Gluconamide derivative

Abstract

To provide novel compounds of a gluconamide derivative, a deoxy-sulfonyloxy gluconamide derivative, a deoxyhalogeno gluconic acid derivative, and a deoxymercapto gluconamide derivative.SOLUTION: Provided is a gluconamide derivative represented by the formula (3). In the formula (3), R1 and R2 are each independently a C1-6 alkyl group, a C2-7 alkylalkoxy group, a C4-6 cycloalkyl group, a C5-20 aryl group which may have a substituent, or a C7-20 aralkyl group. R1 and R2, together with a nitrogen atom bonded by these, may form a heterocyclic ring having 5 to 6 ring members which may further contain at least one hetero atom selected from the group consisting of oxygen, sulfur, and nitrogen. R3, R4, R5, and R6 are each independently a protective group.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to gluconamide derivatives, deoxysulfonyloxygluconamide derivatives, deoxyhalogenogluconic acid derivatives, and deoxymercaptogluconamide derivatives. [Background technology]

[0002] Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are useful as antidiabetic drugs. Known SGLT-2 inhibitors include canagliflozin, empagliflozin, ipragliflozin, dapagliflozin, and luseogliflozin.

[0003] The SGLT-2 inhibitor is represented, for example, by the following formula (I).

[0004] [ka]

[0005] In the above formula (I), Y is a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom, and Z is a variety of substituents.

[0006] As a method for producing an SGLT-2 inhibitor, a method using a protected gluconolactone represented by the following formula (2) has been studied.

[0007] [ka]

[0008] In formula (2), R 3 , R 4 , R 5 , and R 6 are each independently a protecting group. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] JP 2022-159769 A [Patent Document 2] International Publication No. 2016 / 098016 Summary of the Invention [Problem to be solved by the invention]

[0010] An object of the present invention is to provide novel compounds, namely, gluconamide derivatives, deoxysulfonyloxygluconamide derivatives, deoxyhalogenogluconic acid derivatives, and deoxymercaptogluconamide derivatives. [Means for solving the problem]

[0011] According to one aspect, there is provided a gluconamide derivative represented by the following formula (3):

[0012] [ka]

[0013] In formula (3), R 1 and R 2 are each independently an alkyl group having 1 to 6 carbon atoms, an alkylalkoxy group having 2 to 7 carbon atoms, a cycloalkyl group having 4 to 6 carbon atoms, an aryl group having 5 to 20 carbon atoms which may have a substituent, or an aralkyl group having 7 to 20 carbon atoms. 1 and R 2 may form, together with the nitrogen atom to which they are bonded, a heterocycle having 5 to 6 ring members and which may further contain at least one heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen. 3 , R 4 , R 5 , and R 6 are each independently a protecting group.

[0014] According to another aspect, there is provided a deoxysulfonyloxygluconamide derivative represented by the following formula (5):

[0015] [ka]

[0016] In formula (5), R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is the same as in formula (3). 7 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.

[0017] According to another aspect, there is provided a deoxyhalogenogluconic acid derivative represented by the following formula (6):

[0018] [ka]

[0019] In formula (6), R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 has the same meaning as in formula (3). 2 is a halogen atom.

[0020] According to another aspect, there is provided a deoxymercaptogluconamide derivative represented by the following formula (7):

[0021] [ka]

[0022] In formula (7), R1 , R 2 , R 3 , R 4 , R 5 , and R 6 has the same meaning as in formula (3). Effect of the Invention

[0023] According to the present invention, there are provided novel compounds, namely, gluconamide derivatives, deoxysulfonyloxygluconamide derivatives, deoxyhalogenogluconic acid derivatives, and deoxymercaptogluconamide derivatives. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] According to the embodiment, novel compounds, namely, gluconamide derivatives, deoxysulfonyloxygluconamide derivatives, deoxyhalogenogluconic acid derivatives, and deoxymercaptogluconamide derivatives, and methods for producing them are provided. By using them, SGLT-2 inhibitors, particularly luseogliflozin, can be efficiently produced.

[0025] That is, luseogliflozin is a compound represented by the following formula (II).

[0026] [ka]

[0027] In the process for producing luseogliflozin using the above-mentioned protected gluconolactone, a step of introducing a sulfur atom is required.

[0028] 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 failed to obtain the desired compound. 3 , R 4 , R 5 , and R 6 is a protecting group and X is a halogen atom.

[0029] [ka]

[0030] This is believed to be because the reagent used for introducing a thiol group, such as potassium thioacetate, is strongly basic, and therefore the ester bond of the deoxyhalogenogluconic acid derivative is hydrolyzed.

[0031] In response to such problems, the method according to the embodiment provides a gluconamide derivative represented by the above formula (3). This compound has an amide bond instead of an ester bond. Therefore, when the deoxyhalogenogluconic acid derivative represented by the above formula (6) obtained from the gluconamide derivative represented by formula (3) is reacted with a strongly basic reagent such as potassium thioacetate, the deoxymercaptogluconamide derivative represented by the above formula (7) can be obtained without hydrolysis. According to the method using the protected gluconolactone represented by formula (2) as a starting material, luseogliflozin can be produced by omitting several steps, compared with the conventional method using D-glucurono-3,6-lactone or the like as a starting material. Therefore, according to the method according to the embodiment, luseogliflozin can be produced efficiently at low cost.

[0032] The manufacturing method according to the embodiment will be described in detail below.

[0033] (Gluconamide derivatives) The gluconamide derivative is represented by the following formula (3).

[0034] [ka]

[0035] In formula (3), R 1 and R 2are each independently an alkyl group having 1 to 6 carbon atoms, an alkylalkoxy group having 2 to 7 carbon atoms, a cycloalkyl group having 4 to 6 carbon atoms, an aryl group having 5 to 20 carbon atoms which may have a substituent, or an aralkyl group having 7 to 20 carbon atoms. 1 and R 2 may form, together with the nitrogen atom to which they are bonded, a heterocycle having 5 to 6 ring members and which may further contain at least one heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen. 1 and R 2 is preferably an alkyl group having 1 to 6 carbon atoms, or forms a heterocycle. The heterocycle is preferably a morpholino group, a thiomorpholino group, a pyrrolidino group, a piperidino group, or a piperazino group.

[0036] R 3 , R 4 , R 5 , and R 6 are each independently a protecting group. The protecting group includes, for example, at least one selected from the group consisting of a toluoyl group, a benzyl group, an acetyl group, and a benzoyl group. The protecting group is preferably a toluoyl group.

[0037] The gluconamide derivative represented by formula (3) can be obtained, for example, by contacting an amine compound represented by the following formula (1) with a protected gluconolactone represented by the following formula (2).

[0038] [ka]

[0039] In formula (1), R 1 and R 2 has the same meaning as in formula (3).

[0040] The amine compound represented by formula (1) preferably includes at least one of a dialkylamine and a heterocyclic amine, and more preferably includes at least one compound selected from the group consisting of dimethylamine, diethylamine, morpholine, pyrrolidine, piperidine, piperazine, and thiomorpholine.

[0041] [ka]

[0042] In formula (2), R 3 , R 4 , R 5 , and R 6 has the same meaning as in formula (3).

[0043] The amount of the amine compound represented by formula (1) relative to 1 mole of the protected gluconolactone represented by formula (2) is, for example, 1 mole or more and 5 moles or less, and preferably 2 moles or more and 4 moles or less.

[0044] The amine compound represented by formula (1) and the protected gluconolactone represented by formula (2) are preferably contacted under a nitrogen atmosphere.

[0045] The contact between the amine compound represented by formula (1) and the protected gluconolactone represented by formula (2) is preferably carried out at a temperature ranging from 10° C. to 40° C. This contact may also be carried out at room temperature.

[0046] The contact between the amine compound represented by formula (1) and the protected gluconolactone represented by formula (2) is preferably carried out in the presence of a reaction solvent. The reaction solvent is not particularly limited as long as it can dissolve the protected gluconolactone represented by formula (2). The reaction solvent includes, for example, at least one selected from the group consisting of toluene, benzene, dichloromethane, chloroform, tetrahydrofuran (THF), and N,N-dimethylformamide (DMF). The amount of the reaction solvent relative to 1 g of the protected gluconolactone represented by formula (2) is, for example, 0.1 mL or more and 50 mL or less, preferably 1 mL or more and 20 mL or less.

[0047] The gluconamide derivative represented by formula (3) obtained by this production method may be separated by a liquid separation process or the like. The separated crystals may be subjected to a washing process and a drying process. The structure of the gluconamide derivative represented by formula (3) may be confirmed by, for example, nuclear magnetic resonance (NMR) spectroscopic analysis.

[0048] The protected gluconolactone represented by formula (2) can be synthesized by a known method. For example, the protected gluconolactone represented by formula (2) can be obtained by reacting gluconolactone with a solution containing each protecting group.

[0049] (Deoxysulfonyloxygluconamide derivatives) The deoxysulfonyloxygluconamide derivative is represented by the following formula (5).

[0050] [ka]

[0051] In formula (5), R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 has the same meaning as in formula (3).

[0052] R 7is 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. Examples of the substituent include an alkyl group having 1 to 20 carbon atoms, an alkoxy group having 1 to 20 carbon atoms, a chlorine atom, a bromine atom, an iodine atom, or a nitro group. The substituent is preferably a halogen atom. R 7 R is 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. 7 is more preferably a methyl group, a halomethyl group, a phenyl group, a tolyl group, a 2,4,6-trichlorophenyl group, or a 2,4,5-trichlorophenyl group.

[0053] The deoxysulfonyloxygluconamide derivative represented by formula (5) can be obtained, for example, by contacting the gluconamide derivative represented by formula (3) with a sulfonylating agent represented by the following formula (4).

[0054] R 7 -SO2X 1 (4) In formula (4), R 7 has the same meaning as in formula (5).

[0055] X 1 is a halogen atom. X 1 is preferably a chlorine atom.

[0056] The sulfonylating agent includes, for example, at least one compound selected from the group consisting of methanesulfonyl chloride, chloromethanesulfonyl chloride, benzenesulfonyl chloride, 2,4,6-trichlorobenzenesulfonyl chloride, and 2,4,5-trichlorobenzenesulfonyl chloride (TCBS-Cl).

[0057] The amount of the sulfonylating agent represented by formula (4) relative to 1 mole of the gluconamide derivative represented by formula (3) is, for example, 1 mole or more and 3 moles or less. The amount of the sulfonylating agent represented by formula (4) is preferably 1.1 moles or more and 2.0 moles or less.

[0058] The gluconamide derivative represented by formula (3) is preferably contacted with the sulfonylating agent represented by formula (4) in the presence of a base.

[0059] The base includes, for example, at least one organic base selected from the group consisting of trimethylamine, triethylamine, pyridine, 4-dimethylaminopyridine, N-methylimidazole, N,N-diethylaniline, and diisopropylethylamine.

[0060] The amount of the base relative to 1 mole of the gluconamide derivative represented by the formula (3) is, for example, 1 mole or more and 5 moles or less, and preferably 1.5 moles or more and 3.0 moles or less.

[0061] The contact between the gluconamide derivative represented by formula (3) and the sulfonylating agent represented by formula (4) is preferably carried out under a nitrogen atmosphere.

[0062] The contact between the gluconamide derivative represented by formula (3) and the sulfonylating agent represented by formula (4) is preferably carried out at a temperature ranging from −20° C. to 20° C. This contact may also be carried out at room temperature.

[0063] The contact between the gluconamide derivative represented by formula (3) and the sulfonylating agent represented by formula (4) is preferably carried out in the presence of a reaction solvent. The reaction solvent is not particularly limited as long as it can dissolve the gluconamide derivative represented by formula (3). The reaction solvent includes, for example, at least one selected from the group consisting of acetonitrile, N,N-dimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane, and chloroform. The amount of the reaction solvent for 1 g of the gluconamide derivative represented by formula (3) is, for example, 0.1 mL or more and 50 mL or less, preferably 1 mL or more and 20 mL or less.

[0064] The deoxysulfonyloxygluconamide derivative represented by formula (5) obtained by this production method may be separated by a liquid separation process or the like. The separated crystals may be subjected to a washing process and a drying process. The structure of the deoxysulfonyloxygluconamide derivative represented by formula (5) may be confirmed by, for example, nuclear magnetic resonance (NMR) spectroscopic analysis.

[0065] (Deoxyhalogenogluconic acid derivatives) The deoxyhalogenogluconic acid derivative is represented by the following formula (6).

[0066] [ka]

[0067] In formula (6), R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 has the same meaning as in formula (3). 2 is a halogen atom.

[0068] The deoxyhalogenogluconic acid derivative represented by the formula (6) can be obtained, for example, by contacting the deoxysulfonyloxygluconamide derivative represented by the formula (5) with a halogenating agent.

[0069] Examples of halogenating agents include MX 2 The alkali metal halide represented by the formula: M is an alkali metal atom. M is preferably lithium, sodium, potassium or cesium. X 2 has the same meaning as in formula (6).

[0070] The alkali metal halide salt preferably includes at least one selected from the group consisting of lithium halide, sodium halide, potassium halide, and cesium halide, and more preferably includes at least one selected from the group consisting of lithium bromide, sodium bromide, potassium bromide, and cesium bromide.

[0071] The amount of the halogenating agent relative to 1 mole of the deoxysulfonyloxygluconamide derivative represented by formula (5) is, for example, 1 mole or more and 5 moles or less, and preferably 1.5 moles or more and 3.0 moles or less.

[0072] The contact of the deoxysulfonyloxygluconamide derivative represented by formula (5) with the halogenating agent is preferably carried out under a nitrogen atmosphere.

[0073] The contact of the deoxysulfonyloxygluconamide derivative represented by formula (5) with the halogenating agent is preferably carried out within a temperature range of 30°C or higher and 100°C or lower.

[0074] The contact between the deoxysulfonyloxygluconamide derivative represented by formula (5) and the halogenating agent is preferably carried out in the presence of a reaction solvent. The reaction solvent is not particularly limited as long as it can dissolve the deoxysulfonyloxygluconamide derivative represented by formula (5). The reaction solvent includes, for example, at least one selected from the group consisting of 1,3-dimethyl-2-imidazolidinone (DMI), N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO). The amount of the reaction solvent for 1 g of the deoxysulfonyloxygluconamide derivative represented by formula (5) is, for example, 0.1 mL or more and 50 mL or less, preferably 1 mL or more and 20 mL or less.

[0075] The deoxyhalogenogluconic acid derivative represented by formula (6) obtained by this production method may be separated by liquid separation or the like. The separated crystals may be subjected to washing and drying. The structure of the deoxyhalogenogluconic acid derivative represented by formula (6) can be confirmed, for example, by nuclear magnetic resonance (NMR) spectroscopic analysis.

[0076] (Deoxymercaptogluconamide derivatives) The deoxymercaptogluconamide derivative is represented by the following formula (7).

[0077] [ka]

[0078] In formula (7), R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 has the same meaning as in formula (3).

[0079] The deoxymercaptogluconamide derivative represented by formula (7) can be obtained, for example, by contacting the deoxyhalogenogluconic acid derivative represented by formula (6) with a sulfur-containing compound.

[0080] The sulfur-containing compound includes, for example, at least one selected from the group consisting of thioacetic acid, a salt of thioacetic acid, sodium sulfide, sodium hydrosulfide, an alkylthiol, and an aralkylthiol. The salt of thioacetic acid includes, for example, potassium thioacetate.

[0081] When thioacetic acid or a salt of thioacetic acid is used, it is considered that the deoxymercaptogluconamide derivative represented by the above formula (7) is synthesized via the acetylthiogluconamide derivative represented by the following formula (6a) as an intermediate. In formula (6a), R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 has the same meaning as in formula (6).

[0082] [ka]

[0083] The amount of the sulfur-containing compound relative to 1 mole of the deoxyhalogenogluconic acid derivative represented by formula (6) is, for example, 1 mole or more and 10 moles or less, and preferably 2 moles or more and 7 moles or less.

[0084] The contact between the deoxyhalogenogluconic acid derivative represented by formula (6) and the sulfur-containing compound is preferably carried out under a nitrogen atmosphere.

[0085] The contact between the deoxyhalogenogluconic acid derivative represented by formula (6) and the sulfur-containing compound is preferably carried out at a temperature ranging from 10° C. to 40° C. It may also be carried out at room temperature.

[0086] The contact between the deoxyhalogenogluconic acid derivative represented by formula (6) and the sulfur-containing compound is preferably carried out in the presence of a reaction solvent. The reaction solvent is not particularly limited as long as it can dissolve the deoxyhalogenogluconic acid derivative represented by formula (6). The reaction solvent includes, for example, at least one selected from the group consisting of 1,3-dimethyl-2-imidazolidinone (DMI), N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO). The amount of the reaction solvent relative to 1 g of the deoxyhalogenogluconic acid derivative represented by formula (6) is, for example, 0.1 mL or more and 50 mL or less, preferably 1 mL or more and 20 mL or less.

[0087] The deoxymercaptogluconamide derivative represented by formula (7) obtained by this manufacturing method may be separated by liquid separation or the like. The separated crystals may be subjected to washing and drying treatments. The structure of the deoxymercaptogluconamide derivative represented by formula (7) may be confirmed, for example, by nuclear magnetic resonance (NMR) spectroscopic analysis. The deoxymercaptogluconamide derivative represented by formula (7) is useful, for example, as an intermediate for the synthesis of luseofulligrosin. EXAMPLES

[0088] 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:

[0089] <Example 1> (Production of gluconolactone toluoyl protection compound) A p-toluoyl protected derivative of gluconolactone was prepared by the following method.

[0090] [ka]

[0091] 14.0 g of gluconolactone was added to 380 mL of chloroform to obtain a suspension. 0.96 g (0.1 equivalent) of 4-dimethylaminopyridine (DMAP) and 30 mL (4.8 equivalent) of pyridine were added to this suspension to obtain a reaction solution. The reaction solution was cooled to 0°C, and 50 mL (4.8 equivalent) of p-toluoyl chloride was added dropwise over 1 hour and stirred at room temperature. After 19 hours, the reaction solution was washed with 200 mL of 10% hydrochloric acid and 200 mL of water and dried over anhydrous sodium sulfate. After natural filtration, the solvent was distilled off to obtain a white solid. This solid was dissolved by heating (80°C) in 280 mL of acetonitrile, and then allowed to cool and crystallize. The obtained solid was suction filtered and washed with cold acetonitrile, and then the solid was dried at 40°C under reduced pressure to obtain 34.6 g of a white solid. The yield was 67.7%, and the purity by HPLC was 91.3%.

[0092] The NMR spectroscopic analysis results of the gluconolactone toluoyl protected product were as follows. 1 H NMR (400 MHz, chloroform-d)δ7.97-7.76 (m, 8H, Ar-H), 7.25-7.11 (m, 8H, Ar-H), 6.16 (t, J = 9Hz, 1H, CH), 5.94 (t, J = 9 Hz, 1H, CH), 5.63 (d, J=9 Hz, 1H, CH), 5.05 (ddd, J = 9, 4, 3 Hz, 1H, CH), 4.73 (dd, J = 3, 13 Hz, 1H, CH2), 4.64 (d, J = 5, 13 Hz, 1H, CH2), 2.42-2.33 (m, 12H, CH3). (Production of gluconamide derivatives) The glucone dimethylamide derivative was prepared in the following manner.

[0093] [ka]

[0094] 0.835 g of gluconolactone toluoyl-protected product was suspended in 8.4 mL of toluene, and 0.336 mL (2.5 equivalents) of 50% dimethylamine was added and stirred at room temperature for 1.5 hours. After that, 10 mL of 10% hydrochloric acid was added to the reaction solution to separate it, and the hydrochloric acid layer was further extracted with 10 mL of toluene. The toluene layer was washed with 10 mL of 20% saline and dried over anhydrous sodium sulfate. After gravity filtration and distillation, 0.832 g of a white candy-like substance was obtained. The yield was 93.2%, and the purity by HPLC was 71.6%.

[0095] The NMR spectroscopic analysis results of the glucone dimethylamide derivative were as follows: 1 H NMR (400 MHz, chloroform-d)δ7.97-7.78 (m, 8H, Ar-H), 7.27-7.05 (m, 8H, Ar-H), 6.36 (ddd, J = 4.8, 2.6 Hz, 1H, CH), 6.15-6.13 (m, 1H, CH), 5.60 (ddd, J = 8.7, 2.3 Hz, 1H, CH), 4.50 (dd, J = 11.7, 3.0 Hz, 1H, CH2), 4.33 (dd, J = 11.9, 6.0 Hz, 1H, CH2), 4.21-4.19 (m, 1H, CH), 3.05 (s, 3H, NCH3), 2.99 (s, 3H, NCH3), 2.40-2.34 (m, 12H, CH3). <Example 2> The glucone morpholinamide derivative was prepared in the following manner.

[0096] [ka]

[0097] 10.0 g of the gluconolactone toluoyl-protected product obtained in Example 1 was suspended in 100 mL of toluene, 3.3 mL (2.5 equivalents) of morpholine was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 60 minutes. Then, 100 mL of 10% hydrochloric acid was added to the reaction solution to separate it. The hydrochloric acid layer was further extracted with 50 mL of toluene. The toluene layer was washed with 100 mL of water and dried over anhydrous sodium sulfate. After natural filtration, the solvent was distilled off to obtain 11.2 g of a white solid. The yield was 99.1%, and the purity by HPLC was 85.5%.

[0098] The NMR spectroscopic analysis results of the glucone morpholinamide derivative were as follows: 1 H NMR (400 MHz, chloroform-d) δ7.96-7.77 (m, 8H, Ar-H), 7.24-7.06 (m, 8H, Ar-H), 6.38 (dd, J = 7.8, 2.3 Hz, 1H, CH), 6.07 (d, J = 7.3 Hz, 1H, CH), 5.61 (dd, J = 8.7, 2.3 Hz, 1H, CH), 4.51 (dd, J = 11.9, 2.7 Hz, 1H, CH2), 4.37-4.30 (m, 1H, CH2), 4.21-4.18 (m, 1H, CH), 3.72-3.50 (m, 8H, Mor), 2.45-2.32 (m, 12H, CH3). <Example 3> The deoxysulfonyloxyglucone morpholinamide derivative was prepared in the following manner.

[0099] [ka]

[0100] 11.2 g of the glucone morpholinamide derivative obtained in Example 2 was dissolved in 100 mL of acetonitrile, and 5.5 g (1.3 equivalents) of TCBS-CL and 2.4 mL (2.0 equivalents) of N-methylimidazole were added at 0°C and stirred at room temperature for 5 hours. The solvent was then distilled off and the residue was diluted in 100 mL of 5% aqueous sodium bicarbonate solution. Extraction was performed twice with 100 mL of ethyl acetate. The ethyl acetate layer was washed with 100 mL of water and dried over anhydrous sodium sulfate. After natural filtration, the solvent was distilled off to obtain 13.3 g of a pale yellow solid. The yield was 89.3%, and the purity by HPLC was 66.2%.

[0101] The NMR spectroscopic analysis results of the deoxysulfonyloxyglucone morpholinamide derivative were as follows: 1 H NMR (400 MHz, chloroform-d) δ7.98-7.71 (m, 8H, Ar-H), 7.28-7.07 (m, 8H, Ar-H), 6.27 (dd, J = 6.9, 3.2 Hz, 1H, CH), 5.98 (d, J = 7.3 Hz, 1H, CH), 5.81 (t, J = 3.0 Hz, 1H, CH), 5.56-5.54 (m, 1H, CH), 4.80-4.75 (m, 2H, CH2), 3.65-3.51 (m, 8H, Mor), 2.43-2.32 (m, 12H, CH3). <Example 4> The brominated glucone morpholinamide derivatives were prepared in the following manner.

[0102] [ka]

[0103] 9.7 g of the deoxysulfonyloxyglucone morpholinamide derivative obtained in Example 3 was dissolved in 58 mL of DMI, 1.7 g (2.0 equivalents) of lithium bromide was added, and the mixture was stirred at 50° C. under a nitrogen atmosphere. After 3 hours, the reaction solution was dissolved in 120 mL of hexane / chloroform (4:1), and 60 mL of water was added to separate the liquid. The organic layer was washed three times with 60 mL of water and dried over anhydrous sodium sulfate. After natural filtration, the solvent was distilled off to obtain 7.7 g of a white solid. This solid was purified using an automatic purification device to obtain 5.1 g of a white solid. The yield was 62.2%, and the purity by HPLC was 71.3%.

[0104] The NMR spectroscopic analysis results of the brominated glucone morpholinamide derivative were as follows: 1 H NMR (400 MHz, chloroform-d)δ7.97-7.72 (m, 8H, Ar-H), 7.19-7.02 (m, 8H, Ar-H), 6.19 (dd, J = 7.6, 3.9 Hz, 1H, CH), 6.07 (dd, J = 7.8, 2.3 Hz, 1H, CH), 5.90 (d, J = 3.7 Hz, 1H, CH), 4.91-4.87 (m, 1H, CH), 4.71 (dd, J = 11.7, 5.7 Hz, 1H, CH2), 4.43 (dd, J = 11.4, 8.2 Hz, 1H, CH2), 3.76-3.53 (m, 8H, Mor), 2.40-2.33 (m, 12H, CH3). <Example 5> The deoxymercaptoglucone morpholinamide derivative was prepared in the following manner.

[0105] [ka]

[0106] 3.73 g of the brominated glucone morpholinamide derivative obtained in Example 4 was dissolved in 37 mL of 1,3-dimethyl-2-imidazolidinone (DMI), 2.66 g (5.0 equivalents) of potassium thioacetate was added, and the mixture was stirred at room temperature for 4 hours under a nitrogen stream. After stirring, 100 mL of hexane:chloroform (4:1) and 50 mL of water were added to the reaction solution, and the organic layer was separated. The organic layer was washed three times with 50 mL of water and dried over anhydrous sodium sulfate. Filtration and distillation yielded 3.7 g of a pale yellow solid.

[0107] The obtained solid was dissolved in 37 mL of methanol, and the solution was cooled to 0°C, after which 11.7 mL (5.0 equivalents) of 2 mol / L ammonia methanol solution was added and stirred at room temperature for 3 hours under a nitrogen atmosphere. After stirring, the reaction solution was diluted with 37 mL of 10% hydrochloric acid, and methanol was distilled off. The precipitated solid was filtered by suction, washed with a 5% aqueous solution of sodium bicarbonate and water, and dried under reduced pressure at 40°C. After drying, 2.48 g of a pale yellow solid was obtained. The yield was 70.7%, and the purity by HPLC was 53.6%.

[0108] The NMR spectroscopic analysis results of the deoxymercaptoglucone morpholinamide derivative were as follows: 1 H NMR (400 MHz, chloroform-d)δ7.99-7.81 (m, 8H, Ar-H), 7.30-7.12 (m, 8H, Ar-H), 6.36 (dd, J = 7.8, 2.7 Hz, 1H, CH), 5.95 (d, J = 7.8 Hz, 1H, CH), 5.16 (dd, J = 7.3, 2.7 Hz, 1H, CH), 3.71-3.39 (m, 9H, Mor, CH2), 3.13 (dd, J = 12.8, 5.5 Hz, 1H, CH2), 2.56 (d, J = 5.0 Hz, 1H, CH), 2.45 (s, 3H, CH3), 2.42 (d, J = 6.4 Hz, 1H, SH), 2.38-2.35 (m, 9H, CH3). <Comparative Example 1> (Production of glucone ester derivatives) The glucone methyl ester derivative was prepared in the following manner.

[0109] [ka]

[0110] 32.53 g of the gluconolactone toluoyl protected product obtained in Example 1 was dissolved in 650 mL of methanol, 0.7 mL (0.1 equivalent) of triethylamine was added, and the mixture was stirred at room temperature for 15 hours. Then, methanol was distilled off to obtain 37.39 g of a white solid. The yield was 99.5% and the purity by HPLC was 86.5%.

[0111] The NMR spectroscopic analysis of the glucone methyl ester derivative gave the following results: 1 H NMR (400 MHz, chloroform-d)δ7.98-7.76 (m, 8H, Ar-H), 7.24-7.02 (m, 8H, Ar-H), 6.25 (t, J = 3 Hz, 1H, CH), 5.78 (d, J = 3 Hz, 1H, CH), 5.76 (dd, J = 9, 3 Hz, CH), 4.55 (dd, J = 12, 3 Hz, 1H, CH2), 4.33 (dd, J = 12, 6 Hz, 1H, CH2), 4.22 (ddd, J = 12, 6, 3 Hz, 1H, CH), 3.65 (s, 3H, OCH3), 2.40-2.34 (m, 12H, CH3). (Production of deoxysulfonyloxyglucone ester derivatives) The deoxysulfonyloxyglucone methyl ester derivative was prepared in the following manner.

[0112] [ka]

[0113] 31.86 g of glucon methyl ester derivative was dissolved in 330 mL of acetonitrile, 18.25 g (1.3 equivalents) of TCBS-CL was added, and the mixture was cooled. Then, 8.0 mL (2.0 equivalents) of N-methylimidazole was added, and the mixture was stirred at room temperature. After 3 hours, the reaction solution was dissolved in 500 mL of hexane / ethyl acetate (1:1), and 300 mL of water was added to separate the layers. The organic layer was washed twice with 300 mL of water, then washed with 300 mL of saturated saline, and dried with anhydrous sodium sulfate. After natural filtration, the solvent was distilled off to obtain 45.44 g of a white solid. This solid was dried in a vacuum to obtain 41.15 g of a white solid. The yield was 94.7%, and the purity by HPLC was 76.1%.

[0114] The NMR spectroscopic analysis results of the deoxysulfonyloxyglucone methyl ester derivative were as follows: 1 H NMR (400 MHz, chloroform-d)δ7.95-7.72 (m, 8H, Ar-H), 7.24-7.07 (m, 10H, Ar-H), 6.12 (t, J = 4 Hz, 1H, 4 Hz, CH), 6.07 (t, J = 4 Hz, 1H, CH), 5.73 (d, J = 4 Hz, 1H, CH), 5.40 (m, 1H, CH), 4.75 (dd, J = 13, 4 Hz, 1H, CH2), 4.52 (dd, J = 13, 7 Hz, 1H, CH2), 3.63 (s, 3H, OCH3), 2.41-2.37 (m, 12H, CH3). (Production of Brominated Gluconate Derivatives) The brominated glucone methyl ester derivative was prepared in the following manner.

[0115] [ka]

[0116] 13.03 g of deoxysulfonyloxyglucon methyl ester derivative was dissolved in 80 mL of DMI, 2.45 g (2.0 equivalents) of lithium bromide was added, and the mixture was stirred at 50°C. After 5 hours, the reaction solution was dissolved in 150 mL of hexane / chloroform (4:1), and 80 mL of water was added to separate the layers. The organic layer was further washed three times with 80 mL of water and 80 mL of saturated saline, and dried over anhydrous sodium sulfate. After natural filtration, the solvent was distilled off to obtain 9.98 g of a white solid. The obtained solid was crystallized from 600 mL of methanol to obtain 6.69 g of a white solid. The yield was 63.9%, and the purity by HPLC was 96.7%.

[0117] The NMR spectroscopic analysis results of the brominated glucone methyl ester derivative were as follows: 1 H NMR (400 MHz, chloroform-d)δ7.97-7.74 (m, 8H, Ar-H), 7.16-7.06 (m, 8H, Ar-H), 6.30 (dd, J = 8, 3 Hz, 1H, CH), 6.05 (dd, J = 8, 2 Hz, 1H, CH), 5.71 (d, J = 3 Hz, 1H, CH), 4.68 (dd, J = 12, 6 Hz, 1H, CH2), 4.60 (dd, J = 12, 9 Hz, 1H, CH2), 4.38 (m, 1H, CH), 3.69 (s, 3H, OCH3), 2.41-2.34 (m, 12H, CH3). (Production of deoxymercaptoglucone ester derivatives) When an attempt was made to produce a deoxymercaptoglucone methyl ester derivative by the following method, the reaction did not proceed and no deoxymercaptoglucone methyl ester derivative was obtained.

[0118] [ka]

[0119] 1.0 g of the brominated glucon methyl ester derivative was dissolved in 20 mL of 1,3-dimethyl-2-imidazolidinone (DMI), 0.766 g (5.0 equivalents) of potassium thioacetate was added, and the mixture was stirred at room temperature for 40 hours under a nitrogen stream.

[0120] Preferred aspects of the invention are set forth below. [1] A gluconamide derivative represented by the following formula (3):

[0121] [ka]

[0122] In the formula (3), R 1 and R 2 each independently represents an alkyl group having 1 to 6 carbon atoms, an alkylalkoxy group having 2 to 7 carbon atoms, a cycloalkyl group having 4 to 6 carbon atoms, an aryl group having 5 to 20 carbon atoms which may have a substituent, or an aralkyl group having 7 to 20 carbon atoms, R 1 and R 2 may form, together with the nitrogen atom to which they are bonded, a heterocycle having from 5 to 6 ring members and which may further contain at least one heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen; R 3 , R 4 , R 5 , and R 6 are each independently a protecting group. [2] R 1 and R 2 The gluconamide derivative according to [1], wherein, together with the nitrogen atom to which they are bonded, they form a heterocycle having 5 to 6 ring members and which may further contain at least one heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen. [3] The gluconamide derivative according to [1] or [2], wherein the protecting group is selected from the group consisting of a toluoyl group, a benzyl group, an acetyl group, and a benzoyl group. [4] A deoxysulfonyloxygluconamide derivative represented by the following formula (5):

[0123] [ka]

[0124] In the formula (5), R 1 and R 2 each independently represents an alkyl group having 1 to 6 carbon atoms, an alkylalkoxy group having 2 to 7 carbon atoms, a cycloalkyl group having 4 to 6 carbon atoms, an aryl group having 5 to 20 carbon atoms which may have a substituent, or an aralkyl group having 7 to 20 carbon atoms, R 1 and R 2 may form, together with the nitrogen atom to which they are bonded, a heterocycle having from 5 to 6 ring members and which may further contain at least one heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen; R 3 , R 4 , R 5 , and R 6 are each independently a protecting group, R 7 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. [5] A deoxyhalogenogluconic acid derivative represented by the following formula (6):

[0125] [ka]

[0126] In the formula (6), R 1 and R 2 each independently represents an alkyl group having 1 to 6 carbon atoms, an alkylalkoxy group having 2 to 7 carbon atoms, a cycloalkyl group having 4 to 6 carbon atoms, an aryl group having 5 to 20 carbon atoms which may have a substituent, or an aralkyl group having 7 to 20 carbon atoms, R 1 and R 2 may form, together with the nitrogen atom to which they are bonded, a heterocycle having from 5 to 6 ring members and which may further contain at least one heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen; R 3 , R 4 , R 5 , and R 6 are each independently a protecting group, X 2 is a halogen atom. [6] A deoxymercaptogluconamide derivative represented by the following formula (7):

[0127] [ka]

[0128] In the formula (7), R 1 and R 2 each independently represents an alkyl group having 1 to 6 carbon atoms, an alkylalkoxy group having 2 to 7 carbon atoms, a cycloalkyl group having 4 to 6 carbon atoms, an aryl group having 5 to 20 carbon atoms which may have a substituent, or an aralkyl group having 7 to 20 carbon atoms, R 1 and R 2 may form, together with the nitrogen atom to which they are bonded, a heterocycle having from 5 to 6 ring members and which may further contain at least one heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen; R 3 , R 4 , R 5 , and R 6are each independently a protecting group.

Claims

1. A gluconamide derivative represented by the following formula (3): 【Chemistry 1】 In the formula (3), R １ and R ２ each independently represents an alkyl group having from 1 to 6 carbon atoms, an alkylalkoxy group having from 2 to 7 carbon atoms, a cycloalkyl group having from 4 to 6 carbon atoms, an aryl group having from 5 to 20 carbon atoms which may have a substituent, or an aralkyl group having from 7 to 20 carbon atoms, R １ and R ２ may form, together with the nitrogen atom to which they are bonded, a heterocycle having 5 to 6 ring members and which may further contain at least one heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen; R ３ , R ４ , R ５ , and R ６ are each independently a protecting group.

2. R １ and R ２ The gluconamide derivative according to claim 1, wherein, together with the nitrogen atom to which they are bonded, they form a heterocycle having 5 to 6 ring members and which may further contain at least one heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen.

3. 2. The gluconamide derivative of claim 1, wherein the protecting group is selected from the group consisting of a toluoyl group, a benzyl group, an acetyl group, and a benzoyl group.

4. A deoxysulfonyloxygluconamide derivative represented by the following formula (5): 【Chemistry 2】 In the formula (5), R １ and R ２ each independently represents an alkyl group having from 1 to 6 carbon atoms, an alkylalkoxy group having from 2 to 7 carbon atoms, a cycloalkyl group having from 4 to 6 carbon atoms, an aryl group having from 5 to 20 carbon atoms which may have a substituent, or an aralkyl group having from 7 to 20 carbon atoms, R １ and R ２ may form, together with the nitrogen atom to which they are bonded, a heterocycle having 5 to 6 ring members and which may further contain at least one heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen; R ３ , R ４ , R ５ , and R ６ are each independently a protecting group, R ７ represents 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.

5. A deoxyhalogenogluconic acid derivative represented by the following formula (6): 【Chemistry 3】 In the formula (6), R １ and R ２ each independently represents an alkyl group having from 1 to 6 carbon atoms, an alkylalkoxy group having from 2 to 7 carbon atoms, a cycloalkyl group having from 4 to 6 carbon atoms, an aryl group having from 5 to 20 carbon atoms which may have a substituent, or an aralkyl group having from 7 to 20 carbon atoms, R １ and R ２ may form, together with the nitrogen atom to which they are bonded, a heterocycle having 5 to 6 ring members and which may further contain at least one heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen; R ３ , R ４ , R ５ , and R ６ are each independently a protecting group, X ２ is a halogen atom.

6. A deoxymercaptogluconamide derivative represented by the following formula (7): 【Chemistry 4】 In the formula (7), R １ and R ２ each independently represents an alkyl group having from 1 to 6 carbon atoms, an alkylalkoxy group having from 2 to 7 carbon atoms, a cycloalkyl group having from 4 to 6 carbon atoms, an aryl group having from 5 to 20 carbon atoms which may have a substituent, or an aralkyl group having from 7 to 20 carbon atoms, R １ and R ２ may form, together with the nitrogen atom to which they are bonded, a heterocycle having 5 to 6 ring members and which may further contain at least one heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen; R ３ , R ４ , R ５ , and R ６ are each independently a protecting group.

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