Method for producing thiolactone compounds

Abstract

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

Description

[Technical field]

[0001] The present invention relates to a method for producing a thiolactone compound. [Background technology]

[0002] Thiolactone compounds are compounds in which the oxygen atom forming the ring of a lactone compound (a cyclic ester) is replaced with a sulfur atom. Thiolactone compounds are important compounds as synthetic intermediates for various useful compounds including medicines, foods, and cosmetics.

[0003] As one of the synthesis methods utilizing a thiolactone compound as a synthetic intermediate, the following method for producing biotin is known (Non-Patent Document 1): Biotin is a type of water-soluble vitamin.

[0004] [ka]

[0005] Patent Documents 1 and 2 each describe that in stage 4, a lactone compound (LCT) and potassium thioacetate are mixed and stirred at a temperature of 130° C. or 150° C. for 1 hour to obtain a thiolactone compound (DTL). [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 2018 / 025722 [Patent Document 2] International Publication No. 2020 / 110831 [Non-patent literature]

[0007] [Non-Patent Document 1] Pierre J. de Clercq, “Biotin: A Timeless Challenge for Total Synthesis” Chemical Reviews, 1997, Vol. 97, No. 6. Summary of the Invention [Problem to be solved by the invention]

[0008] An object of the present invention is to provide an efficient method for producing a thiolactone compound. [Means for solving the problem]

[0009] According to an embodiment, there is provided a method for producing a thiolactone compound, comprising reacting a lactone compound represented by the following formula (I) with an alkali metal salt of a thiocarboxylate at a reaction temperature of less than 125° C. to obtain a thiolactone compound represented by the following formula (II):

[0010] [ka]

[0011] In formula (I), R 1 and R 2 are each a hydrogen atom, a benzyl group, or a benzyl group having a substituent.

[0012] [ka]

[0013] In formula (II), R 1 and R 2 have the same meanings as in formula (I), respectively. Effect of the Invention

[0014] According to the present invention, an efficient method for producing a thiolactone compound is provided. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] In the method according to the embodiment, the thiolactone compound represented by the above formula (II) is produced by reacting the lactone compound represented by the above formula (I) with an alkali metal salt of a thiocarboxylate at a reaction temperature of less than 125° C. Hereinafter, the lactone compound represented by the formula (I) and the thiolactone compound represented by the formula (II) are also simply referred to as the lactone compound and the thiolactone compound, respectively.

[0016] When the lactone compound and the alkali metal salt of thiocarboxylate are reacted at a temperature within this range, the thiolactone compound can be efficiently produced. That is, the reaction between the lactone compound and the alkali metal salt of thiocarboxylate is an exothermic reaction. When they are reacted at a high temperature of 125°C or higher, the heat generated by the reaction can further accelerate the reaction, and the temperature of the mixture of the lactone compound and the alkali metal salt of thiocarboxylate can further increase. For example, the temperature of the mixture can rise by 10°C or more from the initially set reaction temperature in a short period of time. When the temperature of the mixture rises sharply before the end of the reaction in this way, colored components can be generated in the mixture. The present inventors speculate that the colored components are derived from decomposition products of at least one of the thiolactone compound and the alkali metal salt of thiocarboxylate. That is, when the lactone compound and the alkali metal salt of thiocarboxylate are reacted at a high temperature of 125°C or higher, the yield of the thiolactone compound can decrease, and the process of removing the colored components can be required multiple times.

[0017] In the method according to the embodiment, since the lactone compound and the alkali metal thiocarboxylate are reacted at a reaction temperature of less than 125° C., the thiolactone compound is stably produced without producing colored components. Therefore, the method according to the embodiment improves the production efficiency of the thiolactone compound.

[0018] A rapid increase in reaction temperature in a mixture of a lactone compound and an alkali metal salt of a thiocarboxylate is likely to occur, particularly when a large amount of a thioester compound is produced. Therefore, the method according to the embodiment is suitable when 0.5 kg or more, or 1.0 kg or more of a lactone compound is used as a substrate. There is no particular upper limit to the amount of the lactone compound as a substrate, but in one example, it is 10.0 kg or less, and in another example, it is 5.0 kg or less.

[0019] The manufacturing method according to the embodiment will be described in detail below.

[0020] (Lactone compounds) The lactone compound is represented by the following formula (I): The lactone compound can be used as an intermediate for biotin synthesis.

[0021] [ka]

[0022] In formula (I), R 1 and R 2 are each a hydrogen atom, a benzyl group, or a benzyl group having a substituent.

[0023] The benzyl group has at least one substituent 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.

[0024] (Alkali metal thiocarboxylate) The alkali metal thiocarboxylate is a reagent for introducing sulfur into a lactone compound. As the alkali metal thiocarboxylate, for example, at least one selected from the group consisting of an alkali metal thioacetate and an alkali metal thiobenzoate is used. The alkali metal thioacetate includes sodium thioacetate, potassium thioacetate, and lithium thioacetate. The alkali metal thiobenzoate includes sodium thiobenzoate, potassium thiobenzoate, and lithium thiobenzoate. Only one type of alkali metal thiocarboxylate may be used, or multiple types may be used in combination. As the alkali metal thiocarboxylate, it is preferable to use an alkali metal thioacetate, and it is more preferable to use potassium thioacetate.

[0025] The amount of the alkali metal thiocarboxylate relative to 1 mole of the lactone compound is, for example, 1 to 3 moles, preferably 1 to 2 moles, and particularly preferably 1 to 1.8 moles.

[0026] The alkali metal thiocarboxylate may be a commercially available product or a synthesized product. The alkali metal thiocarboxylate may be synthesized, for example, by reacting a thiocarboxylic acid with an alkali metal salt.

[0027] Specific examples of alkali metal salts include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, etc., alkaline earth metal salts such as magnesium hydroxide, barium hydroxide, etc., alkali metal carbonates such as potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, etc., and alkali metal acetates such as potassium acetate, sodium acetate, etc. Among these alkali metal salts, in terms of reactivity with thiocarboxylic acid and industrial availability, it is preferable to use at least one selected from the group consisting of alkali metal hydroxides and alkali metal acetates, and it is more preferable to use alkali metal acetates.

[0028] As the thiocarboxylic acid, for example, at least one of thioacetic acid and thiobenzoic acid is used, and as the thiocarboxylic acid, thioacetic acid is preferably used.

[0029] The reaction temperature of the thiocarboxylic acid and the alkali metal salt is, for example, 0 to 50° C., preferably 5 to 40° C., and particularly preferably 10 to 30° C. The reaction time is, for example, 0.5 to 4 hours, preferably 0.5 to 3 hours, and particularly preferably 0.5 to 2 hours.

[0030] The amount of the alkali metal salt relative to 1 mole of thiocarboxylic acid is preferably 1 mole or more and 6 moles or less, more preferably more than 1 mole and 6 moles or less, and even more preferably 1.1 moles or more and 4 moles or less. Within the above ranges, the amount (number of moles) of the thiocarboxylic acid used is preferably equal to or more than the number of moles of the lactone compound.

[0031] (Thiolactone compounds) The thiolactone compound is represented by the following formula (II): This thiolactone compound can be used as an intermediate for the synthesis of biotin.

[0032] [ka]

[0033] In formula (II), R 1 and R 2 has the same meaning as in formula (I).

[0034] The thiolactone compound may be white or colorless and transparent, or may have a color. The color of the thiolactone compound is, for example, black, red, reddish brown, red purple, purple, orange, or brown. The color of the thiolactone compound is considered to be derived from contaminants or impurities. Therefore, it is preferable that the thiolactone compound has a small amount of colored components and is highly transparent. According to the manufacturing method of the embodiment, a thiolactone compound with little coloring can be obtained.

[0035] This thiolactone compound can be synthesized into a biotin derivative represented by the following formula (III) (hereinafter also referred to as a biotin derivative).

[0036] [ka]

[0037] In the formula, R 1 and R 2 has the same meaning as in formula (I), and R 3 has the same meaning as in the following formula (IV): The biotin derivative can be synthesized into biotin by a known method.

[0038] A known method can be used to produce a biotin derivative from a thiolactone compound. For example, a method has been reported in which a thiolactone compound is reacted with a zinc reagent represented by the following formula (IV) in the presence of at least one of palladium and nickel catalysts.

[0039] [ka]

[0040] In the formula, R 3 is an alkyl group or an aralkyl group.

[0041] (Tetrahedron Letters 41 (2000) 5099-5101, Organic Syntheses, Vol. 84, p.285-294(2007);Coll. Vol. 11, p.281-288(2009).) (Method of producing thiolactone compound) The thiolactone compound can be obtained by reacting the lactone compound represented by the above formula (I) with an alkali metal salt of a thiocarboxylate at a reaction temperature of less than 125° C. to replace the oxygen constituting the lactone ring with sulfur.

[0042] In this specification, the reaction temperature means the temperature during the reaction between the lactone compound and the alkali metal salt of thiocarboxylate in the mixture obtained by mixing the lactone compound and the alkali metal salt of thiocarboxylate. During these reactions, the temperature may be kept below 125° C., and the temperature of the mixture may increase or decrease, and temperature changes may occur repeatedly.

[0043] From the viewpoints of increasing the stability of the thiolactone compound and making it difficult for colored components to be produced, the reaction temperature is preferably 120° C. or lower, more preferably 110° C. or lower, and even more preferably 105° C. or lower.

[0044] The lower limit of the reaction temperature may be any temperature at which the reaction between the lactone compound and the alkali metal salt of thiocarboxylate proceeds. From the viewpoint of increasing the reactivity between the lactone compound and the alkali metal salt of thiocarboxylate, the reaction temperature is preferably 85° C. or higher, more preferably 90° C. or higher, and even more preferably 95° C. or higher.

[0045] The reaction time of the lactone compound and the alkali metal thiocarboxylate is preferably 6 hours or more. That is, by reacting for a long time at a relatively low reaction temperature of less than 125°C, the thiolactone compound can be produced stably in a high yield. The reaction time is more preferably 8 hours or more, and even more preferably 10 hours or more. There is no particular upper limit to the reaction time, but in one example, it is 20 hours or less, and in another example, it is 15 hours or less. It is preferable that the mixture is stirred during the reaction time.

[0046] The reaction between the lactone compound and the alkali metal thiocarboxylate is preferably carried out in a reaction solvent, such as at least one selected from the group consisting of N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), and N,N-dimethylimidazolidin-2-one (DMI).

[0047] When using a reaction solvent, it is preferable to mix the lactone compound and the alkali metal salt of thiocarboxylate by the following method. First, the lactone compound and the reaction solvent are mixed to prepare a mixed solution. The amount of the solvent in this mixed solution is preferably 1 mL or more and 3 mL or less per 1 g of the lactone compound. This mixed solution is heated until it reaches a temperature within the above-mentioned reaction temperature range. The alkali metal salt of thiocarboxylate is added to the mixed solution after heating. At this time, the alkali metal salt of thiocarboxylate is first dissolved in the reaction solvent, and this reaction is an endothermic reaction. Therefore, when the alkali metal salt of thiocarboxylate is added to the mixed solution, the temperature of the mixed solution may temporarily drop below the initial reaction temperature. After this temporary temperature drop occurs, the temperature of the mixed solution returns to near the initial reaction temperature again, and it is considered that the reaction between the lactone compound and the alkali metal salt of thiocarboxylate begins. It is preferable that the maximum temperature drop is adjusted to be 85°C or more.

[0048] The reaction temperature can be adjusted by a known method, for example, by adjusting the temperature of a heater or the like in contact with a container containing a mixture of a lactone compound and an alkali metal thiocarboxylate.

[0049] The thiolactone compound obtained by the above method is preferably isolated by the following method. First, a quench liquid is added to a reaction liquid containing a thiolactone compound, and the reaction liquid is cooled to 40° C. or less to terminate the reaction. As the quench liquid, for example, water is used. The amount of the quench liquid is, for example, 1 mL or more and 10 mL or less per 1 g of the lactone compound. The temperature of the mixture after the addition of the quench liquid is preferably within a range of 10° C. or more and 35° C. or less.

[0050] The reaction solution to which the quenching liquid has been added is stirred for, for example, 1 hour to 5 hours to obtain a precipitate. The precipitate is taken out by filtration, washed with water, and then thoroughly dried. In this way, a crude thiolactone compound is obtained.

[0051] (Method for purifying thiolactone compounds) The crude thiolactone compound obtained by the above method is preferably purified by the following method.

[0052] First, the crude thiolactone compound is subjected to activated carbon treatment. This makes it possible to remove impurities in the crude. Specifically, the crude thiolactone compound is mixed with an organic solvent and activated carbon, and the mixture is stirred. In the mixture, the precipitate can be dissolved in the organic solvent. As the organic solvent, for example, at least one selected from the group consisting of toluene, xylene, mesitylene, cumene, hexane, heptane, methanol, ethanol, isopropanol (IPA), acetone, methyl ethyl ketone, diethyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, and butyl acetate is used. As the organic solvent, it is preferable to use acetone.

[0053] The amount of activated carbon added is, for example, 1 part by mass or more and 20 parts by mass or less, preferably 2 parts by mass or more and 10 parts by mass or less, and more preferably 3 parts by mass or more and 7 parts by mass or less, based on 100 parts by mass of the crude thiolactone compound (solid content).

[0054] The amount of organic solvent per 1 g of crude 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.

[0055] The stirring temperature of the mixture is, for example, from 10° C. to 70° C., and preferably from 20° C. to 65° C. The stirring time of the mixture is, for example, from 12 minutes to 3 hours, and preferably from 30 minutes to 2 hours.

[0056] After the activated carbon treatment is completed, the mixture is filtered to obtain a filtrate from which the activated carbon has been removed. This filtrate is subjected to a crystallization treatment. That is, the filtrate is mixed with an organic solvent of the same type as the organic solvent described above, and then water is further mixed therewith to precipitate crystals of the thiolactone compound. The mixture is then left at a constant temperature for a certain period of time to grow crystals of the thiolactone compound.

[0057] The amount of organic solvent per 1 g of crude thiolactone compound is, for example, 1 mL to 10 mL, preferably 1 mL to 5 mL. The amount of water per 1 g of crude thiolactone compound is, for example, 3 mL to 10 mL, preferably 4 mL to 8 mL. The crystallization temperature is, for example, 10° C. to 40° C., preferably 15° C. to 30° C. The crystallization time is, for example, 6 minutes to 6 hours, preferably 30 minutes to 3 hours.

[0058] Next, the crystals of the thiolactone compound are isolated from the mixture. The isolation method is not particularly limited, but may be, for example, pressure filtration, vacuum filtration, centrifugation, etc. The isolated crystals of the thiolactone compound are optionally washed with a washing solution and then dried. By the above method, the purified crystals of the thiolactone compound can be obtained.

[0059] According to the method of the embodiment, a lactone compound and an alkali metal thiocarboxylate are reacted at a temperature of less than 125° C., so that a reaction liquid containing a thiolactone compound with a small amount of coloring components, etc. is obtained. Therefore, it is not necessary to repeat the purification treatment of the thiolactone compound multiple times, and a highly pure thiolactone compound can be obtained by crystallization using an organic solvent such as acetone. EXAMPLES

[0060] The present invention will be described in detail below with reference to examples. However, the following examples are specific examples and the present invention is not limited to these.

[0061] <Example 1> (Synthesis of thiolactone compounds) First, a thiolactone compound represented by formula (II) was synthesized by the following method. 1 and R 2 were each represented as a benzyl group.

[0062] 25 g (0.077 mol) of the lactone compound represented by formula (I) was dissolved in 37.5 mL of N,N-dimethylacetamide (DMA) to obtain a lactone compound solution. The lactone compound solution was subjected to vacuum evacuation and nitrogen leak three times. After heating the lactone compound solution to 100°C under a nitrogen atmosphere, 13.5 g (0.118 mol) of potassium thioacetate was added thereto, and the mixture was stirred for 12 hours while maintaining the temperature at 100°C to obtain a reaction solution. In this reaction, no sudden temperature rise was observed in the mixture of the lactone compound solution and potassium thioacetate.

[0063] 125 mL of water was added to the reaction solution at 100°C, and the temperature of the reaction solution was lowered to within the range of 25°C to 30°C. The reaction solution was stirred at this temperature range for 2 hours to precipitate a solid. The precipitate was removed by filtration and washed with 25 mL of water. The washed precipitate was dried with air at a temperature of 60°C for 10 hours to obtain a crude thiolactone compound. The amount of the crude thiolactone compound was 23.1 g, and the yield was 88.0%. The crude thiolactone compound was light brown in color and had little coloring.

[0064] (Purification of thiolactone compounds) Next, crystals of the thiolactone compound represented by formula (II) were obtained by the following method. The entire amount of the crude thiolactone compound was dissolved in 127 mL of acetone to obtain an acetone solution. 1.27 g of activated carbon was added to this acetone solution, and the resulting suspension was stirred at a temperature of 60° C. for 1 hour. The activated carbon was removed from the stirred suspension by celite filtration. The removed activated carbon was washed with 23 mL of acetone heated to 60° C. This operation was performed two more times, and the resulting washing liquid was added to the filtrate to obtain a mixed liquid. 196 mL of water was added to this mixed liquid, and the mixture was stirred at a temperature of 25° C. for 2 hours to precipitate a solid. The precipitate was removed by filtration and washed with a mixed solvent of 23 mL of water and 23 mL of acetone. The washed precipitate was dried at a temperature of 70° C. for 4 hours to obtain a crystal of the thiolactone compound. The amount of crystal of the thiolactone compound was 22.1 g, and the yield from the lactone compound was 84.2%.

[0065] <Example 2> A crude thiolactone compound was obtained in the same manner as in Example 1, except that the amounts of materials and solvents were scaled up by 40 times. The mass of the lactone compound was 1.0 kg. In this reaction, no sudden temperature increase was observed in the mixture of the lactone compound solution and potassium thioacetate. The amount of the crude thiolactone compound obtained was 926 g, and the yield was 88.21%. The color of the crude thiolactone compound was light brown, and it was little colored.

[0066] <Comparative Example 1> A crude thiolactone compound was obtained in the same manner as described in Example 1, except that the reaction temperature of the lactone compound solution and potassium thioacetate was changed to 125°C, and the stirring time after mixing was changed to 4 hours. In this reaction, a temperature rise was observed in the mixture of the lactone compound solution and potassium thioacetate. The amount of the crude thiolactone compound obtained was 19.8 g, and the yield was 75.44%. The color of the crude thiolactone compound was slightly dark brown, and the coloring was somewhat heavy.

[0067] <Comparative Example 2> The experiment was carried out in the same manner as described in Example 1, except that the amounts of materials and solvents were scaled up by 98 times (2.45 kg of lactone compound) and the reaction temperature between the lactone compound solution and potassium thioacetate was changed to 125°C. As a result, 10 minutes after potassium thioacetate was added to the lactone compound solution, the temperature of the mixture rose sharply to 140°C. The reaction between the lactone compound solution and potassium thioacetate was completed in 45 minutes. The amount of crude thiolactone compound obtained was 2.38 kg, and the yield was 92.53%. The crude thiolactone compound was black-brown in color and was highly colored.

[0068] As is clear from Examples 1 and 2 and Comparative Examples 1 and 2, when the reaction temperature of the lactone compound solution and potassium thioacetate was set to less than 125° C., both a high yield of the thiolactone compound and little coloring could be achieved.

Claims

1. The amount of the lactone compound represented by the following formula (I) is 0.5 kg or more and 10.0 kg or less, A method for producing a thiolactone compound represented by the following formula (II), which comprises reacting a lactone compound represented by the following formula (I) with an alkali metal salt of a thiocarboxylate at a reaction temperature of 90° C. or higher and 105° C. or lower: 【Chemistry 1】 In the formula (I), R 1 and R 2 each represent a hydrogen atom, a benzyl group, or a benzyl group having a substituent; 【Chemistry 2】 In the formula (II), R 1 and R 2 are each defined as the same as in the formula (I).

2. The lactone compound represented by the formula (I) and the alkali metal salt of thiocarboxylic acid The method for producing a thiolactone compound according to claim 1, wherein the reaction time is from 6 hours to 20 hours.

3. The method for producing a thiolactone compound according to claim 1 or 2, wherein the alkali metal thiocarboxylate comprises an alkali metal thioacetate.

4. dissolving the thiolactone compound represented by formula (II) in a solvent containing acetone to obtain a solution; The method for producing a thiolactone compound according to any one of claims 1 to 3, further comprising adding water to the solution to precipitate the thiolactone compound represented by formula (II).

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