JP2022091500A - Thionizing agent - Google Patents

Abstract

To provide: a highly safe and industrially usable thionizing agent; and a method for manufacturing a sulfur-containing compound by using the thionizing agent.SOLUTION: A thionizing agent is composed of a reaction liquid between phosphorus sulfide and alkali metal salt in an organic solvent.SELECTED DRAWING: None

Description

The present invention relates to a thiolating agent for substituting an oxygen atom of an oxygen-containing compound with a sulfur atom, and a method for producing a sulfur-containing compound using the thiolating agent.

A hydroxy group is a thiol group, a ketone group is a thioketone group, an amide group is a thioamide group, an ester group is a thioester group, and a reagent for substituting an oxygen atom in an oxygen-containing compound with a sulfur atom is diphosphorus pentasulfide. Such as phosphorus sulfide and Lawson reagents are known.

However, since phosphorus sulfide is insoluble in other than benzene and carbon disulfide, phosphorus sulfide must be reacted as a solid in order to be carried out with other organic solvents, except for the thiolation reaction of liquid oxygen-containing compounds. Is not industrially suitable.
For example, in the synthesis of thioamide from amide, there is a method of dissolving diphosphorus pentasulfide in benzene or carbon disulfide and reacting with amide. However, benzene and carbon disulfide are harmful and highly flammable, dangerous and difficult to use in large quantities. Therefore, Patent Document 1 describes a method for producing thioformamide using a solvent other than benzene or carbon disulfide, but the oxygen-containing compound is limited to formamide which is a liquid. In fact, when it is used in a solvent in which diphosphorus pentasulfide is insoluble, the viscous oily phosphorus compound becomes entangled with the solid substance during the reaction, making stirring difficult and the reaction stops.

Although Lawesson's reagent is suitable for small-quantity synthesis, it is not industrially suitable because it has a problem in treating by-products derived from Lawesson's reagent and anisole remaining in the post-reaction post-treatment and is expensive.
That is, a review article on Lawesson's reagent is described in detail in Non-Patent Document 1. Since the Lawesson's reagent has a methoxyphenyl group, it has a large molecular weight, and only one of the four sulfur atoms can be used, so a large amount of Lawesson's reagent must be used. Further, it is industrially unfavorable because it requires waste treatment of the methoxyphenyl compound (organic phosphorus compound) after the reaction. Further, a Japanese reagent having a phenylthio group similar to Lawesson's reagent and a Beleo reagent having a phenoxyphenyl group have the same drawbacks.

Japanese Unexamined Patent Publication No. 1-305072

Journal of Synthetic Organic Chemistry Vol. 53, No. 12, 1138-1140 (1995)

As described above, conventional thiolating agents have problems such as being applicable only to some oxygen-containing compounds, post-reaction post-treatment, and being expensive, and all of them can be used for industrial production. It wasn't. Further, among sulfur-containing compounds, thioamide compounds are important as pharmaceuticals, pesticides, raw materials, and intermediates, and industrially usable thioagents are desired.
Therefore, an object of the present invention is to provide a thiolating agent which is highly safe and can be industrially used, and a method for producing a sulfur-containing compound using the thiolating agent.

Therefore, the present inventor has studied various applications of phosphorus sulfide. Phosphorus sulfide is insoluble in other than benzene and carbon disulfide as described above, while alkali metal salts are hardly soluble in organic solvents such as ethyl acetate. Therefore, it has been considered that both of these cannot be used to react in an organic solvent solution such as ethyl acetate.
However, when the present inventor added an alkali metal salt and phosphorus sulfide to an ester solvent such as ethyl acetate and a polar organic solvent such as a nitrile solvent, which are versatile as reaction solvents, and stirred for a certain period of time, it was completely unexpected. It was also found that both react and dissolve in these organic solvents. Then, they found that when an oxygen-containing compound was added to this reaction solution and the reaction was carried out, a sulfur-containing compound in which an oxygen atom was replaced with a sulfur atom was obtained in high yield, and post-treatment was easy, and the present invention was made. Was completed.

That is, the present invention provides the following inventions [1] to [6].
[1] A thiolating agent consisting of a reaction solution of phosphorus sulfide and an alkali metal salt in an organic solvent.
[2] The thiolating agent according to [1], wherein the alkali metal salt is an alkali metal salt selected from an alkali metal hydroxide, an inorganic acid alkali metal salt and an organic acid alkali metal salt.
[3] The thiolating agent according to [1] or [2], wherein the organic solvent is a polar organic solvent.
[4] The thiolytic agent according to [1] or [2], wherein the organic solvent is a solvent selected from an ester solvent, a nitrile solvent and an ether solvent.
[5] A sulfur-containing compound in which the oxygen atom in the oxygen-containing compound is replaced with a sulfur atom, which comprises reacting the oxygen-containing compound with the thiolating agent according to any one of [1] to [4]. Manufacturing method.
[6] The oxygen-containing compound is a compound having one or more oxygen-containing groups selected from a hydroxy group, a ketone group and an amide group, and the sulfur-containing compound is selected from a thiol group, a thioketone group and a thioamide group. The production method according to [5], which is a compound having one or more sulfur-containing groups.

The thiolating agent of the present invention is a versatile organic solvent solution easily obtained from phosphorus sulfide and an alkali metal salt, and is useful as a thiolating agent for various oxygen-containing compounds. Further, by using the thiolating agent of the present invention, a sulfur-containing compound can be obtained in a high yield by a simple operation.
The thiolating agent of the present invention is particularly useful as a thiolating agent such as from amide to thioamide, from alcohol to thiol, from ketone to thioketone, and the like. Moreover, since it dissolves in an organic solvent, it can react not only with liquid compounds but also with solid compounds that are difficult to dissolve.
Further, after the reaction, the thiolating agent of the present invention becomes a water-soluble inorganic decomposition product by adding water, so that post-treatment is simple and it can be used industrially as a synthetic reagent. Further, since the thiolating agent of the present invention dissolves in an organic solvent, it is considered that it can also be used in a microreactor.

It is a figure which shows the result of having experimented with the thiolating ability of the thiolating agent of this invention, the maximum number of atoms among the 10 sulfur atoms contained in the thiolating agent, which are used for thiolating.

The thiolating agent of the present invention is a reaction solution of phosphorus sulfide and an alkali metal salt in an organic solvent.

Phosphorus sulfide used includes phosphorus trisulfide (P ₄ S ₃ ), phosphorus pentasulfide (P ₂ S ₅ ) (also referred to as diphosphorus pentasulfide (P ₄ S ₁₀ )), phosphorus heptasulfide (P ₄ S ₇ ), and phosphorus sulfide. Phosphorus pentasulfide (P ₄ S ₅ ) is mentioned, of which phosphorus trisulfide (P ₄ S ₃ ) and phosphorus pentasulfide (P ₂ S ₅ ) are preferable, and phosphorus pentasulfide (P ₂ S ₅ ) is more preferable. ..

Examples of the alkali metal salt include an alkali metal hydroxide, an inorganic acid alkali metal salt, and an organic acid alikari metal salt.
Examples of the alkali metal include lithium, sodium and potassium.

Examples of the inorganic acid include hydrogen sulfide, carbonic acid, and phosphoric acid. Of these, those that are basic as the inorganic acid alkali metal salt are preferable, hydrogen sulfide, carbonic acid, and phosphoric acid are more preferable, and hydrogen sulfide and carbonic acid are more preferable. Therefore, as the inorganic acid alkali metal salt, lithium carbonate, sodium carbonate, potassium carbonate, sodium phosphate, disodium hydrogen phosphate, sodium sulfide and the like are preferable, and lithium carbonate, sodium carbonate, potassium carbonate and sodium sulfide are more preferable.
Further, as the organic acid, an organic carboxylic acid is preferable, and specific examples thereof include acetic acid. Therefore, examples of the organic acid alkali metal salt include sodium acetate, lithium acetate, potassium acetate and the like.
Moreover, sodium hydroxide and potassium hydroxide are also mentioned.

As the organic solvent serving as the reaction solvent of phosphorus sulfide and the alkali metal salt, a polar organic solvent is preferable from the viewpoint of reacting and dissolving phosphorus sulfide and the alkali metal salt, and an ester solvent, a nitrile solvent, and an ether solvent are used. Etc. are more preferable.
Of these, ester-based solvents and nitrile-based solvents are preferable from the viewpoints of versatility, reactivity between phosphorus sulfide and alkali metal salts, ease of post-treatment, and the like. Specific examples thereof include acetic acid esters such as methyl acetate, ethyl acetate, propyl acetate and butyl acetate, acetonitrile, tetrahydrofuran and the like, with acetic acid esters and acetonitrile being preferred, and acetic acid esters being more preferred.

The reaction between phosphorus sulfide and the alkali metal salt is carried out in an organic solvent. The reaction temperature is preferably around 20 ° C. to 30 ° C., and the reaction time is preferably 3 hours to 24 hours.
At high temperatures, the thioacetic acid produced thionates the acetate, and the thioacetate is by-produced. However, this thioacetic acid ester can be removed with the solvent.
Further, since water decomposes phosphorus pentasulfide, it is preferable to use an anhydrous organic solvent and alkali metal salt.

The reaction rate of phosphorus sulfide and the alkali metal salt is greatly affected by the crystal grain size and the stirring rate, and the finer the reaction rate and the faster the stirring rate, the faster the reaction. In the case of sodium carbonate, it can be used in the form of powder or granules, and phosphorus pentasulfide reacts even if it has a particle size of about 2 mm, but powder of 0.5 mm or less is more preferable for small-quantity production.

As a specific reaction example, when diphosphorus pentasulfide and sodium carbonate are suspended in ethyl acetate at room temperature and stirred, carbon dioxide gas is generated and dissolved. Sodium carbonate dissolves in the range of 1 to 2 mol per 1 mol of diphosphorus pentasulfide (molecular formula _{P4 S 10 )} . It is also possible to prepare 1: 1 and 1: 2 solutions according to the raw material charging ratio (hereinafter, 1: 1 thiolating agent is abbreviated as type 1 and 1: 2 is abbreviated as type 2). Reactivity is significantly different between type 1 and type 2, and it can be used according to the purpose.
Depending on the difference in alkali metal salt, there are two types, type 1 and type 2, and one that can only be obtained as type 1.

For example, when one molecule of diphosphorus pentasulfide and sodium sulfide are reacted, the ring is opened and dissolved. This is considered to react as shown in the following equation.

In addition, diphosphorus pentasulfide is similarly ring-opened and added to other alkali metal salts, but it is considered that the reaction with sodium carbonate is as follows because carbon dioxide is generated in equimolar amounts. Be done.

By using the thiolating agent of the present invention, a sulfur-containing compound can be easily produced. That is, by reacting the oxygen-containing compound with the thiolating agent of the present invention, a sulfur-containing compound in which the oxygen atom in the oxygen-containing compound is replaced with a sulfur atom can be produced.
In the production method of the present invention, the oxygen-containing compound is preferably applied to a compound having one or more oxygen-containing groups selected from a hydroxy group, a ketone group and an amide group, and in this case, the obtained sulfur-containing compound is used. The compound is a compound having one or more sulfur-containing groups selected from a thiol group, a thioketone group and a thioamide group.

In order to carry out the thiolation reaction, since the thiolating agent of the present invention is a solution, the oxygen-containing compound to be thiolated may be added to the thiolating agent and the reaction may be performed with stirring.
The reaction temperature is usually preferably 20 to 60 ° C.
The amount of the thiolating agent used varies greatly depending on the structure of the oxygen-containing compound and the type of thiolating agent. FIG. 1 shows the results of an experiment on the thiolation ability of the thiolating agent of the present invention to determine how many of the 10 sulfur atoms contained in the thiolating agent are used for thiolation. As shown in FIG. 1, it greatly affects the difference between basic alkali metal salts. In fact, when reacted with various compounds, the oxygen-containing compound is practically 1 mol to 5 mol with respect to 1 mol of diphosphorus pentasulfide ( _{P4 S 10 )} .

After the completion of the thiolation reaction, the thiolating agent becomes a water-soluble inorganic decomposition product by adding water, so that the post-treatment is extremely simple. Since the thiolating agent of the present invention is soluble in an organic solvent, it is considered that it can also be used in a microreactor.

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

Example 1
Synthesis of N-Phenylacetthioamide (sodium carbonate type 1 method)

When 4 mL of ethyl acetate was added to 1.11 g (2.5 mmol) of diphosphorus pentasulfide and 0.28 g (2.5 mmol) of sodium carbonate and stirred overnight at room temperature, about 30 mL of carbon dioxide was generated and dissolved. Next, 1.69 g (12.5 mmol) of acetanilide and 2 mL of ethyl acetate were added, and the mixture was stirred at 40 ° C. for 24 hours. At this time, the reaction rate was 99.2%. The aqueous layer was separated by adding 10 mL of a 10% aqueous sodium carbonate solution under water cooling, the aqueous layer was extracted twice with 2 mL of ethyl acetate, the extracted ethyl acetate layers were combined, washed with water, and concentrated to dryness. Next, hexane was added, the slurry was washed, and the mixture was dried under reduced pressure to obtain brown crystals.
Yield 1.63g Yield 86.2% HPLC Simple Area Purity 99.0%

Example 2
Synthesis of N-Phenylacetthioamide (lithium carbonate type 1 method)

The sodium carbonate of Example 1 was replaced with 0.19 g (2.5 mmol) of lithium carbonate, and the same synthesis was performed. The reaction rate for 24 hours was 96.5%. After post-treatment, brown crystals were obtained.
Yield 1.70g Yield 89.9% HPLC Simple Area Purity 98.1%

Example 3
Synthesis of N-Phenylacetthioamide (sodium sulfide type 1 method)

The sodium carbonate of Example 1 was replaced with 0.20 g (2.5 mmol) of sodium sulfide, and the same synthesis was performed. The reaction rate for 24 hours was 98.8%. After post-treatment, brown crystals were obtained.
Yield 1.72g Yield 91.0% HPLC Simple Area Purity 98.3%

Example 4
Synthesis of N-Phenylacetthioamide (sodium carbonate type 2 method)

When 6 mL of ethyl acetate was added to 1.67 g (3.76 mmol) of diphosphorus pentasulfide and 0.84 g (7.54 mmol) of sodium carbonate and stirred overnight at room temperature, about 93 mL of carbon dioxide was generated and dissolved. Next, 1.02 g (7.55 mmol) of acetanilide was added, and the mixture was stirred at 50 ° C. for 48 hours. 8 mL of a 10% sodium carbonate aqueous solution was added under water cooling for extraction and washing. The aqueous layer was extracted twice with ethyl acetate, and the extracted ethyl acetate layers were combined and washed with water and then concentrated to dryness. Next, hexane was added, the slurry was washed, and the mixture was dried under reduced pressure to obtain white crystals.
Yield 1.03g Yield 90.3% HPLC Simple Area Purity 99.2%

Example 5
Synthesis of benzthioamide (sodium carbonate type 2 method)

When 8 mL of ethyl acetate was added to 2.22 g (5.0 mmol) of diphosphorus pentasulfide and 0.56 g (5.0 mmol) of sodium carbonate and stirred at room temperature for 2 hours, about 80 mL of carbon dioxide was generated. Further, when 0.56 g (5.0 mmol) of sodium carbonate was additionally added and reacted for 3 hours, about 80 mL of carbon dioxide was generated. Next, 1.21 g (10 mmol) of benzamide and 2 mL of ethyl acetate were added, and the mixture was stirred at 50 ° C. for 72 hours. At this time, the reaction rate was 99.0%. After water cooling, 10 mL of a 10% aqueous sodium carbonate solution was added and stirred, then 10 mL of water was added, and ethyl acetate was concentrated under reduced pressure. The crystals were filtered, washed with water and dried under reduced pressure to obtain pale yellow crystals.
Yield 1.24g Yield 90.4% HPLC Simple Area Purity 99.7%

Example 6
Synthesis of N, N-dimethylbenzthioamide (sodium phosphate method type 1 method)

When 3 mL of ethyl acetate was added to 0.60 g (1.35 mmol) of diphosphorus pentasulfide and 0.33 g (2.0 mmol) of sodium phosphate and stirred at room temperature for 3 hours, diphosphorus pentasulfide was dissolved and excess phosphorus was added. Sodium phosphate remained undissolved. Next, 1.01 g (6.77 mmol) of N, N-dimethylbenzamide and 2 mL of ethyl acetate were added, and the mixture was stirred at 40 ° C. for 48 hours. At this time, the reaction rate was 99.2%. Under water cooling, 5 mL of a 10% sodium carbonate aqueous solution was added for extraction and washing, then the solution was washed and separated with a 5% sodium carbonate aqueous solution, 5 mL of water was added to the ethyl acetate layer, and ethyl acetate was concentrated under reduced pressure. The crystals were filtered, washed with water, and dried under reduced pressure to obtain light brown crystals.
Yield 1.06g Yield 94.7% HPLC Simple Area Purity 99.7%

Example 7
Synthesis of N, N-dimethylbenzthioamide (sodium carbonate type 1 method)

Ethyl acetate (4 mL) was added to 1.11 g (2.5 mmol) of diphosphorus pentasulfide and 0.28 g (2.5 mol) of sodium carbonate, and the mixture was stirred overnight at room temperature to generate and dissolve carbon dioxide gas. Next, 0.75 g (5.0 mmol) of N, N-dimethylbenzamide and 2 mL of ethyl acetate were added, and the mixture was stirred at 50 ° C. for 2 hours. At this time, the reaction rate was 98.8%. 8 mL of a 10% aqueous sodium carbonate solution was added for extraction and washing, 10 mL of water was added, and ethyl acetate was concentrated under reduced pressure. The crystals were filtered, washed with water, washed with hexane, and dried under reduced pressure to obtain pale yellowish green crystals.
Yield 0.77g Yield 92.6% HPLC Simple Area Purity 99.5%

Example 8
Synthesis of phenylacetthioamide (sodium phosphate method type 1 method)

When 3 mL of ethyl acetate was added to 0.60 g (1.35 mmol) of diphosphorus pentasulfide and 0.33 g (2.0 mmol) of sodium phosphate and stirred at room temperature for 3 hours, diphosphorus pentasulfide was dissolved and excess phosphorus was added. The sodium acid content remained undissolved. Next, 1.10 g (8.14 mmol) of phenylacetamide and 2 mL of ethyl acetate were added, and the mixture was stirred at 40 ° C. for 21 hours. At this time, the reaction rate was 98.2%. Under water cooling, 5 mL of a 10% sodium carbonate aqueous solution was added for extraction and washing, and then 5 mL of a 5% sodium carbonate aqueous solution was washed. Next, 5 mL of water was added to the ethyl acetate layer, ethyl acetate was concentrated under reduced pressure, the crystals were filtered, washed with water, and dried under reduced pressure to obtain orange crystals.
Yield 1.12g Yield 91.0% HPLC Simple Area Purity 99.6%

Example 9
Synthesis of triphenylmethanethiol (sodium carbonate type 2 method)

When 4 ml of ethyl acetate was added to 1.11 g (2.5 mmol) of diphosphorus pentasulfide and 0.56 g (5.0 mmol) of sodium carbonate and stirred overnight at room temperature, about 68 mL of carbon dioxide was generated and dissolved. Next, 1.00 g (0.384 mmol) of triphenylmethanol and 2 mL of ethyl acetate were added, and the mixture was stirred at 50 ° C. overnight. 5 mL of ethyl acetate and 5 mL of a 10% aqueous sodium carbonate solution were added under water cooling for extraction and washing. The aqueous layer was recovered with 2 mL of ethyl acetate, and the extracted ethyl acetate layers were collectively washed with 3 mL of 0.5N hydrochloric acid. The cells were washed with saturated brine, dried over sodium sulfate, and then concentrated to dryness. Next, hexane was added, the slurry was washed, and the mixture was dried under reduced pressure to obtain pale yellowish white crystals.
Yield 0.96g Yield 90.4% HPLC Simple Area Purity 99.9%

Example 10
Synthesis of thiobenzophenone (sodium carbonate type 2 method)

When 4 mL of ethyl acetate was added to 1.11 g (2.5 mmol) of diphosphorus pentasulfide and 0.56 g (5.0 mmol) of sodium carbonate and stirred overnight at room temperature, about 36 mL of carbon dioxide was generated and dissolved. 0.91 g (5 mmol) of benzophenone and 0.11 g (0.62 mmol) of isobutyl benzoate as an internal standard were added, and the mixture was stirred at 50 ° C. for 72 hours. As the reaction proceeded, it became a deep blue color peculiar to thiobenzophenone (trimer). When the reaction rate was determined by HPLC based on the internal standard, the reaction rate was 62% at 8 hours, 90% at 14 hours, 94% at 24 hours, and 97% at 72 hours.

Example 11
Synthesis of 4-thiocarbamoylpiperidin-1-carboxylate tert-butyl (sodium carbonate type 2 method)

When 8 mL of ethyl acetate was added to 1.76 g (4 mmol) of diphosphorus pentasulfide and 0.84 g (8.0 mmol) of sodium carbonate, and the mixture was stirred overnight at room temperature, carbon dioxide was generated and dissolved. Next, 1.00 g (4.38 mmol) of tert-butyl 4-carbamoylpiperidin-1-carboxylate and 0.1 g (1 mmol) of sodium carbonate were added, and the mixture was stirred at 50 ° C. for 20 hours. 10 mL of a 10% aqueous sodium carbonate solution was added under water cooling, and the mixture was stirred well, separated, and 10 mL of water was added to the organic layer to concentrate ethyl acetate. The crystals were filtered, washed with water and dried under reduced pressure to obtain pale yellowish white crystals.
Yield 0.97g Yield 90.6% HPLC Simple Area Purity 99.7%

Example 12
Tert-Butyl carbonate = 4-thiocarbamoylphenyl (sodium phosphate method type 1 method)

When 3 mL of ethyl acetate was added to 0.60 g (1.35 mmol) of diphosphorus pentasulfide and 0.33 g (2.0 mmol) of sodium phosphate and stirred at room temperature for 3 hours, diphosphorus pentasulfide was dissolved and excess phosphorus was added. The sodium acid content remained undissolved. Next, 1.07 g (4.51 mmol) of tert-butyl carbonate = 4-carbamoylphenyl and 5 mL of ethyl acetate were added, and the mixture was stirred at 40 ° C. for 48 hours. At this time, the reaction rate was 97.5%. Under water cooling, 5 mL of a 10% aqueous sodium carbonate solution was added for extraction, and 5 mL of water was added to the ethyl acetate layer, and ethyl acetate was concentrated under reduced pressure. The crystals were filtered, washed with water, and dried under reduced pressure to obtain yellow crystals.
Yield 0.872g Yield 76.3% HPLC Simple Area Purity 91.9%

Example 13
Synthesis of 2- (3-fluoro-4-phenylphenyl) propionic acid 4-thiocarbamoylphenyl (sodium carbonate type 1 method)

When 4 mL of ethyl acetate was added to 1.11 g (2.5 mmol) of diphosphorus pentasulfide and 0.28 g (2.5 mmol) of sodium carbonate and stirred overnight at room temperature, about 30 mL of carbon dioxide was generated and dissolved. Next, 1.82 g (5.0 mmol) of 4-carbamoylphenyl 2- (3-fluoro-4-phenylphenyl) propionic acid and 2 mL of ethyl acetate were added, and the mixture was stirred at 40 ° C. for 5 hours. At this time, the reaction rate was 99.8%. Under water cooling, 10 mL of a 10% aqueous sodium carbonate solution was added to extract and separate the liquid, and the aqueous layer was extracted and recovered twice with 2 mL of ethyl acetate. The ethyl acetate layer was combined with water and then concentrated to dryness. Next, 5 mL of diisopropyl ether was added, the slurry was washed, and the mixture was dried under reduced pressure to obtain pale yellow crystals.
Yield 1.80g Yield 94.8% HPLC Simple Area Purity 98.7%
The recrystallized product with ethyl acetate was consistent with the column-purified product of Comparative Example 3 by thermal analysis (TG-DTA).

Example 14
Synthesis of 2- (3-fluoro-4-phenylphenyl) propionic acid 4-thiocarbamoylphenyl (sodium carbonate type 2 method)

When 4 mL of ethyl acetate was added to 1.11 g (2.5 mmol) of diphosphorus pentasulfide and 0.56 g (5.0 mmol) of sodium carbonate and stirred at room temperature for 4 hours, about 60 mL of carbon dioxide was generated and dissolved. Next, 0.91 g (2.5 mmol) of 4-carbamoylphenyl 2- (3-fluoro-4-phenylphenyl) propionic acid and 2 mL of ethyl acetate were added, and the mixture was stirred at 50 ° C. for 72 hours. At this time, the reaction rate was 98.8%. After cooling well with 9 mL of a 10% aqueous sodium carbonate solution under water cooling, 10 mL of water was added to concentrate ethyl acetate. The crystals were filtered, washed with water and dried under reduced pressure to obtain pale yellow crystals.
Yield 0.91g Yield 95.9% HPLC Simple Area Purity 99.5%
The recrystallized product with ethyl acetate was consistent with the column-purified product of Comparative Example 3 by thermal analysis (TG-DTA).

Example 15
Synthesis of 4-thiocarbamoylpyridine (sodium carbonate type 2 method)

When 10 ml of ethyl acetate was added to 2.22 g (5.0 mmol) of diphosphorus pentasulfide and 1.11 g (10.0 mmol) of sodium carbonate, and the mixture was stirred overnight at room temperature, carbon dioxide was generated and dissolved. Next, 0.611 g (5.0 mmol) of 4-pyridinecarboxamide and 4 mL of ethyl acetate were added, and the mixture was stirred at 50 ° C. for 72 hours. At this time, the reaction rate was 98.4%. After adding 20 mL of a 5% aqueous sodium carbonate solution under water cooling and stirring well, ethyl acetate was concentrated. The crystals were filtered, washed with water and dried under reduced pressure to obtain yellow crystals.
Yield 0.558g Yield 80.8% HPLC Simple Area Purity 98.6%

Comparative Example 1
Synthesis of N-Phenylacetthioamide (reaction with diphosphorus pentasulfide)

Ethyl acetate (6 mL) was added to 1.11 g (2.5 mmol) of diphosphorus pentasulfide and 1.69 g (7.5 mmol) of acetanilide, and the reaction was carried out at 40 ° C. for 24 hours. The reaction rate at this time was 91.8%. However, unreacted diphosphorus pentasulfide solidified and precipitated with the oil generated 1 hour after the reaction, and could not be stirred, and the reaction was delayed and stopped. Moreover, the decomposition of the solidified precipitate with water was not easy.

Comparative Example 2
Synthesis of 4-thiocarbamoylpiperidin-1-carboxylate tert-butyl (reaction without making thioagent)

Add 4 mL of ethyl acetate to 0.88 g (2.0 mmol) of diphosphorus pentasulfide, 0.42 g (4.0 mmol) of sodium carbonate, and 0.50 g (2.2 mmol) of tert-butyl 4-carbamoylpiperidin-1-carboxylate. When the mixture was stirred at 50 ° C., carbon dioxide gas was immediately generated and 24 mL was generated in 30 minutes. After reacting for 3 hours and measuring by HPLC, the raw material amide compound and the target thioamide compound were 0%. What was produced was a de-BOC denatured 4-carbamoylpiperidin and an unknown compound.

Comparative Example 3
Synthesis of 2- (3-fluoro-4-phenylphenyl) propionic acid 4-thiocarbamoylphenyl (using Lawesson's reagent)

Add 2 mL of ethyl acetate to 0.36 g (0.99 mmol) of 4-carbamoylphenyl 2- (3-fluoro-4-phenylphenyl) propionic acid and 0.41 g (1.0 mmol) of Lawesson's reagent, and stir at 50 ° C. for 2 hours. did. At this time, the reaction rate was 99.3%. 3 mL of a 10% aqueous sodium carbonate solution was added under water cooling, ethyl acetate was concentrated under reduced pressure, the crystals were filtered, washed with water and dried under reduced pressure to obtain pale yellow crystals.
Yield 0.37g Yield 98.5% HPLC Simple Area Purity 80%
Since the purity of this product does not increase even if it is recrystallized, it was purified on a silica gel column and used as a standard product for comparison.

Claims (6)

A thiolating agent consisting of a reaction solution of phosphorus sulfide and an alkali metal salt in an organic solvent. The thiolating agent according to claim 1, wherein the alkali metal salt is selected from an alkali metal hydroxide, an inorganic acid alkali metal salt and an organic acid alkali metal salt. The thiolating agent according to claim 1 or 2, wherein the organic solvent is a polar organic solvent. The thiolytic agent according to claim 1 or 2, wherein the organic solvent is a solvent selected from an ester solvent, a nitrile solvent and an ether solvent. A method for producing a sulfur-containing compound in which an oxygen atom in the oxygen-containing compound is replaced with a sulfur atom, which comprises reacting the oxygen-containing compound with the thiolating agent according to any one of claims 1 to 4. The oxygen-containing compound is a compound having one or more oxygen-containing groups selected from a hydroxy group, a ketone group and an amide group, and the sulfur-containing compound is one selected from a thiol group, a thioketone group and a thioamide group. The production method according to claim 5, wherein the compound has two or more kinds of sulfur-containing groups.

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