JP7546405B2 - Method for producing thioester derivatives - Google Patents

Description

The present invention relates to a method for producing a thioester derivative.

The thioester derivative shown in the following formula (4) can be used, for example, as an intermediate for the synthesis of diabetes treatment drugs such as canagliflozin (Patent Document 1).

The thioester derivative shown in the above formula (4) can be obtained, for example, by ring-opening the lactone derivative shown in the following formula (5) and then reacting it with decanethiol (Patent Document 1).

In the reaction of such lactone derivatives with thiols, trimethylaluminum is used as a reactant (Patent Document 1 and Non-Patent Document 1).

International Publication No. 2020/129899

Tiffany Malinky Gierasch, Zhangjie Shi, and Gregory L. Verdine, “Extensively Stereodiversified Scaffolds for Use in Diversity-Oriented Library Synthesis” ORGANIC LETTERS, 2003, V ol. 5, No. 5 621-624.

The object of the present invention is to provide an efficient method for producing thioester derivatives.

According to one embodiment, a method for producing a thioester derivative is provided. The method includes contacting a lactone derivative represented by the following formula (1) with a thiol represented by the following formula (2) in the presence of at least one of an alkyl magnesium halide and an aryl magnesium halide to obtain a thioester derivative represented by the following formula (3).

In the above formula (1), R ¹ is represented by -(A) _s -(B) _t -C. A is an alkylene group which may have a halogeno group. s is 0 or 1. B is O, S or NH. t is 0 or 1. C is an alkyl group which may have a halogeno group, an aralkyl group which may have a halogeno group, an aryl group which may have a halogeno group, a vinyl group which may have a halogeno group, or a heterocyclic group which contains at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen and which may have a halogeno group. R ² is represented by -(D) _u -E. D is O, S or NH. u is 0 or 1. E is an alkyl group which may have a halogeno group, an aralkyl group which may have a halogeno group, an aryl group which may have a halogeno group, or a heterocyclic group which contains at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen and which may have a halogeno group. n is 1 or more and 6 or less.

R ³ -SH (2)
In the above formula (2), ^R3 is an alkyl group, an aralkyl group, or an aryl group.

In the above formula (3), R ¹ , R ² and n are the same as those in formula (1), and R ³ is the same as those in formula (2).

According to an embodiment, an efficient method for producing a thioester derivative is provided.

The manufacturing method according to the embodiment includes contacting a lactone derivative represented by the above formula (1) (hereinafter also referred to as a lactone derivative) with a thiol represented by the above formula (2) (hereinafter also referred to as a thiol) in the presence of at least one of an alkyl magnesium halide and an aryl magnesium halide to obtain a thioester derivative represented by the above formula (3) (hereinafter also referred to as a thioester derivative).

In the manufacturing method according to the embodiment, at least one of alkyl magnesium halide and aryl magnesium halide is used as a reactant. Therefore, thioester derivatives can be manufactured safely and efficiently. That is, trimethylaluminum, which has been used as a reactant, is highly flammable and requires careful handling. Since alkyl magnesium halides and aryl magnesium halides are less flammable than trimethylaluminum, relatively little care needs to be taken with respect to the usage environment. Therefore, when at least one of alkyl magnesium halides and aryl magnesium halides is used, thioester derivatives can be manufactured more efficiently than when trimethylaluminum is used, and mass production of thioester derivatives can be realized.

The manufacturing method according to the embodiment will be described in detail below.
(Alkyl and Aryl Magnesium Halides)
Alkyl magnesium halides and aryl magnesium halides act as reactants to open the ring of a lactone derivative and then react it with a thiol.

The alkyl magnesium halide and the aryl magnesium halide are represented, for example, by the following formula (6).
^R4MgX (6)
In formula (6), ^R4 is an alkyl group or an aryl group. The number of carbon atoms of the alkyl group is preferably 1 to 4. The number of carbon atoms of the aryl group is preferably 6 to 10. X is a halogen atom. The halogen atom is preferably Cl, Br, I or F, and more preferably Cl.

It is believed that alkyl magnesium halides and aryl magnesium halides react with thiols (R ³ -SH) to produce hydrocarbons (R ⁴ H) and magnesium thiolates (XMgSR ³ ), as shown in the following formula (7). It is believed that this magnesium thiolate reacts with a lactone derivative to produce a thioester derivative.

As the alkyl magnesium halide, it is preferable to use at least one selected from the group consisting of alkyl magnesium bromide and alkyl magnesium chloride, and it is more preferable to use alkyl magnesium chloride.

Specific examples of alkyl magnesium bromides include methyl magnesium bromide, ethyl magnesium bromide, n-propyl magnesium bromide, isopropyl magnesium bromide, n-butyl magnesium bromide, and isobutyl magnesium bromide.

Specific examples of alkyl magnesium chlorides include methyl magnesium chloride, ethyl magnesium chloride, n-propyl magnesium chloride, isopropyl magnesium chloride, n-butyl magnesium chloride, and isobutyl magnesium chloride.

As the aryl magnesium halide, it is preferable to use at least one selected from the group consisting of aryl magnesium bromide and aryl magnesium chloride, and it is more preferable to use aryl magnesium chloride.

A specific example of an aryl magnesium bromide is phenyl magnesium bromide. A specific example of an aryl magnesium chloride is phenyl magnesium chloride. As the alkyl magnesium halide and the aryl magnesium halide, the specific examples listed above may be used alone or in combination.

The amount of at least one of the alkyl magnesium halide and the aryl magnesium halide per mole of the lactone derivative is, for example, 0.1 moles or more and 3 moles or less, and preferably 1 moles or more and 2 moles or less.

The amount of at least one of the alkyl magnesium halide and the aryl magnesium halide per mole of thiol is, for example, 0.1 moles or more and 3 moles or less, and preferably 0.5 moles or more and 1.5 moles or less. Here, the amount of at least one of the alkyl magnesium halide and the aryl magnesium halide means the amount of the alkyl magnesium halide or the aryl magnesium halide, or the total amount of a mixture thereof.

(Lactone derivatives)
The lactone derivative can be a substrate for the reaction. The lactone derivative is represented by the following formula (1).

In the above formula (1), R ¹ is represented by -(A) _s -(B) _t -C.
A is an alkylene group which may have a halogeno group. The number of carbon atoms in the alkylene group is 1 to 6, and preferably 1. s is 0 or 1.
B is O, S or NH. B is preferably O, i.e., an ether bond. t is 0 or 1.

C is an alkyl group which may have a halogeno group, an aralkyl group which may have a halogeno group, an aryl group which may have a halogeno group, a vinyl group which may have a halogeno group, or a heterocyclic group which contains at least one heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen and which may have a halogeno group. C is preferably an aralkyl group, and more preferably a benzyl group.

The number of carbon atoms in the alkyl group is, for example, 1 to 24. The number of carbon atoms in the aralkyl group is, for example, 7 to 32. The number of carbon atoms in the aryl group is, for example, 4 to 20.

^R2 is represented by -(D) _u -E.
D is O, S or NH. D is preferably O, i.e., an ether bond. u is 0 or 1.

E is an alkyl group which may have a halogeno group, an aralkyl group which may have a halogeno group, an aryl group which may have a halogeno group, or a heterocyclic group which contains at least one heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen and which may have a halogeno group. E is preferably an aralkyl group, and more preferably a benzyl group.

The number of carbon atoms in the alkyl group is, for example, 1 to 24. The number of carbon atoms in the aralkyl group is, for example, 7 to 32. The number of carbon atoms in the aryl group is, for example, 4 to 20.

n is 1 or more and 6 or less. n is preferably 1 or more and 3 or less. That is, the lactone derivative preferably has a 4-membered ring structure, a 5-membered ring structure, or a 6-membered ring structure. When n is 2 or more, ^R2 may have different structures or may have the same structure.

As the lactone derivative, it is preferable to use a lactone derivative represented by the following formula (8).

In the above formula (8), ^C1 may be the same as the functional group listed for C in the above formula (1). ^E1 , ^E2 , and ^E3 may be the same as the functional group listed for E in the above formula (1).

A specific example of a lactone derivative is 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone, which is the compound represented by the above-mentioned formula (5).

As the lactone derivative, a commercially available product may be used, or one synthesized by a known method may be used. Below, a method for producing a lactone derivative will be described using the method for producing the lactone derivative shown in the above formula (5) as an example.

First, a hydroxyl-containing lactone derivative is prepared as a raw material for the synthesis of lactone derivatives. As the hydroxyl-containing lactone derivative, 2,3,4,6-tetra-O-benzyl-D-glucopyranose, a compound shown in the following formula (10), is used.

The hydroxyl-containing lactone derivative represented by formula (10) is dissolved in an organic solvent to obtain a solution. Acetic anhydride is added dropwise to this solution and thoroughly stirred to produce the lactone derivative represented by formula (5). The above reaction is preferably carried out under a nitrogen atmosphere.

(Thiol)
Thiol is represented by the following formula (2).

R ³ -SH (2)
In formula (2), ^R3 is an alkyl group, an aralkyl group, or an aryl group. ^R3 is preferably an alkyl group. The number of carbon atoms of the alkyl group is preferably 1 or more and 20 or less. The number of carbon atoms of the aralkyl group and the aryl group is preferably 7 or more and 31 or less.

As the thiol, for example, at least one selected from the group consisting of ethanethiol, t-butyl mercaptan, thiophenol, benzyl mercaptan, and 1-decanethiol is used. As the thiol, it is preferable to use 1-decanethiol.

The amount of thiol per mole of lactone derivative is, for example, 0.1 moles or more and 3 moles or less, and preferably 1 moles or more and 2 moles or less.

(Production of Thioester Derivatives)
A thioester derivative represented by the following formula (3) can be obtained by contacting a lactone derivative with a thiol in the presence of at least one of an alkyl magnesium halide and an aryl magnesium halide.

In the above formula (3), R ¹ , R ² and n are the same as those in formula (1), and R ³ is the same as those in formula (2).

When the lactone derivative represented by the above formula (8) is contacted with the thiol represented by the formula (2), a thioester derivative represented by the following formula (9) is obtained.

In the above formula (9), C ¹ , E ¹ , E ² and E ³ have the same meanings as those in formula (8), and R ³ has the same meaning as those in formula (2).

When the lactone derivative represented by the above formula (5) is contacted with decanethiol, 2,3,4,6-tetra-O-benzyl-1-thio-D-gluconate, a thioester derivative represented by the following formula (4), is obtained. This compound can be used as an intermediate for the synthesis of canagliflozin, a type of antidiabetic drug.

Conditions for contacting the lactone derivative with the thiol in the presence of at least one of an alkyl magnesium halide and an aryl magnesium halide are not particularly limited. The contact temperature is, for example, from -30°C to 60°C, preferably from -20°C to 40°C, and more preferably from -20°C to 10°C. The contact time (reaction time) is, for example, from 1 hour to 72 hours, preferably from 1 hour to 24 hours, and more preferably from 1 hour to 10 hours. The contact environment is preferably an inert atmosphere, and more preferably a nitrogen atmosphere.

The contact of the lactone derivative with the thiol in the presence of at least one of an alkyl magnesium halide and an aryl magnesium halide is preferably carried out in a reaction solvent. The amount of reaction solvent per 1 g of lactone derivative is, for example, 1 mL or more and 100 mL or less, and preferably 5 mL or more and 50 mL or less.

As the reaction solvent, for example, at least one selected from the group consisting of methylene chloride, chlorobenzene, tetrahydrofuran (THF), 2-methyltetrahydrofuran, toluene, xylene, mesitylene, hexane, and heptane is used. As the reaction solvent, it is preferable to use at least one selected from the group consisting of methylene chloride, THF, and toluene.

The contact of the lactone derivative with the thiol in the presence of at least one of an alkyl magnesium halide and an aryl magnesium halide is preferably carried out by mixing the lactone derivative with the thiol to obtain a first mixture, and then contacting this first mixture with at least one of an alkyl magnesium halide and an aryl magnesium halide. This is believed to further increase the reaction efficiency.

A preferred method for producing the thioester derivatives is described below.
First, a lactone derivative and a thiol are dissolved in a first reaction solvent to obtain a first mixture. At least one of an alkyl magnesium halide and an aryl magnesium halide is dissolved in a second reaction solvent to obtain a first solution. The first and second reaction solvents may be the same as the reaction solvents described above. The first and second reaction solvents may be different from each other or may be the same.

Next, the first solution is added to the first mixture at a predetermined rate, and then stirred for a predetermined time while maintaining the predetermined temperature to obtain a second mixture containing a thioester derivative. The predetermined rate is, for example, 0.03 mL/min to 1 mL/min. The predetermined temperature is, for example, -20°C to 40°C. The predetermined time is, for example, 1 hour to 10 hours. It is preferable to cool or heat the first mixture to the above-mentioned predetermined temperature prior to mixing with the first solution.

(Method for separating thioester derivatives)
In the method for producing a thioester derivative, when a reaction solvent is used, it is preferable to separate the thioester derivative from the second mixture containing the produced thioester derivative and the reaction solvent by the following method.

First, an acid is mixed with the second mixture to separate it into an organic layer and an aqueous layer. For example, hydrochloric acid with a concentration of 1% by mass to 10% by mass is used as the acid. After the organic layer is extracted, an organic solvent is added to the aqueous layer to further separate it into an organic layer and an aqueous layer, and the organic layer is extracted again. The organic solvent may be the same as the reaction solvent described above. This separation and extraction of the organic layer by adding an organic solvent may be repeated multiple times. After mixing the multiple organic layers obtained by the above method, this organic layer is washed with a washing liquid. Distilled water or saline may be used as the washing liquid. After washing the organic layer with distilled water, it may be further washed with saline. The concentration of the saline is, for example, 1% by mass to 20% by mass.

Next, sodium sulfate is added to the washed organic layer to dehydrate the organic layer. The organic layer after the dehydration process is filtered to obtain a filtrate. This filtrate is concentrated under reduced pressure to obtain a solid product of the thioester derivative. By the above method, the thioester derivative can be separated from the second mixture.

The separated thioester derivative may be purified, for example, by silica gel column chromatography.

(HPLC Measurement)
The purity of the thioester derivative obtained by the above method can be measured, for example, by high performance liquid chromatography (HPLC).

The purity of the thioester derivative can be expressed as the ratio of the area value of the peak of the thioester derivative to the total area values of all peaks detected in the HPLC chromatogram obtained for the thioester derivative, i.e., as an area percentage. Note that this peak area value does not include peaks derived from the solvent. The purity of the hydroxyl-containing lactone derivative and the lactone derivative can be calculated in a similar manner.

The reaction conversion rate of the thioester derivative can be calculated from the HPLC chromatogram obtained for the lactone derivative and the HPLC chromatogram obtained for the thioester derivative. That is, the ratio (A3/(A1+A2)×100) of the area value A3 of the thioester derivative in the HPLC chromatogram obtained for the thioester derivative to the total area value (A1+A2) of the area value A1 of the peak of the hydroxyl-containing lactone derivative and the area value A2 of the peak of the lactone derivative in the HPLC chromatogram obtained for the lactone derivative can be regarded as the reaction conversion rate of the thioester derivative.

An example of the HPLC measurement conditions is shown below.
Model: Waters Alliance (registered trademark) e2695 manufactured by Waters Corporation
Detector: Ultraviolet absorption photometer Waters 2489
Measurement wavelength: 254nm
Column: Kinetex (registered trademark) C18, inner diameter 4.6 mm, length 25 cm (particle diameter 5 μm) (Phenomenex)
Column temperature: constant at 30°C Sample temperature: constant at 25°C Mobile phase A: acetonitrile Mobile phase B: formic acid aqueous solution (pH = 5)
Mobile phase delivery:
0-10 min: 40% by volume of mobile phase A, 60% by volume of mobile phase B
10-30 min: Mobile phase A increased from 40 vol% to 95 vol%, mobile phase B decreased from 60 vol% to 5 vol% 30-55 min: Mobile phase A 95 vol%, mobile phase B 5 vol%
Flow rate: 1.0 mL/min Measurement time: 55 minutes.

Under the above HPLC conditions, the retention time of the hydroxyl-containing lactone derivative represented by the above formula (10) is approximately 27.5 minutes, the retention time of the lactone derivative represented by the above formula (5) is approximately 29.0 minutes, and the retention time of the thioester derivative represented by the above formula (4) is approximately 38.8 minutes.

The present invention will be described in detail below with reference to the following examples. The examples are specific examples and the present invention is not limited to these.

<Production Example 1>
(Synthesis of lactone derivatives)
The lactone derivative represented by the above formula (5) was synthesized by the following method.
First, in a nitrogen atmosphere, 15 g (27.74 mmol) of the hydroxyl-containing lactone derivative represented by the above formula (10) and 75 mL of dimethyl sulfoxide were added to a 1000 mL four-neck flask equipped with two stirring blades having a diameter of 9.5 cm, and the mixture was stirred at 25 ° C. for 30 minutes to obtain a reaction solution. 45 mL of acetic anhydride was slowly added dropwise to this reaction solution, and the mixture was stirred at 20 ° C. for 17 hours. After adding 300 mL of toluene to the reaction solution after stirring, 360 mL of 5% by mass hydrochloric acid was slowly added dropwise to separate the reaction solution into an organic layer and an aqueous layer. The extracted organic layer was washed three times with 150 mL of a 5% by mass aqueous sodium bicarbonate solution, and then the organic layer was further washed with distilled water and 10% by mass saline in that order. The organic layer after washing was dehydrated using sodium sulfate. The organic layer after dehydration was filtered, and the obtained filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography to obtain 14.61 g of a product.

The purity of the lactone derivative represented by the above formula (5) and the hydroxyl-containing lactone derivative represented by the above formula (10) in this product by HPLC area percentage was measured by the above method, and the purity of the lactone derivative was 96.31%, and no peak of the hydroxyl-containing lactone derivative was detected. The yield of the lactone derivative was 97.8%.

Example 1
(Production of Thioester Derivatives)
The thioester derivative represented by formula (4) was prepared by the following method.
First, in a nitrogen atmosphere, 0.36 g (2.04 mmol) of 1-decanethiol, 1 g (1.86 mmol) of the lactone derivative shown in formula (5) obtained in Production Example 1, and 10 mL of tetrahydrofuran were added to a 50 mL four-neck flask equipped with a 2.5 cm stirrer, and the mixture was stirred at 25° C. for 10 minutes to obtain a first mixture. Next, 2.04 mmol of isopropyl magnesium chloride was dissolved in tetrahydrofuran to obtain 1.02 mL of a first solution. The first mixture was cooled to −10° C., and the first solution was added dropwise thereto over 15 minutes. Thereafter, the mixture was stirred for 2 hours while maintaining this temperature to obtain a second mixture containing a thioester derivative. The reaction conversion rate of the thioester derivative contained in this second mixture was measured by the above method, and the reaction conversion rate was 92.8%.

15 mL of 5% by mass hydrochloric acid was slowly added dropwise to the second mixture, and the second mixture was separated into an organic layer and an aqueous layer. After the organic layer was extracted, 10 mL of ethyl acetate was added to the aqueous layer, and the organic layer was extracted. This operation was repeated, and all of the extracted organic layers were mixed. The mixed organic layer was washed with distilled water and then with 10% by mass saline. The washed organic layer was dehydrated with sodium sulfate. The dehydrated organic layer was filtered to obtain a filtrate. The filtrate was concentrated under reduced pressure to obtain 1.18 g of residue.

The purities of the lactone derivative shown in formula (5) and the thioester derivative shown in formula (4) in this residue by HPLC area percentage were measured by the above method, and the purity of the lactone derivative was 8.33% and the purity of the thioester derivative was 87.04%. The yield of the thioester derivative was 89.0%.

Next, this residue was purified by silica gel column chromatography. The residue after purification was subjected to ¹ H-NMR spectroscopic analysis at 400 MHz. Deuterated chloroform (CDCl ₃ ) was used as the solvent. This confirmed that the structure of the thioester derivative was that shown in formula (4) above. The results are shown below.

δ 0.88 (t, 3H), 1.24-1.38 (m, 14H), 1.53-1.60 (m, 2H), 2.75 (d, 1H), 2.85 (t , 2H), 3.52-3.61 (m, 2H), 3.75 (dd, 1H), 3.86-3.91 (m, 1H), 4.07 (t, 1H), 4. 37 (d, 1H), 4.45-4.55 (m, 4H), 4.61-4.68 (m, 3H), 4.81 (d, 1H), 7.19-7.21 ( m, 2H), 7.24-7.36 (m, 16H), 7.39-7.41 (m, 2H).

<Reference Example 1>
Except for using a solution in which 2.04 mmol of trimethylaluminum was dissolved in toluene instead of the second solution, a second mixture containing a thioester derivative was obtained in the same manner as described in Example 1. The reaction conversion rate of the thioester derivative contained in this second mixture was measured by the above-mentioned method, and was found to be 91.0%.

As is clear from a comparison of Example 1 and Reference Example 1 above, when isopropyl magnesium chloride is used as a reactant, a reaction conversion rate equal to or higher than that achieved when trimethylaluminum is used as a reactant can be achieved.

Claims (3)

A method for producing a thioester derivative, comprising contacting a lactone derivative represented by the following formula (1) with a thiol represented by the following formula (2) in the presence of at least one of an alkyl magnesium halide and an aryl magnesium halide to obtain a thioester derivative represented by the following formula (3):
In the above formula (1), R ¹ is represented by -(A) _s -(B) _t -C;
A is an alkylene group which may have a halogeno group, s is 0 or 1,
B is O, S or NH; t is 0 or 1;
C represents an alkyl group which may have a halogeno group, an aralkyl group which may have a halogeno group, an aryl group which may have a halogeno group, a vinyl group which may have a halogeno group, or a heterocyclic group which contains at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen and which may have a halogeno group,
^R2 is represented by -(D) _u -E;
D is O, S or NH; u is 0 or 1;
E represents an alkyl group which may have a halogeno group, an aralkyl group which may have a halogeno group, an aryl group which may have a halogeno group, or a heterocyclic group which contains at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen and which may have a halogeno group,
n is 1 or more and 6 or less,
R ³ -SH (2)
In the above formula (2), ^R3 is an alkyl group, an aralkyl group, or an aryl group;
In the above formula (3), R ¹ , R ² and n are the same as those in the above formula (1), and R ³ is the same as those in the above formula (2). The method for producing a thioester derivative according to claim 1, wherein the amount of at least one of the alkyl magnesium halide and the aryl magnesium halide per mole of the lactone derivative represented by formula (1) is 0.1 moles or more and 3 moles or less. A method for producing a thioester derivative according to claim 1 or 2, comprising contacting a first mixture obtained by mixing a lactone derivative represented by formula (1) with a thiol represented by formula (2) with at least one of the alkyl magnesium halide and the aryl magnesium halide.