JP2021151958A - Method for producing thiolactone compound - Google Patents

Abstract

To provide a method for producing a thiolactone compound at high yield.SOLUTION: A method for producing a thiolactone compound includes bringing a lactone compound, in which S in a compound of the formula (II) is replaced with O, into contact with acetic acid alkali metal salt in a first organic solvent to make a first mixture; and bringing the first mixture into contact with a thiocarboxylic acid to make a second mixture including the thiolactone compound of the formula (II) [R1 and R2 each denote H, a benzyl group, or a substituted benzyl group].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 (a type of water-soluble vitamin) represented below is known (Non-Patent Document 1).

Patent Document 1 describes that the thiolactone compound (LCT) is reacted with thioamides in the presence of alkali hydrosulfide, sulfur and a basic substance to obtain the thiolactone compound (DTL). .. Further, Non-Patent Document 2 describes that DTL is obtained by contacting LCT with potassium ethylxanthogenate. However, these methods have problems that the operation is complicated and the reproducibility is poor.

To solve such a problem, Non-Patent Document 3 proposes to obtain DTL by contacting LCT with potassium thioacetate (AcSK). However, since AcSK is an unstable substance, there is a problem that it is not suitable for mass production.

Japanese Unexamined Patent Publication No. 2000-351780

Pierre J. de Clercq, “Biotin: A Timeless Challenge for Total Synthesis” Chemical Reviews, 1997, Vol. 97, No. 6. Fen-Er Chen, Jian-Li Yuan, Hui-Fang Dai, Yun-Yan Kuang, Yong Chu, "Synthetic Studies on d-Biotin, Part 6: An Expeditious and Enantiocontrolled Approach to the Total Synthesis of d-Biotin via a Polymer -Supported Chiral Oxazaborolidine-Catalyzed Reduction of meso-Cyclic Imide Strategy "Synthesis 2003, No. 14. Masahiko Seki, Toshiaki Shimazu, Koichi Inubushi, "A Novel Synthesis of a Key Intermediate for (+)-Biotin from 2003, No.

An object of the present invention is to provide a method for producing a high-yield thiolactone compound.

According to the embodiment, the lactone compound represented by the following formula (I) and the alkali metal acetate are brought into contact with each other in a first organic solvent to obtain a first mixture, and the first mixture and thiocarboxylic acid are combined. Provided is a method for producing a thiolactone compound, which comprises contacting the mixture to obtain a second mixture containing the thiolactone compound represented by the following formula (II).

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).

According to the present invention, a method for producing a high-yield thiolactone compound is provided.

According to the embodiment, the lactone compound represented by the following formula (I) and the alkali metal acetate are brought into contact with each other in a first organic solvent to obtain a first mixture, and the first mixture and thiocarboxylic acid are combined. Provided is a method for producing a thiolactone compound, which comprises contacting the mixture to obtain a second mixture containing the thiolactone compound represented by the following formula (II).

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).

In the method for producing a thiolactone compound according to the embodiment, first, a lactone compound represented by the formula (I) (hereinafter, also referred to as a lactone compound) is brought into contact with an alkali metal acetate, and then the first mixture obtained is obtained. By contacting with thiocarboxylic acid, a thiolactone compound represented by the formula (II) (hereinafter, also referred to as a thiolactone compound) is obtained.

According to this method, a thiolactone compound can be obtained by reacting an alkali metal acetate produced by reacting an alkali metal acetate with a thiocarboxylic acid with a lactone compound in the system. Therefore, it is not necessary to use an unstable alkali metal thioacetic acid salt as a raw material. Further, in the production method according to the embodiment, a relatively stable alkali metal acetate and a lactone compound are brought into contact with each other, and then a relatively unstable thiocarboxylic acid is brought into contact with them, and the alkali thioacetate is brought into contact immediately before the substitution reaction. Produces metal salts. Therefore, the produced alkali metal thioacetic acid salt can be quickly consumed, and the robustness of the reaction can be further enhanced. Therefore, according to the production method according to the embodiment, the thiolactone compound can be stably produced in a high yield, and thus the mass production of the thiolactone compound becomes easy.

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

In the production method according to the embodiment, first, the lactone compound represented by the following formula (I) and the alkali metal acetate are brought into contact with each other in a first organic solvent to obtain a first mixture.

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 the benzyl group having a substituent include a 4-methylbenzyl group, a 4-methoxybenzyl group, a 4-nitrobenzyl group, a 4-aminobenzyl group, and a 4-hydroxybenzyl group.

The alkali metal acetate can be a weak base. When an alkali metal acetate is used, the reaction tends to proceed more gently than when a strong base such as an alkali metal hydroxide is used. In addition, water is less likely to be generated during the reaction. When the amount of water is small, the decrease in yield due to ring opening of the thiolactone compound can be suppressed.

As the alkali metal acetate, for example, at least one selected from the group consisting of sodium acetate, potassium acetate, lithium acetate, cesium acetate, and rubidium acetate is used. Among them, potassium acetate is preferably used as the alkali metal acetate in consideration of reactivity, ease of handling, price and the like.

The amount of alkali metal acetate to 1 mol of the lactone compound is preferably 1 mol or more and 6 mol or less in order to allow the reaction to proceed sufficiently and to facilitate the purification of the product. The amount of alkali metal acetate with respect to 1 mol of the lactone compound is more preferably 1.05 mol or more and 5 mol or less, further preferably 1.10 mol or more and 4 mol or less, and 1.2 mol or more and 4 mol. It is particularly preferable that the amount is less than or equal to the molar amount.

The lactone compound and the alkali metal acetate are preferably brought into contact with each other in a first organic solvent with stirring. As the first organic solvent, it is preferable to use a solvent capable of dissolving the thiocarboxylic acid and the alkali metal acetate. The first organic solvent is, for example, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), and N, N-dimethylimidazolidine-2-. At least one selected from the group consisting of on (DMI) is used. As the first organic solvent, in order to increase the reaction rate of thiolactone formation and more easily increase the purity of the obtained thiolactone compound, it is more preferable to use an amide-based solvent, and it is further preferable to use DMA.

The amount of the first organic solvent with respect to 1 g of the lactone compound is, for example, 0.5 mL or more and 100 mL or less, preferably 1 mL or more and 10 mL or less, and more preferably 1 mL or more and 3 mL or less.

The step of contacting the lactone compound with the alkali metal acetate in the first organic solvent to obtain the first mixture is preferably carried out under a nitrogen stream with stirring at room temperature (for example, 20 ° C. or higher and 30 ° C. or lower). The stirring time is preferably 5 minutes or more and 2 hours or less.

Next, the obtained first mixture is brought into contact with the thiocarboxylic acid to obtain a second mixture containing the thiolactone compound represented by the following formula (II).

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

The thiocarboxylic acid reacts with the alkali metal acetate described above to produce an alkali metal acetate. Thiocarboxylic acids can be unstable substances as compared to alkali metal acetates. In the method according to the embodiment, such a thiocarboxylic acid is brought into contact with the first mixture. According to this method, thioacetic acid is compared with the case where the lactone compound is brought into contact with the previously produced alkali metal thioacetic acid salt and the case where the lactone compound is brought into contact with the thiocarboxylic acid and the alkali metal acetate salt at the same time. Since the presence time of the alkali metal salt can be shortened, a thiolactone compound can be produced more stably.

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 amount of thiocarboxylic acid with respect to 1 mol of the lactone compound is, for example, 1 mol or more and 4 mol or less, preferably 1.05 mol or more and 3 mol or less, and more preferably 1.10 mol or more and 2 mol or less. Yes, more preferably 1.2 mol or more and 2 mol or less.

The amount of substance of thiocarboxylic acid is preferably smaller than the amount of substance of alkali metal acetate. That is, by reacting with thiocarboxylic acid in the presence of an excess amount of alkali metal acetate, the alkali metal thioacetate can be rapidly produced, so that the yield of the thiolactone compound can be increased.

The amount of the alkali metal acetate with respect to 1 mol of thiocarboxylic acid is preferably 1 mol or more and 6 mol or less. Among them, it is considered that the cause is that the alkali metal acetate used is a weak base, but the amount of alkali metal acetate with respect to 1 mol of thiocarboxylic acid may be more than 1 mol and 6 mol or less. More preferably, it is 1.1 mol or more and 4 mol or less. 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.

The reaction between the alkali metal thioacetic acid salt and the lactone compound is preferably carried out at a high temperature. That is, it is preferable that the first mixture is heated to 80 ° C. or higher and then brought into contact with the thiocarboxylic acid. When the temperature of the first mixture is high, the reactivity of the alkali metal thioacetic acid salt with the lactone compound tends to increase. The temperature of the first mixture is more preferably 110 ° C. or higher. There is no particular upper limit of the temperature of the first mixture, but according to one example, it is 170 ° C. or lower, and according to another example, it is 140 ° C. or lower.

The method of contacting the first mixture with the thiocarboxylic acid is not particularly limited. As described above, it is preferable to react the thiocarboxylic acid in the presence of an excessive amount of substance of the alkali metal acetate to rapidly produce the alkali metal acetate. Then, it is preferable that the obtained thioacetic acid alkali metal salt is rapidly subjected to the reaction. Therefore, it is preferable to adopt the following method.

Specifically, it is preferable to adopt a method of adding a thiocarboxylic acid to the first mixture. Among them, in order to stably produce a thiolactone compound in a high yield, it is preferable to add the thiocarboxylic acid to the first mixture in a plurality of times. The number of times the thiocarboxylic acid is added may be appropriately determined depending on the amount of each component to be reacted and the like, but is preferably 2 to 50 times, more preferably 5 to 20 times. The amount added at one time is not particularly limited, but is preferably an amount evenly divided by the number of additions. That is, in consideration of reactivity, it is preferable that the thiocarboxylic acid is gradually added to the first mixture little by little.

Further, the time for adding the thiocarboxylic acid is not particularly limited and may be appropriately determined according to the scale of the reaction, but is preferably in the following range. Specifically, if the time for adding the thiocarboxylic acid is too long, the productivity may be lowered, the thiocarboxylic acid may be deteriorated, and the like. Therefore, the addition time is preferably 10 minutes or more and 2 hours or less. It is preferably 10 minutes or more and 1 hour or less. For example, the thiocarboxylic acid is added to the first mixture at intervals of 1 minute to 10 minutes in 10 portions in a tenth of the total amount. When thiocarboxylic acid is added to the first mixture, it is preferable to stir the first mixture.

The first mixture and the thiocarboxylic acid are brought into contact with each other and sufficiently stirred to obtain a second mixture containing the thiolactone compound. The stirring time is, for example, 6 minutes or more and 5 hours or less, preferably 18 minutes or more and 4 hours or less, and more preferably 30 minutes or more and 3 hours or less. This stirring time is the time after the total amount of the thiocarboxylic acid has been contacted (mixed) with the first mixture. Further, this stirring treatment is preferably performed under the heating shown above (the temperature of the heated first mixture).

According to the production method according to the embodiment described above, the lactone compound and the alkali metal acetate are brought into contact with each other to obtain a first mixture, and then the first mixture is brought into contact with the thiocarboxylic acid, so that the thiolactone compound is produced in a high yield. Can be obtained.

Next, the thiolactone compound contained in the second mixture may be purified by the following method.

That is, the production method according to the embodiment may further include mixing the second mixture and the second organic solvent. The purity of the thiolactone compound can be increased by mixing the second mixture and the second organic solvent, redissolving the thiolactone compound, and then reprecipitating the thiolactone compound.

As the second organic solvent, the same solvent as that of the first organic solvent may be used, or a different kind may be used. Examples of the second organic solvent include N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), and N, N-dimethylimidazolidine-2. At least one selected from the group consisting of − on (DMI) is used. As the second organic solvent, it is more preferable to use an amide-based solvent, and it is further preferable to use DMA.

The amount of the second organic solvent with respect to 1 g of the thiolactone compound is, for example, 0.1 mL or more and 2 mL or less, preferably 0.5 mL or more and 1.5 mL or less.

When the temperature of the second mixture is high, for example, when it is 110 ° C. or higher, the temperature of the second mixture is cooled to more than 50 ° C. and lower than 110 ° C., preferably 60 ° C. or higher and 100 ° C. or lower. Then, it is preferable to mix the second organic solvent.

Next, water is further added to the mixture of the second mixture and the second organic solvent (hereinafter, also referred to as the third mixture). In a preferred embodiment, water is gradually added and the mixture is sufficiently stirred. As a result, a fourth mixture containing a precipitate of the thiolactone compound can be obtained.

The amount of water for 1 g of the thiolactone compound is, for example, 2 mL or more and 6 mL or less, preferably 3 mL or more and 5 mL or less. Water is preferably added gradually over, for example, 5 minutes or longer, preferably 10 minutes or longer, and more preferably 30 minutes or longer. The stirring time is preferably 1 hour or more and 3 hours or less. The purity of the thiolactone compound tends to increase by gradually adding water to the third mixture and stirring for a long time.

When the temperature of the third mixture is high, it is preferable to cool it to a range of 5 ° C. or higher and 50 ° C. or lower before adding water, or to add water and then cool it. The temperature of the third mixture is more preferably 10 ° C. or higher and 40 ° C. or lower.

Next, the precipitate of the thiolactone compound is filtered off from the fourth mixture. The precipitate of the thiolactone compound separated by filtration is washed with a washing liquid. As the cleaning liquid, for example, a third organic solvent, water, or a mixed solvent thereof is used.

The third organic solvent is selected from the group consisting of, for example, toluene, xylene, mesitylene, cumene, hexane, heptane, methanol, ethanol, IPA, acetone, methyl ethyl ketone, diethyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, and butyl acetate. At least one species. The third organic solvent is preferably at least one selected from the group consisting of methanol, ethanol, IPA, and acetone.

Next, the washed precipitate of the thiolactone compound is subjected to activated carbon treatment. Thereby, impurities in the precipitate of the thiolactone compound can be removed. Specifically, the precipitate of the thiolactone compound after washing, the fourth organic solvent, and activated carbon are mixed, and the mixture is stirred. In the mixture, the precipitate of the thiolactone compound can be dissolved in a fourth organic solvent. As the fourth organic solvent, the same solvent as that of the third organic solvent can be used.

The amount of activated carbon is, for example, 1% by mass or more and 20% by mass or less, preferably 2% by mass or more and 10% by mass or less, more preferably 3% by mass or more, when the mass of the thiolactone compound is 100% by mass. Add so as to be less than mass%.

The amount of the fourth organic solvent with respect to 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.

The mixture is then filtered to give a filtrate from which activated carbon has been filtered off. This filtrate is subjected to crystallization treatment. That is, after optionally mixing the above-mentioned washing solution with this filtrate, 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 water for 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 3 hours or less, preferably 30 minutes or more and 2 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. Crystals of the purified thiolactone compound can be obtained by the above method.

According to the purification method described above, a high-purity thiolactone compound can be obtained. The purity of a thiolactone compound can be measured, for example, by high performance liquid chromatography (HPLC). The HPLC conditions are as follows, for example.

Measurement wavelength: 210 nm
Flow velocity: 1.0 mL / min
Mobile phase (at the start of measurement): acetonitrile: water = 40:60
Mobile phase (after 20 minutes): Acetonitrile Column temperature: 30 ° C.
Column: X Bridge C18, particle size 5 μm, inner diameter 4.8 mm, length 150 mm
Retention time: DTL 8.28 min
In addition, ultraviolet (UV) transmittance can also be used as an index of the purity of the thiolactone compound. That is, the high UV transmittance of the thiolactone compound indicates that the sulfur content is low, which means that the purity is high. As the UV transmittance measuring device, for example, a spectrophotometer U-3900H manufactured by Hitachi High-Tech Science Corporation is used. As the measurement sample, for example, a solution prepared by dissolving 50 mg of a thiolactone compound in 10 mL of tetrahydrofuran (THF) is used. The measurement wavelength is, for example, 400 nm.

The thiolactone compound may be purified by a method including the following acid treatment and dehydration treatment. According to this method, in the step of synthesizing the biotin compound represented by the formula (III) described later from the thiolactone compound, the reactivity of the reaction for introducing the side chain can be enhanced, so that the production efficiency of the biotin derivative can be enhanced.

First, the thiolactone compound is acid-treated. Specifically, the second mixture, a poorly water-soluble organic solvent, and an acid are mixed to adjust a mixture having a pH of 2 or less. The mixture is separated into two layers, an aqueous layer and an organic solvent layer. From the mixture, the organic solvent layer is separated and refluxed to further remove water from the organic solvent layer.

The poorly water-soluble organic solvent means an organic solvent having a solubility of 7 g or less in 100 g of water at a temperature of 20 ° C. The poorly water-soluble organic solvent is not particularly limited as long as it dissolves the thiolactone compound. Examples of the poorly water-soluble organic solvent include aliphatic hydrocarbons, aromatic hydrocarbons, ethers, halogenated hydrocarbons and the like. Examples of the aliphatic hydrocarbons include hexane and the like. Examples of aromatic hydrocarbons include benzene and toluene. Examples of ethers include diethyl ether and the like. Examples of halogenated hydrocarbons include dichloromethane, chloroform and the like. These organic solvents may be used alone or in combination of two or more. Among these, aromatic hydrocarbons, particularly toluene, are preferable from the viewpoint of practicality such as ease of availability and ease of handling.

The acid is not particularly limited, and examples thereof include acids such as hydrogen chloride and sulfuric acid. Above all, it is preferable to use hydrogen chloride. An acidic solution such as hydrochloric acid may be used. As the hydrochloric acid, concentrated hydrochloric acid having a concentration of 35% by mass or more may be used.

Next, a pH-adjusted aqueous solution is added to the reflux-treated organic solvent layer to prepare a mixture having a pH of 7.0 or more and 8.0 or less. The mixture is separated into two layers, an aqueous layer and an organic solvent layer. The organic solvent layer is separated from the mixture and concentrated under reduced pressure. The organic solvent layer or the organic solvent layer after concentration under reduced pressure may be treated with activated carbon.

An alkaline aqueous solution can be used as the pH adjusting aqueous solution. The alkaline aqueous solution can be prepared by dissolving a basic alkali metal salt in water. As the basic alkali metal salt, at least one of a strongly basic alkali metal salt such as sodium hydroxide and potassium hydroxide and a weakly basic alkali metal salt such as sodium hydrogen carbonate and potassium hydrogen carbonate can be used.

An organic solvent is added to the organic solvent layer after compression under reduced pressure to dissolve the thiolactone compound, and then the mixture is cooled to precipitate the thiolactone compound. The precipitated thiolactone compound is washed and then dried to obtain crystals of the thiolactone compound.

Alternatively, the thiolactone compound may be purified by the following method using an alcohol solvent having a boiling point of 85 ° C. or higher. According to this method, in the step of synthesizing the biotin compound represented by the formula (III) described later from the thiolactone compound, the reactivity of the reaction for introducing the side chain can be enhanced, so that the production efficiency of the biotin derivative can be enhanced.

First, the precipitate of the thiolactone compound is filtered off by filtering the second mixture. The thiolactone compound precipitate separated by filtration is brought into contact with an alcohol solvent having a boiling point of 85 ° C. or higher, and if necessary, heated to dissolve the thiolactone compound precipitate in the alcohol solvent. The obtained solution may be optionally subjected to activated carbon treatment.

The alcohol solvent having a boiling point of 85 ° C. or higher includes, for example, 1-butanol (boiling point: 117 ° C.), 2-methyl-1-propanol (boiling point: 108 ° C.), and 2-butanol (boiling point: 99 ° C.). Use at least one selected from the group.

Next, the obtained solution is concentrated under reduced pressure to reprecipitate the thiolactone compound. The reprecipitate of the thiolactone compound is separated, washed with an alcohol solvent having a boiling point of 85 ° C. or higher, and dried to obtain crystals of the thiolactone compound.

The thiolactone compound obtained by the above method can be synthesized into a biotin compound represented by the following formula (III) (hereinafter, also referred to as a biotin compound).

In the formula, R ¹ and R ² are synonymous with those in the above formula (I), and R ³ is synonymous with those in the following formula (IV). Biotin compounds can be synthesized into biotin.

As a method for producing a biotin compound 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).)

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 compounds)
First, the thiolactone compound represented by the formula (II) was synthesized by the following method. R ¹ and R ² were each designated as a benzyl group.

The lactone compound represented by the formula (I), potassium acetate salt, and N, N-dimethylacetamide (DMA) were placed in a 200 mL four-necked flask and stirred at room temperature under a nitrogen stream to obtain a first mixture. .. The amount of the lactone compound was 15.00 g (0.047 mol), the amount of potassium acetate salt was 7.31 g (0.074 mol), and the amount of DMA was 22.5 mL.

After heating this first mixture to a temperature of 125 ° C., thioacetic acid is added in 1/10 amounts every 3 minutes, and the mixture is stirred at a temperature of 125 ° C. for 2 hours, as shown in the formula (II). A second mixture containing a thiolactone compound was obtained. The amount of thioacetic acid was 4.25 g (0.056 mol).

(Purification of thiolactone compound)
Next, crystals of the thiolactone compound represented by the formula (II) were obtained by the following method.
The second mixture was cooled to a temperature of 80 ° C. and then 15 mL of DMA was added to give the third mixture. To this third mixture, 40 mL of water was further added over 30 minutes, and the mixture was stirred at a temperature of 25 ° C. or higher and 30 ° C. or lower for 2 hours to obtain a fourth mixture containing a precipitate of a thiolactone compound. The fourth mixture was filtered and the precipitate of thiolactone compound was filtered off. The precipitate of the thiolactone compound separated by filtration was washed with a washing liquid. As the cleaning liquid, a mixed solvent of 10 mL of acetone and 20 mL of water was used. The amount of thiolactone compound precipitate after washing was 16.34 g. When measured under the above-mentioned conditions using HPLC, the amount of the thiolactone compound contained in the precipitate (wet body) of the thiolactone compound after washing was 13.39 g, and the yield from the lactone compound was 85%. rice field.

The washed thiolactone compound precipitate, 75 mL of acetone, and 0.75 g of activated carbon were mixed, and the obtained mixture was stirred for 1 hour while being heated to a temperature of 60 ° C. The mixture was filtered through a glass filter and the filtered solid was washed with a wash solution. 15 mL of acetone was used as the cleaning solution. The obtained filtrate and the washing liquid after use were mixed, 90 mL of water was added thereto, and the mixture was stirred at a temperature of 25 ° C. for 1 hour to precipitate crystals of the thiolactone compound. Crystals of the thiolactone compound were filtered off from this mixed solution and washed with a washing solution. As the cleaning liquid, a mixed solvent of 7.5 mL of acetone and 7.5 mL of water was used. The washed thiolactone compound crystals were air-dried at a temperature of 70 ° C. for 2 hours to obtain purified thiolactone compound crystals.

The amount of crystals of the purified thiolactone compound was 11.82 g, the yield of the thiolactone compound from the precipitate was 90.9%, and the yield from the lactone compound was 77.3%. When the HPLC measurement was performed under the above-mentioned conditions, the purity was 99.55%. Moreover, when the UV transmittance was measured under the above-mentioned conditions, it was 88.4%.

(Synthesis of biotin compound)
Next, the biotin compound represented by the formula (III) by the following method, that is, ethyl (3aS, 4Z, 6aR) -5- (1,3-dibenzyl-2,3,3a, 4,6,6a-hexahydro-) 2-Oxo-1H-thieno [3,4-d] imidazole-5-iriden) pentanoart was obtained. R ³ was an ethyl group (-C ₂ H ₅ ).

29.6 g (453 mmol) of zinc powder was suspended in a mixed solvent of 48 mL THF and 34 mL of toluene to give a suspension. With the suspension maintained at 26-30 ° C, 15.1 g (94.5 mmol) of bromine was added dropwise over 3.5 hours. Then, while maintaining the suspension after dropping bromine at 55 ° C., 48.4 g (189 mmol) of ethyl 5-iodovalerate was added dropwise over 1.5 hours, and the mixture was stirred at 55 ° C. for 3 hours. A first reaction solution containing the zinc reagent represented by the above formula (IV) was obtained. Then, the first reaction solution was cooled to 30 ° C., 45.1 g (135 mmol) of the thiolactone compound and 97 mL of toluene were added thereto, and then a palladium carbon (Pd / C) suspension was further added at the same temperature. Then, the mixture was stirred at the same temperature for 15 hours to obtain a second reaction solution. As the Pd / C suspension, 1.24 g (1.17 mmol) of Pd / C dispersed in 12 mL of N, N-dimethylformamide was used. The ratio of palladium to Pd / C was 10% by mass.

108 mL of 16% by mass hydrochloric acid was added to the second reaction solution at 25 ° C., the mixture was stirred at the same temperature for 1 hour, and then filtered. After adding 30 mL of 10% by mass hydrochloric acid to the obtained filtrate, the mixture was stirred at 40 ° C. for 3 hours to separate the organic layer and the aqueous layer. The extracted organic layer was washed in the order of 93 mL water, 165 mL water, 165 mL water, 165 mL 10 mass% sodium hydrogen carbonate aqueous solution, 165 mL 10 mass% sodium thiosulfate aqueous solution, and 93 mL water.

After concentrating the washed organic layer, 80 mL of toluene was added thereto for further concentration treatment. This operation was repeated to obtain a concentrated residue. The obtained concentrated residue was dissolved in 100 mL of methanol, 1.71 g of activated carbon was added to the obtained solution, and the mixture was stirred at 40 ° C. for 1 hour to obtain a third reaction solution. The third reaction solution was filtered to obtain a methanol solution of the biotin compound represented by the formula (III). The amount of the biotin compound was 54.4 g, and the yield with respect to the thiolactone compound was 90.7%.

<Example 2>
A thiolactone compound was obtained in the same manner as in Example 1 except that the amount of potassium acetate was changed to 13.7 g (0.139 mol). The amount of crystals of the obtained thiolactone compound was 11.6 g, and the yield from the lactone compound was 76%.

<Example 3>
(Synthesis of thiolactone compounds)
First, the thiolactone compound represented by the formula (II) was synthesized by the following method. R ¹ and R ² were each designated as a benzyl group.

6.58 g (0.067 mol) of potassium acetate, 12.00 g (0.038 mol) of lactone compound, and 15 mL of DMA were placed in a 100 mL four-necked flask, and the pressure was reduced and nitrogen was replaced while stirring at room temperature. Was repeated 3 times to obtain the first mixture. After raising the temperature of the first mixture to 125 ° C, 3.97 g (0.052 mol) of thioacetic acid was added in 1/15 amounts every 4 minutes and at a temperature of 125 ° C for 2 hours. Stirring gave a second mixture containing the thiolactone compound of formula (II).

(Purification of thiolactone compound)
Next, crystals of the thiolactone compound represented by the formula (II) were obtained by the following method.
After cooling the temperature of the second mixture to 40 ° C., 12 mL of DMA was added to obtain a third mixture. To this third mixture, 48 mL of water was further added over 10 minutes, and the mixture was stirred at a temperature of 25 ° C. or higher and 30 ° C. or lower for 2 hours to obtain a fourth mixture containing a precipitate of a thiolactone compound. The fourth mixture was filtered to separate the precipitate of the thiolactone compound, which was washed with a washing solution. As the cleaning liquid, a mixed solvent of 12 mL of acetone and 12 mL of water was used. The amount of the thiolactone compound precipitate after washing was 15.92 g. The washed thiolactone compound precipitate was dried in a draft at room temperature for 20 hours to obtain 11.29 g of the dried thiolactone compound. The yield of the dried thiolactone compound precipitate from the lactone compound was 89.6%.

The dried precipitate of thiolactone compound, 60 mL of acetone and 0.60 g of activated carbon were mixed, and the obtained mixture was stirred at a temperature of 60 ° C. for 1 hour. The mixture was filtered through 3.00 g of Celite® and the activated carbon was filtered off. The activated carbon filtered out was washed with a washing liquid. As the cleaning liquid, 12 mL of acetone was used. The obtained filtrate and the cleaning solution after use were mixed, and 72 mL of water was added thereto to obtain a mixed solution. Then, the mixed solution was aged at 25 ° C. for 1 hour, and then filtered to separate the solid. The filtered solid was washed with a mixed solvent of 12 mL of acetone and 12 mL of water. The washed solid was air-dried at 70 ° C. for 2 hours to obtain crystals of the thiolactone compound. The amount of crystals of the thiolactone compound was 10.01 g, and the yield was 91.0%. When the HPLC measurement was performed under the above-mentioned conditions, the purity was 99.64%.

<Comparative example 1>
First, potassium acetate and thioacetic acid were mixed to produce potassium thioacetate. This potassium thioacetate salt, the lactone compound represented by the formula (I), and N, N-dimethylacetamide (DMA) were mixed and sufficiently stirred at 125 ° C. to obtain a mixture containing the thiolactone compound. The amounts of potassium acetate salt, thioacetic acid, and lactone compound were the same as in Example 1, respectively. This mixture was purified by the same method as described in Example 1 to obtain crystals of the thiolactone compound represented by the formula (II).

The amount of crystals of the purified thiolactone compound was 10.41 g, and the yield from the lactone compound was 68.1%. When the HPLC measurement was performed under the above-mentioned conditions, the purity was 97.4%.

As is clear from the comparison between Example 1 and Comparative Example 1, in the method of adding thioacetic acid to the first mixture, potassium acetate and thioacetic acid are mixed to obtain potassium thioacetic acid, and then this and A thiolactone compound could be obtained in a higher yield than the method of reacting with a lactone compound.

Claims (4)

The lactone compound represented by the following formula (I) and the alkali metal acetate are brought into contact with each other in a first organic solvent to obtain a first mixture.
A method for producing a thiolactone compound, which comprises contacting the first mixture with a thiocarboxylic acid to obtain a second mixture containing a thiolactone compound represented by the following formula (II).

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). The method for producing a thiolactone compound according to claim 1, wherein the temperature of the first mixture is 80 ° C. or higher, and the mixture is brought into contact with the thiocarboxylic acid. The method for producing a thiolactone compound according to claim 1 or 2, wherein the amount of the alkali metal acetate with respect to 1 mol of the thiocarboxylic acid is 1 mol or more and 3 mol or less. The method for producing a thiolactone compound according to any one of claims 1 to 3, further comprising mixing the second mixture with a second organic solvent.