JP7665386B2 - Deoxyhalogenogluconic acid derivatives and their production method, and deoxysulfonyloxygluconic acid derivatives and their production method - Google Patents

Description

The present invention relates to a novel compound, a deoxyhalogenogluconic acid derivative, and a method for producing the same, as well as a novel compound, a deoxysulfonyloxygluconic acid derivative, which is useful as an intermediate for deoxyhalogenogluconic acid derivatives, and a method for producing the same.

2,3,4,6-tetra-O-acetyl-D-gluconic acid methyl ester (hereinafter also referred to as "AHM") represented by the following formula (3A) is a useful compound used as a raw material for the synthesis of various pharmaceuticals, such as SGLT2 inhibitors used in the treatment of chronic diseases such as diabetes (Non-Patent Document 1).

Non-Patent Document 1 describes a method in which D-glucono-1,5-lactone (hereinafter also referred to as "GLC") represented by the following formula (1) is mixed into acetic anhydride (Ac ₂ O) containing trifluoroacetic acid (TFA) to obtain 2,3,4,6-tetra-O-acetyl-D-glucono-1,5-lactone (hereinafter also referred to as "ALC") represented by the following formula (2A), and then the ALC is reacted with methanol in the presence of p-toluenesulfonic acid to obtain AHM.

Tetrahedron 58 (2002) 6907-6911

The object of the present invention is to provide a novel compound, a deoxyhalogenogluconic acid derivative, and a method for producing the same, as well as a novel compound, a deoxysulfonyloxygluconic acid derivative, and a method for producing the same.

As a result of intensive research to solve the above problems, the present inventors discovered that a deoxyhalogenogluconic acid derivative represented by formula (5) described below can be produced in high yield by sulfonylation and bromination of a tetraacylgluconic acid derivative represented by formula (3) described below in the presence of a base, and thus completed the present invention.

That is, the deoxysulfonyloxygluconic acid derivative according to one embodiment of the present invention is a compound represented by the following formula (4).

In the formula (4), R ¹ is an alkyl group having 1 to 6 carbon atoms, an aralkyl group having 7 to 20 carbon atoms which may have a substituent, or an aryl group having 6 to 20 carbon atoms which may have a substituent; R ² is an alkyl group having 1 to 6 carbon atoms; and R ³ is an alkyl group having 1 to 12 carbon atoms, a haloalkyl group having 1 to 12 carbon atoms, an aralkyl group having 7 to 20 carbon atoms which may have a substituent, or an aryl group having 6 to 20 carbon atoms which may have a substituent.

A method for producing a deoxysulfonyloxygluconic acid derivative according to another embodiment of the present invention includes contacting a tetraacylgluconic acid derivative represented by the following formula (3) with a sulfonylating agent represented by the following formula (6) in the presence of a base to produce a deoxysulfonyloxygluconic acid derivative represented by the formula (4).

In the formula (3), R ¹ and R ² have the same meanings as those represented by the formula (4).

In the formula (6), R ³ has the same meaning as that represented by the formula (4), and X′ is a halogen atom.

The base preferably includes at least one selected from the group consisting of alkylamine bases and cyclic amine bases. It is also preferable to use 0.001 moles or more and 5.0 moles or less of the base per mole of the tetraacylgluconic acid derivative represented by formula (3).

The sulfonylating agent represented by the formula (6) preferably contains at least one selected from the group consisting of alkylsulfonyl chloride, haloalkylsulfonyl chloride, arylsulfonyl chloride, and haloarylsulfonyl chloride. It is also preferable to use 1.0 mole or more and 5.0 moles or less of the sulfonylating agent represented by the formula (6) per mole of the tetraacylgluconic acid derivative represented by the formula (3).

The contact of the tetraacylgluconic acid derivative represented by the formula (3) with the sulfonylating agent represented by the formula (6) is preferably carried out in a first reaction solvent containing at least one solvent selected from the group consisting of methylene chloride, ethyl acetate, and acetonitrile.

The deoxyhalogenogluconic acid derivative according to another embodiment of the present invention is a compound represented by the following formula (5).

In the formula (5), R ¹ is an alkyl group having 1 to 6 carbon atoms, an aralkyl group having 7 to 20 carbon atoms which may have a substituent, or an aryl group having 6 to 20 carbon atoms which may have a substituent; R ² is an alkyl group having 1 to 6 carbon atoms; and X is a halogen atom.

A method for producing a deoxyhalogenogluconic acid derivative according to another embodiment of the present invention includes contacting a deoxysulfonyloxygluconic acid derivative represented by the following formula (4) with a halogenating agent to produce a deoxyhalogenogluconic acid derivative represented by the following formula (5').

In the formula (4), R ¹ is an alkyl group having 1 to 6 carbon atoms, an aralkyl group having 7 to 20 carbon atoms which may have a substituent, or an aryl group having 6 to 20 carbon atoms which may have a substituent, R ² is an alkyl group having 1 to 6 carbon atoms, and R ³ is an alkyl group having 1 to 12 carbon atoms, a haloalkyl group having 1 to 12 carbon atoms, an aralkyl group having 7 to 20 carbon atoms which may have a substituent, or an aryl group having 6 to 20 carbon atoms which may have a substituent.

In the formula (5'), R ¹ and R ² have the same meanings as those represented by the formula (4), and X'' is a halogen atom derived from the halogenating agent.

It is preferable to use 1.0 mole or more and 5.0 moles or less of the halogenating agent per mole of the deoxysulfonyloxygluconic acid derivative represented by the formula (4).

The contact of the deoxysulfonyloxygluconic acid derivative represented by formula (4) with the halogenating agent is preferably carried out in a second reaction solvent containing an aprotic polar solvent.

A method for producing a deoxyhalogenogluconic acid derivative according to another embodiment of the present invention includes producing a deoxysulfonyloxygluconic acid derivative represented by the formula (4) by the above-mentioned method for producing a deoxysulfonyloxygluconic acid derivative, and then contacting the obtained deoxysulfonyloxygluconic acid derivative represented by the formula (4) with a halogenating agent to produce a deoxyhalogenogluconic acid derivative represented by the following formula (5').

In the formula (5'), R ¹ and R ² have the same meanings as those represented by the formula (4), and X'' is a halogen atom derived from the halogenating agent.

According to an embodiment of the present invention, a novel compound, a deoxyhalogenogluconic acid derivative, and a method for producing the same, as well as a novel compound, a deoxysulfonyloxygluconic acid derivative, and a method for producing the same, are provided.

Hereinafter, an embodiment of the present invention will be described in detail.
As a starting material for azaglucose derivatives, thioglycose derivatives, etc., a deoxyhalogenogluconic acid derivative represented by the following formula (5A-2) ((5S)-2,3,4,6-tetra-O-acetyl-5-deoxy-5-bromo-D-gluconic acid methyl ester, hereinafter also referred to as "ABM") is considered to be an effective compound.

As a method for producing ABM, a method for directly synthesizing it from a gluconic acid derivative represented by the following formula (3') is being investigated.

In the above formula (3'), R ⁵ to R ¹⁰ are an alkyl group, an aralkyl group which may have a substituent, or an aryl group which may have a substituent, and may be the same group or different groups.

However, it is difficult to regioselectively and stereoselectively introduce bromine groups into the gluconic acid derivative represented by the above formula (3'), and thus far no method has been realized for synthesizing ABM directly from the gluconic acid derivative.

The method for producing a deoxyhalogenogluconic acid derivative according to one embodiment of the present invention includes producing a deoxyhalogenogluconic acid derivative, which is a novel compound represented by the following formula (5), from a tetraacylgluconic acid derivative represented by the following reaction formula (3), via a deoxysulfonyloxygluconic acid derivative, which is a novel compound represented by the following formula (4), as a production intermediate.

The deoxysulfonyloxygluconic acid derivative represented by formula (4) and its production method, and the deoxyhalogenogluconic acid derivative represented by formula (5) and its production method will be described in detail below.

[Deoxysulfonyloxygluconic acid derivatives]
The deoxysulfonyloxygluconic acid derivative according to one embodiment of the present invention is a compound (tetraacyl deoxysulfonyloxygluconic acid ester compound) represented by the following formula (4). This deoxysulfonyloxygluconic acid derivative can be used as a raw material for synthesizing various pharmaceuticals such as SGLT2 inhibitors used in the treatment of chronic diseases such as diabetes.

In formula (4), R ¹ is an alkyl group, an aralkyl group, or an aryl group. R ² is an alkyl group. R ³ is an alkyl group, a haloalkyl group, an aralkyl group, or an aryl group. R ¹ may be the same group or different groups. In particular, it is preferable that R ¹ is the same group.

R ¹ is an alkyl group having 1 to 6 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, or an aryl group having 6 to 20 carbon atoms. The aralkyl group or the aryl group may each have a substituent. Examples of the substituent include an alkyl group having 1 to 20 carbon atoms, an alkoxy group having 1 to 20 carbon atoms, a halogen group selected from a chlorine atom, a bromine atom, and an iodine atom, or a nitro group. The substituent is preferably an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a halogen group, or a nitro group. The substituent is more preferably a methyl group, a methoxy group, a halogen group, or a nitro group.

R ¹ is more preferably an alkyl group having 1 to 3 carbon atoms or an aryl group having 6 to 8 carbon atoms, and among these, a methyl group or a phenyl group is preferable. When R ¹ is a methyl group, the acyl group (-C(=O)R ¹ ) is an acetyl group (Ac), and when R ¹ is a phenyl group, the acyl group (-C(=O)R ¹ ) is a benzoyl group (Bz).

^R2 is an alkyl group having 1 to 6 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms, and among these, a methyl group is preferred.

R ³ is an alkyl group having 1 to 12 carbon atoms, a haloalkyl group having 1 to 12 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, or an aryl group having 6 to 20 carbon atoms. The aralkyl group or the aryl group may each have a substituent. Examples of the substituent include an alkyl group having 1 to 20 carbon atoms, an alkoxy group having 1 to 20 carbon atoms, a halogen group selected from a chlorine atom, a bromine atom, and an iodine atom, or a nitro group. The substituent is preferably an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a halogen group, or a nitro group. The substituent is more preferably a methyl group, a methoxy group, a halogen group, or a nitro group, and among these, a methyl group and a halogen group are particularly preferred. In addition, the halogen group is preferably a chlorine atom in consideration of reactivity. Furthermore, ^R3 is more preferably an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, or an aryl group having 6 to 8 carbon atoms which may have a substituent, and specifically, a methyl group, a halomethyl group (particularly a chloromethyl group), a phenyl group, a tolyl group (particularly a p-tolyl group), or a trichlorophenyl group (particularly a 2,4,6-trichlorophenyl group and a 2,4,5-trichlorophenyl group) is preferred.

[Method of producing deoxysulfonyloxygluconic acid derivatives]
The deoxysulfonyloxygluconic acid derivative is obtained by contacting a tetraacylgluconic acid derivative represented by the above formula (3) with a sulfonylating agent represented by the above formula (6) in the presence of a base. That is, a method for producing a deoxysulfonyloxygluconic acid derivative according to one embodiment of the present invention includes contacting a tetraacylgluconic acid derivative represented by the above formula (3) with a sulfonylating agent represented by the above formula (6) in the presence of a base to produce a deoxysulfonyloxygluconic acid derivative represented by the above formula (4).

<Tetraacylgluconic acid derivatives>
The tetraacylgluconic acid derivative is a substrate in the method for producing a deoxysulfonyloxygluconic acid derivative, which is one of the objects of the present production method. The tetraacylgluconic acid derivative is a compound (tetraacylgluconic acid ester compound) represented by the following formula (3).

In formula (3), R ¹ and R ² have the same meanings as those in formula (4).

(Suitable Tetraacylgluconic Acid Derivatives)
Considering the usefulness of the tetraacylgluconic acid derivative represented by the above formula (3), a tetraacetylgluconic acid ester derivative in which R ¹ is a methyl group and a tetrabenzoylgluconic acid ester derivative in which R ¹ is a phenyl group are preferred. Among them, the compounds represented by the following formula (3A) or (3B) are more preferred.

The compound represented by formula (3A) (2,3,4,6-tetra-O-acetyl-D-gluconic acid methyl ester) is a compound in which R ¹ and R ² are both methyl groups in the above formula (3). The compound represented by formula (3B) (2,3,4,6-tetra-O-benzoyl-D-gluconic acid methyl ester) is a compound in which R ¹ is a phenyl group and R ² is a methyl group in the above formula (3). In addition, "Me" in formulas (3A) and (3B) represents a methyl group. Among them, the tetraacylgluconic acid derivative represented by formula (3B) is particularly preferred in terms of good operability.

<Sulfonylating Agent>
The sulfonylating agent is a reactant that acts on the hydroxyl group of a tetraacylgluconic acid derivative to bond a sulfonyl group (-(O=S=O)-) (i.e., sulfonylation). The sulfonylating agent is a compound represented by the following formula (6).

In the formula (6), ^R3 has the same meaning as in the formula (4).

X' is a chlorine atom, a bromine atom, or an iodine atom, of which a chlorine atom is particularly preferred.

That is, preferred examples of the sulfonylating agent represented by formula (6) include the following compounds.
methanesulfonyl chloride (also called "mesyl chloride"; a compound represented by formula (6) in which ^R3 is a methyl group and X' is a chlorine atom), and other alkylsulfonyl chlorides;
haloalkylsulfonyl chlorides such as chloromethanesulfonyl chloride (also called "chloromesyl chloride"; a compound represented by formula (6) in which ^R3 is a chloromethyl group and X is a chlorine atom);
Arylsulfonyl chlorides such as benzenesulfonyl chloride (a compound in which R ³ is a phenyl group and X' is a chlorine atom in the formula (6)) and p-toluenesulfonyl chloride (a compound in which R ³ is a p-tolyl group and X' is a chlorine atom in the formula (6));
Examples of the sulfonylating agent include haloarylsulfonyl chlorides such as 2,4,6-trichlorobenzenesulfonyl chloride (also referred to as "2,4,6-trichlorobenzenesulfonic acid chloride"; a compound in which R ³ is a 2,4,6-trichlorophenyl group and X' is a chlorine atom in the formula (6)), 2,4,5-trichlorobenzenesulfonyl chloride (also referred to as "2,4,5-trichlorobenzenesulfonic acid chloride"; a compound in which R ³ is a 2,4,5-trichlorophenyl group and X' is a chlorine atom in the formula (6)), etc. The above-mentioned preferred sulfonylating agents are summarized in Table 1 below.

As the sulfonylating agent, methanesulfonyl chloride, 2,4,6-trichlorobenzenesulfonyl chloride, or 2,4,5-trichlorobenzenesulfonyl chloride is more preferred. Methanesulfonyl chloride is more preferred in that it increases the yield of the target deoxysulfonyloxygluconic acid derivative and improves crystallinity. 2,4,6-trichlorobenzenesulfonyl chloride and 2,4,5-trichlorobenzenesulfonyl chloride are more preferred in that they not only increase the yield of the target product and improve crystallinity, but also improve reactivity to bromination due to the high elimination ability of the product.

The amount of sulfonylating agent used is not particularly limited, but 1.0 mole or more and 5.0 moles or less of the sulfonylating agent may be used per mole of the tetraacylgluconic acid derivative represented by the above formula (3), and preferably 1.0 mole or more and 3.0 moles or less of the sulfonylating agent is used.

The sulfonylating agent may be of only one type, or may be a mixture of multiple types of sulfonylating agents. When multiple sulfonylating agents are used in combination, the total amount of the multiple sulfonylating agents used should be within the above range.

<Base>
The tetraacylgluconic acid derivative and the sulfonylating agent are contacted in the presence of a base. The base is preferably one that has low nucleophilicity and high basicity in order to suppress the deacylation reaction in which the sulfonylating agent acts on the acyl group to remove the acyl group. The base is preferably an organic base, and may be selected from alkylamine bases, cyclic amine bases, aromatic amine bases, and the like.

The alkylamine base is preferably an alkylamine compound having 1 to 5 carbon atoms, and more preferably triethylamine. The cyclic amine base is a compound containing a nitrogen atom in a cyclic structure. Examples of the compound containing a nitrogen atom in the cyclic structure include pyridine, 4-dimethylaminopyridine, and N-methylimidazole. An example of an aromatic amine base is N,N-diethylaniline. For the above reasons, N-methylimidazole is a suitable base.

The base may also function as a first reaction solvent, which will be described later. Among the above-mentioned bases, for example, pyridine can function as a first reaction solvent in addition to functioning as a base.

The amount of base used is not particularly limited, but 0.001 moles or more and 5.0 moles or less of base may be used per mole of the tetraacylgluconic acid derivative represented by the above formula (3), and preferably 0.05 moles or more and 3.0 moles or less of base are used.

The base may be one type only, or a mixture of multiple types of bases may be used. When a mixture of multiple bases is used, the total amount of the multiple bases used should be within the above range.

<Method for producing deoxysulfonyloxygluconic acid derivatives>
As described above, in the production method according to the present embodiment, a tetraacylgluconic acid derivative is contacted with a sulfonylating agent in the presence of a base to obtain a deoxysulfonyloxygluconic acid derivative. When the tetraacylgluconic acid derivative is contacted with the sulfonylating agent in the presence of a base, the contact is preferably carried out in a first reaction solvent in order to react them uniformly.

(First Reaction Solvent)
Examples of the first reaction solvent include organic solvents such as nitriles such as acetonitrile and propionitrile, ethers such as tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-methylTHF), 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, and methyl cellosolve, ketones such as acetone, halogenated hydrocarbons such as dichloromethane (methylene chloride), chloroform, and 1,2-dichloroethane, esters such as methyl acetate, ethyl acetate, isopropyl acetate, and butyl acetate, and amides such as N,N-dimethylformamide (DMF) and N,N-dimethylacetamide (DMA), and water. These solvents can be used alone or as a mixture of these solvents.

The first reaction solvent is preferably methylene chloride, ethyl acetate, acetonitrile, or a mixture thereof.

The amount of the first reaction solvent used is not particularly limited, but 1 mL to 50 mL of the first reaction solvent may be used per 1 g of the tetraacylgluconic acid derivative represented by the above formula (3), and preferably 2 mL to 30 mL of the first reaction solvent is used. When a mixed solvent is used as the first reaction solvent, the total amount of the mixed solvent should be within the above range.

(Method of Contacting (Mixing) Each Component)
The method for contacting each component is not particularly limited. For example, each component may be charged into a reaction vessel equipped with a stirring mechanism and mixed. By mixing each component, the tetraacylgluconic acid derivative and the sulfonylating agent can be contacted in the presence of a base. The procedure for charging each component into the reaction vessel is not particularly limited.

For example, the tetraacylgluconic acid derivative may be dissolved in a first reaction solvent, the solution may be mixed with a base, and then the mixture may be mixed with a sulfonylating agent. In this case, the mixture of the solution and the base may be mixed with the sulfonylating agent by dropping the sulfonylating agent into the mixture. In this case, the sulfonylating agent may be dropped over a period of, for example, 0.1 to 1.0 hours. The temperature of the mixture when the sulfonylating agent is dropped may be 0°C to 15°C.

For example, a solution in which a tetraacylgluconic acid derivative is dissolved in a first reaction solvent may be mixed with a sulfonylating agent, and then the mixture may be mixed with a base. In this case, the mixture of the solution and the sulfonylating agent may be mixed with the base by dropping the base into the mixture. In this case, the base may be dropped into the mixture over a period of, for example, 0.5 to 3 minutes.

The sulfonylating agent may be added to the dissolving solution over a period of, for example, 0.5 to 3 minutes. The temperature of the dissolving solution when the sulfonylating agent is added may be, for example, 0°C to 15°C. By adding the sulfonylating agent in a relatively short period of time, it is possible to suppress the rapid heat generation caused by the reaction between the tetraacylgluconic acid derivative and the sulfonylating agent.

The sulfonylating agent may be added stepwise while monitoring the consumption of the substrate. The sulfonylating agent and the base may also be added together to the solution in which the tetraacylgluconic acid derivative is dissolved.

The above reaction can be carried out by mixing (contacting) the tetraacylgluconic acid derivative with the sulfonylating agent in the presence of a base. In this case, the reaction temperature when stirring and mixing these components may be, for example, from -10°C to 50°C, and preferably from 0°C to 40°C.

The reaction time can be determined by checking the conversion rate to the deoxysulfonyloxygluconic acid derivative and appropriately determining the time until the reaction is completed. The reaction time can be, for example, from 0.5 hours to 10 hours, and preferably from 1 hour to 6 hours.

After the reaction is completed, it is preferable to purify the deoxysulfonyloxygluconic acid derivative. The purification can be performed, for example, by the following method. That is, water or an organic solvent is added to the reaction solution to dilute and extract, the organic layer is separated, the separated organic layer is washed, and processing such as drying and concentration is performed. As the organic solvent, chloroform, ethyl acetate, etc. can be used. For example, water, saline, etc. can be used to wash the organic layer. At this time, an acid (hydrochloric acid, etc.) or an alkali can be appropriately added to adjust the pH. For example, magnesium sulfate can be used to dry the organic layer. Concentration can be performed by reduced pressure treatment.

The reaction solution is concentrated to obtain a residue. If the target substance is easily crystallized, ethyl acetate or the like may be added to the residue to crystallize it, and the target substance may be purified by filtering. If the target substance is difficult to crystallize, the target substance may be purified using a silica gel column.

<Deoxysulfonyloxygluconic acid derivatives>
When a tetraacylgluconic acid derivative is contacted with a sulfonylating agent in the presence of a base, a deoxysulfonyloxygluconic acid derivative represented by the following formula (4) is obtained.

(Suitable Deoxysulfonyloxygluconic Acid Derivatives)
When a compound represented by formula (3A), which is a suitable raw material, is used as a substrate, a deoxysulfonyloxygluconic acid derivative (tetraacetyl deoxysulfonyloxygluconic acid ester derivative) represented by the following formula (4Aa), (4Ab), (4Ac), (4Ad), (4Ae) or (4Af) can be obtained as the deoxysulfonyloxygluconic acid derivative represented by the above formula (4'). When a compound represented by formula (3B), which is a suitable raw material, is used as a substrate, a deoxysulfonyloxygluconic acid derivative (d) represented by the following formula (4Ba), (4Bb), (4Bc), (4Bd), (4Be) or (4Bf) can be obtained as the deoxysulfonyloxygluconic acid derivative represented by the above formula (4'). In addition, "Ms" in formulas (4Aa) and (4Ba) represents a mesyloxy group (-(O=S=O)CH ₃ ).

The compound represented by formula (4Aa) (2,3,4,6-tetra-O-acetyl-5-deoxy-5-mesyloxy-D-gluconic acid methyl ester) is a compound obtained by contacting the compound represented by formula (3A) with the sulfonylating agent represented by formula (6A) in the presence of a base.

The compound represented by formula (4Ab) (2,3,4,6-tetra-O-acetyl-5-deoxy-5-chloromesyloxy-D-gluconic acid methyl ester) is a compound obtained by contacting the compound represented by formula (3A) with the sulfonylating agent represented by formula (6B) in the presence of a base.

The compound represented by formula (4Ac) (2,3,4,6-tetra-O-acetyl-5-deoxy-5-benzenesulfonyloxy-D-gluconic acid methyl ester) is a compound obtained by contacting the compound represented by formula (3A) with the sulfonylating agent represented by formula (6C) in the presence of a base.

The compound represented by formula (4Ad) (2,3,4,6-tetra-O-acetyl-5-deoxy-5-(p-toluenesulfonyl)oxy-D-gluconic acid methyl ester) is a compound obtained by contacting the compound represented by formula (3A) with the sulfonylating agent represented by formula (6D) in the presence of a base.

The compound represented by formula (4Ae) (2,3,4,6-tetra-O-acetyl-5-deoxy-5-(2,4,6-trichlorobenzenesulfonyl)oxy-D-gluconic acid methyl ester) is a compound obtained by contacting the compound represented by formula (3A) with the sulfonylating agent represented by formula (6E) in the presence of a base.

The compound represented by formula (4Af) (2,3,4,6-tetra-O-acetyl-5-deoxy-5-(2,4,5-trichlorobenzenesulfonyl)oxy-D-gluconic acid methyl ester) is a compound obtained by contacting the compound represented by formula (3A) with the sulfonylating agent represented by formula (6F) in the presence of a base.

The compound represented by formula (4Ba) (2,3,4,6-tetra-O-benzoyl-5-deoxy-5-mesyloxy-D-gluconic acid methyl ester) is a compound obtained by contacting the compound represented by formula (3B) with the sulfonylating agent represented by formula (6A) in the presence of a base.

The compound represented by formula (4Bb) (2,3,4,6-tetra-O-benzoyl-5-deoxy-5-chloromesyloxy-D-gluconic acid methyl ester) is a compound obtained by contacting the compound represented by formula (3B) with the sulfonylating agent represented by formula (6B) in the presence of a base.

The compound represented by formula (4Bc) (2,3,4,6-tetra-O-benzoyl-5-deoxy-5-benzenesulfonyloxy-D-gluconic acid methyl ester) is a compound obtained by contacting the compound represented by formula (3B) with the sulfonylating agent represented by formula (6C) in the presence of a base.

The compound represented by formula (4Bd) (2,3,4,6-tetra-O-benzoyl-5-deoxy-5-(p-toluenesulfonyl)oxy-D-gluconic acid methyl ester) is a compound obtained by contacting the compound represented by formula (3B) with the sulfonylating agent represented by formula (6D) in the presence of a base.

The compound represented by formula (4Be) (2,3,4,6-tetra-O-benzoyl-5-deoxy-5-(2,4,6-trichlorobenzenesulfonyl)oxy-D-gluconic acid methyl ester) is a compound obtained by contacting the compound represented by formula (3B) with the sulfonylating agent represented by formula (6E) in the presence of a base.

The compound represented by formula (4Bf) (2,3,4,6-tetra-O-benzoyl-5-deoxy-5-(2,4,5-trichlorobenzenesulfonyl)oxy-D-gluconic acid methyl ester) is a compound obtained by contacting the compound represented by formula (3B) with the sulfonylating agent represented by formula (6F) in the presence of a base.

[Deoxyhalogenogluconic acid derivatives]
The deoxyhalogenogluconic acid derivative according to one embodiment of the present invention is a compound (tetraacyl deoxyhalogenogluconic acid ester compound) represented by the following formula (5). This deoxyhalogenogluconic acid derivative can be used as a raw material for synthesizing various pharmaceuticals such as SGLT2 inhibitors used in the treatment of chronic diseases such as diabetes.

In formula (5), R ¹ has the same meaning as in formula (4). X is preferably a chlorine atom, a bromine atom, or an iodine atom, and among them, in consideration of reactivity and stability, a bromine atom is more preferable.

[Method for producing deoxyhalogenogluconic acid derivatives]
The deoxyhalogenogluconic acid derivative can be obtained by halogenating the above-mentioned deoxysulfonyloxygluconic acid derivative. That is, the method for producing the deoxyhalogenogluconic acid derivative according to one embodiment of the present invention includes contacting the deoxysulfonyloxygluconic acid derivative represented by the above formula (4) with a halogenating agent to produce the deoxyhalogenogluconic acid derivative.

<Deoxysulfonyloxygluconic acid derivatives>
The deoxysulfonyloxygluconic acid derivative is a substrate in the method for producing a deoxyhalogenogluconic acid derivative. The deoxysulfonyloxygluconic acid derivative is a compound represented by the above formula (4), and the details are as described above for the deoxysulfonyloxygluconic acid derivative.

The deoxysulfonyloxygluconic acid derivative may be prepared by isolating and purifying the deoxysulfonyloxygluconic acid derivative prepared by the above-mentioned method for producing the deoxysulfonyloxygluconic acid derivative, or may be prepared by distilling off the first reaction solvent without purification. Also, the deoxysulfonyloxygluconic acid derivative synthesized by a method other than the above-mentioned method for producing the deoxysulfonyloxygluconic acid derivative may be used.

<Halogenating Agent>
The halogenating agent is a reactant that replaces -O-(O=S=O) ^R3 in the deoxysulfonyloxygluconic acid derivative represented by the above formula (4) with a halogen atom derived from the halogenating agent (hereinafter, also referred to as "halogenation").

Examples of the halogen atom of the halogenating agent include a chlorine atom, a bromine atom, and an iodine atom. Among these, in consideration of reactivity, a bromine atom is preferred as the halogen atom. That is, examples of the halogenating agent include a chlorinating agent, a brominating agent, and an iodinating agent, and a brominating agent is preferred.

The halogenating agent is a compound containing a halogen atom, and is preferably an alkali metal halide containing a halogen atom and an alkali metal, or a compound containing a nitrogen atom.

As the alkali metal in the alkali metal halide, lithium, sodium, potassium or cesium, which have high reactivity, is preferred, and lithium is particularly preferred. That is, the alkali metal halide is preferably a lithium halide, a sodium halide, a potassium halide or a cesium halide, and lithium halide is particularly preferred. Specific examples of suitable alkali metal halides that are halogenating agents include lithium bromide (lithium bromide), sodium bromide (sodium bromide), potassium bromide (potassium bromide) or cesium bromide (cesium bromide), and more preferably lithium bromide (lithium bromide).

The halogenating agent containing a nitrogen atom is preferably a quaternary ammonium salt (quaternary ammonium halide), more preferably a tetraalkylammonium halide, specifically including tetra-N-butylammonium bromide.

The amount of halogenating agent used is not particularly limited, but 1.0 mole or more and 5.0 moles or less of halogenating agent may be used per mole of the deoxysulfonyloxygluconic acid derivative represented by formula (4), and preferably 1.0 mole or more and 3.0 moles or less of halogenating agent are used.

<Method for Producing Deoxyhalogenogluconic Acid Derivatives>
As described above, in the production method according to the present embodiment, a deoxysulfonyloxygluconic acid derivative is obtained by contacting a halogenating agent with a deoxysulfonyloxygluconic acid derivative. When the deoxysulfonyloxygluconic acid derivative is contacted with a halogenating agent, the reaction is preferably carried out in a second reaction solvent in order to react them uniformly.

(Second Reaction Solvent)
Examples of the second reaction solvent include nitriles such as acetonitrile and propionitrile, ethers such as THF, 2-methyl THF, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, and methyl cellosolve, ketones such as acetone, halogenated hydrocarbons such as dichloromethane (methylene chloride), chloroform, and 1,2-dichloroethane, esters such as methyl acetate, ethyl acetate, isopropyl acetate, and butyl acetate, amides such as N,N-dimethylformamide (DMF) and N,N-dimethylacetamide, organic solvents such as sulfoxides such as dimethyl sulfoxide (DMSO), aprotic polar solvents such as 1,3-dimethyl-2-imidazolidinone (DMI), and water. These solvents can be used alone or as a mixture of these solvents.

The second reaction solvent preferably contains 1,3-dimethyl-2-imidazolidinone. This is because aprotic polar solvents such as 1,3-dimethyl-2-imidazolidinone can promote the halogenation reaction.

The amount of the second reaction solvent used is not particularly limited, but 1 mL to 30 mL of the second reaction solvent may be used per 1 g of the deoxysulfonyloxygluconic acid derivative represented by the above formula (4), and preferably 2 mL to 20 mL of the second reaction solvent is used. When a mixed solvent is used as the second reaction solvent, the total amount of the mixed solvent should be within the above range.

(Method of Contacting (Mixing) Each Component)
The method of contacting each component is not particularly limited. For example, each component may be charged into a reaction vessel equipped with a stirring mechanism and mixed. By mixing each component, the deoxysulfonyloxygluconic acid derivative and the halogenating agent can be contacted. The procedure of charging each component into the reaction vessel is not particularly limited. For example, the deoxysulfonyloxygluconic acid derivative may be dissolved in the second reaction solvent, and the solution may be mixed with the halogenating agent.

The reaction between the deoxysulfonyloxygluconic acid derivative and the halogenating agent can be carried out by mixing (contacting) them. The reaction temperature when stirring and mixing these components may be, for example, 10°C or higher and 100°C or lower, and preferably 20°C or higher and 60°C or lower.

The reaction time can be determined by checking the conversion rate to the deoxyhalogenogluconic acid derivative and appropriately determining the time until the reaction is completed. The reaction time can be, for example, from 0.5 hours to 10 hours, and preferably from 1 hour to 8 hours.

After the reaction is completed, it is preferable to purify the deoxyhalogenogluconic acid derivative. The purification can be performed, for example, by diluting the reaction solution with an organic solvent, extracting the aqueous layer or separating the organic layer, washing the separated organic layer, drying and concentrating under reduced pressure to obtain a residue, and then subjecting the residue to a silica gel column. For example, saturated saline may be used to dilute the reaction solution. For example, ethyl acetate may be used as the organic solvent. For example, water, saturated saline, etc. may be used for washing. For example, magnesium sulfate may be used for drying. The purified product may also be dissolved in an organic solvent, stirred and filtered to remove impurities, and then recrystallized for purification.

<Deoxyhalogenogluconic acid derivatives>
When the deoxysulfonyloxygluconic acid derivative is contacted with a halogenating agent, a deoxyhalogenogluconic acid derivative represented by the formula (5') is obtained.

In formula (5'), ^R1 and ^R2 have the same meanings as those in formula (4), and X'' is a halogen atom derived from the halogenating agent.

(Suitable Deoxyhalogenogluconic Acid Derivatives)
When the tetraacetyl deoxysulfonyloxy gluconic acid ester derivatives represented by the above formulas (4Aa) to (4Af) are used as suitable raw materials, deoxyhalogenogluconic acid derivatives (tetraacetyl deoxyhalogenogluconic acid ester derivatives) represented by the following formulas (5A-1) to (5A-3) can be obtained as the deoxyhalogenogluconic acid derivatives represented by the above formula (5').

In addition, when the tetrabenzoyl deoxysulfonyloxy gluconic acid ester derivatives represented by the above formulas (4Ba) to (4Bf) are used, the deoxyhalogenogluconic acid derivatives represented by the above formula (5') can be obtained as deoxyhalogenogluconic acid derivatives (tetrabenzoyl deoxyhalogenogluconic acid ester derivatives) represented by the following formulas (5B-1) to (5B-3).

Among these, the deoxyhalogenogluconic acid derivative represented by formula (5A-2) ((5S)-2,3,4,6-tetra-O-acetyl-5-deoxy-5-bromo-D-gluconic acid methyl ester) and the deoxyhalogenogluconic acid derivative represented by formula (5B-2) ((5S)-2,3,4,6-tetra-O-benzoyl-5-deoxy-5-bromo-D-gluconic acid methyl ester) obtained by using a brominating agent as a halogenating agent are particularly preferred.

The present invention will be described in detail below with reference to the following examples. (I) Examples of the production of tetraacetyl deoxyhalogenogluconic acid ester derivatives (Production Examples 1-2 and Examples 1-5) and (II) Examples of the production of tetrabenzoyl deoxyhalogenogluconic acid ester derivatives (Production Examples 3-4 and Examples 6-7) will be described below. Note that the following examples are illustrative and are not intended to limit the present invention.

(I) Synthesis of Tetraacetyldeoxyhalogenogluconic Acid Ester Derivatives Here, (i) a tetraacetylgluconic acid ester derivative was produced as a raw material (Production Examples 1 and 2), (ii) a tetraacetyldeoxysulfonyloxygluconic acid ester derivative was synthesized from the raw material as a production intermediate for the target product (Examples 1 to 4), and (iii) a tetraacetyldeoxyhalogenogluconic acid ester derivative as the target product was synthesized from the tetraacetyldeoxysulfonyloxygluconic acid ester derivative (Example 5). Each of these will be described in turn.

(i) Production of raw materials <Production Example 1>
(Synthesis of tetraacetylgluconolactone derivatives)
2,3,4,6-tetra-O-acetyl-D-glucono-1,5-lactone (ALC) represented by the following reaction formula (2A) was synthesized using D-glucono-1,5-lactone (GLC) represented by the following reaction formula (1) in the following manner.

Trifluoroacetic acid (50 mL) was added dropwise (15 min/16 → 24°C) to a suspension of D-glucono-1,5-lactone (100 g, 0.56 mmol, 1.0 eq) in acetic anhydride (600 mL) at 16°C. After the dropwise addition, the mixture was stirred at 25°C for 3 hours. The reaction solution was concentrated under reduced pressure, and then substituted and concentrated with toluene (3 x 400 mL) to obtain 2,3,4,6-tetra-O-acetyl-D-glucono-1,5-lactone (200 g, quant.).

The NMR spectroscopic analysis results of 2,3,4,6-tetra-O-acetyl-D-glucono-1,5-lactone represented by formula (2A) were as follows:
¹ H-NMR (CDCl ₃ ) δ: 2.08-2.17 (m, 12H), 4.28-4.40 (m, 2H), 4.60-4.65 (m, 1H), 5.10-5.12 (m, 1H), 5.35-5.40 (m, 1H), 5.54-5.58 (m, 1H).

<Production Example 2>
(Synthesis of tetraacetyl gluconate derivatives)
2,3,4,6-tetra-O-acetyl-D-gluconic acid methyl ester (AHM) represented by the following formula (3A) was synthesized using 2,3,4,6-tetra-O-acetyl-D-glucono-1,5-lactone (ALC) represented by the following reaction formula (2A) in the following manner.

p-Toluenesulfonic acid monohydrate (3 g, 15 mmol, 0.027 eq) was added to a methanol (2 L) solution of 2,3,4,6-tetra-O-acetyl-D-glucono-1,5-lactone obtained in Production Example 1, and the mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. Heptane (500 mL) was added to the concentrated residue, and the mixture was heated under reflux for 15 minutes. After that, the mixture was left at 25°C for 1 hour, and the precipitated crystals were filtered to obtain 2,3,4,6-tetra-O-acetyl-D-gluconic acid methyl ester (211 g, 99.4%).

The analytical results obtained for 2,3,4,6-tetra-O-acetyl-D-gluconic acid methyl ester represented by formula (3A) were as follows:
Melting point (hereinafter also simply referred to as "Mp"): 114-116°C.
IR νmax (KBr) 1730 cm ⁻¹ .
¹ H-NMR (CDCl ₃ ) δ: 5.71-5.73 (m, 1H), 5.30-5.31 (m, 1H), 5.18-5.21 (m, 1H), 4.12-4.14 (m, 2H), 3. 86-3.92 (m, 1H), 3.74 (s, 3H), 3.13 (brs, 1H), 2.17, 2.16, 2.14, 2.10-2.16 (m, 12H).

(ii) Synthesis of Production Intermediate Example 1
2,3,4,6-tetra-O-acetyl-5-deoxy-5-mesyloxy-D-gluconic acid methyl ester represented by the following formula (4Aa) was synthesized using 2,3,4,6-tetra-O-acetyl-D-gluconic acid methyl ester (AHM) represented by the following reaction formula (3A) in the following manner.

Triethylamine (328 mg, 3.24 mmol, 1.62 eq) and N,N-dimethylaminopyridine (5.4 mg, 0.044 mmol, 0.022 eq) were added to a solution of 2,3,4,6-tetra-O-acetyl-D-gluconic acid methyl ester (757 mg, 2 mmol) obtained in Preparation Example 2 in ethyl acetate (4 mL), and methanesulfonyl chloride (458 mg, 4 mmol) was added dropwise at 5°C over 15 minutes. After stirring at the same temperature for 2 hours, water (10 ml) and chloroform (10 mL) were added. The organic layer was washed with water (10 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The concentrated residue was crystallized by adding ethyl acetate and filtered to obtain 2,3,4,6-tetra-O-acetyl-5-deoxy-5-mesyloxy-D-gluconic acid methyl ester (633 mg, 69.3%).

The analytical results obtained for 2,3,4,6-tetra-O-acetyl-5-deoxy-5-mesyloxy-D-gluconic acid methyl ester represented by formula (4Aa) were as follows:
Mp 132-133°C.
IR νmax (KBr) 1758, 1738 cm ⁻¹ .
¹ H-NMR (CDCl ₃ ) δ: 5.31-5.55 (m, 1H), 5.28 (s, 1H), 4.97-4.973 (m, 1H), 4.28-4.38 (m, 2H), 3.75 (s, 3H), 3.09 (s, 3H), 2.10-2.18 (m, 12H).

Example 2
2,3,4,6-tetra-O-acetyl-5-deoxy-5-chloromesyloxy-D-gluconic acid methyl ester represented by the following formula (4Ab) was synthesized using 2,3,4,6-tetra-O-acetyl-D-gluconic acid methyl ester (AHM) represented by the following reaction formula (3A) in the following manner.

To a pyridine (85 mL) solution of 2,3,4,6-tetra-O-acetyl-D-gluconic acid methyl ester (8.46 g, 22.37 mmol, 1.0 eq) obtained in Preparation Example 2, chloromethanesulfonyl chloride (4.02 g, 26.8 mmol, 1.2 eq) was added at 0°C or below, and the mixture was stirred at 25°C for 1 hour. Chloromethanesulfonyl chloride (0.67 g, 4.47 mmol, 0.2 eq) was added and the mixture was stirred for 1 hour. The reaction solution was diluted with ethyl acetate (170 mL) and water (170 mL), and the organic layer was washed with water (170 mL), dilute hydrochloric acid (3 x 160 mL), and saturated saline (160 mL). The organic layer was concentrated under reduced pressure, and the concentrated residue was purified using a silica gel column (ethyl acetate) to obtain 2,3,4,6-tetra-O-acetyl-5-deoxy-5-chloromesyloxy-D-gluconic acid methyl ester (9.93 g, 90%).

The analytical results obtained for 2,3,4,6-tetra-O-acetyl-5-deoxy-5-chloromesyloxy-D-gluconic acid methyl ester represented by formula (4Ab) were as follows:
Mp 61-64°C.
IR νmax (KBr) 1750, 1740 cm ⁻¹ .
¹ H-NMR (CDCl ₃ ) δ: 5.54-5.58 (m, 2H), 5.29-5.30 (m, 1H), 5.03-5.08 (m, 1H), 4.67 (s, 2H), 3.75 (s, 3H), 2.04-2.19 (m, 12H).

Example 3
2,3,4,6-tetra-O-acetyl-5-deoxy-5-(2,4,6-trichlorobenzenesulfonyl)oxy-D-gluconic acid methyl ester represented by the following formula (4Ae) was synthesized using 2,3,4,6-tetra-O-acetyl-D-gluconic acid methyl ester (AHM) represented by the following reaction formula (3A) in the following manner.

A solution of 2,3,4,6-tetra-O-acetyl-D-gluconic acid methyl ester (1.00 g, 2.64 mmol, 1.0 eq) obtained in Preparation Example 2 in acetonitrile (10 mL) was cooled to 5°C, and 2,4,6-trichlorobenzenesulfonic acid chloride (1.00 g, 3.57 mmol, 1.3 eq) was added in 1 minute (no heat generation). Next, N-methylimidazole (0.48 g, 5.84 mmol, 2.2 eq) was added dropwise (1 minute, 5 → 7°C), and the mixture was stirred at 25°C for 3 hours. The reaction solution was diluted with water (40 mL), extracted with ethyl acetate (2 x 30 mL), and washed with brine (2 x 30 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (n-hexane/ethyl acetate = 4:1) to obtain 2,3,4,6-tetra-O-acetyl-5-deoxy-5-(2,4,6-trichlorobenzenesulfonyl)oxy-D-gluconic acid methyl ester (0.90 g, 55%).

The analytical results obtained for 2,3,4,6-tetra-O-acetyl-5-deoxy-5-(2,4,6-trichlorobenzenesulfonyl)oxy-D-gluconic acid methyl ester represented by formula (4Ae) were as follows:
IR νmax (KBr) 1748 cm ⁻¹ .
¹ H-NMR (CDCl ₃ ) δ: 7.51 (s, 2H), 5.51-5.55 (m, 2H), 5.25-5.26 (m, 1H), 5.00-5.02 (m, 1H), 4.18-4.34 (m, 2H), 3.74 (s, 3H), 1.92-2.14 (m, 12H).

Example 4
2,3,4,6-tetra-O-acetyl-5-deoxy-5-(2,4,5-trichlorobenzenesulfonyl)oxy-D-gluconic acid methyl ester represented by the following formula (4Af) was synthesized using 2,3,4,6-tetra-O-acetyl-D-gluconic acid methyl ester (AHM) represented by the following reaction formula (3A) in the following manner.

A solution of 2,3,4,6-tetra-O-acetyl-D-gluconic acid methyl ester (1.00 g, 2.64 mmol, 1.0 eq) obtained in Preparation Example 2 in acetonitrile (10 mL) was cooled to 5°C, and 2,4,5-trichlorobenzenesulfonic acid chloride (1.00 g, 3.57 mmol, 1.3 eq) was added over 1 minute. Next, N-methylimidazole (0.48 g, 5.84 mmol, 2.2 eq) was added dropwise to the reaction solution (1 minute, 5 → 7°C). After the addition was completed, the mixture was stirred at 25°C for 5 hours. The reaction solution was diluted with water (40 mL), extracted with ethyl acetate (2 x 30 mL), and washed with brine (2 x 30 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (n-hexane/ethyl acetate = 4:1) to obtain 2,3,4,6-tetra-O-acetyl-5-deoxy-5-(2,4,5-trichlorobenzenesulfonyl)oxy-D-gluconic acid methyl ester (0.85 g, 52%).

The analytical results obtained for 2,3,4,6-tetra-O-acetyl-5-deoxy-5-(2,4,5-trichlorobenzenesulfonyl)oxy-D-gluconic acid methyl ester represented by formula (4Af) were as follows:
Mp 89-90°C.
IR νmax (KBr) 1748 cm ⁻¹ .
¹ H-NMR (CDCl ₃ ) δ: 8.09 (s, 1H), 7.67 (s, 1H), 5.49-5.51 (m, 2H), 5.26-5.27 (m, 1H), 4.95-4.96 (m, 1H), 4.18-4.34 (m, 2H), 3.71 (s, 3H), 1.93-2.18 (m, 12H).

(iii) Synthesis of Target Product Example 5
(5S)-2,3,4,6-tetra-O-acetyl-5-bromo-D-gluconic acid methyl ester represented by the following formula (5A-2) was synthesized using 2,3,4,6-tetra-O-acetyl-5-deoxy-5-(2,4,5-trichlorobenzenesulfonyl)oxy-D-gluconic acid methyl ester represented by the following reaction formula (4Af) in the following manner.

Lithium bromide (0.14 g, 1.6 mmol, 2.0 eq) was added to a 1,3-dimethyl-2-imidazolidinone (DMI, 4 mL) solution of 2,3,4,6-tetra-O-acetyl-5-deoxy-5-(2,4,5-trichlorobenzenesulfonyl)oxy-D-gluconic acid methyl ester (0.50 g, 0.8 mmol, 1.0 eq) obtained in Example 4, and the mixture was stirred at 50°C for 2 hours. The reaction solution was diluted with saturated saline (30 mL), and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The organic layer was washed with saturated saline (3 x 20 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (n-hexane/ethyl acetate = 3:1) to obtain a colorless oily (5S)-2,3,4,6-tetra-O-acetyl-5-deoxy-5-bromo-D-gluconic acid methyl ester (307 mg, 87%).

The analytical results obtained for (5S)-2,3,4,6-tetra-O-acetyl-5-deoxy-5-bromo-D-gluconic acid methyl ester represented by formula (5A-2) are as follows.
¹ H-NMR (CDCl ₃ ) δ: 5.71-5.74 (m, 1H), 5.40-5.41 (m, 1H), 5.29-5.30 (m, 1H), 4.10-4.29 (m, 3H), 3.73 (s, 3H), 2.04-2.21 (m, 12H).

(II) Synthesis of Tetrabenzoyldeoxyhalogenogluconic Acid Ester Derivatives Here, (i) a tetrabenzoylgluconic acid ester derivative was produced as a raw material (Production Examples 3 and 4), (ii) a tetrabenzoyldeoxysulfonyloxygluconic acid ester derivative was synthesized from the raw material as a production intermediate for the target product (Example 6), and (iii) a tetrabenzoyldeoxyhalogenogluconic acid ester derivative was synthesized as the target product from the tetrabenzoyldeoxysulfonyloxygluconic acid ester derivative (Example 7). Each of these will be described in turn.

(i) Synthesis of raw materials <Production Example 3>
(Synthesis of tetrabenzoylgluconolactone derivatives)
2,3,4,6-tetra-O-benzoyl-D-glucono-1,5-lactone represented by the following reaction formula (2B) was synthesized using D-glucono-1,5-lactone (GLC) represented by the following reaction formula (1) in the following manner.

Pyridine (111 g, 1.40 mol, 5.0 eq) was added to a chloroform solution (500 mL) of D-glucono-1,5-lactone (50 g, 280 mmol, 1.0 eq) and cooled to an internal temperature of 0°C. Benzoyl chloride (197 g, 1.40 mol, 5.0 eq) was added dropwise to this solution (1 hour/0-9°C). As stirring became difficult during the dropwise addition, additional chloroform (300 mL) was added. The mixture was then stirred at 25°C for 5 hours.

The reaction solution was diluted with 1N hydrochloric acid (1 L) and then separated. The organic layer was washed with saturated sodium bicarbonate water (500 mL) and saturated saline (500 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. Toluene (1 L) was added to the concentrated residue, and the solid was dissolved at 70-80°C. The mixture was then stirred at 25°C for 1 hour, and the precipitated solid was filtered. The filtered solid was washed with toluene (200 mL) and hexane (200 mL), and then dried under reduced pressure (reduced pressure, 55°C, 3 hours) to obtain 2,3,4,6-tetra-O-benzoyl-D-glucono-1,5-lactone (93 g, 56%).

The mother liquor was left to stand at room temperature overnight, and the precipitated crystals were filtered and dried to obtain the desired No. 2 crystals (36 g). Total of No. 1 and No. 2 crystals: 129 g (77%).

The analytical results obtained for 2,3,4,6-tetra-O-benzoyl-D-glucono-1,5-lactone of formula (2B) were as follows:
Mp 178-179 ^o C.
IR νmax (Nujol) 1755, 1720 cm ⁻¹ .
¹ H-NMR (CDCl ₃ ) δ: 6.75-8.50 (m, 20H), 5.40-6.50 (m, 3H), 4.40-5.40 (m, 3H).

<Production Example 4>
(Synthesis of tetrabenzoyl gluconate derivatives)
2,3,4,6-tetra-O-benzoyl-D-gluconic acid methyl ester represented by the following formula (3B) was synthesized using 2,3,4,6-tetra-O-benzoyl-D-glucono-1,5-lactone represented by the following reaction formula (2B) in the following manner.

To a solution of 2,3,4,6-tetra-O-benzoyl-D-glucono-1,5-lactone (90 g, 151 mmol) obtained in Production Example 3 in methanol (1.5 L) was added 4N HCl-dioxane (20 mL) at room temperature. After stirring at 25 ^° C for 2 hours, the reaction solution was concentrated under reduced pressure. The concentrated residue was dissolved in ethyl acetate (200 mL) and washed with saturated sodium bicarbonate water (200 mL x 2) and saturated saline (100 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrated residue was purified with a silica gel column (n-hexane/ethyl acetate = 3:1) to obtain 2,3,4,6-tetra-O-benzoyl-D-gluconic acid methyl ester (71 g, 75%).

The analytical results obtained for 2,3,4,6-tetra-O-benzoyl-D-gluconic acid methyl ester represented by formula (3B) were as follows:
IR νmax (Nujol) 1750, 1720 cm ⁻¹ .
¹ H-NMR (CDCl ₃ ) δ: 7.00-8.25 (m, 20H), 5.40-6.50 (m, 3H), 4.00-4.60 (m, 4H), 3.60 (s, 3H).

(ii) Synthesis of Production Intermediate Example 6
2,3,4,6-tetra-O-benzoyl-5-deoxy-5-(2,4,5-trichlorobenzenesulfonyl)oxy-D-gluconic acid methyl ester represented by the following formula (4Bf) was synthesized using 2,3,4,6-tetra-O-benzoyl-D-gluconic acid methyl ester represented by the following reaction formula (3B) in the following manner.

2,3,4,6-Tetra-O-benzoyl-D-gluconic acid methyl ester (30 g, 47.9 mmol, 1.0 eq) obtained in Preparation Example 4 was dissolved in acetonitrile (300 mL) and 2,4,5-trichlorobenzenesulfonyl chloride (17.4 g, 62.2 mmol, 1.3 eq) and N-methylimidazole (8.6 g, 105.3 mmol, 2.2 eq) were added at 5°C, followed by stirring at 25°C for 2 hours.

After filtering the reaction solution, the mother liquor was concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (n-hexane/ethyl acetate = 20:1 → 4:1) to obtain 2,3,4,6-tetra-O-benzoyl-5-deoxy-5-(2,4,5-trichlorobenzenesulfonyl)oxy-D-gluconic acid methyl ester (31.2 g, 75%).

The analytical results obtained for 2,3,4,6-tetra-O-benzoyl-5-deoxy-5-(2,4,5-trichlorobenzenesulfonyl)oxy-D-gluconic acid methyl ester represented by formula (4Bf) were as follows.
IR νmax (KBr) 1724 cm ⁻¹ .
¹ H-NMR (CDCl ₃ ) δ: 7.00-8.25 (m, 22H), 5.20-6.30 (m, 4H), 4.50-4.80 (m, 2H), 3.60 (s, 3H).

(iii) Synthesis of Target Product <Example 7>
(5S)-2,3,4,6-tetra-O-benzoyl-5-bromo-D-gluconic acid methyl ester represented by the following formula (5B-2) was synthesized using 2,3,4,6-tetra-O-benzoyl-5-deoxy-5-(2,4,5-trichlorobenzenesulfonyl)oxy-D-gluconic acid methyl ester represented by the following reaction formula (4Bf) in the following manner.

LiBr (6.00 g, 69.0 mmol, 2.0 eq) was added to a solution of 2,3,4,6-tetra-O-benzoyl-5-deoxy-5-(2,4,5-trichlorobenzenesulfonyl)oxy-D-gluconic acid methyl ester (30 g, 34.5 mmol, 1.0 eq) obtained in Example 6 in 1,3-dimethylimidazolidinone (180 mL), and the mixture was stirred at 50°C for 4 hours.

After diluting the reaction solution with saturated saline and ethyl acetate (400 mL each), the organic layer was washed with saturated saline (200 mL x 3). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (n-hexane/ethyl acetate = 10:1 → 4:1) to obtain crude (5S)-2,3,4,6-tetra-O-benzoyl-5-deoxy-5-bromo-D-gluconic acid methyl ester (19.8 g, 77.3%).

This product was dispersed and stirred in hexane (50 mL), filtered, and dried under reduced pressure (40°C/4 hr) to obtain a solid (16.2 g, 81.9% (purification yield)). The obtained solid (15 g) was dissolved in methanol (15 mL) under heating under reflux, slowly cooled to 25°C, stirred at the same temperature for 1 hour, filtered, and dried to obtain the pure target product as white crystals (11.2 g, 75% (purification yield)).

The analytical results obtained for (5S)-2,3,4,6-tetra-O-benzoyl-5-deoxy-5-bromo-D-gluconic acid methyl ester represented by formula (5B-2) are as follows.
Mp 116-118°C.
IR νmax (KBr) 1738, 1727, 1718 ^{cm −1} .
¹ H-NMR (CDCl ₃ ) δ: 6.70-8.30 (m, 20H), 5.50-6.50 (m, 3H), 3.80-5.00 (m, 3H), 3.60 (s, 3H).

The manufacturing conditions and measurement results for Examples 1 to 4 and 6 are summarized in Table 2 below. The manufacturing conditions and measurement results for Examples 5 and 7 are summarized in Table 3 below.

Claims (10)

A deoxyhalogenogluconic acid derivative represented by the following formula (5):
In the formula (5),
R ¹ is an alkyl group having 1 to 6 carbon atoms, an aralkyl group having 7 to 20 carbon atoms which may have a substituent, or an aryl group having 6 to 20 carbon atoms which may have a substituent;
^R2 is an alkyl group having 1 to 6 carbon atoms;
X is a halogen atom. The method includes contacting a deoxysulfonyloxygluconic acid derivative represented by the following formula (4) with a halogenating agent to produce a deoxyhalogenogluconic acid derivative represented by the following formula (5'):
Method for producing deoxyhalogenosigluconic acid derivatives:
In the formula (4),
R ¹ is an alkyl group having 1 to 6 carbon atoms, an aralkyl group having 7 to 20 carbon atoms which may have a substituent, or an aryl group having 6 to 20 carbon atoms which may have a substituent;
^R2 is an alkyl group having 1 to 6 carbon atoms;
^R3 is an alkyl group having 1 to 12 carbon atoms, a haloalkyl group having 1 to 12 carbon atoms, an aralkyl group having 7 to 20 carbon atoms which may have a substituent, or an aryl group having 6 to 20 carbon atoms which may have a substituent;
In the formula (5'),
R ¹ and R ² are the same as those represented by formula (4).
X'' is a halogen atom derived from the halogenating agent. The halogenating agent is used in an amount of 1.0 mole or more and 5.0 moles or less per mole of the deoxysulfonyloxygluconic acid derivative represented by the formula (4).
A method for producing the deoxyhalogenogluconic acid derivative according to claim 2 . contacting the deoxysulfonyloxygluconic acid derivative represented by formula (4) with the halogenating agent in a second reaction solvent containing an aprotic polar solvent;
A method for producing the deoxyhalogenogluconic acid derivative according to claim 2 or 3 . In the presence of a base,
A tetraacylgluconic acid derivative represented by the following formula (3) is contacted with a sulfonylating agent represented by the following formula (6) to produce a deoxysulfonyloxygluconic acid derivative represented by the formula (4),
and contacting the obtained deoxysulfonyloxygluconic acid derivative represented by formula (4) with a halogenating agent to produce a deoxyhalogenogluconic acid derivative represented by formula (5'):
Method for producing deoxyhalogenogluconic acid derivatives:
In the formula (3),
R ¹ and R ² are defined as those represented by the following formula (4):
In the formula (6),
R3 has the same meaning ^as that represented by the following formula (4),
X' is a halogen atom;
In the formula (4),
R ¹ is an alkyl group having 1 to 6 carbon atoms, an aralkyl group having 7 to 20 carbon atoms which may have a substituent, or an aryl group having 6 to 20 carbon atoms which may have a substituent;
^R2 is an alkyl group having 1 to 6 carbon atoms;
^R3 is an alkyl group having 1 to 12 carbon atoms, a haloalkyl group having 1 to 12 carbon atoms, an aralkyl group having 7 to 20 carbon atoms which may have a substituent, or an aryl group having 6 to 20 carbon atoms which may have a substituent;
In the formula (5'),
R ¹ and R ² are the same as those represented by formula (4).
X'' is a halogen atom derived from the halogenating agent. The base includes at least one selected from the group consisting of an alkylamine base and a cyclic amine base.
A method for producing the deoxyhalogenogluconic acid derivative according to claim 5 . The base is used in an amount of 0.001 moles or more and 5.0 moles or less per mole of the tetraacylgluconic acid derivative represented by the formula (3).
A method for producing the deoxyhalogenogluconic acid derivative according to claim 5 or 6 . The sulfonylating agent represented by the formula (6) includes at least one selected from the group consisting of alkylsulfonyl chlorides, haloalkylsulfonyl chlorides, arylsulfonyl chlorides, and haloarylsulfonyl chlorides.
A method for producing the deoxyhalogenogluconic acid derivative according to any one of claims 5 to 7 . the sulfonylating agent represented by the formula (6) is used in an amount of 1.0 mole or more and 5.0 moles or less per mole of the tetraacylgluconic acid derivative represented by the formula (3);
A method for producing the deoxyhalogenogluconic acid derivative according to any one of claims 5 to 8 . contacting the tetraacylgluconic acid derivative represented by the formula (3) with the sulfonylating agent represented by the formula (6) in a first reaction solvent containing at least one solvent selected from the group consisting of methylene chloride, ethyl acetate and acetonitrile;
A method for producing the deoxyhalogenogluconic acid derivative according to any one of claims 5 to 9 .