JP2022067673A - Production method of thiolactone compound - Google Patents

Abstract

To provide an efficient production method of thiolactone compound.SOLUTION: A thiolactone compound is obtained by reacting a lactone compound represented by the following formula (I) with a thiocarboxylic acid alkali metal salt at a reaction temperature of lower than 125°C. In the formula (I), R1 and R2 are each a hydrogen atom, a benzyl group, or a benzyl group having a substituent.SELECTED DRAWING: None

Description

The present invention relates to a method for producing a thiolactone compound.

The thiolactone compound is a compound having a structure in which an oxygen atom forming a ring of a lactone compound which is a cyclic ester is replaced with a sulfur atom. Thiolactone compounds are important compounds as synthetic intermediates for various useful compounds such as pharmaceuticals, foods and cosmetics.

As one of the synthetic methods utilizing a thiolactone compound as a synthetic intermediate, a method for producing biotin represented below is known (Non-Patent Document 1). Biotin is a type of water-soluble vitamin.

In Patent Documents 1 and 2, respectively, in the above stage 4, the lactone compound (LCT) and potassium thioacetate are mixed and stirred at a temperature of 130 ° C. or 150 ° C. for 1 hour to obtain a thiolactone compound (DTL). It is stated that it will be obtained.

International Publication No. 2018/025722 International Publication No. 2020/110831

Pierre J. de Clercq, "Biotin: A Timeless Challenge for Total Synthesis" Chemical Reviews, 1997, Vol. 97, No. 6.

An object of the present invention is to provide an efficient method for producing a thiolactone compound.

According to the embodiment, a method for producing a thiolactone compound is provided. In this production method, a lactone compound represented by the following formula (I) and a thiocarboxylic acid alkali metal salt are reacted at a reaction temperature of less than 125 ° C. to obtain a thiolactone compound represented by the following formula (II). including.

In formula (I), R ¹ and R ² are benzyl groups having a hydrogen atom, a benzyl group, or a substituent, respectively.

In formula (II), R ¹ and R ² are synonymous with those in formula (I), respectively.

INDUSTRIAL APPLICABILITY According to the present invention, an efficient method for producing a thiolactone compound is provided.

In the method according to the embodiment, the lactone compound represented by the above formula (I) and the thiocarboxylic acid alkali metal salt are reacted at a reaction temperature of less than 125 ° C. to cause the thiolactone compound represented by the above formula (II). To manufacture. Hereinafter, the lactone compound represented by the formula (I) and the thiolactone compound represented by the formula (II) are also simply referred to as a lactone compound and a thiolactone compound, respectively.

When the lactone compound and the thiocarboxylic acid alkali metal salt are reacted at a temperature within this range, the thiolactone compound can be efficiently produced. That is, the reaction between the lactone compound and the thiocarboxylic acid alkali metal salt is an exothermic reaction. When these are reacted at a high temperature of 125 ° C. or higher, the heat generated by the reaction further accelerates these reactions, and the temperature of the mixture of the lactone compound and the thiocarboxylic acid alkali metal salt can be further increased. For example, the temperature of this mixture may rise by more than 10 ° C. above the initially set reaction temperature in a short period of time. If the temperature of the mixture rises sharply before the reaction is completed in this way, colored components may be formed in the mixture. The present inventor speculates that this coloring component is derived from at least one decomposition product of the thiolactone compound and the thiocarboxylic acid alkali metal salt. That is, when the lactone compound and the thiocarboxylic acid alkali metal salt are reacted at a high temperature of 125 ° C. or higher, the yield of the thiolactone compound may decrease and the step of removing the coloring component may be required a plurality of times.

In the method according to the embodiment, since the lactone compound and the thiocarboxylic acid alkali metal salt are reacted at a reaction temperature of less than 125 ° C., coloring components are less likely to be generated, and the thiolactone compound can be stably produced. Therefore, according to the method according to the embodiment, the production efficiency of the thiolactone compound is increased.

A rapid increase in reaction temperature in a mixture of a lactone compound and a thiocarboxylic acid alkali metal salt is particularly likely to occur during the production of large amounts of thioester compounds. Therefore, the method according to the embodiment is suitable when 0.5 kg or more or 1.0 kg or more of the lactone compound is used as the substrate. There is no particular upper limit to the amount of the lactone compound as a substrate, but according to one example, it is 10.0 kg or less, and according to another example, it is 5.0 kg or less.

Hereinafter, the details of the manufacturing method according to the embodiment will be described.

(Lactone compound)
The lactone compound is represented by the following formula (I). Lactone compounds can be used as intermediates for biotin synthesis.

In formula (I), R ¹ and R ² are benzyl groups having a hydrogen atom, a benzyl group, or a substituent, respectively.

The substituent of the benzyl group is, for example, at least one selected from the group consisting of an alkoxy group, a nitro group, an amino group, and a hydroxy group. Examples of benzyl groups having substituents include 4-methylbenzyl group, 4-methoxybenzyl group, 4-nitrobenzyl group, 4-aminobenzyl group, and 4-hydroxybenzyl group.

(Tiocarboxylic acid alkali metal salt)
The thiocarboxylic acid alkali metal salt is a reagent for introducing sulfur into a lactone compound. As the thiocarboxylic acid alkali metal salt, for example, at least one selected from the group consisting of thioacetate alkali metal salt and thiobenzoic acid alkali metal salt is used. Alkali metal thioacetate salts include sodium thioacetate, potassium thioacetate, and lithium thioacetate. Alkali metal salts of thiobenzoate include sodium thiobenzoate, potassium thiobenzoate, and lithium thiobenzoate. Only one kind of thiocarboxylic acid alkali metal salt may be used, or a plurality of kinds may be used in combination. As the thiocarboxylic acid alkali metal salt, it is preferable to use a thioacetic acid alkali metal salt, and it is more preferable to use potassium thioacetate.

The amount of the thiocarboxylic acid alkali metal salt with respect to 1 mol of the lactone compound is, for example, 1 to 3 mol, preferably 1 to 2 mol, and particularly preferably 1 to 1.8 mol.

As the thiocarboxylic acid alkali metal salt, a commercially available one may be used, or a synthetic one may be used. The thiocarboxylic acid alkali metal salt can be synthesized, for example, by reacting the thiocarboxylic acid with the alkali metal salt.

Specific examples of the alkali metal salt include alkali metal hydroxide salts such as sodium hydroxide, potassium hydroxide and lithium hydroxide; alkaline earth metal salts such as magnesium hydroxide and barium hydroxide; potassium carbonate, sodium carbonate and carbonic acid. Alkali metal carbonates such as lithium and cesium carbonate; alkali metal acetates such as potassium acetate and sodium acetate can be mentioned. Among these alkali metal salts, it is preferable to use at least one selected from the group consisting of alkali metal hydroxide salts and alkali metal acetate salts from the viewpoint of reactivity with thiocarboxylic acid and industrial availability. It is more preferable to use an alkali metal salt.

As the thiocarboxylic acid, for example, at least one of thioacetic acid and thiobenzoic acid is used. As the thiocarboxylic acid, it is preferable to use thioacetic acid.

The reaction temperature of the thiocarboxylic acid and the alkali metal salt is, for example, 0 to 50 ° C, preferably 5 to 40 ° C, and particularly preferably 10 to 30 ° C. The reaction time is, for example, 0.5 to 4 hours, preferably 0.5 to 3 hours, and particularly preferably 0.5 to 2 hours.

The amount of the alkali metal salt with respect to 1 mol of thiocarboxylic acid is preferably 1 mol or more and 6 mol or less, more preferably larger than 1 mol and 6 mol or less, and 1.1 mol or more and 4 mol or less. Is even more preferable. Within the above range, the amount (number of moles) of thiocarboxylic acid used is preferably equal to or greater than the number of moles of the lactone compound.

(Thiolactone compound)
The thiolactone compound is represented by the following formula (II). This thiolactone compound can be used as an intermediate for biotin synthesis.

In formula (II), R ¹ and R ² are synonymous with those in formula (I).

The thiolactone compound may be white or colorless and transparent, and may have a color. The color of the thiolactone compound is, for example, black, red, reddish brown, purplish red, purple, orange, or brown. The color of the thiolactone compound is thought to be derived from impurities and impurities. Therefore, it is preferable that the thiolactone compound has few coloring components and high transparency. According to the production method of the embodiment, a thiolactone compound with less coloring can be obtained.

This thiolactone compound can be synthesized into a biotin derivative represented by the following formula (III) (hereinafter, also referred to as a biotin derivative).

In the formula, R ¹ and R ² have the same meaning as those in the above formula (I), and R ³ has the same meaning as those in the following formula (IV). The biotin derivative can be synthesized into biotin by a known method.

As a method for producing a biotin derivative from a thiolactone compound, a known method can be adopted. For example, a method of reacting a thiolactone compound with a zinc reagent represented by the following formula (IV) in the presence of at least one catalyst of palladium and nickel has been reported.

In the formula, R ³ is an alkyl group or an aralkyl group.

(Tetrahedron Letters 41 (2000) 5099-5101, Organic Syntheses, Vol. 84, p.285-294 (2007); Coll. Vol. 11, p.281-288 (2009).)
(Method for producing thiolactone compound)
The thiolactone compound is obtained by reacting the lactone compound represented by the above formula (I) with a thiocarboxylic acid alkali metal salt at a reaction temperature of less than 125 ° C. to replace the oxygen constituting the lactone ring with sulfur. ..

Here, in the present specification, the reaction temperature means the temperature during the reaction between the lactone compound and the thiocarboxylic acid alkali metal salt in the mixture obtained by mixing the lactone compound and the thiocarboxylic acid alkali metal salt. .. During these reactions, the temperature may be kept below 125 ° C., the temperature of the mixture may rise or fall, or the temperature may change repeatedly.

The reaction temperature is preferably 120 ° C. or lower, more preferably 110 ° C. or lower, and further preferably 105 ° C. or lower, from the viewpoint of increasing the stability of the thiolactone compound and making it difficult to generate coloring components. preferable.

The lower limit of the reaction temperature may be any temperature at which the reaction between the lactone compound and the thiocarboxylic acid alkali metal salt proceeds. The reaction temperature is preferably 85 ° C. or higher, more preferably 90 ° C. or higher, still more preferably 95 ° C. or higher, from the viewpoint of enhancing the reactivity between the lactone compound and the thiocarboxylic acid alkali metal salt. ..

The reaction time between the lactone compound and the thiocarboxylic acid alkali metal salt is preferably 6 hours or more. That is, the thiolactone compound can be stably produced in high yield by reacting for a long time at a relatively low reaction temperature of less than 125 ° C. The reaction time is more preferably 8 hours or more, further preferably 10 hours or more. There is no particular upper limit to the reaction time, but according to one example, it is 20 hours or less, and according to another example, it is 15 hours or less. The mixture is preferably stirred during the reaction time.

The reaction between the lactone compound and the thiocarboxylic acid alkali metal salt is preferably carried out in a reaction solvent. Examples of the reaction solvent include N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), and N, N-dimethylimidazolidine-2-one. At least one selected from the group consisting of (DMI) is used.

When a reaction solvent is used, it is preferable to mix the lactone compound and the thiocarboxylic acid alkali metal salt by the following method. First, the lactone compound and the reaction solvent are mixed to prepare a mixed solution. The amount of the solvent in this mixed solution is preferably 1 mL or more and 3 mL or less with respect to 1 g of the lactone compound. This mixed solution is heated until it reaches a temperature within the above reaction temperature range. Add an alkali metal thiocarboxylic acid salt to the heated mixture. At this time, first, the thiocarboxylic acid alkali metal salt is dissolved in the reaction solvent, and this reaction is an endothermic reaction. Therefore, when a thiocarboxylic acid alkali metal salt is added to the mixed solution, the temperature of the mixed solution may be temporarily lowered from the initial reaction temperature. After this temporary temperature drop occurs, it is considered that the temperature of the mixed solution returns to the vicinity of the initial reaction temperature again, and the reaction between the lactone compound and the thiocarboxylic acid alkali metal salt starts. The maximum temperature drop is preferably adjusted to be 85 ° C. or higher.

The reaction temperature can be adjusted by a known method. For example, the reaction temperature of the mixture can be adjusted by adjusting the temperature of a heater or the like in contact with a container containing the mixture of the lactone compound and the alkali metal thiocarboxylic acid salt.

The thiolactone compound obtained by the above method is preferably taken out by the following method. First, the quench solution is added to the reaction solution containing the thiolactone compound, and the reaction solution is cooled to 40 ° C. or lower to terminate the reaction. As the quenching liquid, for example, water is used. The amount of the quench solution is, for example, 1 mL or more and 10 mL or less with respect to 1 g of the lactone compound. The temperature of the mixture after the addition of the quench liquid is preferably in the range of 10 ° C. or higher and 35 ° C. or lower.

The reaction solution to which the quenching solution is added is stirred for, for example, 1 hour or more and 5 hours or less to obtain a precipitate. The precipitate is removed by filtration, washed with water, and then sufficiently dried. In this way, a crude thiolactone compound is obtained.

(Method for purifying thiolactone compounds)
The crude thiolactone compound obtained by the above method is preferably purified by the following method.

First, the crude thiolactone compound is subjected to activated carbon treatment. This makes it possible to remove impurities in the crude body. Specifically, a crude thiolactone compound, an organic solvent, and activated carbon are mixed, and the mixture is stirred. In the mixture, the precipitate can be dissolved in an organic solvent. Examples of the organic solvent include toluene, xylene, mesitylene, cumene, hexane, heptane, methanol, ethanol, isopropanol (IPA), acetone, methyl ethyl ketone, diethyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, and butyl acetate. At least one selected from the above is used. Acetone is preferably used as the organic solvent.

The amount of activated carbon is, for example, 1 part by mass or more and 20 parts by mass or less, preferably 2 parts by mass or more and 10 parts by mass or less, more preferably, when the crude material (solid content) of the thiolactone compound is 100 parts by mass. Add so as to be 3 parts by mass or more and 7 parts by mass or less.

The amount of the organic solvent with respect to the crude product of 1 g of the thiolactone compound is, for example, 1 mL or more and 20 mL or less, preferably 2 mL or more and 10 mL or less, and more preferably 3 mL or more and 6 mL or less.

The stirring temperature of the mixture is, for example, 10 ° C. or higher and 70 ° C. or lower, preferably 20 ° C. or higher and 65 ° C. or lower. The stirring time of the mixture is, for example, 12 minutes or more and 3 hours or less, preferably 30 minutes or more and 2 hours or less.

After the activated carbon treatment is completed, the mixture is filtered to obtain a filtrate from which the activated carbon has been removed. This filtrate is subjected to crystallization treatment. That is, an organic solvent of the same type as the above-mentioned organic solvent is optionally mixed with this filtrate, and then water is further mixed to precipitate crystals of the thiolactone compound. Then, it is left at a constant temperature for a certain period of time to grow crystals of the thiolactone compound.

The amount of the organic solvent with respect to the crude product of 1 g of the thiolactone compound is, for example, 1 mL or more and 10 mL or less, preferably 1 mL or more and 5 mL or less. The amount of water with respect to the crude product of 1 g of the thiolactone compound is, for example, 3 mL or more and 10 mL or less, preferably 4 mL or more and 8 mL or less. The crystallization temperature is, for example, 10 ° C. or higher and 40 ° C. or lower, preferably 15 ° C. or higher and 30 ° C. or lower. The crystallization time is, for example, 6 minutes or more and 6 hours or less, preferably 30 minutes or more and 3 hours or less.

Next, crystals of the thiolactone compound are isolated from the mixture. The isolation method is not particularly limited, and examples thereof include pressure filtration, vacuum filtration, and centrifugation. The crystals of the isolated thiolactone compound are optionally washed with a washing solution and then dried. By the above method, crystals of the purified thiolactone compound can be obtained.

According to the method according to the embodiment, since the lactone compound and the thiocarboxylic acid alkali metal salt are reacted at a temperature of less than 125 ° C., a reaction solution containing a thiolactone compound having a small amount of coloring components and the like can be obtained. Therefore, it is not necessary to repeat the purification treatment of the thiolactone compound a plurality of times, and a highly pure thiolactone compound can be obtained by crystallization with an organic solvent such as acetone.

Hereinafter, the present invention will be described in detail with reference to examples. However, the following examples are specific examples, and the present invention is not limited thereto.

<Example 1>
(Synthesis of thiolactone compound)
First, the thiolactone compound represented by the formula (II) was synthesized by the following method. R ¹ and R ² were each a benzyl group.

25 g (0.077 mol) of the lactone compound represented by the formula (I) was dissolved in 37.5 mL of N, N-dimethylacetamide (DMA) to obtain a lactone compound solution. Evacuation of this lactone compound solution and nitrogen leakage were repeated 3 times. After heating the lactone compound solution to 100 ° C. under a nitrogen atmosphere, 13.5 g (0.118 mol) of potassium thioacetate was added thereto, and the mixture was stirred for 12 hours while maintaining the temperature at 100 ° C. to prepare the reaction solution. Got In this reaction, no rapid temperature rise was observed in the mixture of the lactone compound solution and potassium thioacetate.

125 mL of water was added to the reaction solution at 100 ° C. to lower the temperature of the reaction solution within the range of 25 ° C. to 30 ° C. The reaction solution was stirred over 2 hours in this temperature range to precipitate a solid. The precipitate was removed by filtration and then washed with 25 mL of water. The washed precipitate was air-dried at a temperature of 60 ° C. for 10 hours to obtain a crude thiolactone compound. The amount of crude thiolactone compound was 23.1 g, and the yield was 88.0%. The crude color of the thiolactone compound was light brown and there was little coloring.

(Purification of thiolactone compound)
Next, crystals of the thiolactone compound represented by the formula (II) were obtained by the following method.
The entire amount of the crude thiolactone compound was dissolved in 127 mL of acetone to obtain an acetone solution. 1.27 g of activated carbon was added to this acetone solution, and the obtained suspension was stirred at a temperature of 60 ° C. for 1 hour. Activated carbon was removed from the stirred suspension by filtration through Celite. The removed activated carbon was washed with 23 mL of acetone heated to 60 ° C. This operation was further performed twice, and the obtained washing liquid was added to the filtrate to obtain a mixed liquid. After adding 196 mL of water to this mixture, the mixture was stirred at a temperature of 25 ° C. for 2 hours to precipitate a solid. The precipitate was removed by filtration and then washed with a mixed solvent of 23 mL of water and 23 mL of acetone. The washed precipitate was dried at a temperature of 70 ° C. for 4 hours to obtain crystals of the thiolactone compound. The amount of crystals of the thiolactone compound was 22.1 g, and the yield from the lactone compound was 84.2%.

<Example 2>
A crude thiolactone compound was obtained by the same method as in Example 1 except that the amounts of the material, solvent, etc. were scaled up 40 times. The mass of the lactone compound was 1.0 kg. In this reaction, no rapid temperature rise was observed in the mixture of the lactone compound solution and potassium thioacetate. The amount of the crude product of the obtained thiolactone compound was 926 g, and the yield was 88.21%. The crude color of the thiolactone compound was light brown and there was little coloring.

<Comparative Example 1>
Thiolactone by the same method as described in Example 1 except that the reaction temperature between the lactone compound solution and potassium thioacetate was changed to 125 ° C. and the stirring time after mixing these was set to 4 hours. A crude compound was obtained. In this reaction, a temperature increase was observed in the mixture of the lactone compound solution and potassium thioacetate. The amount of the crude product of the obtained thiolactone compound was 19.8 g, and the yield was 75.44%. The crude color of the thiolactone compound was slightly dark brown, and the coloring was slightly higher.

<Comparative Example 2>
Described in Example 1 except that the amount of the material, solvent, etc. was scaled up 98 times (lactone compound 2.45 kg) and the reaction temperature between the lactone compound solution and potassium thioacetate was changed to 125 ° C. The experiment was carried out in the same way as the above. As a result, 10 minutes after adding potassium thioacetate to the lactone compound solution, a rapid temperature rise was observed in which the temperature of the mixture reached 140 ° C. The reaction between the lactone compound solution and potassium thioacetate was completed in 45 minutes. The amount of the crude product of the obtained thiolactone compound was 2.38 kg, and the yield was 92.53%. The crude color of the thiolactone compound was dark brown, and there was a lot of coloring.

As is clear from Examples 1 and 2 and Comparative Examples 1 and 2, when the reaction temperature between the lactone compound solution and potassium thioacetate is less than 125 ° C., the high yield of the thiolactone compound and the low coloring can be achieved at the same time. rice field.

Claims (6)

A thiolactone compound comprising reacting a lactone compound represented by the following formula (I) with a thiocarboxylic acid alkali metal salt at a reaction temperature of less than 125 ° C. to obtain a thiolactone compound represented by the following formula (II). Manufacturing method:

In the formula (I), R ¹ and R ² are benzyl groups having a hydrogen atom, a benzyl group, or a substituent, respectively.

In the formula (II), R ¹ and R ² are synonymous with those in the formula (I), respectively. The method for producing a thiolactone compound according to claim 1, wherein the reaction temperature is 90 ° C. or higher and 110 ° C. or lower. The method for producing a thiolactone compound according to claim 1 or 2, wherein the reaction time between the lactone compound represented by the formula (I) and the thiocarboxylic acid alkali metal salt is 6 hours or more. The method for producing a thiolactone compound according to any one of claims 1 to 3, wherein the amount of the lactone compound represented by the formula (I) is 0.5 kg or more. The method for producing a thiolactone compound according to any one of claims 1 to 4, wherein the thiocarboxylic acid alkali metal salt contains a thioacetate alkali metal salt. The thiolactone compound represented by the formula (II) is dissolved in a solvent containing acetone to obtain a solution.
The method for producing a thiolactone compound according to any one of claims 1 to 5, further comprising adding water to the solution to precipitate the thiolactone compound represented by the formula (II).