (V) with a halogenating agent.

[0046] [ka]

[0047] In formula (V), R 10 and R 11 are each independently a hydrogen atom, a halogen atom, an alkyl group having 1 to 5 carbon atoms, or an alkoxy group having 1 to 5 carbon atoms. 10 and R 11 has the same meaning as in formula (VI).

[0048] The halogenating agent may be elemental bromine (Br2) or elemental chlorine (Cl2). At least one compound selected from the group consisting of N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, N-chlorosuccinimide, and 1,3-dichloro-5,5-dimethylhydantoin is used. The use of these halogenating agents tends to suppress the formation of positional isomers and increase the yield of the halogeno-2,4-substituted benzoic acid derivative represented by formula (VI) compared to the use of elemental bromine (Br2) or elemental chlorine (Cl2). Furthermore, these compounds are less toxic and volatile than elemental bromine (Br2) or elemental chlorine (Cl2), making them easier to handle. The halogenating agent preferably includes N-bromosuccinimide.

[0049] The amount of the halogenating agent relative to 1 mole of the 2,4-substituted benzoic acid derivative represented by formula (V) is, for example, 1 mole or more and 5 moles or less, and the amount of the halogenating agent is preferably 1 mole or more and 5 moles or less.

[0050] The contact of the 2,4-substituted benzoic acid derivative represented by formula (V) with the halogenating agent is carried out, for example, within a temperature range of 25°C to 80°C. From the viewpoint of increasing the conversion rate to the halogeno-2,4-substituted benzoic acid derivative represented by formula (VI), the contact temperature is preferably a relatively high temperature of 50°C or higher. When the reaction is carried out in the presence of an organic solvent, the temperature may be the reflux temperature of the reaction solvent. From the viewpoint of suppressing the formation of positional isomers, the reaction is preferably carried out at a relatively low temperature of 30°C or lower.

[0051] The contact of the 2,4-substituted benzoic acid derivative represented by formula (V) with the halogenating agent is preferably carried out in the presence of an organic solvent. The organic solvent contains, for example, at least one compound selected from the group consisting of tetrahydrofuran, dichloromethane, N,N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone, and chloroform. From the viewpoint of increasing the yield of the halogeno-2,4-substituted benzoic acid derivative, the organic solvent preferably contains tetrahydrofuran (THF).

[0052] The amount of organic solvent relative to 1 g of the 2,4-substituted benzoic acid derivative represented by formula (V) is, for example, 1 mL or more and 20 mL or less, and preferably 2 mL or more and 10 mL or less.

[0053] The contact of the 2,4-substituted benzoic acid derivative represented by formula (V) with the halogenating agent is preferably carried out in the presence of an acid catalyst. The acid catalyst is, for example, at least one selected from the group consisting of sulfuric acid, hydrochloric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, and trifluoromethanesulfonic acid. 95% by mass of sulfuric acid is preferably used as the acid catalyst.

[0054] The amount of the acid catalyst relative to 1 g of the 2,4-substituted benzoic acid derivative represented by formula (V) is, for example, 0.1 mL or more and 1 mL or less, preferably 0.2 mL or more and 0.5 mL or less.

[0055] (1-2. Method for producing benzophenone derivatives) The 1,2-benzophenone derivative is represented by the following formula (VIII).

[0056] [ka]

[0057] In formula (VIII), Ar 1 is an arylene group having 5 to 12 carbon atoms, or a heteroarylene group having 4 to 10 carbon atoms and 1 to 3 heteroatoms. 1 is preferably a phenylene group or a thienyl group. 1 can be benzothiophene.

[0058] A is a direct bond or an oxygen atom.

[0059] R 13R is an alkyl group having 1 to 5 carbon atoms, an aryl group having 5 to 8 carbon atoms which may have a halogen atom as a substituent, or a heterocycloalkane group having 3 to 6 carbon atoms and 1 to 2 heteroatoms. 13 is preferably a methyl group, an ethyl group, a fluorophenyl group, or a tetrahydrofuran group.

[0060] The 1,2-benzophenone derivative represented by formula (VIII) can be obtained, for example, by contacting the halogeno-2,4-substituted benzoic acid derivative represented by formula (VI) above with a compound represented by formula (VII) below.

[0061] [ka]

[0062] In formula (VII), Ar 1 , A, and R 13 has the same meaning as in formula (VIII).

[0063] Specific examples of the compound represented by formula (VII) include methoxybenzene, ethoxybenzene, benzothiophene, 2-(4-fluorophenyl)thiophene, and the like.

[0064] The amount of the compound represented by formula (VII) relative to 1 mole of the halogeno-2,4-substituted benzoic acid derivative represented by formula (VI) is, for example, 1 mole or more and 2 moles or less, preferably 1 mole or more and 1.5 moles or less.

[0065] The contact of the halogeno-2,4-substituted benzoic acid derivative represented by formula (VI) with the compound represented by formula (VII) is preferably carried out in the presence of a catalyst, such as cobalt(II) chloride, titanium tetrachloride, boron trifluoride, aluminum chloride, iron(III) chloride, methanesulfonic acid, or trifluoromethanesulfonic acid.

[0066] The contact of the halogeno-2,4-substituted benzoic acid derivative of formula (VI) with the compound of formula (VII) is preferably carried out in the presence of a carboxylic acid activator, such as oxalyl chloride.

[0067] The contact of the halogeno-2,4-substituted benzoic acid derivative represented by formula (VI) with the compound represented by formula (VII) is preferably carried out in the presence of an organic solvent, such as at least one compound selected from the group consisting of dichloromethane, chloroform, 1,2-dichloroethane, carbon disulfide, and nitrobenzene.

[0068] The amount of organic solvent relative to 1 g of the halogeno-2,4-substituted benzoic acid derivative represented by formula (VI) is, for example, 1 mL or more and 10 mL or less, and preferably 5 mL or more and 10 mL or less.

[0069] (1-3. Method for producing halogenobenzene derivatives) The halogenobenzene derivative is represented by the following formula (IX).

[0070] [ka]

[0071] In formula (IX), R 10 , R 11 , and X 10 has the same meaning as in formula (VI). 1 , A, and R 13 has the same meaning as in formula (VII).

[0072] Specific examples of the halogenobenzene derivative represented by formula (IX) are shown below.

[0073] [ka]

[0074] The halogenobenzene derivative can be obtained, for example, by reducing the benzophenone derivative represented by the above formula (VIII).

[0075] This reduction reaction is carried out, for example, by contacting the benzophenone derivative represented by formula (VIII) with a reducing agent.

[0076] The reducing agent used may be, for example, at least one selected from the group consisting of metal borohydrides, silane compounds, hydrogen, and metal aluminum hydrides. Metal borohydrides include sodium borohydride, lithium borohydride, potassium borohydride, calcium borohydride, magnesium borohydride, etc. Silane compounds include triethylsilane, tetramethyldisiloxane, etc. The reducing agent preferably includes a metal borohydride, more preferably sodium borohydride.

[0077] The amount of the reducing agent relative to 1 mole of the benzophenone derivative represented by formula (VIII) is, for example, 0.25 moles or more and 5 moles or less, and preferably 1 mole or more and 2 moles or less.

[0078] This reduction reaction may be carried out in the presence of a Lewis acid, such as titanium chloride (TiCl4), boron trifluoride, or iodine.

[0079] The amount of Lewis acid relative to 1 mole of the benzophenone derivative represented by formula (VIII) is, for example, 1 mole or more and 3 moles or less, and preferably 1 mole or more and 2 moles or less.

[0080] This reduction reaction is preferably carried out in the presence of an organic solvent, such as at least one compound selected from the group consisting of 1,2-dimethoxyethane, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, methanol, ethanol, and isopropyl alcohol.

[0081] The amount of organic solvent relative to 1 g of the benzophenone derivative represented by formula (VIII) is, for example, 10 mL or more and 50 mL or less, and preferably 20 mL or more and 40 mL or less.

[0082] <2. Method for producing Grignard reagent> The Grignard reagent is represented, for example, by the following formula (IV-M):

[0083] [ka]

[0084] In formula (IV-M), R 10 and R 11 are each independently a hydrogen atom, a halogen atom, an alkyl group having 1 to 5 carbon atoms, or an alkoxy group having 1 to 5 carbon atoms. 1 is an arylene group having 5 to 12 carbon atoms, or a heteroarylene group having 4 to 10 carbon atoms and 1 to 3 heteroatoms. A is a direct bond or an oxygen atom. R 13 is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an aryl group having 5 to 8 carbon atoms which may have a halogen atom as a substituent, or a heterocycloalkane group having 3 to 6 carbon atoms and 1 to 2 heteroatoms. 10 is a chlorine atom or a bromine atom. 10 , R 11 , X 10 , Ar 1 , A, and R 13 has the same meaning as in formula (IX).

[0085] The Grignard reagent can be obtained, for example, by contacting the halogenobenzene derivative represented by the above formula (IX) with magnesium. The magnesium can be in the form of granules or cuttings.

[0086] The amount of magnesium relative to 1 mole of the halogenobenzene derivative represented by formula (IX) is, for example, 0.1 moles or more and 10 moles or less, and preferably 0.5 moles or more and 2 moles or less.

[0087] The contact of the halogenobenzene derivative represented by formula (IX) with magnesium is preferably carried out in the presence of an activator. Examples of activators include iodine (I2) and 1,2-dibromoethane. These activators dissolve the oxide film on the surface of magnesium. Iodine is preferably used as the activator. Using iodine allows the production of a highly pure Grignard reagent. The iodine is preferably in granular form.

[0088] The amount of the activator relative to 1 mole of the halogenobenzene derivative represented by formula (IX) is preferably 0.01 mole to 0.05 mole, and by using the activator in this range, a Grignard reagent containing fewer impurities can be obtained.

[0089] The amount of the activator relative to 1 mole of magnesium is preferably 0.005 mole or more and 0.025 mole or less.

[0090] The contact of the halogenobenzene derivative represented by formula (IX) with magnesium is preferably carried out in the presence of an organic solvent, such as at least one compound selected from the group consisting of tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane.

[0091] The amount of organic solvent relative to 1 g of the halogenobenzene derivative represented by formula (IX) is, for example, 2 mL or more and 20 mL or less, and preferably 5 mL or more and 10 mL or less.

[0092] The contact of the halogenobenzene derivative represented by formula (IX) with magnesium is carried out, for example, within a temperature range of 20° C. or higher and 80° C. or lower. This contact is preferably carried out at a temperature of 50° C. or higher and 80° C. or lower.

[0093] The contact of the halogenobenzene derivative represented by formula (IX) with magnesium is preferably carried out under an inert atmosphere. Examples of inert gases include nitrogen and argon. This contact may also be carried out in the presence of a lithium salt.

[0094] <3. Sugar production> The sugar moiety includes a thiogluconolactone ring. The production method according to the embodiment is particularly suitable for a method in which a thiogluconolactone derivative is used as the sugar moiety, i.e., a method for producing luseogliflozin.

[0095] Methods for producing a sugar moiety containing a thiogluconolactone ring include, for example, obtaining a halocarboxylic acid derivative represented by formula (1) from a gluconolactone derivative represented by formula (3a), obtaining an acetylthiocarboxylic acid derivative represented by formula (2) from a halocarboxylic acid derivative represented by formula (1), obtaining an acetylthioacid chloride derivative represented by formula (3) from an acetylthiocarboxylic acid derivative represented by formula (2), obtaining an acetylthioketone derivative represented by formula (4) from an acetylthioacid chloride derivative, and obtaining a thioglycoside derivative represented by formula (5) from an acetylthioketone derivative represented by formula (4).

[0096] (3-1. Method for producing halocarboxylic acid derivatives) The halocarboxylic acid derivative is represented by the following formula (1).

[0097] [ka]

[0098] In formula (1), R 1 , R 2 , R 3 , and R 4 are each independently a protecting group. The protecting group is, for example, selected from the group consisting of a toluoyl group, a benzyl group, an acetyl group, a benzoyl group, and a methoxymethyl group. The protecting group is preferably a toluoyl group, a benzyl group, or a benzoyl group, and more preferably a toluoyl group. R1 , R 2 , R 3 , and R 4 are preferably all the same protecting groups.

[0099] X 1 is a halogen atom. X 1 is preferably a bromine atom, a chlorine atom, or an iodine atom, and more preferably a bromine atom.

[0100] The halocarboxylic acid derivative represented by formula (1) can be obtained, for example, by contacting a halogenogluconic acid derivative represented by the following formula (3b) or a gluconolactone derivative represented by the following formula (3a) with hydrogen halide. A mixture of the halogenogluconic acid derivative represented by formula (3b) and the gluconolactone derivative represented by formula (3a) may be used to produce the halocarboxylic acid derivative.

[0101] [ka]

[0102] In formula (3b), R 1 , R 2 , R 3 , R 4 , and X 1 has the same meaning as in formula (1).

[0103] R 5 is an alkyl group having 1 to 6 carbon atoms. 5 is preferably a methyl group or an ethyl group, and more preferably a methyl group. The halogenogluconic acid derivative represented by formula (3b) can be obtained, for example, by the method described in Patent Document 1.

[0104] [ka]

[0105] In formula (3a), R 1 , R2 , R 3 , and R 4 has the same meaning as in formula (1).

[0106] The hydrogen halide includes, for example, at least one compound selected from the group consisting of hydrogen chloride, hydrogen bromide, and hydrogen iodide. The hydrogen halide is preferably hydrogen chloride or hydrogen bromide. When a halogenoglucone derivative represented by formula (3b) is used, it is more preferable to use hydrogen chloride. When a gluconolactone derivative represented by formula (3a) is used, it is more preferable to use hydrogen bromide. When a gluconolactone derivative represented by formula (3a) is used, the hydrogen halide is X of the halocarboxylic acid derivative represented by formula (1). 1 It can be a source of

[0107] The hydrogen halide may be an acid solution. That is, hydrochloric acid, hydrobromic acid, hydroiodic acid, or a mixture thereof may be used as the hydrogen halide. The concentration of the hydrogen halide in these acids is, for example, 10% by mass or more and 55% by mass or less. The concentration of the hydrogen halide is preferably 20% by mass or more and 40% by mass or less. As the solvent for the acid solution, water or a reaction solvent described below may be used.

[0108] The amount of hydrogen halide relative to 1 mole of the halogenogluconic acid derivative represented by formula (3b) or the gluconolactone derivative represented by formula (3a) is, for example, 15 to 50 moles, preferably 20 to 45 moles, more preferably 30 to 35 moles.

[0109] The contact of the halogenogluconic acid derivative represented by formula (3b) or the gluconolactone derivative represented by the following formula (3a) with hydrogen halide is preferably carried out in a reaction solvent. As the reaction solvent, for example, at least one organic solvent selected from the group consisting of dioxane, diethylene glycol dimethyl ether, acetic acid, and tetrahydrofuran is used. As the reaction solvent, acetic acid is preferably used. The reaction solvent may be a mixed solvent of an organic solvent and water.

[0110] The amount of reaction solvent per 1 g of the halogenogluconic acid derivative represented by formula (3b) or the gluconolactone derivative represented by formula (3a) is, for example, 2 mL to 20 mL, preferably 5 mL to 15 mL, and more preferably 8 mL to 12 mL.

[0111] The contact of the halogenogluconic acid derivative represented by formula (3b) or the gluconolactone derivative represented by the following formula (3a) with hydrogen halide is carried out, for example, within a temperature range of 50° C. to 118° C. The contact temperature is preferably 60° C. to 100° C., more preferably 70° C. to 80° C.

[0112] The halocarboxylic acid derivative represented by formula (1) obtained by this production method may be separated by a separation process or the like. The separated crystals may be subjected to a washing process and a drying process. The structure of the halocarboxylic acid derivative represented by formula (1) can be confirmed by, for example, nuclear magnetic resonance (NMR) spectroscopic analysis. The halocarboxylic acid derivative represented by formula (1) is useful, for example, as an intermediate for the synthesis of luseoligrosin.

[0113] (3-2. Method for producing acetylthiocarboxylic acid derivatives) The acetylthiocarboxylic acid derivative is represented by the following formula (2).

[0114] [ka]

[0115] In equation (2), R 1 , R 2 , R 3 , and R 4 are each independently a protecting group. 1 , R 2 , R 3 , and R 4 has the same meaning as in formula (1).

[0116] The acetylthiocarboxylic acid derivative represented by formula (2) can be obtained, for example, by contacting the halocarboxylic acid derivative represented by the above formula (1) with thioacetic acid or a salt thereof.

[0117] The amount of thioacetic acid or a salt thereof relative to 1 mole of the halocarboxylic acid derivative represented by formula (1) is, for example, 2 moles or more and 10 moles or less, preferably 2 moles or more and 5 moles or less, and more preferably 2 moles or more and 3 moles or less.

[0118] The contact of the halocarboxylic acid derivative represented by formula (1) with thioacetic acid or a salt thereof is preferably carried out in a reaction solvent, such as at least one organic solvent selected from the group consisting of dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1,3-dimethyl-2-imidazolidinone (DMI), N-methyl-2-pyrrolidone (NMP), acetonitrile, methanol, ethanol, and isopropyl alcohol.

[0119] The amount of the reaction solvent relative to 1 g of the halocarboxylic acid derivative represented by formula (1) is, for example, 1 mL or more and 10 mL or less, preferably 2 mL or more and 8 mL or less, and more preferably 4 mL or more and 6 mL or less.

[0120] The contact of the halocarboxylic acid derivative represented by formula (1) with thioacetic acid or a salt thereof is carried out, for example, within a temperature range of 0° C. to 50° C. The contact temperature is preferably 10° C. to 30° C., and more preferably 20° C. to 25° C.

[0121] The acetylthiocarboxylic acid derivative represented by formula (2) obtained by this production method may be separated by a separation process or the like. The separated crystals may be subjected to a washing process and a drying process. Alternatively, they may be subjected to a reaction with a chlorinating agent described below without being separated. The structure of the acetylthiocarboxylic acid derivative represented by formula (2) can be confirmed, for example, by nuclear magnetic resonance (NMR) spectroscopic analysis. The acetylthiocarboxylic acid derivative represented by formula (2) is useful, for example, as an intermediate for the synthesis of roseofligrosin.

[0122] (3-3. Method for producing acetylthiochloride derivatives) The acetylthioacid chloride derivative is represented by the following formula (3).

[0123] [ka]

[0124] In equation (3), R 1 , R 2 , R 3 , and R 4 has the same meaning as in formula (2).

[0125] The acetylthioacid chloride derivative represented by formula (3) can be obtained, for example, by contacting the acetylthiocarboxylic acid derivative represented by formula (2) above with a chlorinating agent.

[0126] The chlorinating agent includes, for example, at least one compound selected from the group consisting of thionyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus pentachloride, phosphoryl chloride, and oxalyl chloride.

[0127] The amount of the chlorinating agent relative to 1 mole of the acetylthiocarboxylic acid derivative represented by formula (2) is, for example, 1 mole or more and 5 moles or less, preferably 1 mole or more and 3 moles or less, and more preferably 1 mole or more and 2 moles or less.

[0128] The contact of the acetylthiocarboxylic acid derivative represented by formula (2) with the chlorinating agent is preferably carried out in a reaction solvent, such as at least one organic solvent selected from the group consisting of dimethylformamide (DMF), dichloromethane, chloroform, 1,2-dichloroethane, toluene, and tetrahydrofuran (THF).

[0129] The amount of the reaction solvent relative to 1 g of the acetylthiocarboxylic acid derivative represented by formula (2) is, for example, 1 mL to 10 mL, preferably 2 mL to 5 mL, and more preferably 4 mL to 5 mL.

[0130] The contact of the acetylthiocarboxylic acid derivative represented by formula (2) with the chlorinating agent is carried out, for example, within a temperature range of −20° C. to 25° C. The contact temperature is preferably −10° C. to 15° C., more preferably −5° C. to 5° C.

[0131] The acetylthioacid chloride derivative represented by formula (3) obtained by this production method may be separated by a separation process or the like. The separated crystals may be subjected to a washing process and a drying process. The structure of the acetylthioacid chloride derivative represented by formula (3) can be confirmed by, for example, nuclear magnetic resonance (NMR) spectroscopic analysis. The acetylthioacid chloride derivative represented by formula (3) is useful, for example, as an intermediate for the synthesis of roseofligrosin.

[0132] (3-4. Method for producing acetylthioketone derivatives) The acetylthioketone derivative is represented by the following formula (4).

[0133] [ka]

[0134] In equation (4), R 1 , R 2 , R 3 , and R 4is the same as in formula (3). 10 , R 11 , Ar 1 , A, and R 13 has the same meaning as in formula (IX).

[0135] The acetylthioketone derivative represented by formula (4) can be obtained, for example, by contacting a copper complex with the acetylthioacid chloride derivative represented by the above formula (3). The copper complex can be obtained by contacting a Grignard reagent with a monovalent copper ion reagent.

[0136] The acetylthioketone derivative represented by formula (4) may be obtained by contacting a Grignard reagent with an acetylthioacid chloride derivative represented by formula (3) in the presence of a monovalent copper ion reagent.

[0137] The acetylthioketone derivative represented by formula (4) may be obtained by contacting a halogenobenzene derivative represented by formula (IX), magnesium, and the acetylthioacid chloride derivative represented by formula (3) above in the presence of a monovalent copper ion reagent.

[0138] Examples of monovalent copper ion reagents that can be used include copper(I) cyanide, copper(I) chloride, copper(I) bromide, copper(I) iodide, and copper(I) thiophene-2-carboxylate.

[0139] The amount of the monovalent copper ion reagent relative to 1 mole of the Grignard reagent is, for example, 1 mole or more and 4 moles or less, preferably 1 mole or more and 3 moles or less, and more preferably 1 mole or more and 1.5 moles or less.

[0140] The Grignard reagent and the monovalent copper ion reagent may be contacted in a reaction solvent, such as at least one organic solvent selected from the group consisting of tetrahydrofuran (THF), 1,2-dimethoxyethane, dioxane, diethyl ether, and toluene.

[0141] The amount of reaction solvent per 1 g of Grignard reagent is, for example, 5 mL to 40 mL, preferably 10 mL to 30 mL, and more preferably 15 mL to 20 mL.

[0142] The Grignard reagent and the monovalent copper ion reagent are contacted, for example, within a temperature range of 0° C. to 40° C. The contact temperature is preferably 10° C. to 30° C., and more preferably 20° C. to 25° C.

[0143] The contact of the copper complex with the acetylthiochloride derivative represented by formula (3) may be carried out in a reaction solvent, such as at least one organic solvent selected from the group consisting of tetrahydrofuran (THF), 1,2-dimethoxyethane, dioxane, diethyl ether, and toluene.

[0144] The amount of the reaction solvent relative to 1 g of the acetylthioacid chloride derivative represented by formula (3) is, for example, 5 mL to 40 mL, preferably 10 mL to 30 mL, and more preferably 15 mL to 20 mL.

[0145] The contact of the copper complex with the acetylthioacid chloride derivative represented by formula (3) is carried out, for example, within a temperature range of −15° C. to 10° C. The contact temperature is preferably −10° C. to 10° C., and more preferably −5° C. to 5° C.

[0146] Specific examples of the acetylthioketone derivative represented by formula (4) include the compound represented by the following formula (IV).

[0147] [ka]

[0148] In formula (4A), R 1 , R 2 , R 3 , and R4 has the same meaning as in formula (4).

[0149] The acetylthioketone derivative represented by formula (4A) can be obtained, for example, by contacting a copper complex obtained by contacting a Grignard reagent represented by the following formula (IVA) with a monovalent copper ion reagent, and then contacting the copper complex with an acetylthioacid chloride derivative represented by formula (3).

[0150] [ka]

[0151] In formula (IVa), X 10 is a chlorine atom or a bromine atom. (3-5. Method for producing thioglycoside derivatives) The thioglycoside derivative is represented by the following formula (5A).

[0152] [ka]

[0153] The thioglycoside derivative represented by formula (5A) can be obtained, for example, by contacting the acetylthioketone derivative represented by formula (4A) with a base.

[0154] The base may be at least one selected from the group consisting of metal hydroxide salts and metal alkoxides.

[0155] The amount of base relative to 1 mole of the acetylthioketone derivative represented by formula (4A) is, for example, 1 mole or more and 10 moles or less, preferably 1 mole or more and 5 moles or less, and more preferably 1 mole or more and 3 moles or less.

[0156] The contact of the acetylthioketone derivative represented by formula (4A) with the base may be carried out in a reaction solvent, such as at least one organic solvent selected from the group consisting of methanol, ethanol, isopropyl alcohol, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).

[0157] The amount of the reaction solvent relative to 1 g of the acetylthioketone derivative represented by formula (4A) is, for example, 1 mL to 10 mL, preferably 2 mL to 8 mL, and more preferably 4 mL to 6 mL.

[0158] The contact of the acetylthioketone derivative represented by formula (4A) with the base is carried out, for example, within a temperature range of 0° C. to 50° C. The contact temperature is preferably 10° C. to 30° C., and more preferably 20° C. to 25° C.

[0159] (3-6. Manufacturing method of luseogliflozin) Luseogliflozin can be produced, for example, from a thioglycoside derivative represented by the above formula (5A) by a known method, for example, by reducing a methyl thioglycoside derivative represented by the following formula (6A), which is obtained by dehydration condensation of the thioglycoside derivative represented by formula (5A).

[0160] [ka]

[0161] For the dehydration condensation reaction of the thioglycoside derivative represented by formula (5A), for example, methanesulfonic acid, trifluoromethanesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, etc. are used.

[0162] For the reduction reaction of the methylthioglycoside derivative represented by formula (6A), for example, triethylsilane, boron trifluoride, a metal salt of aluminum hydride, trimethylsilyl trifluoromethanesulfonate, borane, hydrogen, or the like is used.

[0163] Luseogliflozin hydrate can be obtained by crystallization of luseogliflozin obtained by the above method. [Example]

[0164] The present invention will be described in detail below with reference to examples, but the present invention is not limited by these examples. It is not limited to:

[0165] Example 1 (Production of acetylthiocarboxylic acid) Acetylthiocarboxylic acid was prepared in the following manner.

[0166] [ka]

[0167] 0.102 g (0.14 mmol) of bromocarboxylic acid was dissolved in 0.851 mL of DMF, 39.8 mg (2.5 eq.) of potassium thioacetate was added, and the mixture was stirred at room temperature for 1 hour. After stirring, 10 mL of 10% hydrochloric acid was added to the reaction mixture, and the mixture was extracted twice with 10 mL of toluene. The toluene layer was washed with 10 mL of 5% sodium bicarbonate and 10 mL of 10% hydrochloric acid, respectively, and dried over anhydrous sodium sulfate. After drying, the solvent was distilled off, and 0.0848 g of a yellow solid (acetylthiocarboxylic acid) was obtained in an 83.7% yield. 1H NMR (600 MHz, CHLOROFORM-D) δ 7.89-7.74 (m, 8H), 7.16-7.12 (m, 8H), 6.20-6.19 (m, 1H), 6.04 (dd, J = 5.8, 4.9 Hz, 1H), 5.81 (d, J = 4.0 Hz, 1H), 5.58-5.56 (m, 1H), 3.60 (dd, J = 14.5, 3.6 Hz, 1H), 3.24 (dd, J = 14.5, 7.5 Hz, 1H), 2.90 (d, 1H), 2.42-2.35 (m, 12H), 2.24 (s, 3H). <Example 2> (Production of acetylthioketone) Acetyl thioketone was prepared in the following manner.

[0168] [ka]

[0169] [Production of acetylthiochloride] 1.44 g (1.13 mmol) of acetylthiocarboxylic acid was dissolved in 5.8 mL of dichloromethane, 7.7 μL (0.05 eq.) of DMF was added, and the solution was cooled to 0°C. 0.319 mL (1.9 eq.) of oxalyl chloride was then added, and the mixture was stirred at 0°C for 3.5 hours. After stirring, the solvent was evaporated, and the residue was dissolved in 5 mL of toluene, and the toluene was evaporated. This procedure was repeated twice. Finally, a brown oily substance was obtained. [Preparation of Grignard Reagent] (Production of 5-bromo-4-methoxy-2-methylbenzoic acid) 5-Bromo-4-methoxy-2-methylbenzoic acid was prepared in the following manner.

[0170] [ka]

[0171] 8.0 g (0.048 mol) of 4-methoxy-2-methylbenzoic acid and 15.4 g (1.8 eq.) of NBS were dissolved in 40 mL of THF, and 3.08 mL of concentrated sulfuric acid (95%) was added and stirred for 1.3 hours. After heating was stopped, 240 mL of water was added and the mixture was cooled on ice. The precipitated solid was collected by suction filtration and washed with 80 mL of water. The wet mixture was dried under reduced pressure at 40 °C to obtain 18.8 g of a white solid. The resulting solid was suspended in 84 mL of ethanol and dissolved under reflux conditions. The mixture was then allowed to cool to room temperature, and the precipitated solid was collected by suction filtration. The solid was washed with 34 mL of ethanol and dried under reduced pressure at 40 °C to obtain 5-bromo-4-methoxy-2-methylbenzoic acid in 32.2% yield and 95% purity. (Preparation of (5-bromo-4-methoxy-2-methylphenyl)(4-ethoxyphenyl)methanone) (5-Bromo-4-methoxy-2-methylphenyl)(4-ethoxyphenyl)methanone was prepared in the following manner.

[0172] [ka]

[0173] 3.0 g (0.012 mol) of 5-bromo-4-methoxy-2-methylbenzoic acid was dissolved in 15 mL of chloroform, 9.5 μL (0.01 eq.) of DMF was added, and the temperature was adjusted to 0°C. 1.14 mL (1.1 eq.) of oxalyl chloride was then added, and the mixture was stirred at 0-6°C for 2 hours. After stirring, the solvent was evaporated, and 5 mL of toluene was added to the residue, followed by evaporation again. This procedure was repeated twice. Finally, 3.2 g of a white solid was obtained.

[0174] The resulting white solid was dissolved in 12 mL of dichloromethane. The solution was then cooled to 10°C, and 2.0 mL (1.5 eq.) of titanium(IV) chloride dissolved in 12 mL of dichloromethane was added dropwise over 25 minutes. After the dropwise addition, the solution was stirred for 15 minutes and cooled to 5-8°C. 1.69 mL (1.1 eq.) of phenetole was added, and the mixture was stirred at 5-8°C for 2 hours. After stirring, the reaction mixture was cooled to 0°C, and 20 mL of water was added. The organic and aqueous layers were separated, and the organic layer was washed with 20 mL of saturated brine and dried over anhydrous sodium sulfate. After gravity filtration, the solvent was evaporated to yield 3.15 g of a yellow solid. The yellow solid was crystallized from 30 mL of hexane at 0°C to obtain 5-bromo-4-methoxy-2-methylphenyl)(4-ethoxyphenyl)methanone in 62.7% yield and 93.6% purity. (Production of 1-bromo-5-[(4-ethoxyphenyl)methyl]-2-methoxy-4-methylbenzene) 1-Bromo-5-[(4-ethoxyphenyl)methyl]-2-methoxy-4-methylbenzene was prepared by the following method.

[0175] [ka]

[0176] 2.0 g (0.0056 mol) of 5-bromo-4-methoxy-2-methylphenyl)(4-ethoxyphenyl)methanone was suspended in 20 mL of 1,2-dimethoxyethane, and 0.323 g (1.5 eq.) of sodium borohydride was added and refluxed for 3 hours. The reaction mixture was then allowed to cool to 31°C, and 0.936 mL (1.5 eq.) of titanium(IV) chloride dissolved in 20 mL of dichloromethane was added dropwise over 40 minutes. After the dropwise addition, the mixture was stirred at 40°C for 3 hours. 75 mL of cold water was added, and the organic and aqueous layers were separated. The aqueous layer was extracted with 20 mL of dichloromethane and combined with the organic layer. The combined organic layer was washed with 20 mL of saturated brine and dried over anhydrous sodium sulfate. After drying, the mixture was gravity filtered, and the solvent was evaporated to obtain 1.86 g of a colorless oil. The yield was 97.4%. (Preparation of Grignard Reagent) 1.33 g (2.0 eq. relative to the acetylthiocarboxylic acid) of 1-bromo-5-[(4-ethoxyphenyl)methyl]-2-methoxy-4-methylbenzene obtained by the above method, 0.115 g (2.2 eq. relative to the acetylthiocarboxylic acid) of magnesium, and one iodine (granular) grain were suspended in 13 mL of THF and stirred for 1 hour at 50° C. After stirring, the reaction solution was allowed to cool and used in the next reaction. [Production of acetyl thioketone] 0.362 g (2.0 eq.) of copper(I) cyanide was suspended in 5 mL of THF and stirred at room temperature for 15 minutes. The entire Grignard reagent prepared at room temperature was then added dropwise and stirred at room temperature for 30 minutes. After stirring, the suspension was cooled to 0 °C, and the entire amount of the acid chloride dissolved in 10 mL of THF was added. The mixture was stirred at 0 °C for 2 hours, and 50 mL of water was added. The reaction mixture was filtered through Celite and washed with 25 mL of ethyl acetate. After separation, the aqueous layer was extracted with 25 mL of ethyl acetate. The combined ethyl acetate layers were washed with 25 mL of saturated brine and dried over anhydrous sodium sulfate. After drying, the mixture was gravity filtered, and the solvent was evaporated to yield 2.1 g of a yellow solid. The resulting solid was purified using an automated purification system to obtain 0.8 g of a yellow solid as acetylthioketone in a 51.9% yield. 1 H NMR (400 MHz, CHLOROFORM-D) δ 7.91-7.69 (m, 8H), 7.37 (s, 1H), 7.15-7.06 (m, 8H), 6.85 (s, 1H), 6.76-6.66 (m, 5H), 6.27 (dd, J = 4.8, 3.4 Hz, 1H), 6.14 (t, J = 5.5 Hz, 1H), 5.64 (td, J = 6.9, 3.4 Hz, 1H), 3.96 (q, J = 7.0 Hz, 2H), 3.81 (s, 3H), 3.69 (s, 2H), 3.61-3.51 (m, 2H), 3.32 (q, J = 7.3 Hz, 1H), 2.38-2.33 (m, 12H), 2.21 (s, 3H), 2.16 (s, 3H), 1.38 (t, J = 6.9 Hz, 4H). MS (ESI+) 965.26 (M+H), 987.21 (M+Na), 1003.22 (M+K). Preferred aspects of the invention are listed below. [1] An acetylthiocarboxylic acid derivative represented by the following formula (2):

[0177] [ka]

[0178] In the formula (2), R 1 , R 2 , R 3 , and R 4 are each independently a protecting group. [2] The halocarboxylic acid derivative according to [1], wherein the protecting group is selected from the group consisting of a toluoyl group, a benzyl group, an acetyl group, a benzoyl group, and a methoxymethyl group. [3] An acetylthioacid chloride derivative represented by the following formula (3):

[0179] [ka]

[0180] In the formula (3), R 1 , R 2 , R 3 , and R 4 are each independently a protecting group. [4] An acetylthioketone derivative represented by the following formula (4A):

[0181] [ka]

[0182] In the formula (4A), R 1 , R2 , R 3 , and R 4 are each independently a protecting group. [5] A method for producing an acetylthiocarboxylic acid derivative, comprising contacting a halocarboxylic acid derivative represented by the following formula (1) with thioacetic acid or a salt thereof to obtain the acetylthiocarboxylic acid derivative according to [1] or [2]:

[0183] [ka]

[0184] In the formula (1), R 1 , R 2 , R 3 , and R 4 are each independently a protecting group, X 1 is a halogen atom. [6] A method for producing an acetylthioacid chloride derivative, comprising contacting the acetylthiocarboxylic acid derivative represented by formula (2) according to [1] or [2] with a chlorinating agent to obtain an acetylthioacid chloride derivative represented by formula (3):

[0185] [ka]

[0186] In the formula (3), R 1 , R 2 , R 3 , and R 4 has the same meaning as in the above formula (2). [8] The method according to [6], wherein the chlorinating agent contains at least one compound selected from the group consisting of thionyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus pentachloride, phosphoryl chloride, and oxalyl chloride. [9] A method for producing an acetylthioketone derivative, comprising contacting a copper complex obtained by contacting a Grignard reagent represented by the following formula (IVA) with a monovalent copper ion reagent, with the acetylthioacid chloride derivative represented by (3) described in [3], to obtain an acetylthioketone derivative represented by the following formula (4A):

[0187] [ka]

[0188] In the formula (IVa), X 10 is a chlorine atom or a bromine atom,

[0189] [ka]

[0190] In formula (4A), R 1 , R 2 , R 3 , and R 4 has the same meaning as in the above formula (3). [9] [4] The acetyl thioketone derivative represented by the formula (4A) is contacted with a base to obtain a compound represented by the following formula (5A):

[0191] [ka]

[0192] A method for producing a thioglycoside derivative, comprising obtaining a thioglycoside derivative represented by the formula:

Claims

1. An acetylthiocarboxylic acid derivative represented by the following formula (2): 【Chemistry 1】 In the formula (2), R １ , R ２ , R ３ , and R ４ are each independently a protecting group.

2. 2. The halocarboxylic acid derivative according to claim 1, wherein the protecting group is selected from the group consisting of a toluoyl group, a benzyl group, an acetyl group, a benzoyl group, and a methoxymethyl group.

3. An acetylthioacid chloride derivative represented by the following formula (3): 【Chemistry 2】 In the formula (3), R １ , R ２ , R ３ , and R ４ are each independently a protecting group.

4. An acetylthioketone derivative represented by the following formula (4A): 【Transformation 3】 In the formula (4A), R １ , R ２ , R ３ , and R ４ are each independently a protecting group.

5. A method for producing an acetylthiocarboxylic acid derivative, comprising contacting a halocarboxylic acid derivative represented by the following formula (1) with thioacetic acid or a salt thereof to obtain the acetylthiocarboxylic acid derivative according to claim 1: 【Chemistry 4】 In the formula (1), R １ , R ２ , R ３ , and R ４ are each independently a protecting group, X １ is a halogen atom.

6. A method for producing an acetylthioacid chloride derivative, comprising contacting the acetylthiocarboxylic acid derivative represented by formula (2) according to claim 1 with a chlorinating agent to obtain an acetylthioacid chloride derivative represented by the following formula (3): 【Transformation 5】 In the formula (3), R １ , R ２ , R ３ , and R ４ has the same meaning as in the above formula (2).

7. 7. The method according to claim 6, wherein the chlorinating agent comprises at least one compound selected from the group consisting of thionyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus pentachloride, phosphoryl chloride, and oxalyl chloride.

8. A method for producing an acetylthioketone derivative, comprising contacting a copper complex obtained by contacting a Grignard reagent represented by the following formula (IVA) with a monovalent copper ion reagent with the acetylthioacid chloride derivative represented by (3) according to claim 3, to obtain an acetylthioketone derivative represented by the following formula (4A): 【Transformation 6】 In the formula (IVa), X １０ is a chlorine atom or a bromine atom, 【Transformation 7】 In formula (4A), R １ , R ２ , R ３ , and R ４ has the same meaning as in the above formula (3).

9. The acetylthioketone derivative represented by the formula (4A) according to claim 4 is contacted with a base to produce a compound represented by the following formula (5A): 【Transformation 8】 A method for producing a thioglycoside derivative, comprising obtaining a thioglycoside derivative represented by the formula:

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