JP2021028314A - Method for producing thiolactone compound - Google Patents

Abstract

To provide a production method for obtaining a high-purity thiolactone compound.SOLUTION: A production method includes a process in which a liquid mixture, obtained by bringing a solution comprising a thiolactone compound of the formula and a poorly water-soluble organic solvent into contact with a cleaning liquid containing water, is controlled to have a pH of 7-8, and the compound is extracted from the liquid mixture, where R1 and R2 each denote H or a ureine protection group.SELECTED DRAWING: None

Description

The present invention relates to a novel 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 (see Patent Document 1).

In the above synthesis method, a lactone compound is synthesized by starting with a dicarboxylic acid compound through a reaction of three steps, and then a thiolactone compound is obtained by a sulfurization reaction. Next, a zinc reagent having an ethyl pentanoate group is brought into contact with this in the presence of a palladium catalyst to introduce a side chain of biotin. It is then reported that biotin can be produced through a two-step reaction.

U.S. Pat. No. 3,876,656

When the present inventors retested the above-mentioned prior art, it was confirmed that the thiolactone compound could be produced in good yield.

However, it has been found that the next step, the reaction for introducing the side chain of biotin (hereinafter, also simply referred to as the side chain introduction reaction) may be difficult to proceed.

Therefore, an object of the present invention is to provide a production method for obtaining a high-purity thiolactone compound capable of proceeding the side chain introduction reaction with good reproducibility and in a high yield.

The present inventors have made extensive studies to solve the above problems. As a result, it has been found that the above-mentioned problems can be solved by setting the solution containing the thiolactone compound in a specific pH range before producing the thiolactone compound and using it for the next reaction. That is, they have found that when a solution containing a thiolactone compound is used in the reaction of the next step (side chain introduction reaction) after setting the pH in a specific pH range, the reaction can proceed efficiently, and the present invention has been completed. ..
In addition, according to the present invention, it has been found that the yield of the thiolactone compound itself can be maintained high, and the present invention has been completed.

That is, the present invention
The following formula (I)

(In the formula, R ¹ and R ² are hydrogen atoms or urein group protecting groups, respectively, and may be the same group or different groups, respectively.) A thiolactone compound represented by (hereinafter, simply "thiolactone". A solution containing a "compound") and a poorly water-soluble organic solvent (hereinafter, also referred to as "first solution"),
Cleaning liquid containing water (hereinafter, also simply referred to as cleaning water),
After setting the pH of the mixed solution (hereinafter, also referred to as “second solution”) obtained by contacting with each other in the range of 7.0 to 8.0,
A method for producing a thiolactone compound, which comprises taking out the thiolactone compound from the mixed solution.

According to the method of the present invention, the side chain introduction reaction using the thiolactone compound proceeds in good yield while maintaining a high yield of the thiolactone compound itself. The reason for this is not clear, but according to the present invention, it is considered that the substance (toxic substance) that reduces the activity of the catalyst used for the side chain introduction reaction contained in the thiolactone compound as a raw material can be reduced. .. As a result, it is considered that the side chain introduction reaction proceeds efficiently.

In the present invention, the pH of a mixture obtained by contacting a solution containing a thiolactone compound and a poorly water-soluble organic solvent with washing water is set in the range of 7.0 to 8.0, and then the thiolactone compound is used as described above. It is characterized by being taken out from the mixed solution.

Hereinafter, the production method of the present invention will be described in detail.

(Thiolactone compound)
The thiolactone compound is a compound represented by the following formula (I).

[Explanation of ^{R 1} and R ^2]
In the formula (I), R ¹ and R ² are hydrogen atoms or urein group protecting groups, respectively. These R ¹ and R ² may be the same or different groups.

As the urein group protective group, an arylalkyl type protective group which may have a substituent is preferable, and a benzyl group, a substituted benzyl group having 8 to 10 carbon atoms having a substituent on the benzene ring, or a substituent on benzyl carbon is preferable. Examples thereof include a substituted benzyl group having 8 to 10 carbon atoms.

Examples of the substituted benzyl group having 7 to 11 carbon atoms having a substituent on the benzene ring include a 4-methylbenzyl group, a 4-methoxybenzyl group, a 4-nitrobenzyl group, a 4-aminobenzyl group, and a 4-hydroxybenzyl group. And so on. As a matter of course, the 1st position of the benzene ring is the position where _{−CH 2− is bonded.}

Examples of the substituted benzyl group having a substituent on the benzyl carbon include an α-methylbenzyl group, a benzhydryl group, a trityl group and the like.

^{Among the thiolactone compounds, both R 1} and R ² are preferably urein-protecting groups, particularly preferably benzyl groups, in consideration of efficiency of the reaction in the next step and production of the thiolactone compounds themselves. ..

The thiolactone compound can be produced by the method described in the patent document. Usually, according to the method described in the patent document, a compound having an HPLC (high performance chromatography) purity (peak area%) of about 85 to 95% can be obtained. In the present invention, a thiolactone compound having such a purity can be targeted.

The method for producing the thiolactone compound targeted in the present invention is a particularly simple method, and the thiolactone compound can be obtained in a high yield, and thus the following formula (II)

(R ¹ and R ² in the formula are synonymous with those in the formula (I).)
It is preferable to use a method in which the lactone compound represented by (hereinafter, also simply referred to as a lactone compound) and a thiocarboxylic acid alkali metal salt are brought into contact with each other.

Hereinafter, a method for obtaining a thiolactone compound by contacting a lactone compound with an alkali metal thiocarboxylic acid salt will be described.

<Method for producing thiolactone compound>
<< Production method of thiolactone compound / Lactone compound >>
The lactone compound represented by the formula (II) can be produced by a known method, that is, the method described in the patent document. Moreover, if a commercially available product exists, it can be used.

<< Production method of thiolactone compound / Alkali metal salt of thiocarboxylic acid and its production method >>
Examples of the thiocarboxylic acid alkali metal salt used in producing the thiolactone compound include thioacetate alkali metal salt (for example, sodium thioacetate, potassium thioacetate, lithium thioacetate, etc.), ammonium thioacetate, and thiobenzoic acid alkali metal salt (for example). , Sodium thiobenzoate, potassium thiobenzoate, lithium thiobenzoate, etc.), ammonium thiobenzoate and the like.

Commercially available commercially available thiocarboxylic acid alkali metal salts may be used.

Alternatively, the corresponding thiocarboxylic acid can be reacted with a basic alkali metal salt (for example, alkali metal hydroxide salt, alkali metal carbonate salt, alkali metal acetate) to produce a thiocarboxylic acid alkali metal salt, which can also be used. good. When a reaction of a thiocarboxylic acid and a basic alkali metal salt is used, the thiocarboxylic acid alkali metal salt obtained outside the reaction system can be taken out and used. Above all, in consideration of continuous reaction, it is preferable to use a thiocarboxylic acid alkali metal salt obtained by reacting a thiocarboxylic acid with a basic alkali metal salt without taking it out of the reaction system.

When the thiocarboxylic acid alkali metal salt obtained without taking it out of the reaction system is used, it is preferable to produce the thiocarboxylic acid alkali metal salt by the following method. Specifically, it is preferable to use 1 to 2 mol of the thiocarboxylic acid, more preferably 1 to 1.4 mol, and 1.1 to 1.25 mol with respect to 1 mol of the basic alkali metal salt. It is more preferred to use. Since the obtained thiocarboxylic acid alkali metal salt is unstable, it is preferable to use more thiocarboxylic acid than the basic alkali metal salt.

When the thiocarboxylic acid and the basic alkali metal salt are reacted, the reaction proceeds by stirring and mixing the two in a reaction solvent. The reaction solvent used for reacting the two (hereinafter, also referred to as the first reaction solvent) is not particularly limited as long as it sufficiently dissolves the two. Specifically, amides (eg, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA)), N-methyl-2-pyrrolidone (NMP), N, N-dimethylimidazolidine- 2-On (DMI) can be used. Among them, amides, particularly N, N-dimethylacetamide (DMA), are preferably used from the viewpoint of solubility of basic alkali metal salts and thiocarboxylic acid alkali metal salts and stability to them. When both are mixed, it is preferable to add thiocarboxylic acid to the basic alkali metal salt, although it is not particularly limited. The amount of the first reaction solvent used may be appropriately determined in consideration of the volume of the reaction vessel and the like, but is usually 0.5 to 10 parts by mass, preferably 1 to 5 parts by mass with respect to 1 part by mass of the lactone compound. It may be used within the range of.

The reaction temperature for producing the alkali metal thiocarboxylic acid salt is usually in the temperature range of 0 to 50 ° C., preferably 5 to 40 ° C., particularly preferably 10 to 30 ° C. The reaction time is not particularly limited and may be appropriately determined according to the performance of the reactor, but is 0.5 to 4 hours, preferably 0.5 to 3 hours, particularly preferably 0.5 to 2. The time range is sufficient.

The present inventors presume as one factor that causes the effect of the present invention as follows. That is, a sulfur compound such as thiocarboxylic acid used in producing this unstable thiocarboxylic acid alkali metal salt is contained in the thiocarboxylic acid alkali metal salt, and it is used in the reaction of the next step (side chain introduction reaction). It is presumed that it will be a substance (toxic substance) that reduces the activity of the catalyst. Then, when a thiolactone compound is produced by reacting a thiocarboxylic acid alkali metal salt with a lactone compound, the pH of the reaction system containing them is set to 7.0 to 8.0 to remove toxic substances. , It is presumed that the decomposition of thiolactone compounds can be suppressed.

In the present invention, it is considered that the effect is exhibited by the above action mechanism. Therefore, even when a commercially available thiocarboxylic acid alkali metal salt (the thiocarboxylic acid alkali metal salt once taken out of the reaction system) is used, the effect is exhibited. That is, even in the reaction using a commercially available alkali metal thiocarboxylic acid salt, there is a possibility that the reaction solution contains a substance that becomes a toxic substance. In this case, the effect is surely obtained by carrying out the present invention. Is demonstrated.

In the reaction between the thiocarboxylic acid alkali metal salt and the lactone compound, the amount of the thiocarboxylic acid alkali metal salt used may be a sufficient amount for the lactone compound to react. Specifically, it may be used in the range of 1 to 3 mol, preferably 1 to 2 mol, and particularly preferably 1 to 1.8 mol with respect to 1 mol of the lactone compound. When the thiocarboxylic acid alkali metal salt is used without being taken out of the reaction system, the raw material used in a small amount may be used as a reference in the reaction between the thiocarboxylic acid and the basic alkali metal salt. That is, in the production of the thiocarboxylic acid alkali metal salt, the case where the amount of the basic alkali metal salt used is small is the most preferable embodiment, but in this case, the amount of the thiocarboxylic acid alkali metal salt is the amount of the basic alkali metal salt. You can think of it as the same as the quantity.

<< Production of thiolactone compound / Reaction solvent >>
In order to facilitate the contact between the lactone compound and the alkali metal thiocarboxylic acid salt, it is preferable to use a reaction solvent (hereinafter, also referred to as a second reaction solvent) in both reactions.

The second reaction solvent is not particularly limited. Specifically, ethers (eg, t-butylmethyl ether (TBME)), aromatics (eg, chlorobenzene, toluene, xylene), amides (eg, N, N-dimethylformamide (DMF), N, Reaction solvents such as N-dimethylacetamide (DMA)), N-methyl-2-pyrrolidone (NMP), N, N-dimethylimidazolidine-one (DMI) and the like can be mentioned. These reaction solvents may be used alone or as a mixed solvent of the above reaction solvents. Among such reaction solvents, a mixed solvent of amides and aromatics is preferable, and a mixed solvent of N, N-dimethylacetamide (DMA) and toluene is particularly preferable. By using a reaction solvent in which such a reaction solvent having high solubility of the alkali metal thiocarboxylic acid salt and a reaction solvent capable of satisfactorily proceeding the reaction between the alkali metal thiocarboxylic acid metal salt and the lactone compound are used, thiolactone The compound can be obtained in good yield. When the thiocarboxylic acid alkali metal salt is used without being taken out of the reaction system, an aromatic such as toluene is mixed with the first reaction solvent used in the production of the thiocarboxylic acid alkali metal salt for the second reaction. It can be a solvent. The second reaction solvent may also contain water. In the second reaction solvent, the ones specifically listed among the poorly water-soluble organic solvents described in detail below correspond to the poorly water-soluble organic solvents used in the present invention.

The amount of the second reaction solvent to be used may be appropriately determined in consideration of the volume of the reaction vessel and the like, but is usually 0.5 to 100 parts by mass, preferably 1 to 10 parts by mass with respect to 1 part by mass of the lactone compound. , Particularly preferably, it may be used in the range of 1 to 3 parts by mass. When the mixed solvent is used, the ratio of each solvent constituting the mixed solvent cannot be unconditionally determined because it depends on the type of the solvent. In the case of a mixed solvent of amides and aromatics, amides: aromatics = 5 to 1: 1 (volume ratio) is preferable.

<< Production of thiolactone compound / Contact between lactone compound and thiocarboxylic acid alkali metal salt >>
The method of contacting the lactone compound with the alkali metal salt of thiocarboxylic acid is not particularly limited, and may be appropriately determined in consideration of the configuration of the manufacturing apparatus and the like. Specifically, the alkali metal thiocarboxylic acid salt can be dispersed in a reaction solvent (second reaction solvent) and then mixed with a lactone compound. Alternatively, the lactone compound may be dispersed in a reaction solvent (second reaction solvent) and then mixed with a thiocarboxylic acid alkali metal salt. When the thiocarboxylic acid alkali metal salt is used without being taken out of the reaction system, a solution obtained by mixing the thiocarboxylic acid and the alkali metal salt in a reaction solvent (first reaction solvent) may be used.

The above reaction is preferably carried out under reflux conditions while removing water from the reaction system. Therefore, the reaction temperature cannot be unconditionally determined because it depends on the boiling point of the reaction solvent (second reaction solvent). In the case of a mixed solvent of amides and aromatics, 110 to 140 ° C. is preferable. It should be noted that this water is the water contained in the second reaction solvent before the reaction, the water generated during the reaction, and more importantly, the water in which the thiolactone compound of the product is ring-opened. It is considered to be water generated when the ring is closed. The method of draining water is not particularly limited, and examples thereof include a method using a Dean-Stark apparatus.

The reaction time is preferably set in the range of 0.5 to 5 hours, preferably 0.3 to 3 hours, and particularly preferably 0.5 to 2 hours.

The pressure during the reaction is also not particularly limited. Specifically, the reaction may be carried out under any of atmospheric pressure, reduced pressure, and pressurized pressure. Considering operability, it is preferable to carry out under atmospheric pressure. Further, the atmosphere at the time of reaction is not particularly limited. Specifically, it can be carried out in an air atmosphere or an inert gas (nitrogen, argon, etc.) atmosphere. Considering the stable progress of the reaction, it is preferable to carry out the reaction in an inert gas atmosphere, particularly in a nitrogen atmosphere.

After completion of the reaction between the lactone compound and the alkali metal thiocarboxylic acid salt, crystals of the thiolactone compound can be precipitated by mixing the obtained reaction solution with water. The amount of water to be added is not particularly limited as long as the obtained thiolactone compound can be sufficiently precipitated. Specifically, it is preferable to mix 2 to 8 mL of water with 1 g of the lactone, and it is preferable to mix 4 to 6 mL of water. (If the solvent already contains water at the time of the reaction, it is preferable that the total amount of the contained water and the newly mixed water satisfies the above range). The amount of the water is preferably 1 to 5 mL of water mixed with 1 mL of the reaction solvent (second reaction solvent), and preferably 1.5 to 4 mL of water. The precipitated thiolactone compound may be isolated by a known method. When the isolated thiolactone compound is used, the obtained thiolactone compound and the poorly water-soluble organic solvent described in detail below are mixed to obtain a solution containing the thiolactone compound and the poorly water-soluble organic solvent. Can be done.

As described above, the thiolactone compound can be once taken out of the reaction system (separated from the solvent), but it should be used in the next step without being isolated (while still dissolved in the solvent). Is preferable. In order to do so, a method of using a poorly water-soluble organic solvent as a reaction solvent when producing a thiolactone compound, or a method of mixing the reaction system (solution) with the poorly water-soluble organic solvent after the reaction is completed can be mentioned. Be done. Further, as a matter of course, a water-soluble organic solvent can be used as the reaction solvent, and a poorly water-soluble organic solvent can be further mixed in the reaction system. By doing so, the solution containing the thiolactone compound and the poorly water-soluble organic solvent can be obtained without isolating the thiolactone compound, and can be used in the next step.

As described above, the thiolactone compound obtained by such a method has an HPLC purity of about 85 to 95%.

In the present invention, the solution containing the thiolactone compound and the poorly water-soluble organic solvent obtained by the above method and the cleaning solution containing water can be brought into contact with each other. However, since the thiolactone compound may contain a ring-opened compound, the following treatment is preferable.

<< Production of thiolactone compounds / other treatments (acid treatment / dehydration treatment) >>
According to the present invention, in order to increase the yield of the thiolactone compound, it is preferable to treat it by the following method. Specifically, it is preferable to perform the following acid treatment / dehydration treatment. By such treatment, it is presumed that the ring-opened thiolactone compound is cyclized again to return to the thiolactone compound, and the yield can be improved.

First, as an acid treatment, a solution containing a thiolactone compound and a poorly water-soluble organic solvent is brought into contact with an acid (hereinafter, as described above, the solution to be brought into contact with an acid may be used as the first solution). In this case, the concentration of the first solution may be 10 to 50 parts by mass for a reaction solvent other than the poorly water-soluble organic solvent and 80 to 120 parts by mass for water with respect to 100 parts by mass of the poorly water-soluble organic solvent. It is preferable that the reaction solvent is 20 to 40 parts by mass and water is 90 to 110 parts by mass. In this case, the total solvent (including water when water is contained) is preferably 5 to 15 and the total solvent is 8 to 13 with respect to 1 part by mass of the solid content containing the thiolactone compound. Is more preferable. If necessary, a poorly water-soluble organic solvent, water, and other organic solvents can be added to the reaction system so as to satisfy such a range. In addition, you may make contact with activated carbon before contacting with acid.

It is preferable that the pH of the first mixed solution obtained by mixing the first solution and the acid is in the range of 0 to 2. The pH of the first solution is usually less than 5 to 7, although it depends on the amount of the thiocarboxylic acid alkali metal salt and the solvent used. By mixing the first solution and the acid, it is preferable that the pH of the first solution is in the range of 0 to 2 (the first solution having a pH of 0 to 2 may be used as the first mixed solution). ).

The acid used is not particularly limited, and among the acids such as hydrogen chloride and sulfuric acid, hydrogen chloride (hydrochloric acid) is preferably used. When an acid containing water such as hydrochloric acid is used, the pH of the first mixed solution in which both are stirred and mixed is preferably in the range of 0 to 2. When the stirring and mixing is stopped and allowed to stand, the first mixed solution is separated into an organic layer and an aqueous layer. In this case, the pH range of the aqueous layer is preferably in the range of 0 to 2.

The temperature of this first mixed solution is preferably 50 to 80 ° C. in order to increase the yield of the thiolactone compound. Therefore, the pH of the first mixture at 50 to 80 ° C. is preferably 0 to 2. The pH is measured by the method described in detail below. In order to set the temperature of the first mixed solution to 50 to 80 ° C., the temperatures of the first mixed solution and the acid can be adjusted in advance, or after the first mixed solution is prepared, the temperature is set to 50 to 80. It can also be ° C. The time of 50 to 80 ° C. is not particularly limited, and may be 0.2 to 1 hour.

Then, the poorly water-soluble organic solvent layer is taken out by separating the obtained first mixed solution. Water is removed from the reaction system while refluxing the obtained poorly water-soluble organic solvent layer at the reflux temperature. The time required for removing water is not particularly limited, but is preferably 0.5 to 5 hours.

It is considered that the yield of the thiolactone compound is improved by performing the above operation. Then, in the present invention, the solution after removing water can be used as a solution (first solution) containing a thiolactone compound and a poorly water-soluble organic solvent, which is brought into contact with a cleaning solution containing water described in detail below. preferable.

Next, a step of bringing the solution (first solution) into contact with a cleaning solution containing water to prepare a mixed solution will be described.

<Step of preparing a mixed solution having a pH of 7.0 to 8.0>
It is preferable to prepare a solution (first solution) containing the thiolactone compound and the poorly water-soluble organic solvent by the method as described above. First, as described above, the poorly water-soluble organic solvent in the present invention will be described.

(Slightly water-soluble organic solvent)
In the present invention, the poorly water-soluble organic solvent is used to dissolve the thiolactone compound, bring the obtained solution into contact with a cleaning solution described later, and extract and remove the water-soluble substance contained in the solution into the cleaning solution. .. Here, "slightly water-soluble" means that the solubility in 100 g of water at a temperature of 20 ° C. is 7 g or less.

The poorly water-soluble organic solvent is not particularly limited as long as it dissolves the thiolactone compound. Therefore, a known organic solvent can be used. Examples of such an organic solvent include aliphatic hydrocarbons, aromatic hydrocarbons, ethers, halogenated hydrocarbons and the like.

Examples of the aliphatic hydrocarbons include hexane (solubility:> 0.2 g) and the like.

Examples of aromatic hydrocarbons include benzene (solubility:> 0.2 g) and toluene (solubility:> 0.2 g).

Examples of ethers include diethyl ether (solubility: 6.9 g) and the like.

Examples of the halogenated hydrocarbons include dichloromethane (solubility: 1.3 g), chloroform (solubility: 0.8 g) 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 amount of these poorly water-soluble organic solvents used is not particularly limited. Above all, in order to sufficiently dissolve the thiolactone compound, it is preferable to use 1 to 100 ml of a poorly water-soluble organic solvent with respect to 1 g of the thiolactone compound. If the first solution satisfies the above concentration range, it can be directly mixed with a cleaning solution containing water. If the concentration range is not satisfied, the concentration may be adjusted by concentrating or adding a poorly water-soluble organic solvent before contacting with a cleaning solution containing water.

(Solution containing thiolactone compound and poorly water-soluble organic solvent; first solution)
The first solution is not particularly limited as long as it contains a thiolactone compound and a poorly water-soluble organic solvent. Therefore, for example, it may be a reaction solution obtained by producing a thiolactone compound. However, in this case, the solvent used for producing the thiolactone is selected from the poorly water-soluble organic solvent.

Further, it may be a solution capable of isolating the thiolactone compound once after producing the thiolactone compound and bringing the thiolactone compound into contact with a poorly water-soluble organic solvent.

Further, when the solvent used for the solvent used for producing the thiolactone is a water-soluble organic solvent, it may be a solution obtained by mixing the reaction solution obtained after the reaction and the poorly water-soluble organic solvent. The poorly water-soluble organic solvent used at this time is not particularly limited as long as it is selected from the poorly water-soluble organic solvents.

Most preferred is a solution obtained by producing a thiolactone compound and then subjecting it to acid treatment and dehydration treatment as described above.

(Cleaning solution containing water; cleaning solution)
The cleaning solution used in the present invention is not particularly limited as long as it is an aqueous solution in which the pH of the mixed solution described later is in the range of 7.0 to 8.0. Above all, it is preferable to use an alkaline aqueous solution having a pH in the range of 7.0 to 8.0. When an alkaline aqueous solution is used, a normal commercially available product can be used. Alternatively, prepare by dissolving a basic alkali metal salt (for example, a strongly basic alkali metal salt such as sodium hydroxide or potassium hydroxide, or a weak basic alkali metal salt such as sodium hydrogen carbonate or potassium hydrogen carbonate) in water. You can also.

The amount of these cleaning solutions used depends on the concentration of the alkaline aqueous solution, the type of the basic alkali metal salt, etc., and cannot be unconditionally determined. However, as a guide, a 5 wt% sodium hydrogen carbonate aqueous solution, 0. It is preferably 1 to 50 parts by volume, preferably 1 to 4 parts by volume.

(Mixed solution obtained by contacting the first solution and washing water; second solution)
In the present invention, the method of bringing the first solution into contact with the washing water is not particularly limited, and the first solution can be brought into contact with each other by stirring and mixing them in a reaction vessel equipped with a stirrer.

The greatest feature of the present invention is that the pH of the mixed solution (second solution) obtained by bringing the first solution into contact with the washing water is in the range of 7.0 to 8.0. This pH value is a value measured by immersing the electrode in a mixture in which the first solution and the washing water are stirred and mixed, and using a general method for measuring pH. When the stirring and mixing is temporarily stopped and allowed to stand, the second solution is separated into an organic layer and an aqueous layer. However, even if the electrode is immersed in the separated aqueous layer and the pH is measured, 7. It is preferably in the range of 0 to 8.0.

If the pH is less than 7.0, the side chain introduction reaction will not proceed easily. The reason for this is not clear, but it is presumed that the cause is that the component that becomes the toxic substance of the side chain introduction reaction remains. On the other hand, when the pH exceeds 8.0, the thiolactone ring is opened and the yield of the thiolactone compound taken out from the mixed solution is lowered.

When the pH of the second solution is in the range of 7.0 to 8.0, the thiolactone compound can be taken out as it is. If the pH is not in the range of 7.0 to 8.0, specifically, if the pH is less than 7.0, an alkaline aqueous solution is further added to adjust the pH. As described above, if the pH exceeds 8.0, the yield of the thiolactone compound decreases. Therefore, it is necessary to adjust the pH while checking the pH so that the pH does not exceed 8.0 during the adjustment of the pH. ..

Although not particularly limited, the mixed solution (second solution) having a pH of 7.0 to 8.0 is preferably in the temperature range of 50 to 80 ° C. In order to make the temperature range, the first solution and the cleaning solution whose temperatures are adjusted in advance so that the second solution being mixed may satisfy the temperature range may be mixed. Further, the temperature of the second solution obtained by mixing the two may be 50 to 80 ° C. Even in the second solution in the temperature range of 50 to 80 ° C., the pH needs to satisfy 7.0 to 8.0.

The time for contacting the organic solution with the washing water (time for stirring the mixed solution) is not particularly limited. Usually, it is 0.1 to 2 hours, preferably 0.3 to 0.5 hours.

(Removal of thiolactone compound)
The mixed solution (second solution) having a pH in the range of 7.0 to 8.0 according to the above method is then preferably treated as follows to take out the thiolactone compound.

That is, after the liquid is separated to obtain an organic layer (water-insoluble organic solvent layer), the organic layer may be treated with activated carbon, if necessary. Alternatively, the organic layer may be concentrated under reduced pressure, the obtained residue and a solvent may be mixed, and the obtained solution may be treated with activated carbon. The method of the activated carbon treatment is not particularly limited. Therefore, the treatment can be performed by bringing the organic layer (the solution) into contact with activated carbon.

The solvent to be mixed with the residue is not particularly limited as long as it dissolves the residue. Therefore, an organic solvent having a boiling point of 85 ° C. or higher is preferable, and aliphatics and alcohols having a boiling point of 85 ° C. or higher are more preferable. Specifically, toluene and 2-butanol are preferably used. The amount of the solvent used depends on the type of solvent and cannot be unconditionally determined. 2-Butanol may be used in the range of 80 to 150 parts by volume with respect to 1 g of the residue.

The treatment temperature (the temperature at which the organic layer (the solution) is brought into contact with the activated carbon) is preferably in the temperature range of 50 to 100 ° C., preferably 70 to 90 ° C.

The treatment time (time for contacting the organic layer (the solution) with the activated carbon) is preferably 0.2 to 3 hours, preferably 0.5 to 2 hours.

As a preferable method for taking out the thiolactone compound, the organic layer is concentrated under reduced pressure, the obtained residue and 2-butanol are mixed and heated to about 70 to 90 ° C. to dissolve the residue. Examples thereof include a method in which the obtained solution and activated carbon are mixed, stirred at the same temperature for about 0.5 to 2 hours, and the activated carbon is filtered off to obtain a filtrate.

Since this activated carbon treatment is not essential, the thiolactone compound described in detail below can be crystallized in the organic layer (solution) without being mixed with activated carbon.

After the activated carbon treatment, the organic layer (the filtrate) is cooled to crystallize the thiolactone compound, and the thiolactone compound in the crystals can be taken out. The cooling temperature is not particularly limited, but is preferably in the range of 3 to 25 ° C. in order to further increase the purity of the thiolactone compound. It is preferable to concentrate the organic layer (the filtrate) under reduced pressure before crystallization in order to increase the yield of the thiolactone compound by crystallization. Preferably, the thiolactone compound is crystallized from an organic layer (the filtrate) containing 5 to 10 g of an organic solvent with respect to 1 g of thiolactone.

By performing the above method, the thiolactone compound obtained by the present invention can be suitably used as a raw material to be used in the following method for producing a biotin derivative.

(Method for producing biotin derivative)
The thiolactone compound uses it as a raw material and has the following formula (IV).

(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 (III).)
The biotin derivative represented by is can be effectively produced.

As a method for producing a biotin derivative from the thiolactone compound, a known method can be adopted. For example, in the presence of at least one catalyst selected from a palladium catalyst and a nickel catalyst, the thiolactone compound and the following formula (III)

(In the formula, R ³ is an alkyl group or an aralkyl group.)
A method using a zinc reagent represented by (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.

The evaluation in Examples and Comparative Examples was carried out by the following method.
<Measurement conditions for high performance liquid chromatography (HPLC)>
Equipment: High Performance Liquid Chromatography (HPLC).
Detector: Ultraviolet absorptiometer (measurement wavelength: 254 nm).
Column, packing material: L-volume, C18, 5 μm (4.6 × 150 mm);
X Bridge, C18, 5 μm (4.8 mm x 150 mm)
Column temperature: 40 ° C.
Mobile phase: Acetonitrile: 50 mM KH ₂ PO ₄ aqueous solution (pH 3) = 50:50
Flow velocity: 1.0 mL / min.

Under the above HPLC measurement conditions, peaks are confirmed at about 6.9 minutes for the lactone compound, about 9.1 minutes for the thiolactone compound, and about 30.5 minutes for the biotin derivative.

In the following Examples and Comparative Examples, the purity values of the lactone compound, the thiolactone compound, and the biotin derivative are all the area values of all peaks measured according to the above HPLC measurement conditions (excluding the peaks derived from the solvent). It is a value obtained from the ratio of the peak area value of each compound to the total of.
<Measurement conditions for transmittance>
A tetrahydrofuran solution containing 0.5 wt% of the obtained thiolactone compound was placed in a quartz cell, and the transmittance was measured at a wavelength of 290 nm.

(Manufacturing Example 1)
<Manufacturing of thiolactone compounds>
The reaction represented by the following formula was carried out to synthesize a thiolactone compound.

<< Production of Potassium Thiocarboxylate >>
95.5% potassium hydroxide (12.8 g, 229 mmol; basic alkali metal salt) was dissolved in N, N-dimethylacetamide (81 mL; first reaction solvent) at 20 to 30 ° C. under a nitrogen atmosphere. Thioacetic acid (19.7 g, 258 mmol; thiocarboxylic acid) was added dropwise thereto over 20 minutes so as to maintain the above temperature, and the mixture was further stirred at the same temperature for 30 minutes.

<< Production of thiolactone compounds >>
Toluene (27 mL) was added to the reaction solution obtained in the above << Production of Potassium Thiocarboxylate >> (at this time, the reaction solvent was a mixture of N, N-dimethylacetamide (81 mL) and toluene (27 mL). Solvent (108 mL; second reaction solvent). Then, a lactone compound (53.7 g, 166 mmol) was added, and the mixture was stirred at 125 ° C. for 3 hours. At this time, stirring was performed while separating and removing water contained in the reaction system with a Dean-Stark apparatus.

The reaction mixture was cooled to 65 ° C., and toluene (268 mL) and water (268 mL) were added while maintaining the same temperature.

<< Acid treatment after production of thiolactone compound >>
The pH of the reaction solution obtained in << Production of Thiolactone Compound >> was adjusted to 1.1 by adding 37% hydrochloric acid (25 g) at 65 ° C. This reaction solution was transferred to a separating funnel to separate the aqueous layer. The organic layer was stirred under reflux (110 ° C.) with a Dean-Stark apparatus for 1 hour while removing water contained in the reaction system. Then, it cooled to 65 degreeC, and obtained the solution containing the thiolactone compound and the poorly water-soluble organic solvent (toluene).

(Example 1)
<Get the second solution by contacting the solution with the cleaning solution>
In a solution (pH 1.1) containing the thiolactone compound and the poorly water-soluble organic solvent obtained in <Acid treatment after production of the thiolactone compound> of Production Example 1, 5% sodium bicarbonate solution (134 mL) at the same temperature (65 ° C.). Was added over 30 minutes. While adding the 5% aqueous sodium hydrogen carbonate, it was confirmed that the pH of the mixed solution did not exceed 8.0. The pH when the total amount of the above 5% sodium bicarbonate solution was added was 7.3.

<Removal of thiolactone compound>
The mixed solution (second solution) having a pH of 7.3 obtained in the above <contacting the solution with the washing solution to obtain a second solution> was transferred to a separating funnel to separate and remove the aqueous layer, and obtained. The organic layer was washed with water (50 mL) while maintaining 65 ° C., and then the organic layer was concentrated under reduced pressure.

2-Butanol (671 ml) was added to the obtained residue, and the mixture was heated to 80 ° C. to dissolve it. Activated carbon (2.7 g) was added to this solution, and the mixture was stirred at the same temperature for 1 hour and then filtered to obtain a filtrate. At this time, the filtrate adhering to the activated carbon was washed away with 2-butanol (54 mL, 80 ° C.), and the washed-out filtrate was mixed with the above filtrate to obtain a 2-butanol solution (hereinafter, the residue). From the addition of 2-butanol to the above-mentioned 2-butanol solution is also referred to as activated carbon treatment).

The obtained 2-butanol solution was concentrated under reduced pressure (weight after concentration was 376 g), and then the obtained concentrated solution was heated to 90 ° C. to dissolve it. Then, the solution was cooled to 25 ° C. for 2 hours, cooled to 25 ° C. for 2 hours, further cooled to 6 ° C. for 1 hour, and then stirred at 6 ° C. for 4 hours. The precipitated solid was filtered off, washed with 2-butanol (54 ml, 6 ° C.), and air-dried (80 ° C., 15 hours) to obtain a thiolactone compound (45.1 g, yield: 80%) ( Hereinafter, the process from concentrating the 2-butanol solution obtained by the activated charcoal treatment under reduced pressure to obtaining the thiolactone compound is also referred to as recrystallization treatment). The transmittance of the tetrahydrofuran solution containing the thiolactone compound was 99.1%.

<Production of biotin derivative (side chain introduction reaction)>
Zinc powder (29.6 g, 453 mmol) was suspended in a mixture of tetrahydrofuran (48 mL) and toluene (34 mL). Then, bromine (15.1 g, 94.5 mmol) was added dropwise over 3.5 hours so as to maintain 26 to 30 ° C. The obtained solution was heated to 55 ° C., and ethyl 5-iodovalerate (48.4 g, 189 mmol) was added dropwise over 1.5 hours so as to maintain the same temperature. The obtained solution was stirred at the same temperature for 3 hours and then cooled to 30 ° C. Then, at the same temperature, N, of the thiolactone compound (45.1 g, 135 mmol), toluene (97 mL), and 10% Pd / C (1.24 g, 1.17 mmol) obtained in the above <Removal of thiolactone compound>. A suspension of N-dimethylformamide (12 mL) was added and stirred. As a result of confirming the reaction conversion rate by HPLC after stirring for 2 hours, it was confirmed that the biotin derivative was formed by> 99%. The mixture was further stirred at the same temperature for 13 hours.

After stirring for a total of 15 hours, 16% hydrochloric acid (108 mL) was added to the obtained reaction solution at 25 ° C., and the mixture was stirred at the same temperature for 1 hour and then filtered. After adding 10% hydrochloric acid (30 mL) to the obtained filtrate, the mixture was stirred at 40 ° C. for 3 hours. After stirring, the mixture was allowed to stand and separated into two layers, an aqueous layer and an organic layer, and the aqueous layer was removed. The obtained organic layer was prepared in the order of water (93 mL), water (165 mL), water (165 mL), 10% aqueous sodium hydrogen carbonate solution (165 mL), 10% aqueous sodium thiosulfate solution (165 mL), and water (93 mL). Washed.

After concentrating the organic layer, toluene (80 mL) was added to concentrate, and the same operation was performed again. The obtained concentrated residue was dissolved in methanol (100 mL), activated carbon (1.71 g) was added, and the mixture was stirred at 40 ° C. for 1 hour. The reaction solution was filtered to obtain a methanol solution of a biotin derivative (54.4 g, yield (based on thiolactone compound): 90.7%).

(Example 2)
In the activated carbon treatment of <Removal of thiolactone compound> of Example 1, toluene was used instead of 2-butanol.

Further, in the recrystallization treatment of <Removal of thiolactone compound> of Example 1, toluene was used instead of 2-butanol.

Other than these, the same operation as in Example 1 was carried out to obtain a thiolactone compound (33.8 g, yield: 60%).

The transmittance of the tetrahydrofuran solution containing the thiolactone compound was 100%.

Using the obtained thiolactone compound (30 g, 89.8 mmol), the same procedure as in <Production of biotin derivative (side chain introduction reaction)> of Example 1 was carried out, and the biotin derivative (36.2, yield (thiolactone). Compound standard): 90.7%) methanol solution was obtained.

(Example 3)
In <Removal of thiolactone compound> of Example 2, the same operation as in Example 1 was carried out except that the organic layer after washing with water was concentrated under reduced pressure to 376 g without performing the activated carbon treatment, and the thiolactone compound (46. 8 g, yield: 83%) was obtained.

The transmittance of the tetrahydrofuran solution containing the thiolactone compound was 92.4%.

Using the obtained thiolactone compound (45.1 g, 135 mmol), the same operation as in <Production of biotin derivative (side chain introduction reaction)> of Example 1 was carried out, but the reaction conversion rate after stirring for 2 hours was high. It was confirmed that it was about 60%.

A 10% Pd / C (0.18 g, 0.167 mmol) N, N-dimethylformamide (1.7 mL) suspension was added to this solution having a reaction conversion rate of about 60%, and the mixture was stirred at the same temperature for 15 hours. Then, it was confirmed that the biotin derivative was formed> 99%.

(Comparative Example 1)
A solution containing the thiolactone compound and the poorly water-soluble organic solvent obtained in <Acid treatment after production of thiolactone compound> in Production Example 1 in <Getting a second solution by contacting the solution with the washing solution> in Example 1. 5% sodium bicarbonate solution (110 mL) was added to (pH 1.1), and the pH when the total amount of the 5% aqueous sodium bicarbonate solution was added was set to 6.5.

Further, in the activated carbon treatment of <Removal of thiolactone compound> of Example 1, toluene was used instead of 2-butanol.

Then, in the recrystallization treatment of <Removal of thiolactone compound> of Example 1, toluene was used instead of 2-butanol.

Other than these, the same operation as in Example 1 was carried out to obtain a thiolactone compound (33.8 g, yield: 60%).

The transmittance of the tetrahydrofuran solution containing the thiolactone compound was 65%.

Using the obtained thiolactone compound (30 g, 89.8 mmol), the side chain introduction reaction was carried out in the same manner as in Example 1, but it was confirmed that the reaction did not proceed at all after stirring for 2 hours.

A suspension of 10% Pd / C (1.24 g, 1.17 mmol) of N, N-dimethylformamide (12 mL) was added to the solution in which this reaction did not proceed, and the mixture was stirred at the same temperature for 15 hours. The reaction proceeded (reaction conversion rate 60%))
(Comparative Example 2)
A solution containing the thiolactone compound and the poorly water-soluble organic solvent obtained in <Acid treatment after production of thiolactone compound> in Production Example 1 in <Getting a second solution by contacting the solution with the washing solution> in Example 1. To (pH 1.1) was added 5% aqueous sodium bicarbonate solution (150 mL) over 30 minutes. While the 5% aqueous sodium hydrogen carbonate was being added, the pH of the second solution exceeded 8.0, but the pH was 8.4 when the addition was continued and the total amount of the above 5% aqueous sodium hydrogen carbonate was added.

Further, in the activated carbon treatment of <Removal of thiolactone compound> of Example 1, toluene was used instead of 2-butanol.

Then, in the recrystallization treatment of <Removal of thiolactone compound> of Example 1, toluene was used instead of 2-butanol.

Other than these, the same procedure as in Example 1 was carried out to obtain a thiolactone compound (27.4 g, yield: 48%).

The transmittance of the tetrahydrofuran solution containing the thiolactone compound was 99%.

Using the obtained thiolactone compound (25 g), the side chain introduction reaction was carried out in the same manner as in Example 1 for 2 hours, and as a result, it was confirmed that the reaction conversion rate was> 99%.

After further stirring at the same temperature for 13 hours, the same operation as in Example 1 was carried out to obtain a methanol solution of a biotin derivative (30.6 g, yield (based on thiolactone compound): 92%).

Comparing Example 2 and Comparative Example 2, in Comparative Example 2 in which the pH of the second solution exceeded 8.0, the side chain introduction reaction using the obtained thiolactone compound proceeded in good yield, but thiolactone. It can be seen that the yield of the compound itself is decreasing.

Claims (6)

The following formula (I)

(In the formula, R ¹ and R ² are hydrogen atoms or urein protecting groups, respectively, and may be the same or different groups.) A thiolactone compound represented by the above, and a poorly water-soluble organic solvent. With a solution containing
After setting the pH of the mixed solution obtained by contacting the cleaning solution containing water with the cleaning solution in the range of 7.0 to 8.0,
A method for producing a thiolactone compound, which comprises taking out the thiolactone compound from the mixed solution. The method for producing a thiolactone compound according to claim 1, wherein the temperature of the mixed solution having a pH in the range of 7.0 to 8.0 is set to 50 to 80 ° C., and then the thiolactone compound is taken out from the mixed solution. The thiolactone compound contained in the mixed solution is
Under an inert gas atmosphere
The following formula (II)

(R ¹ and R ² in the formula are synonymous with those in the formula (I).)
The lactone compound indicated by, the thiocarboxylic acid alkali metal salt, and
It was obtained by contacting
The method for producing a thiolactone compound according to claim 1 or 2. The thiocarboxylic acid alkali metal salt is obtained by reacting a thiocarboxylic acid with an alkali metal salt.
The method for producing a thiolactone compound according to claim 3. The solution containing the thiolactone compound and the poorly water-soluble organic solvent before contact with the cleaning solution
By mixing the first solution containing the thiolactone compound and the poorly water-soluble organic solvent with the acid, the pH of the first solution was adjusted to the range of 0 to 2, and then
The method for producing a thiolactone compound according to any one of claims 1 to 4, which is obtained by heating the first solution having a pH in the range of 0 to 2 to a reflux temperature and dehydrating it. After producing the thiolactone compound by performing the method for producing the thiolactone compound according to any one of claims 1 to 5,
In the presence of at least one catalyst selected from palladium and nickel catalysts
With the obtained thiolactone compound
The following formula (III)

(In the formula, R ³ is an alkyl group or an aralkyl group.)
With the zinc reagent represented by
In contact with
The following formula (IV)

(In the formula, R ¹ and R ² are synonymous with those in the formula (I), and R ³ is synonymous with those in the formula (III).)
A method for producing a biotin derivative represented by.