Halocarboxylic acid derivative and method for producing the same, carboxylic acid chloride and method for producing the same, and method for producing thiolactone derivative

Abstract

To provide a halocarboxylic acid derivative and a method for producing the same, a carboxylic acid chloride and a method for producing the same, and a method for producing a thiolactone derivative.SOLUTION: According to one aspect, a halocarboxylic acid derivative represented by formula (1) is provided. According to another aspect, a carboxylic acid chloride represented by formula (2) is provided. In formulas (1) and (2), R1, R2, R3, and R4 are each independently a protecting group. X1 is a halogen atom.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a halocarboxylic acid derivative and a method for producing the same, a carboxylic acid chloride and a method for producing the same, and a method for producing a thiolactone derivative.

Background Art

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

[0003] SGLT-2 inhibitors are represented by, for example, the following formula (I).

[0004]

Chemical formula

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

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

[0007]

Chemical formula

[0008] In formula (Ia), 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 Laid-Open No. 2022-159769 [Patent Document 2] International Publication No. 2016 / 098016 [Summary of the Invention] [Problems to be Solved by the Invention]

[0010] An object of the present invention is to provide a halocarboxylic acid derivative, a method for producing the same, a carboxylic acid chloride, a method for producing the same, and a method for producing a thiolactone derivative. [Means for Solving the Problems]

[0011] According to one aspect, a halocarboxylic acid derivative is provided. The halocarboxylic acid derivative is represented by the following formula (1).

[0012] [Chemical Formula]

[0013] In formula (1), R 1 , R 2 , R 3 , and R 4 are each independently a protecting group. X 1 is a halogen atom.

[0014] According to another aspect, a carboxylic acid chloride is provided. The carboxylic acid chloride is represented by the following formula (2).

[0015] [Chemical Formula]

[0016] In formula (2), R 1 , R 2 , R 3 , and R 4 are each independently a protecting group. X 1 is a halogen atom.

[0017] According to another aspect, a method for producing a halocarboxylic acid derivative is provided. This production method includes contacting a halogenogluconic acid derivative represented by the following formula (3) or a gluconolactone derivative represented by the following formula (3a) with hydrogen halide.

[0018]

Chemical formula

[0019] In formula (3), R 1 , R 2 , R 3 , R 4 , and X 1 are synonymous with those in formula (1). R 5 is an alkyl group having 1 to 6 carbon atoms.

[0020]

Chemical formula

[0021] In formula (3a), R 1 , R 2 , R 3 , and R 4 are synonymous with those in formula (1).

[0022] According to another aspect, a method for producing a carboxylic acid chloride is provided. The carboxylic acid chloride is represented by the above formula (2). This production method includes contacting a halocarboxylic acid derivative represented by formula (1) with a halogenating agent.

[0023] According to another aspect, a method for producing a thiolactone derivative is provided. This production method includes contacting a carboxylic acid chloride represented by formula (2) according to another aspect with a sulfurizing agent to obtain a thiolactone derivative represented by the following formula (4).

[0024]

Chemical formula

[0025] In formula (4), R 1 , R 2 , R 3 , and R 4 are synonymous with those in formula (1).

Advantages of the Invention

[0026] According to the present invention, a halocarboxylic acid derivative and a method for producing the same, a carboxylic acid chloride and a method for producing the same, and a method for producing a thiolactone derivative are provided.

Embodiments for Carrying Out the Invention

[0027] According to the embodiment, a halocarboxylic acid derivative and a method for producing the same, a carboxylic acid chloride and a method for producing the same, and a method for producing a thiolactone derivative are provided. These production methods can be efficient production methods for SGLT-2 inhibitors, particularly luseogliflozin.

[0028] That is, luseogliflozin is a compound represented by the following formula (II).

[0029]

Chemical Formula

[0030] In the step of producing luseogliflozin using the glucuronolactone protecting group described above, a step of introducing a sulfur atom is required.

[0031] When the inventors tried to introduce a thiol group into the deoxyhalogenogluconic acid derivative represented by the following formula (III) obtained from the glucuronolactone protecting group, the target compound could not be obtained. In formula (III), R 3 , R 4 , R 5 , and R 6 are protecting groups, and X is a halogen atom.

[0032] [Chemical formula]

[0033] This is presumably because the reagent such as potassium thioacetate used for the introduction of the thiol group is strongly basic, and the ester bond of the deoxyhalogenogluconic acid derivative is hydrolyzed.

[0034] In response to such problems, according to the method according to the embodiment, the halocarboxylic acid derivative represented by the above formula (1) is provided. This compound has a carboxyl group instead of the methyl ester group in formula (III). When the carboxylic acid chloride represented by the above formula (2) obtained from the halocarboxylic acid derivative represented by the above formula (1) is used and reacted with a strongly basic reagent such as potassium thioacetate, the thiolactone derivative represented by the above formula (4) can be obtained without hydrolysis. According to the method using such a halocarboxylic acid derivative represented by the formula (1) as an intermediate, compared with the conventional method, several steps can be omitted to produce lesoglivflozin. Therefore, according to the method according to the embodiment, lesoglivflozin can be produced at low cost and efficiently.

[0035] Hereinafter, the manufacturing method according to the embodiment will be described in detail.

[0036] (Halocarboxylic acid derivative) The halocarboxylic acid derivative is represented by the following formula (1).

[0037] [Chemical formula]

[0038] In formula (1), R 1 , R 2 , R 3 , and R 4are each independently a protecting group. The protecting group is selected from the group consisting of, for example, a toluoyl group, a benzyl group, an acetyl group, a benzoyl group, and a methoxymethyl group. The protecting group is preferably a toluoyl group, a benzyl group, or a benzoyl group, and more preferably a toluoyl group. R 1 , R 2 , R 3 , and R 4 are preferably all the same protecting group.

[0039] X 1 is a halogen atom. X 1 is preferably a bromine atom, a chlorine atom, or an iodine atom, and more preferably a bromine atom.

[0040] The halocarboxylic acid derivative represented by formula (1) can be obtained, for example, by contacting a halogenogluconic acid derivative represented by the following formula (3) or a gluconolactone derivative represented by the following formula (3a) with hydrogen halide. For the production of the halocarboxylic acid derivative, a mixture of a halogenogluconic acid derivative represented by formula (3) and a gluconolactone derivative represented by the following formula (3a) may be used.

[0041] [Chemical formula]

[0042] In formula (3), R 1 , R 2 , R 3 , R 4 , and X 1 have the same meanings as those in formula (1).

[0043] R 5 is an alkyl group having 1 to 6 carbon atoms. R 5is preferably a methyl group or an ethyl group, more preferably a methyl group. That is, the compound represented by formula (3) can be the compound represented by formula (III) described above. The halogenogluconic acid derivative represented by formula (3) can be obtained, for example, by the method described in Patent Document 1.

[0044]

Chemical formula

[0045] In formula (3a), R 1 , R 2 , R 3 , and R 4 have the same meanings as those in formula (1). That is, the compound represented by formula (3) can be the compound represented by formula (Ia) described above.

[0046] The hydrogen halide contains at least one compound selected from the group consisting of, for example, hydrogen chloride, hydrogen bromide, and hydrogen iodide. The hydrogen halide is preferably hydrogen chloride or hydrogen bromide. When using the halogenoglucon derivative represented by formula (3), it is more preferable to use hydrogen chloride. When using the gluconolactone derivative represented by formula (3a), it is more preferable to use hydrogen bromide. When using the gluconolactone derivative represented by formula (3a), the hydrogen halide can be a source of X 1 of the halocarboxylic acid derivative represented by formula (1).

[0047] The hydrogen halide may be an acid solution. That is, as the hydrogen halide, hydrochloric acid, hydrobromic acid, hydroiodic acid, or a mixture thereof may be used. The concentration of the hydrogen halide in these acids is, for example, 10% by mass or more and 55% by mass or less. The concentration of the hydrogen halide is preferably 20% by mass or more and 40% by mass or less. As the solvent of the acid solution, water may be used, or the reaction solvent described later may be used.

[0048] The amount of hydrogen halide relative to 1 mol of the halogenogluconic acid derivative represented by formula (3) or the gluconolactone derivative represented by the following formula (3a) is, for example, 15 mol or more and 50 mol or less. The amount of hydrogen halide is preferably 20 mol or more and 45 mol or less, and more preferably 30 mol or more and 35 mol or less.

[0049] The contact between the halogenogluconic acid derivative represented by formula (3) or the gluconolactone derivative represented by the following formula (3a) and hydrogen halide is preferably carried out in a reaction solvent. As the reaction solvent, for example, at least one organic solvent selected from the group consisting of dioxane, diethylene glycol dimethyl ether, acetic acid, and tetrahydrofuran is used. It is preferable to use acetic acid as the reaction solvent. The reaction solvent may be a mixed solvent of an organic solvent and water.

[0050] The amount of the reaction solvent relative to 1 g of the halogenogluconic acid derivative represented by formula (3) or the gluconolactone derivative represented by the following formula (3a) is, for example, 2 mL or more and 20 mL or less. The amount of the reaction solvent is preferably 5 mL or more and 15 mL or less, and more preferably 8 mL or more and 12 mL or less.

[0051] The contact between the halogenogluconic acid derivative represented by formula (3) or the gluconolactone derivative represented by the following formula (3a) and hydrogen halide is carried out, for example, within a temperature range of 50°C or more and 118°C or less. The contact temperature is preferably 60°C or more and 100°C or less, and more preferably 70°C or more and 80°C or less.

[0052] The halocarboxylic acid derivative represented by formula (1) obtained by this production method may be separated by liquid separation treatment or the like. The separated crystals may be subjected to washing treatment and drying treatment. The structure of the halocarboxylic acid derivative represented by formula (1) can be confirmed, for example, by nuclear magnetic resonance (NMR) spectroscopic analysis. The halocarboxylic acid derivative represented by formula (1) is useful, for example, as an intermediate for the synthesis of luceofriedelin.

[0053] (Carboxylic acid chloride) The carboxylic acid chloride is represented by the following formula (2).

[0054] [Chemical formula]

[0055] In formula (2), R 1 , R 2 , R 3 , and R 4 are each independently a protecting group. X 1 is a halogen atom. R 1 , R 2 , R 3 , R 4 , and X 1 have the same meanings as those in formula (1).

[0056] The carboxylic acid chloride represented by formula (2) can be obtained, for example, by contacting the halocarboxylic acid derivative represented by the above formula (1) with a halogenating agent.

[0057] The halogenating agent includes, for example, at least one compound selected from the group consisting of thionyl chloride and oxalyl chloride. It is preferable to use thionyl chloride as the halogenating agent.

[0058] The amount of the halogenating agent relative to 1 mol of the halocarboxylic acid derivative represented by formula (1) is, for example, 1 mol or more and 50 mol or less. The amount of the halogenating agent is preferably 2 mol or more and 30 mol or less, and more preferably 4 mol or more and 25 mol or less.

[0059] The contact between the halocarboxylic acid derivative represented by formula (1) and the halogenating agent may be carried out in a reaction solvent. As the reaction solvent, for example, at least one organic solvent selected from the group consisting of dichloromethane, toluene, N,N-dimethylformamide, tetrahydrofuran, and chloroform is used.

[0060] For 1 g of the halocarboxylic acid derivative represented by formula (1), the amount of the reaction solvent is, for example, 1 mL or more and 20 mL or less. The amount of the reaction solvent is preferably 2 mL or more and 10 mL or less, and more preferably 4 mL or more and 8 mL or less.

[0061] The contact between the halocarboxylic acid derivative represented by formula (1) and the halogenating agent is carried out, for example, within a temperature range of 25°C or more and 100°C or less. The contact temperature is preferably 40°C or more and 80°C or less, and more preferably 70°C or more and 80°C or less.

[0062] The contact between the halocarboxylic acid derivative represented by formula (1) and the halogenating agent is preferably carried out under a nitrogen atmosphere.

[0063] The carboxylate chloride represented by formula (2) obtained by this production method may be separated by liquid separation treatment or the like. The separated crystals may be subjected to washing treatment and drying treatment. The structure of the carboxylate chloride represented by formula (2) can be confirmed, for example, by nuclear magnetic resonance (NMR) spectroscopic analysis. The carboxylate chloride represented by formula (2) is useful, for example, as an intermediate for the synthesis of lucidofungin.

[0064] (Production of thiolactone derivative) The thiolactone derivative is represented by the following formula (4).

[0065]

Chemical formula

[0066] In formula (4), R 1 , R 2 , R 3 , and R 4 have the same meanings as those in formula (2).

[0067] The thiolactone derivative represented by formula (4) is obtained, for example, by contacting the carboxylate chloride represented by formula (2) with a sulfurizing agent.

[0068] The sulfurizing agent contains at least one compound selected from the group consisting of, for example, sodium sulfide and sodium hydrogen sulfide. The sulfurizing agent is preferably sodium sulfide.

[0069] The sulfurizing agent may be a hydrate or an aqueous solution. The concentration of the sulfurizing agent in the aqueous solution is, for example, 10% by mass or more and 55% by mass or less.

[0070] The amount of the sulfurizing agent relative to 1 mol of the thiolactone derivative represented by the formula (4) is, for example, 1 mol or more and 30 mol or less. The amount of the sulfurizing agent is preferably 1 mol or more and 10 mol or less, and more preferably 1 mol or more and 5 mol or less.

[0071] The contact between the thiolactone derivative represented by the formula (4) and the sulfurizing agent may be carried out in a reaction solvent. As the reaction solvent, for example, at least one organic solvent selected from the group consisting of dichloromethane, chloroform, and toluene is used.

[0072] The amount of the reaction solvent relative to 1 g of the thiolactone derivative represented by the formula (4) is, for example, 1 mL or more and 50 mL or less. The amount of the reaction solvent is preferably 3 mL or more and 30 mL or less, and more preferably 5 mL or more and 20 mL or less.

[0073] The contact between the thiolactone derivative represented by the formula (4) and the sulfurizing agent is carried out, for example, within a temperature range of 0°C or more and 100°C or less. The contact temperature is preferably 10°C or more and 80°C or less, and more preferably 25°C or more and 60°C or less.

[0074] The thiolactone derivative represented by the formula (4) obtained by this production method may be separated by liquid separation treatment or the like. The separated crystals may be subjected to washing treatment and drying treatment. The structure of the thiolactone derivative represented by the formula (4) can be confirmed, for example, by nuclear magnetic resonance (NMR) spectroscopy. The thiolactone derivative represented by the formula (4) is useful, for example, as an intermediate for the synthesis of lucofrigine.

Example

[0075] 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 by these examples. 〈Example 1〉 (Production of Halocarboxylic Acid) A halocarboxylic acid was produced by the following method.

[0076]

Chemical formula

[0077] 3.0 g of the glucuronolactone toluoyl protected body was suspended in 30 mL of a 30% hydrobromic acid acetic acid solution and heated to 80 °C for dissolution. Then, it was stirred at 80 °C for 5 hours. After stirring, the reaction solution was poured into ice water, and the precipitated solid was suction filtered. The filtered solid was washed with water and then dried under reduced pressure at 40 °C to obtain 2.7 g of a white solid. The yield was 80.4%, and the purity by HPLC was 65.0%. The obtained target halocarboxylic acid was confirmed by NMR analysis as follows. 1H NMR (400 MHz DMSO-d6) δ 7.62 - 7.98 (m, 8H), 7.07 - 7.42 (m, 8H), 6.10 (quin, 1H), 5.99 - 6.05 ( m, 1H), 5.56 - 5.70 (m, 2H), 4.05 (dd, 1H), 3.88 (dd, 1H), 2.28 - 2.42 (m, 12H) 〈Example 2〉 (Production of Halocarboxylic Acid) A halocarboxylic acid was produced by the following method.

[0078]

Chemical formula

[0079] 1.0 g of a halogenogluconic acid derivative was dissolved in 10 mL of diglyme, and 2.0 mL of 35% hydrochloric acid was added. Then, the mixture was stirred at 80 °C for 5 hours. After stirring, the reaction solution was poured into ice water and extracted three times with ethyl acetate. The obtained organic layers were combined, dried over sodium sulfate, filtered to remove the sodium sulfate, and the obtained filtrate was concentrated under reduced pressure to obtain 1.1 g of a white solid. The purity by HPLC was 46.9%. The formation of the target halocarboxylic acid was confirmed by NMR analysis. <Example 3> (Production of carboxylic acid chloride) The carboxylic acid chloride was produced by the following method.

[0080] [Chemical formula]

[0081] 0.5 g of the halocarboxylic acid was dissolved in 1 mL of thionyl chloride and refluxed under a nitrogen atmosphere. After 1 hour, the thionyl chloride was distilled off, and the residue was dried in vacuo to obtain 0.49 g of a yellow oily substance. By reacting the obtained carboxylic acid chloride with methanol to form a methyl ester, and by analysis by HPLC, the retention time was confirmed to be the same as that of the standard product, indirectly confirming the formation of the carboxylic acid chloride. <Example 4> (Production of thiolactone derivative) The thiolactone derivative was produced by the following method.

[0082] [Chemical formula]

[0083] 0.2 g of the carboxylic acid chloride was dissolved in 2 mL of dichloromethane, cooled to 0 °C, and 2.9 mL of a 15% aqueous sodium sulfide solution was added dropwise. After returning to room temperature, the mixture was stirred for 3 hours. Dichloromethane and saturated brine were added, and liquid separation was performed. The obtained organic layer was dried over sodium sulfate, filtered to remove the sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain a residue. The formation of the target thiolactone derivative was confirmed by MS spectrum. Molecular formula C 38 H 34 O9S Exact mass 666.1924 ESI(+) m / z 667.1987 [M+H] + , 684.2245 [M+H2O] + , 689.1811 [M+Na] + The following are the preferred aspects of the invention. [1] The halocarboxylic acid derivative represented by the following formula (1):

[0084]

Chemical formula

[0085] In the above formula (1), R 1 , R 2 , R 3 , and R 4 are each independently a protecting group, X 1 is a halogen atom. [2] The protecting group is selected from the group consisting of a toluoyl group, a benzyl group, an acetyl group, a benzoyl group, and a methoxymethyl group, and the halocarboxylic acid derivative described in [1]. [3] The carboxylic acid chloride represented by the following formula (2):

[0086]

Chemical formula

[0087] In the above formula (2), R 1 , R 2 , R 3 , and R 4 are each independently a protecting group, X 1 is a halogen atom. [4] A method for producing a halocarboxylic acid derivative, comprising contacting a halogenogluconic acid derivative represented by the following formula (3) or a gluconolactone derivative represented by the following formula (3a) with hydrogen halide to obtain the halocarboxylic acid derivative described in [1] or [2]:

[0088]

Chemical formula

[0089] In the formula (3), R 1 、R 2 、R 3 、R 4 、and X 1 have the same meanings as those in formula (1), R 5 is an alkyl group having 1 to 6 carbon atoms,

[0090]

Chemical formula

[0091] In the formula (3a), R 1 、R 2 、R 3 、and R 4 have the same meanings as those in formula (1). [5] The method for production according to [4], wherein the hydrogen halide contains at least one compound selected from the group consisting of hydrogen chloride, hydrogen bromide, and hydrogen iodide. [6] The method for production according to [4] or [5], wherein the contact between the halogenogluconic acid derivative represented by the formula (3) or the gluconolactone derivative represented by the formula (3a) and the hydrogen halide is carried out in a reaction solvent containing at least one organic solvent selected from the group consisting of dioxane, diethylene glycol dimethyl ether, acetic acid, and tetrahydrofuran. [7] A method for producing a carboxylic acid chloride, comprising contacting a halocarboxylic acid derivative represented by the formula (1) according to [1] or [2] with a chlorinating agent to obtain a carboxylic acid chloride represented by the following formula (2):

[0092]

Chemical formula

[0093] In the formula (2), R 1 , R 2 , R 3 , R 4 , and X 1 are synonymous with those in the formula (1). [8] The production method according to [7], wherein the halogenating agent comprises at least one compound selected from the group consisting of thionyl chloride and oxalyl chloride. [9] A method for producing a thiolactone derivative, comprising contacting a carboxylic acid chloride represented by the formula (2) according to [7] with a sulfurizing agent to obtain a thiolactone derivative represented by the following formula (4):

[0094]

Chemical formula

[0095] In the formula (4), R 1 , R 2 , R 3 , and R 4 are synonymous with those in the formula (2).

[10] The production method according to [9], wherein the sulfurizing agent comprises at least one compound selected from the group consisting of sodium sulfide and sodium hydrogen sulfide.

Claims

1. A halocarboxylic acid derivative represented by the following formula (1): 【Chemical 1】 In the formula (1), R １ 、 R ２ 、 R ３ 、 and R ４ are each independently a protecting group, X １ is a halogen atom.

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

3. A carboxylic acid chloride represented by the following formula (2): 【Chemical 2】 In the formula (2), R １ 、 R ２ 、 R ３ 、 and R ４ are each independently a protecting group, X １ is a halogen atom.

4. A method for producing a halocarboxylic acid derivative, comprising contacting a halogenogluconic acid derivative represented by the following formula (3) or a gluconolactone derivative represented by the following formula (3a) with hydrogen halide to obtain the halocarboxylic acid derivative according to claim 1: 【Chemical Formula 3】 In the formula (3), R １ 、 R ２ 、 R ３ 、 R ４ 、 and X １ are synonymous with those in formula (1), R ５ is an alkyl group having 1 to 6 carbon atoms, [Chemical Formula 4] In the formula (3a), R １ 、 R ２ 、 R ３ 、 and R ４ have the same meaning as those in formula (1).

5. The production method according to claim 4, wherein the hydrogen halide contains at least one compound selected from the group consisting of hydrogen chloride, hydrogen bromide, and hydrogen iodide.

6. The production method according to claim 4, wherein the contact of the halogenogluconic acid derivative represented by the formula (3) or the gluconolactone derivative represented by the formula (3a) with hydrogen halide is carried out in a reaction solvent containing at least one organic solvent selected from the group consisting of dioxane, diethylene glycol dimethyl ether, acetic acid, and tetrahydrofuran.

7. A method for producing a carboxylic acid chloride, comprising contacting the halocarboxylic acid derivative represented by the formula (1) according to claim 1 with a chlorinating agent to obtain a carboxylic acid chloride represented by the following formula (2): [Chemical Formula 5] In the formula (2), R １ 、 R ２ 、 R ３ 、 R ４ 、 and X １ are synonymous with those in formula (1).

8. The production method according to claim 7, wherein the chlorinating agent contains at least one compound selected from the group consisting of thionyl chloride and oxalyl chloride.

9. A method for producing a thiolactone derivative, comprising contacting the carboxylic acid chloride represented by the formula (2) according to claim 7 with a sulfurizing agent to obtain a thiolactone derivative represented by the following formula (4): 【Chemical Formula 6】 In the formula (4), R １ , R ２ , R ３ , and R ４ are synonymous with those in formula (2).

10. The production method according to claim 9, wherein the sulfurizing agent contains at least one compound selected from the group consisting of sodium sulfide and sodium hydrogen sulfide.

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