Method for producing thiolactone derivative

Abstract

To provide a novel method for producing a thiolactone derivative.SOLUTION: There is provided a method for producing a thiolactone derivative. The production method comprises contacting a deoxymercaptogluconamide derivative represented by the following formula (7) with phosphoric acid to obtain a thiolactone derivative represented by the following formula (8). In the formula (7), R1 and R2 each independently is an alkyl group having 1 or more and 6 or less carbon atoms, an alkylalkoxy group having 2 or more and 7 or less carbon atoms, a cycloalkyl group having 4 or more and 6 or less carbon atoms, an aryl group having 5 or more and 20 or less carbon atoms which may have a substituent or an aralkyl group having 7 or more and 20 or less carbon atoms. R1 and R2 may form a heterocyclic ring which have 5 or more to 6 or less ring members and may further contain at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, together with the nitrogen atom to which they are bonded.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for producing a thiolactone derivative. [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. are various 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 equation (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] Japanese Patent Application Publication No. 2022-159769 [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 a novel method for producing a thiolactone derivative. [Means for solving the problem]

[0011] According to one aspect, there is provided a method for producing a thiolactone derivative, which comprises contacting a deoxymercaptogluconamide derivative represented by the following formula (7) with phosphoric acid to obtain a thiolactone derivative represented by the following formula (8):

[0012] [ka]

[0013] In equation (7), 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 be combined with the nitrogen atom to which they are bonded to 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.

[0014] R 3 , R 4 , R 5 , and R 6 are each independently a protecting group.

[0015] [ka]

[0016] In equation (8), R 3 , R 4 , R 5 , and R 6 has the same meaning as in equation (7). [Effects of the Invention]

[0017] According to the present invention, a novel method for producing a thiolactone derivative is provided. DETAILED DESCRIPTION OF THE INVENTION

[0018] According to embodiments, novel methods for producing thiolactone derivatives are provided, which can be used to efficiently produce SGLT-2 inhibitors, particularly luseogliflozin.

[0019] That is, luseogliflozin is a compound represented by the following formula (II):

[0020] [ka]

[0021] In the process for producing luseogliflozin using the above-mentioned protected gluconolactone, a step of introducing a sulfur atom is required.

[0022] The present inventors attempted to introduce a thiol group into the deoxyhalogenogluconic acid derivative represented by the following formula (III) obtained from the protected gluconolactone, but were unable to obtain the desired compound. 3 , R 4 , R 5 , and R 6 is a protecting group and X is a halogen atom.

[0023] [ka]

[0024] This is thought to be because the reagent used to introduce the thiol group, such as potassium thioacetate, is strongly basic, and therefore the ester bond of the deoxyhalogenogluconic acid derivative is hydrolyzed.

[0025] To address this problem, the present inventors have discovered that by using a gluconoamide derivative having an amide bond instead of an ester bond, it is possible to obtain the deoxymercaptogluconamide derivative represented by the above formula (7) without hydrolysis.

[0026] The thiolactone derivative represented by the formula (8) can be obtained by hydrolyzing the deoxymercaptogluconamide derivative represented by the formula (7). However, as described above, since the amide bond is not easily hydrolyzed, it has been difficult to obtain the thiolactone derivative represented by the formula (8). The present inventors have found that the thiolactone derivative represented by the formula (8) can be synthesized from the deoxymercaptogluconamide derivative represented by the formula (7) by using phosphoric acid.

[0027] According to the method using such a protected gluconolactone represented by formula (2) as a starting material, luseogliflozin can be produced by omitting several steps compared to conventional methods using D-glucurono-3,6-lactone as a starting material. Therefore, according to the method of the embodiment, luseogliflozin can be produced efficiently at low cost.

[0028] The manufacturing method according to the embodiment will be described in detail below.

[0029] (Method of producing thiolactone derivatives) The method for producing a thiolactone derivative according to the embodiment includes contacting a deoxymercaptogluconamide derivative represented by the following formula (7) with phosphoric acid to obtain a thiolactone derivative represented by the following formula (8).

[0030] [ka]

[0031] In equation (7), 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 R may be bonded to the nitrogen atom to form a heterocycle having 5 to 6 ring members and optionally further containing 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.

[0032] 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.

[0033] [ka]

[0034] In equation (8), R 3 , R 4 , R 5 , and R 6 has the same meaning as in equation (7).

[0035] As the phosphoric acid, for example, it is preferable to use an 85% by mass phosphoric acid aqueous solution with a concentration of 70% by mass or more and 98% by mass or less.

[0036] The amount of phosphoric acid relative to 1 mole of the deoxymercaptogluconamide derivative represented by formula (7) is, for example, 10 moles or more and 500 moles or less, and preferably 100 moles or more and 300 moles or less.

[0037] The amount of phosphoric acid relative to 1 g of the deoxymercaptogluconamide derivative represented by formula (7) is, for example, 0.5 mL or more and 50 mL or less, and preferably 1 mL or more and 15 mL or less.

[0038] The contact of the deoxymercaptogluconamide derivative represented by formula (7) with phosphoric acid is carried out, for example, within a temperature range of 60° C. to 200° C. The contact is preferably carried out within a range of 80° C. to 180° C., more preferably within a range of 100° C. to 150° C.

[0039] In contacting the deoxymercaptogluconamide derivative represented by formula (7) with phosphoric acid, a reaction solvent may be omitted or used, such as water, alcohols, ethers, etc.

[0040] The thiolactone derivative represented by formula (8) obtained by this production method may be separated by a separation process or the like. The separated crystals may be subjected to a washing process and a drying process. The structure of the thiolactone derivative represented by formula (8) can be confirmed, for example, by nuclear magnetic resonance (NMR) spectroscopic analysis. The thiolactone derivative represented by formula (8) is useful, for example, as an intermediate for the synthesis of luseoligrosin.

[0041] (Method of producing deoxymercaptogluconamide derivatives) The deoxymercaptogluconamide derivative represented by formula (7) can be synthesized, for example, using the protected gluconolactone represented by formula (2) as a starting material and intermediates such as a gluconamide derivative represented by formula (3), a deoxysulfonyloxygluconamide derivative represented by formula (5), and a deoxyhalogenogluconic acid derivative represented by formula (6). Details are described below.

[0042] First, an amine compound represented by the following formula (1) is contacted with a protected gluconolactone represented by the following formula (2) to obtain a gluconamide derivative represented by the following formula (3).

[0043] [ka]

[0044] In formula (1), R 1 and R 2 has the same meaning as in equation (7).

[0045] 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.

[0046] [ka]

[0047] In equation (2), R 3 , R 4 , R 5 , and R 6 has the same meaning as in equation (7).

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

[0049] [ka]

[0050] In equation (3), R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 has the same meaning as in equation (7).

[0051] 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.

[0052] The amine compound represented by formula (1) and the protected gluconolactone represented by formula (2) are preferably contacted under a nitrogen atmosphere.

[0053] 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.

[0054] The amine compound represented by formula (1) and the protected gluconolactone represented by formula (2) are preferably contacted 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 solvent selected from the group consisting of toluene, benzene, dichloromethane, chloroform, tetrahydrofuran (THF), and N,N-dimethylformamide (DMF). The amount of reaction solvent per 1 g of the protected gluconolactone represented by formula (2) is, for example, 0.1 mL to 50 mL, preferably 1 mL to 20 mL.

[0055] Next, the gluconamide derivative represented by formula (3) is contacted with a sulfonylating agent represented by the following formula (4) to obtain a deoxysulfonyloxygluconamide derivative represented by the following formula (5).

[0056] R 7 -SO2X 1 (4) In equation (4), 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. 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 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.

[0057] X 1 is a halogen atom. X 1 is preferably a chlorine atom.

[0058] 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).

[0059] [ka]

[0060] In equation (5), R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is the same as in equation (7). 7 has the same meaning as in formula (4).

[0061] 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, and preferably 1.1 moles or more and 2.0 moles or less.

[0062] The contact of the gluconamide derivative represented by formula (3) with the sulfonylating agent represented by formula (4) is preferably carried out in the presence of a base.

[0063] 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.

[0064] The amount of the base relative to 1 mole of the gluconamide derivative represented by 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.

[0065] The contact of the gluconamide derivative represented by formula (3) with the sulfonylating agent represented by formula (4) is preferably carried out under a nitrogen atmosphere.

[0066] The contact of the gluconamide derivative represented by formula (3) with 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.

[0067] 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 reaction solvent per 1 g of the gluconamide derivative represented by formula (3) is, for example, 0.1 mL to 50 mL, preferably 1 mL to 20 mL.

[0068] Next, the deoxysulfonyloxygluconamide derivative represented by formula (5) is contacted with a halogenating agent to obtain a deoxyhalogenogluconic acid derivative represented by the following formula (6).

[0069] [ka]

[0070] In equation (6), R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is the same as in formula (7). 2 is a halogen atom.

[0071] Examples of halogenating agents include MX 2An alkali metal halide salt 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 equation (6).

[0072] 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.

[0073] 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.

[0074] The contact of the deoxysulfonyloxygluconamide derivative represented by formula (5) with the halogenating agent is preferably carried out under a nitrogen atmosphere.

[0075] 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.

[0076] The contact of the deoxysulfonyloxygluconamide derivative represented by formula (5) with 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 solvent selected from the group consisting of 1,3-dimethyl-2-imidazolidinone (DMI), N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO). The amount of reaction solvent per 1 g of the deoxysulfonyloxygluconamide derivative represented by formula (5) is, for example, 0.1 mL to 50 mL, preferably 1 mL to 20 mL.

[0077] Next, the deoxyhalogenogluconic acid derivative represented by formula (6) is contacted with a sulfur-containing compound to obtain the deoxymercaptogluconamide derivative represented by formula (7).

[0078] [ka]

[0079] 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 alkyl thiol, and an aralkyl thiol. The salt of thioacetic acid includes, for example, potassium thioacetate.

[0080] When thioacetic acid or a salt of thioacetic acid is used, it is believed 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 equation (7).

[0081] [ka]

[0082] 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.

[0083] The contact of the deoxyhalogenogluconic acid derivative represented by formula (6) with the sulfur-containing compound is preferably carried out under a nitrogen atmosphere.

[0084] The contact of the deoxyhalogenogluconic acid derivative represented by formula (6) with 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.

[0085] The contact of the deoxyhalogenogluconic acid derivative represented by formula (6) with 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 reaction solvent per 1 g of the deoxyhalogenogluconic acid derivative represented by formula (6) is, for example, 0.1 mL to 50 mL, preferably 1 mL to 20 mL.

[0086] The deoxymercaptogluconamide derivative represented by formula (7) obtained by this production method may be separated by a separation treatment or the like. The separated crystals may be subjected to a washing treatment and a drying treatment. The structure of the deoxymercaptogluconamide derivative represented by formula (7) can be confirmed by, for example, nuclear magnetic resonance (NMR) spectroscopic analysis. [Example]

[0087] 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:

[0088] Example 1 (Production of deoxymercaptogluconamide derivatives) A deoxymercaptogluconamide derivative represented by the following formula (7a) was produced by the following method.

[0089] [ka]

[0090] First, a p-toluoyl protected form of gluconolactone was prepared as shown below.

[0091] [ka]

[0092] 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 equivalents) 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 equivalents) 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 gravity filtration, the solvent was distilled off to obtain a white solid. This solid was dissolved in 280 mL of acetonitrile by heating (80°C) and then allowed to cool and crystallize. The resulting solid was suction filtered, washed with cold acetonitrile, and then dried under reduced pressure at 40°C to obtain 34.6 g of a white solid. The yield was 67.7%, and the purity by HPLC was 91.3%.

[0093] The NMR spectroscopic analysis results of the gluconolactone toluoyl protected compound were as follows. 1 H NMR (400 MHz, chloroform-d) δ 7.97-7.76 (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). Next, a glucone dimethylamide derivative was prepared by the following method.

[0094] [ka]

[0095] 0.835 g of the gluconolactone toluoyl-protected compound 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. The reaction mixture was then separated by the addition of 10 mL of 10% hydrochloric acid, and the hydrochloric acid layer was extracted with 10 mL of toluene. The toluene layer was washed with 10 mL of 20% brine and dried over anhydrous sodium sulfate. After gravity filtration and evaporation, 0.832 g of a white, syrupy substance was obtained. The yield was 93.2%, and the purity by HPLC was 71.6%.

[0096] The NMR spectroscopic analysis results of the glucone dimethylamide derivative were as follows: 1 H NMR (400 MHz, chloroform-d) δ 7.97-7.78 (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). Next, a glucone morpholinamide derivative was prepared by the following method.

[0097] [ka]

[0098] 10.0 g of the gluconolactone toluoyl-protected compound was suspended in 100 mL of toluene, and 3.3 mL (2.5 equivalents) of morpholine was added. The mixture was stirred at room temperature under a nitrogen atmosphere for 60 minutes. 100 mL of 10% hydrochloric acid was then added to the reaction mixture for separation. The hydrochloric acid layer was then extracted with 50 mL of toluene. The toluene layer was washed with 100 mL of water and dried over anhydrous sodium sulfate. After gravity 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%.

[0099] The NMR spectroscopic analysis results of the glucone morpholinamide derivative were as follows: 1 H NMR (400 MHz, chloroform-d) δ 7.96-7.77 (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). Next, a deoxysulfonyloxyglucone morpholinamide derivative was prepared by the following method.

[0100] [ka]

[0101] 11.2 g of the glucone morpholinamide derivative 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. The mixture was stirred at room temperature for 5 hours. The solvent was then evaporated, and the residue was diluted with 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 gravity filtration, the solvent was evaporated to obtain 13.3 g of a pale yellow solid. The yield was 89.3%, and the purity by HPLC was 66.2%.

[0102] The NMR spectroscopic analysis results of the deoxysulfonyloxyglucone morpholinamide derivative were as follows: 1 H NMR (400 MHz, chloroform-d) δ 7.98-7.71 (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). Next, a brominated glucone morpholinamide derivative was prepared by the following method.

[0103] [ka]

[0104] 9.7 g of the deoxysulfonyloxyglucone morpholine amide derivative was dissolved in 58 mL of DMI, and 1.7 g (2.0 equivalents) of lithium bromide was added. The mixture was stirred at 50°C under a nitrogen atmosphere. After 3 hours, the reaction mixture was dissolved in 120 mL of hexane / chloroform (4:1), and 60 mL of water was added for phase separation. The organic layer was washed three times with 60 mL of water and dried over anhydrous sodium sulfate. After gravity filtration, the solvent was distilled off to obtain 7.7 g of a white solid. This solid was purified using an automated purification system to obtain 5.1 g of a white solid. The yield was 62.2%, and the purity by HPLC was 71.3%.

[0105] The NMR spectroscopic analysis results of the brominated glucone morpholinamide derivative were as follows: 1 H NMR (400 MHz, chloroform-d) δ 7.97-7.72 (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). Next, a deoxymercaptogluconamide derivative represented by formula (7a) was prepared by the following method.

[0106] [ka]

[0107] 3.73 g of the brominated glucone morpholinamide derivative was dissolved in 37 mL of 1,3-dimethyl-2-imidazolidinone (DMI), and 2.66 g (5.0 equivalents) of potassium thioacetate was added. The mixture was stirred at room temperature for 4 hours under a nitrogen atmosphere. After stirring, 100 mL of hexane:chloroform (4:1) and 50 mL of water were added to the reaction mixture, 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 evaporation yielded 3.7 g of a pale yellow solid.

[0108] The resulting solid was dissolved in 37 mL of methanol, and the solution was cooled to 0°C. 11.7 mL (5.0 equivalents) of 2 mol / L ammonia methanol solution was added, and the mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere. After stirring, the reaction mixture was diluted with 37 mL of 10% hydrochloric acid, and the methanol was distilled off. The precipitated solid was filtered by suction, washed with 5% aqueous 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%.

[0109] The NMR spectroscopic analysis results of the deoxymercaptogluconamide derivative were as follows: 1 H NMR (400 MHz, chloroform-d) δ 7.99-7.81 (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). (Production of thiolactone derivatives) The deoxymercaptogluconamide derivative represented by formula (7a) was used to prepare the thiolactone derivative represented by formula (8a).

[0110] [ka]

[0111] 5 mL of phosphoric acid was added to 0.5 g of the deoxymercaptogluconamide derivative and stirred at 120°C for 3 hours. After cooling to room temperature, saturated aqueous sodium bicarbonate was added and the mixture was extracted twice with ethyl acetate. The resulting organic layer was dried over sodium sulfate and then filtered to remove the sodium sulfate. The filtrate was concentrated under reduced pressure to obtain 0.44 g of residue. The residue was purified by column chromatography and subjected to 1H NMR analysis.

[0112] The NMR spectroscopic analysis results of the thiolactone derivative were as follows: 1H NMR (400MHz CDCl3)δ 7.77-7.99(m,8H) ,7.06-7.35(m,8H),6.14(t,1H),5.95(d,1H),5.67(d,1H),5.29(dd,1H),2.88-3.02(m,2H),2.35-2.49(m,12H) <Comparative Example 1> To 0.1 g of the deoxymercaptogluconamide derivative, 1 mL of toluene and 53 mg of p-toluenesulfonic acid monohydrate were added, and the mixture was stirred at reflux temperature.

[0113] <Comparative Example 2> To 0.1 g of the deoxymercaptogluconamide derivative, 1 mL of toluene and 141 mg of p-toluenesulfonic acid monohydrate were added, and the mixture was stirred at 80°C.

[0114] <Comparative Example 3> To 0.1 g of the deoxymercaptogluconamide derivative, 2 mL of methanol and 0.1 mL of concentrated hydrochloric acid were added, and the mixture was stirred at reflux temperature.

[0115] <Comparative Example 4> To 0.1 g of the deoxymercaptogluconamide derivative, 0.5 mL of 2-butanol and 2 mL of 10% hydrochloric acid were added, and the mixture was stirred at reflux temperature.

[0116] <Comparative Example 5> To 0.1 g of the deoxymercaptogluconamide derivative, 1 mL of tetrahydrofuran and 45.4 μL of methanesulfonic acid were added, and the mixture was stirred at 80°C.

[0117] <Comparative Example 6> 1 mL of 30% hydrogen bromide-acetic acid was added to 0.1 g of the deoxymercaptogluconamide derivative and stirred at 100°C.

[0118] <Comparative Example 7> 0.9 mL of tetrahydrofuran was added to 0.1 g of the deoxymercaptogluconamide derivative, and the mixture was cooled to −40° C. 28 mg of sodium methoxide was added at −40° C., and the mixture was allowed to return to room temperature and stirred.

[0119] <Comparative Example 8> 0.9 mL of tetrahydrofuran was added to 0.1 g of the deoxymercaptogluconamide derivative, and the mixture was cooled to −40° C. 58 mg of potassium tert-butoxide was added at −40° C., and the mixture was allowed to return to room temperature and stirred.

[0120] <Comparative Example 9> 0.9 mL of tetrahydrofuran was added to 0.1 g of the deoxymercaptogluconamide derivative, and the mixture was cooled to 0° C. 77.4 μL of diazabicycloundecene was added at 0° C., and the mixture was allowed to return to room temperature and stirred.

[0121] Example 1 and Comparative Examples 1 to 9 are summarized in Table 1 below.

[0122] [Table 1]

[0123] Preferred aspects of the invention are listed below. [1] A method for producing a thiolactone derivative, comprising contacting a deoxymercaptogluconamide derivative represented by the following formula (7) with phosphoric acid to obtain a thiolactone derivative represented by the following formula (8):

[0124] [ka]

[0125] 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 be combined with the nitrogen atom to which they are bonded to form 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,

[0126] [ka]

[0127] In the formula (8), R 3 , R 4 , R 5 , and R 6 has the same meaning as in equation (7). [2] The method according to [1], wherein the contact is carried out at a temperature within a range of 60°C or more and 200°C or less. [3] The method according to [1] or [2], wherein the amount of phosphoric acid per 1 g of the deoxymercaptogluconamide derivative represented by the formula (7) is 1 mL or more and 15 mL or less. [4] The method according to any one of [1] to [3], wherein the protecting group is a toluoyl group, a benzyl group, an acetyl group, or a benzoyl group.

Claims

1. A method for producing a thiolactone derivative, comprising contacting a deoxymercaptogluconamide derivative represented by the following formula (7) with phosphoric acid to obtain a thiolactone derivative represented by the following formula (8): 【Chemical 1】 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 be combined with the nitrogen atom to which they are bonded to form 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, 【Chemistry 2】 In the formula (8), R ３ , R ４ , R ５ , and R ６ has the same meaning as in formula (7).

2. The method according to claim 1 , wherein the contacting is carried out at a temperature ranging from 60° C. to 200° C.

3. The method according to claim 1, wherein the amount of phosphoric acid per 1 g of the deoxymercaptogluconamide derivative represented by formula (7) is 1 mL or more and 15 mL or less.

4. The method according to claim 1 , wherein the protecting group is a toluoyl group, a benzyl group, an acetyl group, or a benzoyl group.

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